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Six-Membered Heterocycles
C H A P T E R
2 Six-Membered Heterocycles 2.1 STRUCTURE AND REACTIVITY ASPECTS Replacement of the methine (CH) group of benzene and methylene group (CH2) in cyclohexane by a heteroatom such as nitrogen, sulfur, and oxygen gives an important class of six-membered heterocyclic compounds. The introduction of nitrogen in benzene gives an important compound called pyridine. The introduction of nitrogen, however, does not alter the aromatic behavior of the resulting ring. Similarly, the replacement of methylene by NH in cyclohexane results in a saturated heterocyclic compound called piperidine.
Six membered nitrogen heterocycles.
Introduction of oxygen in benzene results in heterocycles where oxygen is divalent, the lone pair is involved in bonding, and the oxygen atom carries a positive charge. The resulting compound is called pyrylium salt and is not very stable, though it possesses some aromatic character. The other oxygen-containing six-membered heterocycles are 2H-pyran, 4H-pyran, 3,4-dihyro-2H-pyran, and tetrahydropyran.
Six membered oxygen heterocycles.
Similarly, sulfur analogs are designated thiopyrylium salts, thiopyran, 1,4-dithiin, and 1,3-dithirane.
Six membered sulfur heterocycles.
2.1.1 Six-Membered Nitrogen Heterocycles Insertion of the electronegative nitrogen into the benzene ring causes significant polarization of the molecule, which not only leads to the generation of more resonating structures but additionally stabilizes those structures in which the negative charge is on the nitrogen atom. The resonance energy of pyridine was found to be 31.9 kcal/mol.
The Chemistry of Heterocycles. https://doi.org/10.1016/B978-0-12-819210-8.00002-3
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© 2019 Elsevier Ltd. All rights reserved.
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2. Six-Membered Heterocycles
N
N
N
N
N
Resonating structures of pyridine.
The importance of charged structures in the resonance hybrid is well reflected by the high value of the dipole moment (2.26 D). The resonance hybrid structures of pyridine are well supported by the bond length values; the CC bond length values are intermediate between those known for a single bond (154 pm) and a double bond (134 pm). The CN bond length is shorter than the CC bond length but again is intermediate between the CN single bond (147 pm) and the CN double bond (125 pm). The smaller CN bond length value leads to slight deviation of bond angle values of a perfect hexagon (120 degrees).
Bond length and bond angles of pyridine.
Though pyridine is isoelectronic with benzene the presence of the nitrogen atom in the ring influences its chemical reactivity. Due to the presence of electronegative nitrogen in the ring, electron density at the 2,4- and 6-positions is decreased, whereas electron density is greater at nitrogen and at position 3. Pyridine is basic in nature but a weaker base compared to its saturated analog. The basic properties of pyridine are largely due to the presence of a lone pair of electrons on nitrogen. As a result, it readily forms pyridinium salts on reaction with acids. Lewis acids, which are good electron acceptors, react with pyridine to form tetrahedral salts. The electronegative nitrogen of pyridine causes significant polarization of the molecule, and as a result there is electron withdrawal from the ring toward the nitrogen (see resonance structures). The ring carbons are electron deficient and thus highly deactivated toward electrophilic substitution reactions. In addition, electrophilic substitution reactions take place under acidic conditions, which first protonate the nitrogen atom resulting in the formation of pyridinium salts. The resultant positive charge on nitrogen causes the electrons from the ring to drift toward it, thereby deactivating the C-2, C-4, and C-6 carbon atoms. Hence, electrophilic substitution reaction takes place, if at all, only under extreme conditions and that too at C-3 and C-5 carbon atoms.
2.1.2 Six-Membered Oxygen Heterocycles In the pyrylium cation the positively charged oxygen still has a lone pair of electrons in an sp2 hybrid orbital, which is in the plane of the ring. Hence the pyrylium cation is aromatic and a number of resonating structures are possible with a positive charge on C-2, C-4, and C-6.
Resonating structures of pyrylium cation.
As the pyrylium cation is aromatic, it should be stable, but it is highly reactive and does not undergo electrophilic substitution reaction. Instead, the pyrylium cation reacts rapidly with nucleophiles to produce adducts, which are not aromatic. 2H- and 4H-pyrans contain a methylene group in the ring; as a consequence they lack the conjugated double bond characteristic. Hence they are unsaturated, closed chain compounds devoid of aromatic character.
2.1 Structure and Reactivity Aspects
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2.1.3 Benzene-Fused Nitrogen Heterocycles A pyridine ring fused with a benzene ring gives rise to new heterocyclic compounds like quinoline, isoquinoline, and quinolizinium salt.
Benzene fused nitrogen heterocycles.
These compounds possess 10π electrons, are aromatic in nature, and undergo electrophilic substitution reactions quite readily. Quinoline and isoquinoline are weakly basic because the lone pair of electrons on nitrogen is not involved in formation of delocalized π molecular orbital. As a result, both these compounds also undergo nucleophilic substitution reactions on the heterocyclic ring. Quinolizinium salts, however, do not undergo electrophilic substitution reaction. Nevertheless, they undergo nucleophilic substitution at C-4.
2.1.4 Benzene-Fused Oxygen Heterocycles A six-membered oxygen heterocyclic ring fused with a benzene ring gives rise to new heterocyclic compounds like 2H-chromene, 4H-chromene, chroman, 1-benzopyrylium salt, and 2-benzopyrylium salt.
Benzene fused oxygen heterocycles.
2H- and 4H-chromenes, because of the presence of a double bond in the heterocyclic ring, undergo addition as well as cycloaddition reactions. The benzopyrylium salt in which the oxygen carries a positive charge makes the ring aromatic. The positive charge of the benzopyrylium salt is distributed unevenly over the heterocyclic ring. As a result, the following resonance structures are possible. The benzopyrylium salts are extremely susceptible to attack by nucleophilic reagents but are inert to attack by electrophilic reagents.
Resonating structures of benzopyrylium cation.
2.1.5 Six-Membered Heterocycles With Two Heteroatoms When two carbon atoms of the benzene ring are replaced by nitrogen, oxygen, and sulfur, six-membered heterocycles with two heteroatoms result. Diazines are six-membered aromatic heterocyclic compounds with two nitrogen atoms in the ring. There are three isomers of diazines: pyridazine (1,2-diazine), pyrimidine (1,3-diazine), and pyrazine (1,4-diazine).
Diazine isomers.
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2. Six-Membered Heterocycles
There are four bicyclic variants of these diazenes in which a benzene ring is fused to the diazine moiety. These bicyclic diazines, commonly called the benzodiazines, are still known by their trivial names and are designated as cinnoline (benzo[c]pyridazine), phthalazine (benzo[d]pyridazine), quinazoline (benzo[d]pyrimidine), and quinoxaline (benzo[e]pyrazine).
Benzodiazine isomers.
Dioxanes are six-membered, saturated, heterocyclic compounds containing two oxygen atoms in the ring. There are three isomers of dioxane and their names indicate the position in which hydrogen atoms of the cyclohexane ring have been replaced by oxygen, namely 1,2-dioxane, 1,3-dioxane, and 1,4-dioxane. 1,4-Dioxin is a six-membered heterocyclic, which contains two carbon-carbon double bonds and four carbon-oxygen bonds. This heterocyclic ring, which is made up of 8π electrons, is nonplanar and is classified as nonaromatic.
Six membered heterocycles with two oxygen atoms.
Structures equivalent to dioxanes in which oxygen atoms have been replaced by sulfur are referred to as dithianes, whereas structures analogous to dioxins are referred to as dithiins.
Six membered heterocycles with two sulfur atoms.
1,3-Dioxane and dithiane are cyclic acetals and thioacetals and they are commonly used as protecting groups for aldehydes and ketones.
2.1.6 Tautomerism in Six-Membered Heterocycles The hydroxyl derivatives of pyridine are both weak acids and bases and thus can exist as zwitterions. However, the 2- and 4-hydroxyl derivatives of pyridine are stabilized by mesomerism with uncharged canonical structures, which are thus more stable than the zwitterions. Thus 2- and 4-hydroxyl derivatives of pyridine exist chiefly in their carbonyl tautomeric form commonly known as 2- and 4-pyridones, respectively. The pyridone forms are favored in the solid phase or in polar medium, whereas their hydroxyl derivatives are the predominant tautomer in very dilute solutions, in nonpolar solvent or in the gas phase.
Tautomeric structures of 2-hydroxy and 4-hydroxypyridine.
2.2 Importance in Natural Products, Medicines, and Materials
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The preference for the two pyridones to exist in the amide form is the presence of a strong carbonyl group and still the aromaticity of the compound is preserved. There are two electrons each on the two carbon-carbon double bonds and one lone pair on the trigonal nitrogen, and delocalization of the lone pair of electrons on nitrogen proves the point.
2.2 IMPORTANCE IN NATURAL PRODUCTS, MEDICINES, AND MATERIALS Six-membered heterocycles are derivatives of benzene or cyclohexane in which one of the carbon atoms has been replaced by a heteroatom like nitrogen, oxygen, and sulfur. These heterocycles are not only widely distributed in nature but are also the major components of biological molecules like RNA and DNA. Nucleic acid in the form of DNA and RNA, which control cellular function and heredity, have bases like adenine, guanine, uracil, thymine, and cytosine, which are important purine and pyrimidine derivatives. A number of compounds containing six-membered heterocyclic nuclei play an important part in metabolism. For example, vitamin B3 (nicotinamide) and vitamin B6 (pyridoxine) are required for the biosynthesis of nicotinamide adenine dinucleotide phosphate (NADP+) and pyridoxal phosphate (PLP). A six-membered heterocyclic nucleus is not only present in drugs, vitamins, natural products, biomolecules, and biologically active compounds exhibiting antitumor, antiinflammatory, antifungal, antibacterial, antidepressant, anti-HIV, antimicrobial, antimalarial, and antidiabetic activity but they are also the key structural unit of pharmaceutical drugs and agrochemicals available in the market. A number of six-membered heterocycles also find application in material science such as dye stuffs, fluorescent sensors, brightening agents, and analytical reagents.
2.2.1 Nitrogen Heterocycles Nitrogen heterocycles like pyridine and its derivatives, piperidine, quinoline, isoquinoline, diazines, and triazines, are the most developable heterocyclic rings and have been widely used in drug design. They are structurally very important because these nuclei are present in a large number of drugs, which offer a broad range of biological as well as pharmaceutical activities. A simple glance at the Food and Drug Administration database shows that nearly 60% of the drugs are nitrogen-based heterocycles. A list of a few important, biologically active compounds, drugs, pharmaceutical agents, insecticides, pesticides, etc. are shown in the following diagram (for details consult the individual chapter).
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2. Six-Membered Heterocycles
2.2 Importance in Natural Products, Medicines, and Materials
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Drugs, insecticide, pesticide and herbicides containing nitrogen heterocycles.
2.2.2 Oxygen Heterocycles Oxygen-containing heterocycles, in which one or more oxygen atoms are present in the ring, constitute an important class of heterocyclic compound due to their natural abundance and diverse biological activity. They are usually classified as monocyclic oxygen heterocycles and fused oxygen heterocycles. Some of the common six-membered monocyclic oxygen heterocyclic compounds are dioxanes, pyrans, dioxins, tetrahydropyran, etc. For fused heterocycles, examples include chromenes, chromans, coumarins, etc. A number of oxygen heterocycles have the potential to be used as solvents in organic reactions. For example, tetrahydropyran has been found to be an excellent solvent for organic as well as organometallic reactions. Oxygen heterocycles also form the basis of sugar chemistry and many of their derivatives have shown potential to be used in pharmaceuticals as drugs to treat certain types of diseases. Many natural and synthetic six membered and their fused counterparts are known and find wide application in the treatment of some deadly diseases. A list of a few of these biologically active compounds is shown in the following diagram (for details consult the individual chapter).
Drugs containing oxygen heterocycles.
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2. Six-Membered Heterocycles
2.2.3 Sulfur Heterocycles Sulfur heterocycles that exist as isolated and fused systems are regarded as thioethers, alkylaryl, and diarylthioethers. Some of the common examples are thiane, dithiane, and thianthrene. These sulfur heterocycles are determinants in many biological systems and are often known to form metal complexes with metal ions. A few biologically active sulfur heterocycles are shown in the following diagram (for details consult the individual chapter).
2.3 SIX-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH ONE NITROGEN ATOM 2.3.1 Pyridine Pyridine, also called azabenzene, is a six-membered basic heterocycle consisting of five carbon atoms and one nitrogen atom. It is structurally related to benzene with one of the methine groups (CH) of benzene is replaced by nitrogen. The name pyridine is derived from the Greek word for fire pyr and the suffix idine used to signify the aromatic base. Pyridine was first discovered by Scottish chemist Thomas Anderson in 1849 as one of the constituents of bone oil.
Compounds containing the pyridine nucleus play an important part in metabolism. For example, vitamin B3 (nicotinamide) and vitamin B6 (pyridoxine) are required for the biosynthesis of NADP+ and PLP. A number of pyridine-based compounds are of commercial interest because they are easily available in the market as drugs and agroproducts such as herbicides, insecticides, fungicides, and plant growth regulators.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
Natural products, drugs, herbicide and vitamins containing pyridine nucleus.
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2. Six-Membered Heterocycles
Structural and Reactivity Aspects1a 1. Structure of pyridine The structure of pyridine is quite similar to benzene, except that one of the methine groups (CH) of the ring has been replaced by nitrogen. The cyclic structure of pyridine is thus made of five carbon atoms and one nitrogen atom, each of which is sp2 hybridized. Because the lone pair of electrons on nitrogen is not involved in the ring system, it is readily available for protonation. Thus pyridine behaves as a tertiary base. Like benzene, pyridine is also planar but the ring system is slightly distorted. Insertion of the electronegative nitrogen into the benzene ring causes significant polarization of the molecule, which not only leads to the generation of more resonating structures but additionally stabilizes those structures in which the negative charge is on the nitrogen atom. The resonance energy of pyridine was found to be 31.9 kcal/mol.
Resonating structures of pyridine.
The importance of charged structures in the resonance hybrid is well reflected by the high value of the dipole moment (2.26 D). The resonance hybrid structures of pyridine are well supported by the bond length values. The CC bond length values are intermediate between those known for the single bond (154 pm) and double bond (134 pm). The CN bond length is shorter than the CC bond length but again intermediate between the CN single bond (147 pm) and CN double bond (125 pm). The smaller CN bond length value leads to slight deviation of bond angle values of a perfect hexagon (120 degrees) (Fig. 2.1).
FIG. 2.1 Bond length and bond angles.
2. Molecular orbital structure of pyridine The nitrogen atom of pyridine is sp2 hybridized. It has three sp2 hybrid orbitals and one unhybridized p orbital perpendicular on the hybrid orbitals. Two of the sp2 hybrid orbitals contain one electron each, whereas the third hybrid orbital contains a lone pair of electrons. The five carbon atoms of the pyridine are also sp2 hybridized and each contains three sp2 hybrid orbitals with one electron each and one unhybridized p orbital. Two hybrid orbitals of nitrogen are involved in bond formation with two adjacent carbon atoms, C-2 and C-6, forming two sp2–sp2 CN sigma bonds. Each of the three carbon atoms, C-3, C-4, and C-5, is bonded to two adjacent carbon atoms, thus forming five sp2–sp2 CC sigma bonds. Each of the five carbon atoms still has one hybrid orbital, which overlaps with the 1s orbital of hydrogen forming five CH sigma bonds. An unhybridized 2p orbital, which is perpendicular to the plane of the sp2 orbital, still remains on each sp2-hybridized carbon and nitrogen atom. These unhybridized 2p orbitals can overlap with the other two neighboring atoms in two possible ways (Fig. 2.2), resulting in the formation of three π molecular orbitals.
FIG. 2.2 Two possible sideways overlap of unhybridized 2p orbitals.
The overlapping of these unhybridized p orbitals results in the formation of a continuous π ring system, which encompasses all the six atoms (five carbon and one nitrogen) containing all the six π electrons. As a result, the six π electrons are delocalized over all six atoms (Fig. 2.3). As each p orbital consists of two lobes, this delocalization acquires two doughnut-shaped electron clouds, one of which lies above and the other below the plane of the ring.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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FIG. 2.3 pi electron cloud above and below the plane of the ring.
3. Spectroscopic data1a Due to the presence of electronegative nitrogen atom in the aromatic ring, the α-hydrogen and α-carbon atoms experience a strong deshielding effect. The typical 1H and 13C NMR chemical shift values of pyridine are given in the following table. H and 13C NMR spectral data of pyridine
1
1
H NMR δ (ppm)
13 C NMR δ (ppm)
H-2/H-6: 8.5 9 H-3/H-5: 7.38 H-4: 7.75
C-2/C-6: 149.8 C-3/C-5: 123.6 C-4: 135.7
The UV spectrum of pyridine in ethanol shows two absorption bands at 251 and 270 nm. The first band is due to π→π* transition, whereas the second one is due to n→π* transition. Synthesis 1. Industrially, pyridine is manufactured by aerobic gas phase condensation of crotonaldehyde, formaldehyde, and ammonia.
2. Chichibabin pyridine synthesis1b–d: This reaction is named after Aleksei Chichibabin, a Russian organic chemist, and is still being used in the industry. The reaction involves condensation of an aldehyde, ketone, α,βunsaturated carbonyl compound, or any combination of the foregoing with ammonia or an ammonia derivative under pressure.
Acetaldehyde and formaldehyde undergo Knoevenagel-type condensation forming acrolein, which is then condensed with acetaldehyde and ammonia into dihydropyridine and finally to pyridine with the aid of a solid-state catalyst.
3. [2 + 2 + 2] cycloaddition reaction-Bonnemann cyclization: The first paper concerning acetylene heterocyclization with nitriles in the presence of cobalt complex as a catalyst was reported to obtain substituted pyridine2 in 23% yield by Japanese researchers. This cycloaddition reaction later came to be known as
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2. Six-Membered Heterocycles
Bonnemann cyclization after the German chemist Professor H. Bonnemann. This reaction was catalyzed by a low-valence Co complex formed in situ by the reduction of compounds of di- or trivalent cobalt with the use of NaBH4, BuLi, EtMgX, Hg, Li, LiH, and LiAlH4, leading to the construction of monosubstituted pyridine3 with high atom efficiency.3 Another important feature of this reaction is that acetylene and nitriles are efficiently co-cyclized under mild photochemical conditions in the most environmentally friendly solvent, water.
According to the proposed mechanism, oxidative coupling of alkyne with the catalyst would generate the unsaturated cobalt-cyclopentadiene complex A, which then coordinates with nitrile to give nitrile complex B, which subsequently transforms to metallocycloheptatriene C or intermediate D, finally yielding substituted pyridine derivative.4
Cobalt-catalyzed synthesis of pyridines from chiral nitriles and symmetrical alkynes has also been reported5 in good yields. The [2+2+2] cycloaddition of alkynes and nitriles has also been carried out efficiently for the construction of substituted pyridines6 in the presence of rhodium-(I) complexes as catalyst.
The cyclotrimerization of acetylene and hydrogen cyanide over a red-hot iron tube to yield pyridine7 was first observed by Sir William Ramsay.
Since then, arene-iron complexes, which are isoelectronic with CpCo species, have been used for the synthesis of substituted pyridine derivatives.8
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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Transition metals like Ti and Zr have also been used for the synthesis of pyridine derivatives via [2+2+2] cycloaddition of alkynes and nitriles.9 The reaction involves formation of dialkoxytitanacyclopentadiene from the acetylenes and the divalent titanium alkoxide (η2-propene)Ti(O-i-Pr)2 (generated in situ from Ti(O-i-Pr)4 and i-PrMgCl). Addition of a third alkyne gives a single aryl titanium compound and the addition of a nitrile gives a single metalated pyridine derivative, which is easily demetalated by hydrolytic workup.
A titanium-mediated [2+2+2] pyridine synthesis involving the reaction of an alkyne, a nitrile, and isopropyl magnesium chloride with titanium isopropoxide has also been reported.10 It has been observed that metallocyclopentadienes are formed by the coupling of 2 mol of alkynes with nitriles, leading to the generation of a single pyridine derivative. However, if two different alkynes and a nitrile are used, a mixture of regioisomers is obtained. A method has been reported in which aza zirconacyclopentadiene prepared in situ from an alkyne and nitrile reacts with a different alkyne to afford a single isomer of pyridine.11
4. [5 + 1] Condensation reaction: Condensation of a δ-dicarbonyl compound with ammonia or any other suitable nitrogen source led to the construction of pyridine derivatives.
Several variations of this method have been developed.12 These 1,5-dicarbonyl compounds have been prepared13 by a variety of methods, such as ozonolysis of 1,6-diene.
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2. Six-Membered Heterocycles
A novel method for the synthesis of substituted pyridine has been reported.14 The reaction involves zinc triflatepromoted [1+5] cycloaddition of isonitrile with N-formylmethyl-substituted enamide, facile aerobic oxidative aromatization, and intermolecular acyl transfer from pyridinium nitrogen to 5-hydroxy oxygen followed by acylation of the 4-amino group by acyl chloride yielding 2-substituted-4-acylamino-5-acyloxypyridines.
5. From enamines: Suitably substituted enamines under acidic and basic conditions undergo cyclization to yield pyridine derivatives.
Tetrasubstituted pyridines are obtained by treating dienones with N-bromosuccinimide. 6. Hantzsch synthesis: This synthesis is also known as Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis, and is a reaction reported by the German chemist Arthur Rudolf Hantzsch in 1881. This is a multicomponent synthesis, involving a reaction between an aldehyde, 2 equivalents of β-dicarbonyl compound, and ammonia or any appropriate amine.15 The initial product of the reaction is a dihydropyridine derivative, which on subsequent oxidation yields pyridine. The driving force for the second step is aromatization and it can easily be carried out with nitric acid, ferric chloride, manganese dioxide, and potassium permanganate.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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The initial product of the reaction is 1,4-dihydropyridine, also called Hantzsch product, and is important because of its structural resemblance to the reduced nicotinamide adenine dinucleotide, which has interesting biological activity as an antihypertensive agent. Since then a number of antihypertensive agents of this class of compounds have been synthesized.16
Antihypertensive agents containing 1,4-dihydropyridine nucleus.
A clean and effective one-pot procedure for the synthesis of 1,4-dihydropyridine via Hantzsch reaction in water without the use of catalyst and/or organic solvent has been reported.17 Hantzsch dihydropyridine synthesis has also been carried out in a microwave flow reactor.18 Mechanism: The first step is visualized as proceeding through a Knoevenagel-type condensation reaction leading to the generation of an intermediate I. In the next step the second intermediate, an ester enamine II, is produced by the condensation of a second equivalent of β-ketoester with ammonia.
Condensation between the two intermediates leads to the generation of a dihydropyridine derivative.
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2. Six-Membered Heterocycles
7. Guareschi synthesis: This reaction, which is a modification of Hantzsch synthesis, is named after the Italian chemist Icilio Guareschi and is also known as a Guareschi-Thorpe reaction. The reaction deals with the synthesis of pyridine derivatives by condensation of an amide of cyanoacetic ester (a primary amide) with acetoacetic ester in the presence of ammonia.19
This method has been used in the synthesis of ethionamide, an antibiotic prodrug used for the treatment of tuberculosis.
8. Boger reaction: This is a hetero [4+2] cycloaddition reaction named after its inventor Dale L. Boger,20 an American medicinal and organic chemist. The process involves the reaction of an enamine (generated in situ from a ketone and an amine) with 1,2,4-triazine to form substituted pyridine derivatives.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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The mechanism involves reaction of ketone with an amine (like pyrrolidine) leading to the generation of enamine, which undergoes a hetero Diels-Alder reaction with 1,2,4-tirazine. The initial adduct formed expels nitrogen followed by rearomatization and extrusion of amine leading to the formation of substituted pyridines.
9. Bohlmann-Rahtz pyridine synthesis: This is a cycloaddition reaction reported21 by H. Bohlmann and D. Rahtz in 1957 for the synthesis of trisubstituted pyridine derivatives. The reaction involves Michael addition of ethynyl ketone with enamine leading to the generation of aminoketone, which after cyclodehydration afforded the trisubstituted pyridine derivatives.
However, no mechanistic studies have been carried out, but the intermediate isolated and characterized by 1H NMR points toward the following mechanism. In the first step of the reaction, Michael addition of ethynyl ketone to enamine and subsequent proton transfer led to the generation of aminoketone as intermediate, which on heating at higher temperatures facilitated E/Z isomerization and cyclodehydration to produce substituted pyridines.
The Bohlmann-Rahtz reaction has been used for the synthesis of thiopeptide antibiotic.22 Some of the drawbacks of the Bohlmann-Rahtz reaction, like purification of the intermediate and high temperature for cyclodehydration, have been overcome by Bagley and coworkers.23
Synthesis of trisubstituted pyridine in a continuous flow microreactor involving the use of Brønsted acid catalyst, without the isolation of intermediate by the Bohlmann-Rahtz procedure, has been reported.24 10. Krohnke pyridine synthesis: This is a reaction named after Fritz Krohnke between α-pyridinium methyl ketone salts and α,β-unsaturated carbonyl compounds, which led to the construction of pyridine derivatives.25
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2. Six-Membered Heterocycles
A simple and efficient synthesis of 2,4,6-triarylpyridines by Kroknke procedures involving reaction between chalcones and ammonium acetate under solvent-free conditions has been reported.26 Mechanism:
11. Ciamician-Dennstedt rearrangement: This is a [2+1] cycloaddition reaction in which pyrrole reacts with dichlorocarbene under basic conditions (by heating sodium chloroacetate) yielding a bicyclic product, which after elimination of hydrogen chloride produced 3-chloropyridine.27
12. Diels-Alder reaction: Oxazoles and acyclic acid undergo Diels-Alder reaction, leading to the generation of an adduct, which under acidic conditions eliminated a molecule of water yielding pyridine 4-carboxylic acid derivative.
Oxazole also reacts with acrylonitrile in the presence of triethylamine to yield 4-cyanopyridine, which on hydrolysis yields pyridine.
13. By ring transformation reactions: A new approach for the synthesis of di- and trisubstituted pyridines has been developed28a by heating a mixture of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles with ammonium acetate or ammonium carbonate in pyridine at 120°C for 4 h. Disubstituted pyridines, 2-amino-6-arylpyridines were obtained by knocking out the 4-methylthio group through hydrogenation in the presence of Raney Ni as catalyst in ethanol for 6 h.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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Tetrasubstituted pyridines have also been obtained28b by the base-catalyzed ring transformation of 6-aryl-4- methylthio-2H-pyran-2-one-3-carbonitriles by using cyanamide as a nitrogen nucleophile. Base-catalyzed ring transformation of methyl 6-aryl-4-methylthio-2H-pyran-2-one-3-carboxylates by formamidine acetate in dimethylformamide using powdered KOH as a base at room temperature gave methyl 6-aryl-4- methylthiopyridine-3-carboxylate in more than 65% yields after usual workup and purification.28c
The precursor 6-(4-pyridyl)-4-methylthio-2H-pyran-3-carbonitrile is highly versatile for the construction of dipyridinyl, terpyridinyl, and polypyridinyl with a phenyl spacer by selecting mono- and diacetyl ketones as a source of carbanion for successive base-catalyzed ring transformation28d, e reactions.
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2. Six-Membered Heterocycles
Pyrillium salts on reaction with ammonia yield pyridine derivatives.
14. [3 + 3] Condensation reaction: A [3+3]-type condensation reaction of o-acetyl ketoximes and α,β-unsaturated aldehydes that are synergistically catalyzed by salts of copper(I) and an amine leading to the synthesis of substituted pyridines is reported. This reaction allows modular synthesis of a variety of substituted pyridines under mild conditions.28f
15. K.T. Potts and his coworkers prepared symmetrical and asymmetrical 2,6-disubstituted 4-methylthiopyridines by enolate addition of ketone to α-oxoketene dithioacetals in the presence of potassium tert-butoxide to afford 1,5-diketones, which on further reaction with ammonium acetate in acetic acid delivered 2,6-diaryl 4-methylthio pyridines.29
Physical Properties Pyridine is a colorless hygroscopic liquid with a boiling point (bp) of 115.2°C and a characteristic unpleasant odor. It is miscible with water and virtually all organic solvents. It is used as a polar, basic, low reactive solvent for a number of condensation, dehalogenation, elimination, and esterification reactions. Chemical Reactivity Though pyridine is isoelectronic with benzene the presence of a nitrogen atom in the ring influences its chemical reactivity. Due to the presence of electronegative nitrogen in the ring, the electron density at the 2,4- and 6-positions is decreased, whereas electron density is greater at nitrogen and at position 3. 1. Electrophilic reaction at nitrogen: Pyridine is basic in nature but is a weaker base compared to its saturated analog. The basic properties of pyridine are largely due to the presence of a lone pair of electrons on nitrogen. As a result, it readily forms pyridinium salts on reaction with acids. Lewis acids, which are good electron acceptors, react with pyridine to form tetrahedral salts. For example, pyridine reacts with aluminum chloride to form a complex in which the unshared pair of electrons on nitrogen fills the sp2 orbital of aluminum.
Some of these pyridinium salts are crystalline, quite stable, and are of synthetic importance, for example, pyridinium polyhydrogen fluoride is a convenient source of hydrogen fluoride for the addition across carbon-carbon double bonds and for conversion of alcohols to alkyl halides.30 Pyridinium chlorochromate (Corey reagent) and pyridinium dichromate are good oxidizing agents, chiefly used for the oxidation of alcohols.
Some important pyridinium salts.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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Pyridinium tribromide, which finds use as a brominating agent, is obtained by first treating pyridine with hydrogen bromide followed by treating the pyridine hydrogen bromide with bromine. This complex is used as a brominating agent.
Similarly, pyridine sulfur trioxide complex, which finds use as a sulfonating agent is obtained by treating pyridine with sulfur trioxide.31
Amination of nitrogen is achieved by treating pyridine with hydroxylamine O-sulfonic acid followed by acid treatment with hydriodic acid, producing 1-aminopyridinium iodide.32
Pyridinium salts with alkyl and acyl groups bonded to nitrogen are formed by reaction of pyridine with alkyl, acyl, or sulfonyl halides.33 These N-acyl salts have been found to serve as acyl transfer agents for the synthesis of esters and amides.
Pyridine also reacts with peracids, or a mixture of hydrogen peroxide and acids, yielding pyridine-N-oxide, which is of immense synthetic importance. 2. Electrophilic substitution reactions at carbon: The electronegative nitrogen of pyridine causes significant polarization of the molecule, and as a result there is electron withdrawal from the ring toward the nitrogen (see resonance structures). The ring carbons are electron deficient and thus highly deactivated toward electrophilic substitution reactions. In addition, electrophilic substitution reactions take place under acidic conditions, which first protonate the nitrogen atom resulting in the formation of pyridinium salts. The resultant positive charge on nitrogen causes the electrons from the ring to drift toward it, thereby deactivating C-2, C-4, and C-6 carbon atoms. Hence electrophilic substitution reaction takes place, if at all, only under extreme conditions also at C-3 and C-5 carbon atoms. This can be seen from the following resonating structures in which the electronegative nitrogen does not acquire a positive charge (structures I and II are least stable), hence the transition state leading to substitution at C-3 is energetically more favorable.
24
2. Six-Membered Heterocycles
From the foregoing resonating structures it can be seen that when the attack takes place at C-2 and C-4 there are two resonating structures marked I and II, respectively, in which there is a positive charge on the electronegative nitrogen atom. These structures are particularly very unstable. However, there is no such structure in which the attack takes place at C-3. Thus the carbocations generated from attack at C-3 are relatively more stable in comparison to carbocations generated from attack at the C-2- and C-4-positions. Thus electrophilic substitution takes place at C-3. (a) Halogenation: Direct halogenation of pyridine does not take place. However, bromination takes place in the presence of oleum at 130°C with the intermediate formation of pyridinium 1-sulfonate.34
Chlorination can also be carried out in the presence of aluminum chloride at 200°C.35
Iodination of pyridine via α-metalation using lithium di-tert-butyltetramethylpiperidino-zincate (TMP-zincate) takes place at room temperature using iodine as an electrophile.
(b) Sulfonation: Pyridine does not undergo sulfonation in the presence of concentrated sulfuric acid or oleum. However, heating pyridine with fuming sulfuric acid with a catalytic amount of mercuric sulfate at 230°C gives a 70% yield of pyridine 3-sulfonic acid.36
(c) Nitration: 3-Nitropyridine in low yield is obtained37 by heating pyridine with a mixture of nitric acid and sulfuric acid at 300°C. 3-Nitropyridine in high yield is obtained by carrying out nitration with
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
25
dinitrogen pentoxide in organic solvent, followed by treating the reaction mixture with aqueous SO2/ H2SO3− solution38
(d) Mercuration: Pyridine on heating at 180°C with mercuric acetate gave a salt, which rearranged to 3-pyridylmercuric acetate. The mercury derivative is then converted to pyridine mercuric chloride39 and finally to 3-bromopyridine40on reaction with bromine.
(e) Alkylation: 4-Ethylpyridine has been synthesized41 by heating pyridine with zinc dust and acetic anhydride. 4-Ethylpyridine was synthesized42 earlier by heating N-ethylpyridinium iodide in a sealed tube at 300°C. Heating pyridine with ethyl iodide43 or by distilling 4-ethylpyridine carboxylic acid with lime44 yielded pyridine.
(f) Acylation: Pyridine and related heterocycles cannot be directly acylated because of the presence of nitrogen, which deactivates the ring for attack by cations. Hence Friedel-Crafts and related reactions fail. However, heterogenous bimolecular reduction of pyridine with metal has led to the generation of C-acylated derivatives. The process involves treating pyridine with aluminum or magnesium metal and ethyl benzoate in the presence of mercury. The acylation is proposed to take place by the following mechanism.45
26
2. Six-Membered Heterocycles
3. Nucleophilic substitution reaction: Because pyridine contains an electronegative nitrogen in the ring, it undergoes nucleophilic substitution reaction with strong nucleophiles like amide ions, hydroxides, or organolithium compounds. The substitution takes place preferably at C-2 or C-4 and less readily at C-3. In addition, it is important to note that the last step of the nucleophilic substitution reaction is different from the electrophilic substitution reaction. In the electrophilic substitution reaction there is loss of proton, whereas in the nucleophilic substitution reaction the hydrogen is lost as hydride.
(a) Chichibabin reaction: This is a nucleophilic reaction used for the amination of pyridines, quinolines, and other nitrogen-containing heterocycles with alkali metal amides. Amination takes place at the α-position because of the close proximity of this position to the nitrogen, and the sigma complex formed is easily stabilized. The reaction involves heating pyridine with sodium amide in toluene at 100°C.
Mechanism: The nucleophile attacks the 2-position of the heterocyclic ring followed by loss of the hydride ion and subsequent elimination of the hydrogen molecule with the formation of sodium salt of 2-aminopyridine, which on treatment with water yielded 2-aminopyridine.
(b) Pyridine reacts with hydroxide ion at high temperatures to yield 2-pyridone, the stable isomer of 2-hydroxypyridine.
Reaction of pyridine with phenyllithium in dry ether at 110°C for 8 h under stirring produced 2-phenylpyridine.46
Nucleophilic substitution reaction takes place more readily47when the pyridine ring is already substituted with electron-withdrawing groups like nitro, cyano, or halogens.
The C-2 selective alkenylation of pyridine is achieved by activating the pyridine ring in situ through the addition of a catalytic quantity of mild Lewis acid like dimethylzinc or trimethylaluminum. When dimethylzinc is used as a
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
27
catalyst, C-2 monoalkenylated product is obtained, whereas in the presence of trimethylaluminum as catalyst, C-2 alkenylated product is obtained.48
4. Reduction reactions: Pyridine or its derivatives are more easily reduced as compared to benzene. Reduction to piperidine has been carried out by numerous methods like electrolysis49, 50 and hydrogenation over palladium (H2-Pd), but reduction with lithium triethylborohydride is most efficient.
Selective reduction of pyridine to 1,4-dihydropyridine has also been carried out under Birch reduction conditions.
Formation of 1,2-dihydropyridine was accomplished by reduction of pyridine with sodium borohydride in the presence of methyl chloroformate to methyl pyridine-1(2H)-carboxylate (60%) and methyl pyridine-1(4H)-carboxylate (40%).51
Sodium borohydride as reducing agent has also been used for the synthesis of N-sulfonyl-1,2- and 1,4-dihydropyridine but the yield of this reaction depends on the type of solvent used. When reaction is carried out with methanesulfonyl chloride in methanol at −65°C, a 1,2-dihydro derivative is formed in 35% yields. However, when benzenesulfonyl chloride is used,52 the ratio of 1,2 to 1,4 was 8:1.
Activation of acetic anhydride using a catalytic amount of Lewis acid like copper(II) triflate led to the regioselective introduction of the methoxycarbonylmethyl group at the C-2-position, allowing the practical synthesis of N-acetyl-1,2-dihydropyridyl acetic acid as the major product.53
Reduction of pyridine to 1-acyl-1,2-dihydropyridines with the arylacetylene group at the C-2-position was achieved by use of zinc salts in stoichiometric quantity. During the reaction, 1-ethoxycarbonylpyridinium chloride was generated in situ by mixing pyridine and ethyl chloroformate in acetonitrile. Phenylacetylene was then added in the presence of zinc bromide and N,N-diisopropylethylamine affording a 1,2-dihydro derivative54
28
2. Six-Membered Heterocycles
Reduction of pyridine to its dihydro derivative is also achieved55 by indium-promoted allylation of Nacylpyridinium salts.
Tris(pentafluorophenyl)borane-catalyzed silylative reduction of pyridines has been reported.56 Depending on the nature and position of the substituent, structurally diverse azacycles were synthesized. Reduction with formic acid, however, leads to the formation of N,N-dimethylpiperidinium formate.57
5. Dimerization: 2,2′-Bipyridine which is an important chelating reagent was earlier synthesized58a by heating pyridine with ferric chloride, or with iodine58b or nickel-alumina catalyst58c at temperatures ranging from 300 to 400°C. It is now prepared59 by heating pyridine with a Raney nickel catalyst (W7-J) at moderate temperature.
The reaction is considered to involve an anion radical resulting from the transfer of electrons from metal to heterocycle.
6. Photochemical reactions: Photolysis of pyridine at 254 nm in butane solution at −15°C for 15 min led to the formation of Dewar pyridine, which reverted back to pyridine at elevated temperature. When irradiated in aqueous sodium borohydride solution, Dewar pyridine is trapped by reaction with water followed by reduction of a double bond to yield the stable bicyclic compound 2-azabicyclo[2.2.0]hex-5-ene. Similarly, when irradiated in water, hydration takes place with addition of water across the imine double bond. The unstable hydrated Dewar pyridine then undergoes a ring-opening process to yield 5-amino-2,4-pentadienal. The intermediacy and structure of Dewar pyridine has been proved by NMR spectroscopy.60
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
29
Flash photolysis of pyridine yielded acetylene and hydrogen cyanide as the product,61 whereas irradiation of the pyridine matrix isolated in argon at 8 K gave hydrogen cyanide and cyclobutadiene as secondary products.62 Existence of azaprefulvene intermediate has been suggested as a result of the deactivation of the S2 (π, π*) state of pyridine.63 The deactivation pathway for excited pyridine was also studied and it was observed that the primary product from the vibrationally excited S2 (π, π*)vib pyridine molecule was a vibrationally excited ring-opened biradical, formed by the cleavage of the CN bond.64
7. Diels-Alder reaction: Normally, pyridine, like any other aromatic compound, does not undergo Diels-Alder reaction but under certain conditions it reacts with a powerful dienophile like dimethyl acetylenedicarboxylate (DMAD) to yield a 1:2 adduct. Initially, a zwitterion is formed, which after cyclization and rearrangement yields the adduct 65
8. Minisci reaction of pyridine: A new method66 for the generation of alkyl radicals by silver-catalyzed oxidative decarboxylation of carboxylic acids with peroxydisulfate has been reported. By this method, nucleophilic addition to protonated pyridinium ion takes place, which on oxidation gave an alkylated product.
Pyridine is also attacked by admantyl radical to give a mixture of C-2 and C-4 isomers.67
30
2. Six-Membered Heterocycles
9. Ring-opening reactions: Pyridine is a stable compound and is not cleaved by acid. However, the pyridine ring is cleaved in the form of its pyridinium salts (addition compound) with sulfur trioxide, chlorosulfonic acid, etc. The most important cleavage reaction is the treatment of pyridinium salt of sulfur trioxide with strong aqueous sodium hydroxide, which gave a sodium salt of glutaconic aldehyde.
The pyridine ring is also opened by nucleophilic reagent. 2,4-Dinitropyridinium chloride is formed by the reaction of pyridine with 2,4-dinitrochlorobenzene at 110°C, which on reaction with KOH formed a deep red-colored compound. Treatment of this intermediate compound with dilute aniline and acid gave 2,4-dinitroaniline and glutaconic aldehyde dianil.
3-Acetylaminopyridine on reaction with cyanogen bromide in the presence of primary aromatic amine yields pentamethinium salt.
10. Reactions via pyridyne intermediate: Polyfunctionalized pyridine derivatives, which are of immense importance, can easily be accessed through a reactive pyridine intermediate. Pyridyne, which is analogous with benzyne, exists in two isomeric forms: 2,3-pyridyne (2,3-didehydropyridine) and 3,4-pyridyne (3,4-didehydropyridine). They are formed by reaction of 3-chloro-, 3-bromo-, and 3-iodopyridine with a strong base like potassium amide in liquid ammonia. The pyridynes formed react with a variety of reagents to yield a product that could not be formed by reaction with pyridine. Studies have shown that the stability of 3,4-pyridyne is 9.0 kcal/mol more compared to 2,3-pyridine. Besides, 3,4-pyridyne has more triple bond character than 2,3-pyridyne. Though 2,3-pyridyne could not be isolated, there are a number of reactions in which this intermediate has been trapped. The first reported trapping of 2,3-pyridyne with furan was reported in 1962. In this reaction 2-chloro-3- bromopyridine was treated with lithium amalgam and furan in a sealed tube for 7 days. The product of the reaction was quinolone. It was proposed that quinolone was produced by 2,3-pyridyne being trapped with furan to give epoxyquinoline, which could then be transformed to quinolone via oxygen abstraction by lithium.
Further proof for the intermediacy of 2,3-pyridyne was obtained by reaction of 4-ethoxypyridine with lithium amalgam and furan.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
31
A number of reactions have been reported showing the existence of 2,3-pyridyne. However, in 1992, Walter, Carter, and Banerjee confirmed the existence of 2,3-pyridyne by NMR spectroscopic method.68 In this reaction, the 2,3-pyridyne generated was trapped with three different furans. When 2-methylfuran trapped the pyridyne intermediate, two regioisomeric products were formed and their ratio was determined on the basis of NMR.
2.3.2 Pyridine N-Oxide
Pyridine N-oxide is an oxidation product of pyridine characterized by the presence of a so-called “donative” (or coordinate covalent) bond between nitrogen and oxygen. This bond is formed by the overlap of the nonbonding pair of electrons on nitrogen with the empty orbital on the oxygen atom. This bond is usually represented by an arrow or by formal charges (formula I or II; in this book, formula II has been used).
Pyridine N-oxide is a planar, colorless, hygroscopic, crystalline compound obtained by the oxidation of pyridine. It is chiefly used as an oxidizing agent in organic synthesis and as a ligand in coordination chemistry. Structural and Reactivity Aspects The molecular structure of pyridine N-oxide was determined by gas phase electron diffraction.69 The bond lengths and bond angles were determined by applying least square analysis on the experimental molecular analysis. N1C1= 1.384 ± 0.11 Å, C2C3 = 1.381 ± 0.009 Å, C3C4 = 1.393 ± 0.008 Å, N1O = 1.290 ± 0.015 Å. ∠C2N1C6 = 120.9 ± 1.8 degrees, ∠C3C4C6 = 114.1 ± 2.5 degrees. The 1H and 13C NMR spectral data70, 71 of pyridine N-oxide are given in the following table. H and 13C NMR spectral data of pyridine N-oxide
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 8.23; H-3, 7.70; H-4, 7.30
C-2, 139.4; C-3, 127.2; C-4, 125.7
The chemistry and application of pyridine N-oxide have attracted great attention because this nucleus has been found to be present in a number of pharmaceuticals, biologically active agents, and natural products.
32
2. Six-Membered Heterocycles
A number of pyridine N-oxide derivatives not only possess antiviral activity but they also qualify as potential anti-HIV agents.72
Pyridine N-oxide derivatives possessing antiviral activity.
Three naturally occurring compounds with a pyridine N-oxide nucleus and a disulfide functional group have been reported to possess significant antibacterial activity.73
Pyridine N-oxide derivatives possessing antibacterial activity.
Besides a number of pharmaceutical drugs, the analgesic and antiinflammatory drugs niflumic acid, pranoprofen, and the antiulcer drug omeprazole are manufactured involving the use of heterocyclic N-oxides. Additionally, these N-oxides have been used as protecting groups, auxiliary agents, oxidants, ligands in metal complexes, and catalysts. Synthesis 1. By oxidation of pyridines: Pyridine N-oxide is prepared by the oxidation of pyridine with peracetic acid.74 Oxidation has also been carried out with perbenzoic acid,75 monoperphthalic acid,76 peracetic acid, and hydrogen peroxide.77–79 A higher yield of pyridine N-oxide is obtained by carrying out reactions with methyl isonicotinate in the presence of MTO catalyst.80.
2. Transformation of isoxazole rings: 5-Cyanomethyl-2-isoxazoline on reaction with a catalytic amount of 1,5-diazobicyclo[5.4.0]undec-5-ene (DBU) in boiling xylene yields 6-substituted-2-aminopyridine N-oxide. The reaction is thought to proceed through the reactive Z-vinylene hydroxylamine.81
Physical Properties Pyridine N-oxide is a stable dipolar molecule and is more reactive in comparison to the parent pyridine molecule. Enhanced reactivity is due to the electron release of the oxygen into the ring. This fact is proved by the value of the dipole moment, which in the case of pyridine N-oxide is 4.25 D, almost twice that of pyridine (2.23 D). The difference in dipole moment between pyridine N-oxide and pyridine is much lower than expected. The smaller difference in dipole moment between them points to a significant contribution from the resonance structures derived due to movement of electrons from oxygen to the ring. In these structures the oxygen is neutral, whereas ring carbons at C-2 and C-4 are negatively charged, implying that these positions are susceptible to electrophilic substitution reaction.
Resonating structures of pyridine N-oxide showing movement of electrons from oxygen to ring.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
33
However, if the direction of polarization is reversed, then in that case the C-2 and C-4 carbon atoms of the ring become positively charged, thus making the ring susceptible to nucleophilic substitution reaction.
Resonating structures of pyridine-N-oxide showing movement of electrons from the ring.
Chemical Reactivity 1. Electrophilic substitution reaction (a) Chlorination: Reaction of pyridine N-oxide with phosphorous oxychloride yields 2-chloropyridine as the major product, while 4-chloropyridine is the minor product.
(b) Nitration: Pyridine N-oxide reacts when heated with fuming nitric acid and concentrated sulfuric acid at 130°C for 3.5 h, yielding 4-nitropyridine N-oxide.82, 83 The pyridine derivative is regenerated by carrying out deoxygenation with triphenylphosphine.
(c) Sulfonation: Sulfonation of pyridine N-oxide takes place under drastic conditions by heating it with oleum and mercuric sulfate at 220–240°C affording 3-sulfonylpyridine N-oxide.
(d) Acylation: Reaction of pyridine N-oxide with acetic anhydride yielded 2-acetoxypyridine as the major product and 3-acetoxypyridine as the minor product. However, when reaction with acetic anhydride is carried out in boiling anisole or benzonitrile a number of other minor products like 2-(p-methoxyphenyl)pyridine, 2-(mmethoxyphenyl)pyridine, 2-(p-cyanophenyl)pyridine, and 2-(m-cyanophenyl)pyridine, respectively, were also obtained.84
(e) Reaction of pyridine N-oxide with mercaptans like methylmercaptan in the presence of acetic anhydride yielded a 2-substituted product. However, when bulky groups like tert-butylmercaptan are used, substitution may also take place at the 3-position.85
34
2. Six-Membered Heterocycles
The reaction has been found to take place by the following mechanism.
2. Reactions via metalation (a) Direct alkylation of pyridine N-oxide is achieved by treating it with n-butyllithium in inert nonprotonic solvent, which abstracts a proton from the α-position of the pyridine N-oxide yielding a carbanion, which is then trapped with aldehydes or ketones to yield 2-(1-hydroxycyclohexyl)- and 2,6-bis-(1-hydroxyalkyl) pyridine-1-oxide.86
(b) Direct arylation of pyridine N-oxide to prepare its 2-aryl derivatives in the presence of Pd(OAc)4 and PtBu3 has been reported. The reaction takes place with the formation of a PtBu3-ligated arylpalladium acetate complex. Mechanistic studies of the reaction have also been reported.87
(c) Heteroarylation of pyridine N-oxide is reported. The reaction is catalyzed by Pd(II) with copper(I) oxidative cross-coupling between pyridine N-oxide and electron-rich heteroarenes such as thiophene and furan. Cu(OAc)2-H2O was used as oxidant during the reaction.88
Palladium(II)-catalyzed coupling between pyridine N-oxide and N-substituted indoles has also been reported.89, 90 (d) A novel method for the selective 2-substitution of pyridine N-oxide via directed ortho metalation has been reported. The reaction involves the addition of iso-PrMgCl to pyridine N-oxide in tetrahydrofuran (THF) at −78°C that generated an ortho-metalated species, which could be trapped with aldehydes, ketones, and halogens to generate 2-substituted pyridine N-oxides.91
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
35
(e) Reaction with Grignard reagent: Reaction of pyridine N-oxide with phenyl magnesium bromide in THF yielded 2-phenylpyridine. In this reaction an intermediate product was also obtained, which on treatment with acetic anhydride was also converted to 2-phenylpyridine.92
Another method for the synthesis of 2-substituted alkyl-, alkynyl-, and arylpyridines has also been reported. The reaction involves addition of Grignard reagent to pyridine N-oxide in THF, followed by treatment of the resulting 2,4-dienal oxime with acetic anhydride at 120°C, resulting in the formation of 2-substituted pyridines.93
3. Deoxygenation of pyridine N-oxide: Deoxygenation of pyridine N-oxide is carried out with potential reducing agents. Sulfur and some of its compounds, on reaction with pyridine N-oxide at 115–150°C, form pyridine with oxygen atoms being bonded to sulfur or released as water.94
Deoxygenation by selective transfer of oxygen from pyridine N-oxide to triphenylphosphine in the presence of rhenium catalyst yielded pyridine.95
Similarly, pyridine N-oxide is transformed to pyridine by treating it with 2-chloroalkyl-trichlorophosphonium hexachlorophosphorates.96
Deoxygenation has also been reported to be carried out with phosphorous oxychloride97 and trifluoroacetic anhydride.98 4. O-Alkylation: Alkylation of pyridine N-oxide with alkyl halide in acetonitrile afforded N-alkoxypyridinium halide.99
5. Cycloaddition reaction: Pyridine N-oxide undergoes a cycloaddition reaction with nitrilium salt in methylene chloride at 0–23°C for 20–45 min. 1,5-Sigmatropic rearrangement take place yielding salt.100
36
2. Six-Membered Heterocycles
Pyridine N-oxide reacts with strained 3,3,6,6-tetramethyl-1-thia-4-cycloheptyne at room temperature and gave an unstable intermediate (A), which rearranged to spiro-3H-azepine derivative (C) via azanorcaradiene (B).101
6. Synthesis of substituted pyridines from pyridine N-oxide (a) Oxidative addition of Heck acceptors to pyridine N-oxide in the presence of palladium acetate, silver carbonate, and a pyridine additive in 1,4-dioxane provided 2-alkenylated pyridine N-oxide in moderate to excellent yield, which on deoxygenation yielded 2-alkenylpyridines. Arylation was also carried out under similar reaction conditions affording 2-phenylpyridine N-oxide102
(b) In the presence of a nickel catalyst, pyridine N-oxide underwent regio- and stereoselective insertion of alkynes to afford (E)-2-alkenylpyridine N-oxide in good yield, which on deoxygenation yielded substituted pyridines.103
(c) 2-Aryl pyridines are best synthesized by reacting pyridine N-oxide with 4-bromotoluene in the presence of lead acetate and phosphonium salt yielding 2-(4′-methylphenyl)-pyridine N-oxide, which is then treated with zinc dust.104, 105
A method for the transition metal-free regiospecific synthesis of 2-substituted alkyl-, alkynyl-, and arylpyridines has been reported. The reaction involves addition of Grignard reagent to pyridine N-oxide in THF, followed by treatment of resulting 2,4-dienal oxime with acetic anhydride at 120°C, resulting in the formation of 2-substituted pyridines.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
37
(d) A general and efficient method for converting pyridine N-oxides to 2-aminopyridines in one step has been reported. The reaction takes place with the use of commercially available reagents like t-BuNH2, Ts2O, and trifluoroacetic acid (TFA).106
2-Aminopyridine amides in excellent yield are formed by warming a mixture of imidoly chloride (formed in situ by reaction of a secondary amide with a stoichiometric amount of oxalyl chloride and 2,6-lutidine in CH2Cl2 at 0°C) with pyridine N-oxide at room temperature.107
Synthesis of 2-aminopyridines has also been reported by the reaction of pyridine N-oxide with activated isocyanides.108
(e) A transition metal-free method for the direct introduction of acetylenes into the heterocyclic system using SNH methodology has been reported. This method, which is complementary to a Sonogashira cross-coupling reaction, provides a versatile tool for the synthesis of a series of ethynyl azines.109
(f) Deoxydative substitution of pyridine N-oxide by thiophenol in the presence of sulfonyl halide leads to the generation of 2-phenylthiopyridine and 3-phenylthiopyridine.110
7. Reissert-Henze reaction: Pyridine N-oxide can be converted to 2-cyanopyridine or 4-cyanopyridine in a ReissertHenze reaction by activation of an N-oxide function by O-acylation111 or O-alkylation.112 However, activation of N-oxide and subsequent cyanation can be carried out in one step by heating the N-oxide in acetonitrile with 3–4 equivalents of trimethylsilyl cyanide in the presence of triethylamine.113
38
2. Six-Membered Heterocycles
8. Photochemical reactions (a) Photolysis of pyridine N-oxide in basic aqueous solution gave anion A114 as the quantitative product.
(b) In the presence of secondary amines, added either before or after photolysis of the pyridine N-oxide solution, conjugated nitrile B was obtained.115
(c) UV irradiation of pyridine N-oxide leads to 2-formylpyrrole. According to initial mechanistic hypothesis, UV irradiation of pyridine N-oxide to 2-formylpyrrole takes place through the successive formation of the following four intermediates: 1-aza-7-oxa-norcaradiens (A), 1,2-oxazepine (B), vinylic nitrene (C), and pyrrolenine (D).116
2.3.3 Picolines Methylpyridines, formerly called picolines, are referred to as α,β- and γ- or 2,3- and 4-methyl derivatives of pyridine with the chemical formula C6H7N. The three compounds are structural isomers and their name is designated with the position of methyl group presence.
Structural and Reactivity Aspects117 All three methylpyridines are colorless liquids at room temperature. They are comparatively stronger bases compared to the parent compound, pyridine, primarily due to the +I effect of the methyl group, which increases the availability of the lone pair of electrons on nitrogen. Among all three methylpyridines, 2-methylpyridine (pKa 5.96) and 4-methylpyridine (pKa 6.05) are stronger bases compared to 3-methylpyridine (pKa 5.68). The dipole moments of 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine are 1.96, 2.30, and 2.57 D, respectively.117
39
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
Physical data of methylpyridines Compound
Boiling Point (°C)
Density (d20)
Solubility in Water
2-Methylpyridine
129.5
0.9462
Miscible
3-Methylpyridine
143.9
0.957
Miscible
4-Methylpyridine
144.9
0.9558
Miscible
H NMR data of methylpyridines (chemical shifts in δ, ppm)
1
1
H NMR spectral data of methylpyridines H-2
H-3
H-4
H-5
H-6
2-Methylpyridine (CDCl3)
2.54 (methyl)
7.12
7.53
7.08
3-Methylpyridine
8.44
2.32 (methyl)
7.465
7.159
8.499
4-Methylpyridine
8.44
7.08
2.32 (methyl)
7.08
8.44
8.47
C NMR data of methylpyridines (chemical shifts in δ, ppm)
13
C NMR spectral data of methylpyridines
13
C-2
C-3
C-4
C-5
C-6
2-Methylpyridine
158.7
123.5
136.1
120.8
149.5
3-Methylpyridine
150.9
133.1
136.4
123.4
147.3
4-Methylpyridine
150.1
125.0
147.0
125.0
150.1
Methylpyridines form stable salts with both organic and inorganic acids. They do not form stable salts with weaker acids like sodium acid succinate and sodium bisulfite but form stable salts with a stronger base such as 2,3,5,6-tetramethylpyridine. Importance in Natural Product, Medicine, and Materials Methylpyridines are of immense importance because they have been used for the synthesis of a variety of agrochemicals and pharmaceuticals. For example, 2-methylpyridine has been used for the synthesis of picloram-a herbicide and amprolium-a coccidiostat. 3-Methylpyidine has been used for making insecticides such as chloropyrifos and herbicides such as fluazifop-butyl. 4-Methylpyidine has been used for the synthesis of the antitubercular drug isoniazid.
2.3.4 2-Picoline (2-Methylpyridine)
2-Methylpyridine is a liquid and finds use as a solvent or as an intermediate in the dye and resin industry. 2-Methylpyridine was the first pyridine derivative, isolated from coal tar in 1846 by T. Anderson. Synthesis 1. It was chiefly synthesized by the condensation of acetaldehyde with ammonia in the gaseous phase.118
40
2. Six-Membered Heterocycles
2. Industrially, 2-methylpyridine is manufactured from acetone. The process involves reaction of acetone with acrylonitrile in the presence of isopropylamine as catalyst yielding 5-oxohexanenitrile as intermediate followed by cyclization in the gas phase over supported metal catalysts like Ni/SiO2 or Pd/Al2O3 in the presence of hydrogen.119
3. 2-Methylpyridine is also synthesized by the reaction of acetaldehyde imine with 2 equivalents of acrylamine. The intermediate product formed underwent cyclization to dihydropyridine derivative, which on deamination and oxidation afforded the desired product.
4. Bonnemann cyclization: Reaction of 2 mol of acetylene with 1 mol of acetonitrile in the presence of Co(I) catalyst leads to the generation of 2-methylpyridine.120
5. β,γ-Unsaturated ketoxime of hex-4-en-2-one in the presence of sodium phenoxide and palladium-based catalyst, delivered 2-methylpyridine.
6. Thermal decarboxylation of 2-pyridylacetic acid in water affords the corresponding methylpyridine derivative.121
7. 2-Methylpyridine has also been synthesized by the reaction of ethanol and ammonia in the presence of oxygen over ZSM-5 zeolite promoted by Cd, Co, or Fe and H-Y zeolites.122 The reaction is thought to take place by the following mechanism.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
41
2-Methylpyridine has also been synthesized by heating acetone, formaldehyde, methanol, and ammonia over ZMS-5 at higher temperatures.123 8. Cyclization of pent-4-en-2-one oxime in the presence of a catalytic amount of palladium halogenide yields 2-methylpyridine.124
Chemical Reactivity 1. 2-Methylpyridine reacts with chloroform or bromoform in strongly alkaline medium to give a carbylamine test.117 2. 2-Methypyridine is widely used in the synthesis of 2-vinylpyridine, which on copolymerization with butadiene and styrene leads to the formation of an adhesive used for bonding textiles to elastomers. The synthesis of 2-vinylpyridine is achieved by the addition of aqueous formaldehyde to 2-picoline followed by dehydration of the resultant product.
3. Oxidation of 2-picoline with potassium permanganate afforded picolinic acid.125
4. Photochemical irradiation of 2-methylpyridine vapors at 238–266 nm resulted in the formation of 3-methyl- and 4-methylpyridine in a 10:1 ratio.126 The reaction takes place with the intermediate formation of azaprismane.
42
2. Six-Membered Heterocycles
However, Caplain and coworkers reported127 that irradiation of 2-methylpyridine resulted in the formation of 4-methylpyridine as an exclusive product. They reported evidence to show that the reaction takes place by the involvement of radical intermediates by irradiating 2-methylpyridine in cyclohexane,128 which led to the formation of 6- and 4-cyclohexyl-2-methylpyridine, biscyclohexane, and methylcyclohexane.
5. Coniine, an alkaloid, was synthesized by treating 2-methylpyridine with phenyllithium. The alkyllithium generated on nucleophilic substitution with bromoethane followed by reduction yields coniine.
Alternatively, reaction of 2-picoline with acetaldehyde in the presence of anhydrous zinc chloride gives a product, which on reduction with sodium and ethanol yields 2-propylpiperidine. Both the reactions had been used for establishing the structure of coniine.
6. 2-Methylpyridine is oxidized to its corresponding aldehyde by treating it with 1 equivalent of iodine at room temperature. The crystalline complex so formed was dissolved in dimethyl sulfoxide (DMSO) and the reaction mixture heated at 140–160°C yielded picolin-2-aldehyde.129
7. Sulfonation of 2-methylpyridine with oleum at 250°C results in the formation of 2-methylpyridine-5-sulfonic acid.
8. The presence of nitrogen atoms in pyridine has an important influence on the activation of the methyl group. The main feature of the reactivity is the deprotonation of the hydrogen of the methyl group by a strong base. The anion produced is mesomerically stabilized involving the ring nitrogen. Since such anions are stabilized in the same way as enolates, the term “enaminate” has been used to describe nitrogen containing enolates like anion.
The enaminate anion produced can undergo a wide variety of reactions. Alternatively, side chain reactions can also be performed by first carrying out electrophilic addition on nitrogen, thereby making the side chain hydrogens more acidic. Deprotonation generates an enamine or enamide.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
43
(a) 2-Methylpyridine can readily undergo aldol condensation and this reaction is best carried out in the presence of acetic anhydride or Lewis acid such as zinc chloride. 2-Methylpyridine reacts with aldehyde at 200°C in the presence of zinc chloride or acetic anhydride to yield 2-styrylpyridine (stilbazole).130
Chloral also condenses with 2-methylpyridine. (b) 2-Methylpyridine can easily be benzoylated in the presence of phenyllithium.
(c) Nitration of 2-methylpyridine can be carried out with sodamide in liquid ammonia in the presence of propyl nitrate131 at −35°C.
(d) 2-Pyridylacetone was prepared132 first by metalation of 2-methylpyridine with butyllithium followed by the action of dimethylacetamide (DMA).
Similarly, 2-methylpyridine reacts with butyllithium. The methyl anion generated reacts with methyl 3,3-dimethylpentanoate and 1-cyano-3-butene to give two different ketones in moderate yields.133 (e) 2-Methylpyridine can be easily alkylated by treating with an alkyl halide like butyl chloride in the presence of sodium amide.134
(f) 2-Picoline on reaction with phenyllithium or sodamide yields a carbanion-like intermediate, which reacts with a variety of electrophiles to yield different products.
44
2. Six-Membered Heterocycles
9. 2-Picoline on reaction with α-bromopyruvate leads to the generation of an intermediate, which was cyclized to indolizine in the presence of sodium carbonate.
10. Cationic surfactants, which find use in gene therapy, were synthesized. The procedure involves reaction of 2-methylpyridine with butyllithium and α,ω-dibromoalkane, leading to the generation of a base, which on quaternization with dodecyl methanesulfonate yields the surfactant molecule.135
11. Ethyl 2-pyridylacetate is prepared by treating 2-picoline with phenyllithium.136 The resulting picolyllithium solution on reaction with dry carbon dioxide gave lithium salt of acid, which was esterified by treating with ethanolic HCl.
12. Free radical chlorination of 2-picoline by N-chlorosuccinimide yields a mixture of mono- and dichlorinated products.137
Similarly, free bromination of 2-picoline by N-bromosuccinimide yields 2-bromomethylpyridine as the exclusive product.138
13. Benzylic sulfonation of 2-methylpyridine is achieved by quenching 2-lithiomethylpyridine with 1-(phenylsulfonyl)benzotriazole at −78°C in THF.139
14. 2-Methylpyridine on treatment with n-butyllithium followed by treatment with 1,6-dibromohexane yields 1,8-bis(2-pyridyl)octane.140
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
45
15. Reaction of 2-methylpyridine with 2-bromoacetylthiophene in refluxing dry THF afforded 2 picolinium salt, which has been used for the synthesis of a variety of aniline and thiophene derivatives possessing antimicrobial activities.141
16. 2-Methylpyridine condenses with chloral to yield an alcohol, which undergoes dehydration to yield the unsaturated product.
2.3.5 3-Picoline (3-Methylpyridine)
Synthesis 1. Reaction of a mixture of acetaldehyde and formaldehyde with ammonia in the gas phase over HZSM-5 catalyst yields 3-methylpyridine as a major product in addition to pyridine as a minor product.142
2. 1,5-Diamino-2-methylpentane (a derivative of 2-methylglutaronitrile) in the presence of zeolites is cyclized to 3-methylpiperidine, and then aromatized to 3-methylpyridine by catalytic dehydrogenation.143
3. Reaction of a mixture of acrolein and propionaldehyde with ammonia in the gas phase yielded 3-methylpyridine.
46
2. Six-Membered Heterocycles
4. Reaction of lithium aluminum hydride with excess pyridine yields lithium tetrakis (N-dihydropyridyl) aluminate, which on reaction with methyl iodide produced 3-methylpyridine.144
Chemical Reactivity 1. 3-Methylpyridine has been easily oxidized in the gas phase using a fixed-bed reactor charged with vanadium pentoxide on high surface titanium dioxide to nicotinic acid.145 Oxidation of 3-methylpyridine with potassium permanganate also yields nicotinic acid.146
2. Ammoxidation of 3-methylpyridine, followed by partial hydrolysis of the intermediate 3-cyanopyridine, yielded pyridine 3-carboxamide.
Ammoxidation of 3-picoline to nicotinonitrile was also carried out with a V-Mo-P oxide catalyst prepared from 11-molybdo-1-vanado phosphoric acid by thermal decomposition.147 3. 3-Methylpyridine can be aminated at position 2 with sodium amide yielding 2-amino-3-methylpyridine and 2-amino-5-methylpyridine. The introduction of the amino group by Chichibabin reaction has been widely used for the replacement of the amino group by other groups.148
4. Free radical chlorination of 3-picoline by N-chlorosuccinimide yields 3-chloromethylpyridine exclusively by a free radical mechanism.149
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
47
2.3.6 4-Picoline (4-Methylpyridine)
Synthesis 1. 4-Methylpyridine is chiefly synthesized by the condensation of acetaldehyde with ammonia.
2. Thermal decarboxylation of 4-pyridylacetic acid in water affords the corresponding 4-methylpyridine.150
3. 4-Methylpyridine N-oxide, when reduced with oxorhenium catalyst in the presence of triphenylphosphine in benzene, afforded 4-methylpyridine.151
Chemical Reactivity 1. 4-Methylpyridine is comparatively more basic than pyridine. 2. 4-Methylpyridine reacts with chloroform or bromoform in strongly alkaline medium to give a carbylamine test. 3. N-Alkylation of 4-methylpyridine can be carried out by treating it with methyl iodide to yield quaternary salt.
4. 4-Methylpyridine can be successfully aminated at 150°C at position 2 giving a reasonable yield of 4-methylpyridin-2-amine.
48
2. Six-Membered Heterocycles
5. As in the case of 2-methylpyridine, 4-methylpyridine is also reactive and on formation of enaminate anion by the base it reacts with styrene to form 4-(3-phenylpropyl)pyridine.
6. Nitration of 4-methylpyridine can also be carried152 out with sodamide in liquid ammonia in the presence of propyl nitrate at −33°C.
7. 4-Methylpyridine can be oxidized with potassium permanganate affording isonicotinic acid.
8. 4-Methylpyridine readily undergoes aldol condensation with carbonyl compounds and this reaction is best carried out in the presence of acetic anhydride or Lewis acid such as zinc chloride.153
Condensation of 4-methylpyridine with different aryl aldehydes afforded heterostilbenes.
9. Reduction of 4-methylpyridine to its 1,2-dihydro derivative was achieved by carrying out the addition of silylboronic acid ester in the presence of palladium catalyst, 1,2-silaboration took place leading to the generation of N-boryl-2-silyl-1,2-dihydropyridine regioselectively.154
10. A reaction of 4-methylpyridine with fluorine gas at −78°C followed by reaction with isonitrile at −50 to 0°C led to the formation of picolinamide. The reaction is thought to proceed with the initial formation of carbene, which undergoes an addition reaction with isonitrile, followed by aromatization and hydrolysis to finally yield picolinamide.155
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
49
11. 4-Methylpyridine on reaction with phenyllithium undergoes phenylation at the 2-position and the product is carboxylated by treating with carbon dioxide yielding 4-methyl-6-phenylpyridine-3-carboxylic acid.156
12. Photochemistry: Vapor phase photolysis of 4-methylpyridine with a mercury arc lamp for 72 h produced 2-methylpyridine and pyridine.157
However, Caplain and coworkers reported158 that irradiation of 4-methylpyridine in cyclohexane resulted in its photoisomerization to 2-methylpyridine and photosubstitution with cyclohexane to 6- and 4-cyclohexyl-2-methylpyridine.
13. Reaction with sulfur: 4-Picoline on boiling with elemental sulfur at 145°C under argon yielded products like 1,2-di[4-pyridyl]-ethane (1), 1,2-di[4-pyridyl]-ethene (2), 2,3-tri[4-pyridyl]-propane (3), tetra[4-pyridyl]thiophene (8), E and Z isomers of 1,2,3-tri[4-pyridyl]-propene (4 and 5), 6-[4-pyridyl]-thieno[3,2-c]pyridine (6), and 10-[4-pyridyl]-pyrido[3″4″:5′.4′]cyclopenta[2′,3′:4,5]thieno[2,3-]pyridine (7).159
50
2. Six-Membered Heterocycles
2.3.7 Piperidine
Piperidine, also referred to as azacyclohexane, is one of the most recognizable structural entities among heterocyclic molecules. Piperidine has a structure similar to cyclohexane with one of the methylene groups being replaced by the secondary amino (NH) group. In 1853 piperidine was first isolated from the alkaloid piperine, which is abundantly found in the black pepper Piper nigrum. Structural and Reactivity Aspects160 1. Conformation Like cyclohexane, piperidine prefers the chair conformation. In the stable chair conformation the lone pair of electron or hydrogen on nitrogen can occupy either the axial or equatorial position. Thus piperidine is thought to exist in four different chair conformations in which structures I and IV are equivalent and structures II and III are equivalent. Conformer I, in which the NH bond is equatorial, is more stable in the gas phase and in solution as compared to II and III, in which the NH bond is axial.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
51
Conformations of piperidine.
2. Structural data: Spectral methods have been quite helpful in studying the conformational analysis of piperidines160 The 1H and 13C NMR spectra of piperidine are given in the following table. H and 13C NMR spectral data of piperidine
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2/H-6, 2.77; H-3/H-4/H-5, 1.52
C-2/C-6, 47.5; C-3/C-5, 27.2; C-4, 25.5
Importance in Natural Products, Medicines, and Materials The piperidine nucleus is present in numerous natural alkaloids like quinine, pergoline, etc. Besides being the structural feature of a number of alkaloids, the piperidine nucleus has also been found to be present in a number of pharmaceuticals.
Drugs containing piperidine nucleus.
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2. Six-Membered Heterocycles
Piperidine has been used as a solvent in a number of reactions. In addition, it is a reactant in the synthesis of dipyridamole, a vasodilator, and etiozoline, a diuretic. Synthesis 1. Piperidine is mostly prepared by catalytic reduction of pyridine. Reduction has been carried out by a number of methods such as catalytic hydrogenation over platinum oxide,161 Na/C2H5OH,162 Raney nickel,163 copperchromium oxide,164 H2-Pd,165 and H2-Pt,166 but reduction with lithium triethylborohydride is highly efficient.
Reduction of pyridine in the presence of sodium and protic solvent is quite similar to Birch reduction of arenes that takes place in two steps. The first step is transfer of a single electron forming a radical anion followed by 1,2- or 1,4-addition of hydrogen.
2. Cyclization of 1,5-dichloropentane in the presence of ammonia results in the formation of piperidine.
3. Reductive cyclization of 1,5-dicyanopentane or 1,5-diaminopentane with hydrogen in the presence of copper chromite as catalyst yields piperidine.
4. Reaction of tetrahydrofurfuryl alcohol with ammonia under reductive conditions yields piperidine.
5. Hofmann-Löffler-Freytag reaction: A new method for the selective iodine-catalyzed CH amination of 2-arylsubstituted piperidines has been reported. The reaction involves visible light-induced initiation of a radical CH and an iodine-catalyzed CN bond formation. Under these conditions the preference for formation of pyrrolidine within the Hofmann-Löffler domain is altered in favor of free radical-promoted piperidiene.167
6. Synthesis of C2 symmetric piperidines: The process involves reaction of enantiomerically pure (S)-1,2epoxypropane with a solution of methyl phenyl sulfone dianion (from methyl phenyl sulfone and 2 equivalents
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
53
of n-butyllithium) yielding 4-(benzenesulfonyl)-(2S,6S)-heptanediol, which on reaction with p-toluenesulfonyl chloride afforded a bis(tosylate) derivative. Heating the neat solution of bis(tosylate) in an excess of benzylamine produced only the antipiperidine168
7. Photo-irradiation of a deareated suspension of cadmium sulfide particles in an aqueous solution of a mixture of stereoisomers of 2,6-diaminopimelic acid (DAP) [(S,S):R,S):(R,R)] afforded piperidine-2,6-dicarboxylic acid (PDC) via a redox-combined mechanism. The ratio of PDC produced depends on the kind of CdS photocatalysis, its pretreatment, and loading of platinum (or its oxides) particles. However, synthesis of optically pure (R,R) or (S,S)-PDC could be achieved by photocatalytic reaction of activated CdS particles with (R,R) or (S,S)-DAP, respectively.169
Physical Properties Piperidine is a colorless liquid with a bp of 106°C and an unpleasant odor. It is miscible with water. It behaves as a secondary amine (pKa = 11.2) and is a stronger base than pyridine (pKa = 5.2). Piperidine is as polar as diethyl ether or benzene, but is less polar compared to chloroform or ethyl acetate. The dielectric constant of piperidine is 5.8, which is quite similar to that of diethyl ether or benzene but much weaker compared to pyridine (12.4).
54
2. Six-Membered Heterocycles
Chemical Reactivity 1. Hofmann exhaustive methylation: This reaction is quite useful in studying the nature of nitrogen. A primary amine consumes 3 mol of methyl iodide, secondary amine 2 mol, and tertiary amine 1 mol. The quaternary ammonium iodide formed on reaction with moist silver oxide is converted to hydroxide, which on heating undergoes Hofmann elimination. Piperidine undergoes methylation in two stages. After the second stage a nitrogen-free molecule, penta-1,4-diene, is formed, which rearranges to 1,3-diene under conditions of the reaction.
2. Piperidine undergoes nucleophilic addition to methoxycarbonylacetylene in a variety of solvents. This has often been used as a standard reaction to establish a solvent effect on reaction rates in case of nucleophilic addition to the carbon-carbon triple bond.170
3. Piperidine on reaction with benzoyl chloride yields 1-benzoyl piperidine.171 The benzoyl derivative on reaction with phosphorous tribromide yields 1,5-dibromopentane.172
4. Piperidine on reaction with methyl iodide yields 1-methylpiperidine. The N-methyl derivative on reaction with cyanogen bromide undergoes ring fission.
5. N-Ethylpiperidine can also be obtained by treating it with ethylene.173
6. Naphthyl derivatives of piperidine are prepared by heating it with sodium naphthalene 2-sulfonate in the presence of sodamide.174
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
55
7. Reaction of piperidine with quinolizinium iodide yields trans, trans-1-piperidinyl-4-(2-pyridyl)butadiene in good yields.
8. Asymmetric α-alkynylation of piperidine was carried out in four steps involving transformation to chiral nonracemic N-sulfinylpiperidine, which on anodic oxidation is transformed to N-sulfinyliminium ion equivalent. Alkynylation followed by acidic deprotection yielded the asymmetric product.175
9. Diarylmethylamine derivatives of piperidine are of interest because they have been used in the synthesis of drugs like cetirizine, flunarizine, and manidipine. The synthesis was achieved in one step by heating piperidine with 4-bromoanisole and 4-fluorobenzaldehyde in the presence of cobalt bromide.176
10. Spirodienones are useful intermediates in the synthesis of paracyclophanes used as building blocks for nanotubes. Spirocyclohexenone and spirocyclohexadienone have been synthesized by the reaction of piperidine with cyclooctanecarboxyaldehyde, yielding a product, which on reaction with methyl vinyl ketone, followed by reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), yields the desired product.177
56
2. Six-Membered Heterocycles
11. Piperidine on reaction with calcium hypochlorite in the presence of glacial acetic acid yields Nchloropiperidine, which on heating with ethanolic potassium hydroxide yields tripiperidine.178
12. Piperidine when refluxed with a solution of benzaldehyde in toluene containing a few drops of acetic acid yields 3,5-dibenzylpyridine.179
13. Oxidation of piperidine with hydrogen peroxide in the presence of selenium dioxide as a catalyst at room temperature yields nitrones, which are easily transformed to isoxazolidines by 1.3-dipolar cycloaddition.180 Isoxazolidines have been found to be useful intermediates for the synthesis of β-amino ketones, β-amino acid esters, and β-lactams.
14. α-Metalation of piperidine via tert-butylformamide has been accomplished. Alkylation of these α-amino carbanions via their lithio or cuprate derivatives yields α-alkylated piperidines in good yields.181
15. Aromatization and alkylation/arylation: A benzene solution of aldehyde and piperidine when passed over alumina at 420°C yields 3-alkylpyridine.182
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
57
The reaction is proposed to take place by the following mechanism.183
16. Piperidines on reaction with doubly activated ketene dithioacetals in alcohol at reflux temperature undergo addition followed by elimination to yield N,S- and N,N-acetals depending on the stoichiometry of the added piperidine.184, 185 However, in the case of less reactive ketene dithioacetals, more vigorous reaction conditions are required and the products isolated are characterized as a mixture of N,S- and N,N-acetals.186, 187
17. Piperidines react with suitably functionalized 2H-pyran-2-ones such as 6-aryl-4-methylthio-2H-pyran-2one-3-carbonitriles or carboxylates in alcohol at reflux temperature to produce the cyclic aminal 6-aryl-4piperidino-2H-pyran-3-carbonitriles/carboxylates through Michael addition followed by elimination of methyl mercaptan.188
58
2. Six-Membered Heterocycles
2.3.8 Pyridones The pyridine ring carries many substituents. The hydroxy derivatives of pyridine are both weak acids and bases and thus can exist as zwitterions. However, the 2- and 4-hydroxy derivatives of pyridine are stabilized by mesomerism with uncharged canonical structures, which are thus more stable than zwitterions. Thus 2- and 4-hydroxy derivatives of pyridine exist chiefly in their carbonyl tautomeric form, commonly known as 2- and 4-pyridones, respectively. The pyridone form is favored in the solid phase or in polar medium, while their hydroxy derivatives are the predominant tautomer in very dilute solution, nonpolar solvent, or the gas phase.
Tautomeric form of 2- and 4-hydroxypyridine.
The preference for the two pyridones to exist in amide form is the presence of a strong carbonyl group and still the aromaticity of the compound is preserved. There are two electrons each on the two carbon-carbon double bonds and one lone pair on the trigonal nitrogen, and the delocalization of lone pair of electrons on nitrogen proves the point.
The 3-hydroxy derivative in polar solvents, however, exists in equilibrium with the zwitterionic tautomeric form. The exact ratio of either of the forms, however, depends on the type of solvent that has been used.
2.3.9 2-Pyridone
2-Pyridone, which is also known as 2-hydroxypyridine, 2(1H)-pyridinone, 2-pyridinol, 1,2-dihydro-2-oxopyridine, finds use in peptide synthesis. It is known to form hydrogen-bonded structures related to the base-pairing mechanism found in RNA and DNA. Structural and Reactivity Aspects The structure of 2-pyridone has been examined by Penfold189 and on the basis of X-ray crystalline data the bond lengths in Å and bond angles in degrees were determined and are shown in the following diagram.
Bond lengths and bond angles of 2-pyridone.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
59
2-Pyridone is stable and there is strong intermolecular hydrogen bonding between the nitrogen of one molecule and the oxygen of another, and this arrangement is repeated throughout the structure linking molecules in endless helices. This conclusion is drawn from the fact that the NH bond distance is 1.02 Å, which is nearly similar to the covalent bond length of 1.0 Å. The observed bond lengths and bond angles are best explained in terms of contributions from the five resonance structures.
Percentage contribution of different resonating structures.
On the basis of electronegative trends, canonical structures with a negative charge on oxygen have greater significance than those with a negative charge on carbon. The former structures therefore cause a high polarity in the NHO hydrogen bond. 2-Pyridone can also form a dimer with two hydrogen bonds. This dimeric form is present in solution. However, the ratio of dimerization depends on the polarity of the solvent.
Hydrogen bonding between two pyridones forming a dimer.
The 1H and 13C NMR data190a of 2-pyridone confirm that they may be regarded as a 6π-delocalized electron system with aromatic character. H and 13NMR spectral data of 2-pyridone
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-3, 6.60; H-5, 6.60; H-4, 7.30; H-6, 7.23
C-2,162.3; C-3, 119.8; C-5, 104.8; C-4, 140.8; C-6, 135.2
In the infrared (IR) spectrum of 2-pyridone, a medium intensity band at 3198 cm−1 and a strong band at 3165 cm−1 are for the NH stretching vibration. A strong band at 1650 cm−1 for the carbonyl group suggests the existence of a 2-hydroxy derivative of pyridine in carbonyl tautomeric form. Importance in Natural Products, Medicines, and Materials Functionalization of the 2-pyridone core has attracted much attention because this nucleus has been found to be present in a number of pharmaceutical agents, biologically active agents, and unnatural products.191 A number of drugs containing a 2-pyridone skeleton such as amrinone,192 milrinone,193 perampanel,194 and pirfenidone195 are in clinical use.
60
2. Six-Membered Heterocycles
Drugs containing 2-pyridone skeleton.
In addition, 2-pyridone has been used in the synthesis of rosiglitazone—an antidiabetic drug. Synthesis 1. Pyridine on oxidation with hydrogen peroxide forms pyridine N-oxide, which undergoes a rearrangement reaction with acetic anhydride to form 2-pyridone.196
2. 2-Pyrone obtained by the cyclization of 5-oxopent-2-enoic acid is converted to 2-pyridone via an exchange reaction with ammonia or an equivalent nitrogen source.
3. Pyridine N-oxide forms a stable complex with antimony pentachloride, which on thermolysis followed by hydrolysis yields 2-pyridone by regioselective transfer of oxygen to the 2-position.
4. Photolysis of pyridine N-oxide leads to the generation of 2-pyridone. The reaction is thought to proceed via a singlet excited state with oxaziridine as the postulated intermediate.
5. When an N-methylpyridinium ion reacts with sodium hydroxide, the hydroxide ion is added reversibly and exclusively at position 2, forming 2-hydroxy-1,2-dihydro-N-methylpyridine, which on oxidation yields N-methyl-2-pyridone.197
6. Pyridine reacts with the hydroxide ion at higher temperatures to yield 2-pyridone.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
61
7. Heating 2-fluoropyridine with lithium hydroxide and hydrogen peroxide at 50oC for 21 h yields 2-pyridone.198
8. 2-Pyridone in high yield is obtained by the reaction of 2-bromopyridine with CuI and N,Ndimethylethylenediamine (DMEDA) in the presence of potassium phosphate under microwave irradiation.199
9. 2-Pyridone in excellent yield is obtained by reduction of 2-benzoyloxypyridine in the presence of 10% palladium and activated carbon.200
10. Reaction of 6-chloro-3-nitropyridine-2-amine with NaOH in methanol and water under milder conditions yields 2-pyridone.201
11. Guareschi synthesis: Stirring a mixture of sodium methoxide, acetone, and ethyl formate yields sodium formyl acetone, which on refluxing with cyanoacetamide and piperidine acetate for 2 h delivered 3-cyano-6-methyl-2(1)-pyridone.202
12. 1,4-Addition of 2-(phenylsulfinyl)acetamide to α,β-unsaturated ketone followed by cyclization and sulfoxide elimination yields 2-pyridones.203
13. Microwave-assisted synthesis of 2-pyridone: Carbonyl compounds were made to react with N,N-dimethylformamide dimethylacetal yielding enaminones, which without purification reacted with methylene nitriles at 100oC for 5 min in 2-propanol in the presence of a catalytic amount of piperidine and afforded 2-pyridones.204
14. Buchwald-Hartwig amination: An efficient synthesis of amino-substituted 2-pyridone under microwave irradiation was carried out by amination of bromo-2-benzyloxypyridines in the presence of palladium catalyst followed by hydrogenolysis of benzyl ether.205
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2. Six-Membered Heterocycles
15. Michael addition: A number of 2-pyridone derivatives have been synthesized involving Michael addition of an acetonitrile derivative to an appropriate α,β-unsaturated carbonyl substrate. 3-Cyanopyridone was synthesized in good yield by the reaction of enones and enals with cyanoacetamide.206a
3-Cyanopyridones were also synthesized by Knoevenagel condensation of acetophenone with ethyl cyanoacetate in the presence of sodium acetate. The α,β-unsaturated carbonyl compound is then converted to enaminonitrile, which on reaction with primary amine under solvent-free conditions yielded the pyridone derivative. Recently, Ram et al. reported206b a synthesis of highly functionalized 2-pyridones through ring transformation of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylate with formamidine acetate in moderate yields.
Physical Properties 2-Pyridone is a colorless crystalline solid with a melting point (mp) of 105–107°C. It is soluble in water, methanol, and acetone. Chemical Reactivity 1. Electrophilic aromatic substitution reaction: 2-Pyridone containing an activating group readily undergoes substitution reaction at either the C-3- or C-5-position.
2. Replacement of oxygen function (a) The carbonyl group of pyridines can be replaced by a good leaving group. The reaction involves treatment of pyridone with phosphoryl chloride or phosphorous pentachloride leading to the generation of chloropyridine. The chloro group is a good leaving group and thus chloropyridine can undergo a cross-coupling reaction with organometallic reagent to form a new carbon-carbon bond.
(b) The carbonyl group of pyridone can also be replaced with a suitable leaving group by heating it at high temperature with a secondary amine like pyrolidine in the presence of phosphorous pentoxide.207
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
63
(c) The oxygen of pyridone can also be replaced by sulfur by treating it with Lawesson’s reagent yielding thiopyridones.
3. Alkylation, arylation, and acylation: 2-Pyridone is a weak acid (pKa ≈ 11), hence deprotonation in basic medium produces ambident anions, and as a result electrophilic attack may take place at O, N, and C. (a) When 2-pyridone reacts with diazomethane, methylation of nitrogen as well as oxygen takes place, in which the N-substituted pyridone predominates.208
Alkylation of 2-pyridone can also be carried out by first preparing its metal salts and then treating them with different alkyl halides. A mixture of N-alkyl and O-alkyl products are obtained.209a
N- as well as O-alkylation of 2-pyridone takes place under Mitsunobu reaction conditions. The reaction does not require the presence of a strong base because primary and secondary alcohols were used. In comparison to Nalkylated product, O-alkylated was the major product.209b
(b) O-Alkylation can also be achieved by heating 2-pyridone with methyl iodide or ethyl iodide in the presence of silver carbonate.
Reaction of sodium salt of 2-pyridone with triethyloxonium fluoroborate yields N-ethyl-2-pyridone, 2-ethoxypyridine, and N-ethyl-2-ethoxypyridinium fluoroborate.210
Irradiation of 2-pyridone with benzyl bromide in a microwave for 5 min at 196°C under solvent-free conditions afforded a mixture of 3-benzyl-2-pyridone, 5-benzyl-2-pyridone, and 3,5-dibenzyl-2-pyridone. However, on conventional heating of 2-pyridone with benzyl bromide in DMSO in an oil bath at 196°C for 5 min only 1-benzyl-2- pyridone was obtained.211
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Manganese-mediated C-3 alkylation and arylation of 2-pyridones with diethylmalonate and arylboronic acid, respectively, has been reported.212
C-3 arylation of N-alkyl-2-pyridone with arylboronic acid in the presence of an environmentally friendly and abundant iron catalyst under mild reaction protocols has been reported.213
N-Methyl-2-pyridones are easily arylated in one step at the C-3-position by alkylboronic acid in the presence of iron catalyst.214
4. Acyl derivatives of 2-pyridone are best prepared by acylation of the sodium derivative of pyridone.
5. Cycloaddition reaction: Cycloaddition of 2-pyridone and its N-methyl derivative with dimethylacetylene dicarboxylate produced a [4+2] cycloadduct product.
6. Reaction in which the hydroxyl group predominates: 2-Hydroxypyridine on reaction with aqueous sodium hypochlorite and alcoholic sodium iodide yields 2-hydroxy-5-iodopyridine in 48% yield.214
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65
7. Kolbe-Schmitt reaction: Sodium salt of 2-pyridone undergoes a Kolbe-Schmitt reaction, and instead of the expected introduction of the carboxylic group at the ortho-position, the carboxylic group enters the 5-position.
2.3.10 4-Pyridone
4-Pyridone is also known as 4-hydroxypyridine, 4(1H)-pyridinone, and 4-pyridinol. 1H-Pyridine-4-one is an important scaffold among the N-alkylated heterocycles because this structural motif is an essential core in natural products and medicinal targets. Structural and Reactivity Aspects The 1H and 13C NMR data215of 4-pyridone confirm that it may be regarded as a 6π-delocalized electron system with aromatic character. 1
H and 13C NMR spectral data of 4-pyridone
1
H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-2/H6, 7.98; H-3/H5, 6.63
C-2/C-6, 139.8; C-4, 175.7; C-3/C-5, 115.9
The IR spectrum of 4-pyridone shows a medium intensity band at 3200 cm−1. A strong band at 3104 cm−1 is for the NH stretching vibration and a strong band at 1638 cm−1 is for the carbonyl group. Importance in Natural Products, Medicines, and Materials The 4-pyridone nucleus has attracted much attention in the development of antimalarial drugs resistant to P. falcifarum malaria. Drugs included in this category are GW844520, GW308678, and GSK932121 the diaryl ether substituted derivatives of anticoccidial drug clopidol.
Drugs containing 4-pyridone nucleus.
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2. Six-Membered Heterocycles
The 4-pyridone nucleus is also present in ciprofloxacin, an important antibacterial drug. 4-Pyridone has been used as a precursor for the synthesis of propyliodone, a diagnostic agent used in X-rays as a contrast agent and as an intermediate in the synthesis of pericyazine, a psychotropic agent. Synthesis 1. γ-Pyrone on reaction with ammonia yields 4-pyridone.
2. Cyclocondensation of heptane-2,4,6-trione with primary amine or ammonia yields 4-pyridone.
3. A simple method for the synthesis of 4-pyridones involves dimerization of N-acetoacetamides in the presence of sodium persulfate (Na2S2O8).216
Physical Properties 4-Pyridone is a crystalline compound with mp of 150°C and is soluble in water. Chemical Reactivity 1. Alkylation, arylation, acylation, and benzoylation: 4-Pyridone reacts with aliphatic acid anhydrides, acid chlorides, or free acids in the presence of dicyclohexylcarbodiimide and yields only the N-acyl derivative, i.e., 1-acetyl-4-pyridone, as the isolable product.217 This N-acyl derivative, however, equilibrates in solution affording a mixture with 4-acetoxypyridine.218
Similarly, 4-pyridone undergoes benzoylation with benzoyl chloride to yield the pyridine derivative.
N-Alkylation of 4-pyridone is achieved by first converting it into its O-trimethylsilyl ether derivative, selective reaction at nitrogen and subsequent removal of silicon yields N-alkylpyridone.219
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Metalation followed by alkylation is achieved by first deprotonation of the α-proton of 1-methyl-4-pyridone with n-butyllithium, yields a 2-lithio derivative, which is used for the generation of 2-substituted 4-pyridone derivatives. The 2-lithio-4-pyridone was subsequently treated with THF at −78°C to 0°C with a range of acylating and alkylating agents, which generated a series of 2-substituted 4-pyridones.220
Reaction of 4-pyridone anions (obtained by the reaction of 4-pyridone with potassium tert-butoxide) with benzhydrylium ions (diarylcarbenium ions) and structurally related Michael acceptors in DMSO or CH3CN yielded N- and O-substituted derivatives.221
2. Electrophilic substitution reaction (a) Nitration of 4-pyridone takes place by heating it with a mixture of nitric and sulfuric acid yielding 3-nitropyridone.222
(b) Bromination of 4-pyridone with bromine in aqueous potassium bromide, buffered in the pH range of 3–5, yielded 3-bromopyridone as the major product. However, when bromination was carried out with concentrated hydrobromic acid, 3,5-dibromo-4-pyridone was the major product.223
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2. Six-Membered Heterocycles
The reaction has been proposed to proceed by the following mechanism.
3. Replacement of oxygen: Chlorination of 4-pyridone with phosphorous oxychloride yields 4-chloropyridine.
4. Kolbe-Schmitt reaction: Sodium salt of 4-pyridone undergoes a Kolbe-Schmitt reaction, yielding a mixture of 4-oxo-1,4-dihydropyridine-3-carboxylic acid and 4-oxo-1,4-dihydropyridine-3,5-dicarboxylic acid.
5. Addition reaction: N-Protected pyridones like N-tert-butoxylcarbonyl-4-pyridone undergo 1,4-addition reaction with Grignard reagent in the presence of chlorotrimethylsilane (TMSCl) or boron trifluoride etherate (BF3·Et2O) yielding 2-substituted 2,3-dihydropyridones in excellent yield. The substituted pyridone derivative may react further with Grignard reagent to yield trans-2,6-disubstituted piperidones.224
2.3.11 Quinoline (Benzo[b]Pyridine)
Quinoline, also known as 1-aza-naphthalene, benzo[b]pyridine, or benzazine, is a bicyclic derivative of pyridine obtained by ortho-condensation of the benzene ring to the pyridine ring. Quinoline was first isolated from coal tar in 1834 by Friedlieb Ferdinand Runge, a German analytical chemist. Coal tar still remains the principal source of commercial quinoline. The name quinoline is derived from the alkaloid quinine, which has been used for centuries for the treatment of malaria.
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Structural and Reactivity Aspects225 Due to the presence of a nitrogen atom in the molecule there is unequal distribution of electron density in the pyridine as well as benzene rings. As a result, there is alteration in the physicochemical reactivity of the quinoline moiety. The electronegative nitrogen not only causes inductive polarization in the σ bond framework but also in the π electron system. The electronegative nitrogen also helps to stabilize those canonical structures in which nitrogen is negatively charged. The molecular dimensions of quinoline have not been accurately determined. The bond length and bond angles determined from X-rays of the Ni complex of quinoline were found to be different from those reported for quinolinium ion. The electron density calculations for quinoline and its protonated form as obtained by HMO treatment are listed in the following diagram.225
Hückel calculation shows there is π electron deficiency at positions 2 and 4, while the highest electron densities are at positions 1(N), 8, 3, and 6. On protonation there is an increase in the π electron density at position 3. The chemical reactivity of quinoline toward nucleophilic substitution (I) by −OH, BF4−, and CN− and toward electrophilic substitution (II) by sulfonation, nitration, and mercuration is shown in the following diagram.225
The 1H and 13C NMR data of quinoline confirm it to be a 10π-delocalized electron system with aromatic character.225 H and 13C spectral data of quinoline
1
1 H NMR (CCl4) δ (ppm)
13
C NMR (CCl4) δ (ppm)
H-2, 8.80; H-3, 7.26; H-4, 8.00; H-5, 7.68; H-6, 7.43; H-7, 7.61; H-8, 8.05
C-2, 150.89; C-3, 121.67; C-4, 136.12; C-5, 128.46; C-6, 129.95; C-7, 129.86; C-8, 130.5; C-9, 149.28; C-10, 128.89
Importance in Natural Products, Medicines, and Materials The quinoline nucleus is present in a number of natural products like tecleabine, tecleoxime, and quinine, which are significant with respect to medicinal chemistry and biomedical use. In addition, the quinoline nucleus has also been identified in a number of naturally occurring alkaloids having diverse biological and pharmaceutical properties. These compounds have been found to display antimalarial, antibacterial, antifungal, anticancer, and anti-HIV activities.226
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2. Six-Membered Heterocycles
Natural products and drugs containing quinoline nucleus.
Quinoline is also used as a reactant for the synthesis of 8-hydroxyquinoline, which is a versatile chelating agent. Furthermore, quinoline on oxidation yields pyridine-2,3-dicarboxylic acid, which is a precursor to an herbicide sold under the brand name Assert. Synthesis 1. During structure elucidation of quinoline, its structure was confirmed by synthesis in which allylaniline was passed over glowing lead oxide to form 1-nitrocinnamaldehyde.227
2. Quinoline is synthesized by the reaction of aniline with acrolein. During the process, two new bonds were formed leading to the generation of a new ring.
3. Skraup synthesis: This reaction is named after the Czech chemist Zdenko Hans Skraup.228 The process involves heating aniline or its derivative having a vacant ortho-position with glycerol, concentrated sulfuric acid, and an oxidizing agent.
Mechanism: The reaction most likely proceeds with the acid-catalyzed dehydration of glycerol to α,β-unsaturated aldehyde-acrolein (generated in situ).
Aniline adds to the carbon-carbon double bond of acrolein to yield a product, which then undergoes a ring closure process. Dehydration yields 1,2-dihydroquinoline, which on oxidation yields quinoline.
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Several modifications for the synthesis of quinoline derivatives by Skraup reaction have also been reported.229 4. Doebner-Miller synthesis: The reaction named after German chemists Oscar Doebner and Wilhelm von Miller is in fact a modification of Skraup synthesis and involves reaction of primary arylamine with the unsubstituted ortho-position with a carbonyl compound in the presence of proton acid and oxidant to yield quinoline.230
The reaction initially allows the formation of Schiff’s base. Two molecules of this base undergo self-condensation to form quinoline.
Several modifications for the synthesis of quinoline derivatives by Doebner-Miller reaction have also been reported.229, 231 5. Doebner synthesis: The reaction named after Oscar Doebner involves a reaction of aniline with an aldehyde and pyruvic acid to yield 2-substituted quinoline 4-carboxylic acid, which decarboxylates to give 2-substituted quinoline.232
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2. Six-Membered Heterocycles
Mechanism: The best pathway involves condensation of aniline with aldehyde to form a Schiff’s base, which is then attacked by the enol form of pyruvic acid to yield an intermediate, which undergoes intramolecular cyclization yielding a product that is oxidized to a quinoline derivative.
6. Combes quinoline synthesis: This reaction is named after Alphonse-Edmond Combes, a French chemist, who first reported the reaction in 1888.233 The reaction involves condensation of arylamines with 1,3-diketones. Enamine formed during the reaction undergoes ring closure in the presence of concentrated sulfuric acid to yield a quinoline derivative.
Mechanism: The reaction involves nucleophilic addition of aniline to the protonated carbonyl carbon of the 1,3-diketone. Proton transfer followed by loss of a molecule of water leads to an enamine, which under the influence of sulfuric acid undergoes ring closure, followed by aromatic annulation, yielding a quinoline derivative.
7. Friedlander quinoline synthesis: This reaction is named after German chemist Paul Friedlander is another useful method for the synthesis of quinoline. The reaction involves condensation of 2-aminobenzaldehyde or 2-aminoacetophenone with an aldehyde or ketone containing an active methylene group in the presence of an acid or base.234 The acids and bases more commonly used are trifluoroacetic acid, toluenesulfonic acid, Lewis acids, and sodium hydroxide.
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Mechanism: The first step of the reaction is the formation of a Schiff’s base, which then undergoes ring closure leading to the generation of quinoline.
Several modifications of the Friedlander reaction have been reported. For example Niementowski reaction and Pfitzinger synthesis. (a) Niementowski reaction235: By this reaction, 4-hydroxyl quinoline derivatives are synthesized by reaction of anthranilic acid with ketones.
Mechanism: As in the case of the Friedlander reaction, this reaction also takes place with the formation of an imine intermediate.
(b) Pfitzinger synthesis236: This is also known as the Pfitzinger-Borsche reaction. It involves the condensationcyclization of 2-aminophenylglyoxalic acid derived by alkaline hydrolysis of isatin with acetone to yield quinoline 4-carboxylic acids.
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2. Six-Membered Heterocycles
Quinoline derivative in excellent yield is also obtained by reaction of isatin with chloropyruvic acid.237
Faced with several difficulties, a number of improvements have been made238 and this condensation reaction can now also be performed under acidic conditions.239 A microwave-assisted Pfitzinger-type condensation reaction was carried out between isatin and sodium pyruvate yielding quinoline-2,4-dicarboxylic acid.240
8. Meth-Cohn synthesis241: This reaction, also known as the “Vilsmeier approach,” is the conversion of acetanilides into 2-chloro-3-substituted quinolones by a reaction with Vilsmeier’s reagent in warm phosphorous oxychloride.242
2-Substituted quinoline derivatives in good yield were produced by the cyclization of deactivated acetanilide in the presence of trimethylammonium bromide under Vilsmeier-Haach conditions244 or when Meth-Cohn synthesis was ultrasonically irradiated.245 9. Conrad-Limpach synthesis: Discovered by Max Conrad and Leonhard Limpach this is the reaction of anilines with β-ketoesters to yield 4-hydroxyquinoline.
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10. Gould-Jacobs reaction: Condensation of aniline with acetyl malonic ester or ethoxymethylenemalonate generates anilinomethylenemalonic ester, which on heating at high temperature underwent cyclization to yield an ester. Saponification of the ester followed by decarboxylation produced 4-hydroxyquinoline.246
A microwave-assisted condensation reaction between aromatic amine and ethoxymethylenemalonate under s olvent-free conditions not only increases the yield but also shortens the reaction time.247, 248 11. Knorr quinoline synthesis: The reaction named after Ludwig Knorr is one of the oldest but is still a useful method for the synthesis of quinoline. The reaction requires condensation between arylamine and βketoester forming an anilide derivative, which in the presence of sulfuric acid undergoes cyclization forming 2-hydroxyquinoline.249
12. Camps quinoline synthesis: o-Acylaminoacetophenone in the presence of aqueous alkali is transformed to a mixture of 2-hydroxyquinoline and 4-hydroxyquinoline.250
13. Baylis-Hillman synthesis: This reaction is also known as the Morita-Baylis-Hillman reaction. It is a useful method for the formation of a carbon-carbon single bond yielding a product with a new stereocenter called Baylis-Hillman adduct.251 This reaction procedure has been used for the synthesis of a quinoline Baylis-Hillman adduct of o-halobenzaldehes.252
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2. Six-Membered Heterocycles
14. Heck quinoline synthesis: One-pot synthesis of substituted quinolines via Heck reaction of 2-bromoanilines with allylic alcohol followed by dehydrogenation with diisopropyl azodicarboxylate (DIAD) has been reported.253
15. By reduction: o-Nitrocinnamic aldehyde or ketone on reduction cyclizes in situ to yield a quinoline derivative.
When reduction is carried out with triethylphosphite, alkoxyquinoline is the product.
16. From oxazole: Acid-catalyzed condensation of an o-chlorobenzaldehyde derivative with 4,5-dihydrooxazole leads to the generation of a 3-substituted-2-quinolone derivative.
Palladium-catalyzed hydrogenation/heterocyclization of acetylenic derivatives yields quinolines.254
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77
Palladium-catalyzed reaction of 2-aminobenzyl alcohol with ketones in toluene or polyethylene glycol255 afforded quinoline in good yields. 17. A new, convenient, efficient and eco-friendly montmorillonite K10 clay-catalyzed synthesis of a quinoline derivative has been reported. The reaction involves treating aniline derivative with cinnamaldehyde under solvent-free conditions with the assistance of microwave irradiation.256
18. A new photochemical method for the synthesis of 2,4-diiodoquinoline derivative by cyclization of o-alkynylaryl isocyanide with iodine has been developed.257
Physical Properties Quinoline is a colorless, hygroscopic liquid with a smell similar to pyridine. Quinoline is only sparingly soluble in water but miscible with nearly all organic solvents. Quinoline when exposed to light for a longer duration turns yellow and subsequently brown. The bp of quinoline at 760 mm was found to be 237.1°C. Its freezing point was reported to be −14.94°C, whereas the calculated value was −14.85°C. The density of quinoline at 25°C has been reported to be 1.08981. The dipole moment of quinoline has been determined both in the vapor phase and in the liquid phase. In the vapor phase the dipole moment was 2.29 D, whereas in carbon tetrachloride it was found to be 2.27 D. Quinoline is a base because the lone pair of electrons on the nitrogen atom of pyridine is not involved in the formation of a delocalized π-molecular orbital. Quinoline is aromatic with a resonance energy of 47.3 and is considered to be a resonance hybrid of the following contributing structures.
Resonance structures of quinoline.
Structures I, II, and III are of lower energy; however, additional charged structures IV–VIII are also possible because of the presence of the electronegative nitrogen atom. The dipole moment of quinoline is 2.10 D, which confirms the presence of charge separation within the ring. Chemical Reactivity 1. Electrophilic substitution reaction: The nitrogen atom of quinoline has a deactivating effect on the ring toward the substitution reaction. Consequently, the electrophilic substitution reaction does not take place in the pyridine ring but in the benzene ring substitution can take place at the C-5- and C-8-positions. Attack at C-5 and C-8 is favored because the intermediate produced as a result of electrophilic attack at these positions can be represented by resonance structures in which the aromaticity of the heterocyclic ring is still preserved.
Electrophilic substitution at C-5 and C-8.
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2. Six-Membered Heterocycles
(a) Sulfonation: Sulfonation of quinoline with oleum at 90°C yields chiefly quinoline-8-sulfonic acid. However, because this product is sterically hindered, at higher temperatures it rearranges to 6-sulfonic acid.258
(b) Nitration: In comparison to pyridine, nitration of quinoline can be carried out under mild conditions. Nitration with the nitrating mixture (HNO3 + H2SO4) gives a mixture of 5- and 8-nitroquinoline in equal amount.
On nitration with transition metal salts like zirconium nitrate, quinoline yields a 7-nitro derivative.
Reaction with acetyl nitrate yields mainly 3-nitroquinoline. The reaction is thought to proceed by the 1,4-addition of acetyl nitrate to quinoline, followed by electrophilic attack on the 1,4-dihydro derivative.
(c) Halogenation: The product obtained after reaction of halogens with quinoline depends on the type of reagent used and the reaction conditions employed. For example, bromination of quinoline in the presence of silver sulfate and 98% sulfuric acid gave a mixture of 5- and 8-monosubstituted quinoline (when quinoline is used in excess). When bromine is used in excess, in addition to the two monosubstituted derivatives, 5,8-disubstituted quinoline is also formed.259
When bromination is carried out with bromine in the presence of pyridine, 3-bromoquinoline is the only product.260
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79
Formation of 3-bromoquinoline most likely takes place by the addition-elimination mechanism.
Regioselective iodination of quinoline at the C-3-position under metal-free conditions has also been reported, by carrying out a reaction in the presence of tert-butyl hydroperoxide and 1,2-dichloroethene.261
Iodination of quinoline is also achieved by reacting quinoline, K2S2O8, and sodium iodide in the presence of metal salts like bismuth nitrate or cerium nitrate.262
Iodination of quinoline at the 8-position (major product) is achieved via α-metalation using lithium di-tert- butyltetramethyl-piperidinozincate (TMP) at room temperature and using iodine as electrophile. However, 2-iodoisoquinoline is obtained as the minor product.263
(d) Mercuration: At room temperature quinoline reacts with mercuric acetate forming quaternary N-mercuric acetate. However, at higher temperatures further substitution takes place and in the presence of sodium chloride a mixture of 3- and 8-quinolinemercurichlorides is obtained.
2. Nucleophilic substitution reaction: Nucleophilic addition reactions give tetrahydroquinolines, which are important synthetic intermediates and structural units of alkaloids and biologically active compounds.264 However, nucleophilic substitution reaction takes place in the quinoline in the heterocyclic ring and also at the 2- or 4-positions. (a) Chichibabin reaction: Quinoline reacts with potassium amide in liquid ammonia at −70°C to yield 2-amino-1, 2-dihydroquinoline (the 2-quinoline adduct rearranges to 4-quinoline adduct at higher temperatures), which on oxidation with potassium permanganate yields 2-aminoquinoline.
(b) Hydroxylation: Quinoline is hydroxylated directly by reacting it with potassium hydroxide at high temperature. The formation of 2-quinolone is thought to proceed by the SNAr process with hydride ion as the leaving group.265
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(c) Alkylation of quinoline with ethylene over a silicon-alumina catalyst gave 2-ethylquinoline as intermediate.266 Similarly, reaction of quinoline with formaldehyde in boiling alcohol gave 2-(2-hydroxyethyl)quinoline as intermediate.267 Both the intermediates on dehydrogenation and dehydration yielded 2-vinylquinoline.
Alkylation of quinoline was also achieved by treating it with olefins in the presence of an Rh(I)-phosphine catalyst. The reaction proceeds with the intermediacy of a substrate-based N-heterocyclic carbene complex.268
An enantioselective Petasis-type reaction of quinoline with phenylboronic acid in the presence of a thiourea catalyst resulted in the formation of 1,2-adduct.269
Reaction of quinoline with allyltrimethylsilane in the presence of chloroformate only took place when silver triflate was present in a catalytic amount. It was found that silver triflate increased the electrophilicity of N-acylquinolinium salt.270, 271
The attack of different Grignard and organolithium reagents on the quinoline nucleus yields the dihydro intermediate, which after hydrolysis and oxidation principally yields a 2-substituted quinoline derivative.272, 273
3. Substitution reaction by a free radical mechanism: Irradiation of quinoline in neutral ether sensitized by benzophenone gave 2- and 4-substituted quinolones. The reaction proceeds via an excited quinoline (due
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81
to π→π* transition). The C-2 radical and C-4 radical could combine with the α-oxyalkyl radical to give dehydrogenated C-2- and C-4-substituted quinolones.274, 275
Nitration of quinoline with dinitrogen tetroxide gave 7-nitro as the major product276 and nitration with pernitrous acid gave an equal amount of 6- and 7-nitroquinoline.277 The mechanism involved an attack by a hydroxyl radical to give intermediates, which on combination with a nitro radical followed by elimination of a molecule of water yielded 7-nitroquinoline.
4. Addition reactions: The most important addition reactions of quinoline are reduction reactions. Direct hydrogenation of quinoline is the most convenient route to tetrahydroquinolines, which are important synthetic intermediates. Due to the stability of 1,2-dihydroquinoline, there are a variety of addition reactions. Reduction of quinoline can be carried out with a variety of reagents. However, the pyridine ring is more easily reduced in comparison to the benzene ring. (a) Catalytic hydrogenation of quinoline with nickel occurs rapidly, generating 1,2,3,4-tetrahydroquinoline (A).278, 279 Catalytic hydrogenation can also be carried out with PtO2, ammonium acetate, and Pd/C. Extended hydrogenation times or under more drastic conditions generated cis-decahydroquinoline (C) and trans-decahydroquinoline (D).280 Catalytic hydrogenation of quinoline also led to the generation of 5,6,7,8-tetrahydroquinoline (D)281 along with 1,2,3,4-tetrahydroquinoline in a ratio of 47:2. 5,6,7,8-tetrahydroquinoline282 is also obtained by carrying out hydrogenation with platinum oxide and concentrated hydrochloric acid at room temperature with a hydrogen pressure of 50 psi.
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2. Six-Membered Heterocycles
Sodium in liquid ammonia reduces quinoline to 1,2-dihydroquinoline. However, 1,2-dihydroquinoline was found to be unstable and later on it was reported that it was not 1,2- but 1,4-dihydroquinoline.283 Nevertheless, reduction with lithium in liquid ammonia with no proton source gave 1,2,3,4-tetrahydroquinoline. If methanol is present during the reduction process, 5,8-dihydroquinoline is the product.284
Reductive alkylation of quinoline with lithium metal in liquid ammonia gave 1,4-dihydro-1-alkyl derivative in high yield.285
One-pot reductive alkylation of quinoline was also carried out by treating it with sodium borohydride in carboxylic acid media yielding N-alkyl-1,2,3,4-tetrahydroquinoline.286
Enantioselective hydrogenation of quinoline derivatives using an iridium/phosphine/iodine system led to the synthesis of a tetrahydroquinoline derivative in excellent yield. This procedure has been applied for the synthesis of three naturally occurring alkaloids: angustureine, galipimine, and cuspareine.287
Enantioselective addition of organolithium reagent to quinoline in the presence of diamines, which are used as a chiral reagent, have led to the synthesis of enantiomerically enriched 2-substituted 1,2-dihydroquinoline.288 (b) Reissert reaction: Addition of KCN to quinoline in the presence of benzoyl chloride yields 1-benzoyl-2-cyano1,2-dihydroquinoline, also known as Reissert compound. The Reissert compound on hydrolysis in acidic medium yields an aldehyde and quinoline 2-carboxylic acid (quinaldic acid). Similarly, ethyl chloroformate and potassium cyanide react with quinoline to give a Reissert addition compound.
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The first enantioselective Reissert-type reaction was reported in 2001. The reaction involved reacting quinoline with electron-rich aromatic acid, a low polarity solvent, in the presence of a Lewis acid/Lewis base bifunctional catalyst.289
(c) Alkylation or arylation of quinoline with alkyl- or aryllithium (Reissert reaction) yields exclusively 2-alkylor 2-arylquinoline. The reaction takes place with the addition of organolithium reagent in a 1,2-fashion yielding an adduct, which on hydrolysis yields a 1,2-dihydroquinoline derivative. The dihydro derivative on oxidation with nitrobenzene yields 2-alkylquinoline and on reduction with sodium in ethanol, 2-substituted 1,2,3,4-tetrahydroquinoline is the product.
Quinoline reacts with phosphoryl chloride and phosphorochloridate to give a quaternary compound, which on reaction with indole yields a 1,2-dihydroquinoline derivative.290
5. Oxidation reactions (a) Depending on the type of reagent, oxidation affects both rings of quinoline. When oxidation is carried out with alkaline potassium permanganate solution, the pyridine ring remains intact, while the benzene ring is oxidized leading to the generation of quinolinic acid291 (pyridine 2,3-dicarboxylic acid). However, acidic permanganate solution oxidizes the pyridine ring, while the benzene ring remains intact leading to the formation of Nacylanthranilic acid.
(b) Ozonolysis of quinoline at −25 to −35°C yields glyoxal and 2,3-diformylpyridine.292 However, ozonolysis in dilute acetic acid gave a high yield of nicotinic acid, probably through a quinolinic acid intermediate. Nicotinic acid is also obtained by oxidation with potassium permanganate.
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(c) Oxidation of quinoline with peracid afforded quinoline N-oxide.
6. Ring-opening reaction: When quinoline reacts with thiophosgene in the presence of a base, fission of the Nheterocyclic ring takes place leading to the generation of 2-isothiocyanato-cinnamaldehyde.293
The reaction is thought to proceed with the formation of a dihydro intermediate, which underwent ring fission to yield Z-isothiocyanate, which subsequently isomerizes in situ to an E-isomer.
7. Formation of biquinolines: Heating quinoline with rhodium on carbon gave a high yield of 2,2′-biquinoline and an appreciable quantity of 2,3′-biquinoline.294
8. Nucleophilic substitution: The nitrogen atom of quinoline, by means of inductive and conjugative effects, activates the halogen atom at the 2- and 4-positions toward a nucleophilic substitution reaction.
For 4-haloquinoline, an elimination-addition mechanism with the formation of aryne intermediate has been proposed. As a result, a mixture of products is obtained.
2.3.12 Isoquinoline (Benzo[c]quinoline)
Isoquinoline, also known as 2-azanaphthalene, benzo[c]pyridine, or 2-benzanine, is a structural isomer of quinoline. It was first isolated in 1885 by Hoogewerf and van Dorp295 from the quinoline fraction of coal tar by fractional crystallization.
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Structural and Reactivity Aspects296 Isoquinoline has structural and spectroscopic properties similar to quinoline. Like quinoline it has been classified as a π-deficient system. The X-ray analysis of 3-methylisoquiline establishes it to be a planar molecule. The two CN bond lengths of 1.300 Å for the C1N bond and 1.366 Å for the NC3 bond are quite similar to the 1.34 Å bond distance for the CN bond in pyridine. Various bond lengths of 3-methylisoquinoline are listed in the following diagram.
Bond lengths of 3-methylisoquinoline.
The UV spectra of isoquinoline showed three wavelength bands [λmax nm/εmax] at 217 (37,000), 266 (4030), and 318 (3100) that correspond to π→π* transition. The n→π* transition band was not observed because it may have been masked by the π→π* transition band. The 1H and 13C NMR data of isoquinoline confirms it to be a 10π-delocalized electron system with aromatic character. 1
H and 13C NMR spectral data of isoquinoline
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1, 9.15; H-3, 8.45; H-4, 7.50; H-5, 7.51; H-6, 7.57; H-7, 7.50; H-8, 7.87
C-1, 150.89; C-3, 143.1; C-4, 120.4; C-5, 126.5; C-6, 130.6; C-7, 127.2; C-8, 127.5; C-4a, 135.7; C-8a, 128.8
Due to the presence of a lone pair of electrons on nitrogen, isoquinoline is basic, reacts with proton or electrophilic species at nitrogen, and yields isoquinolium salts. Basicity is increased by electron-donating substituents and decreased by electron-withdrawing groups. Since the lone pair of electrons on the nitrogen of isoquinoline is not delocalized into the π aromatic system of the molecule, isoquinoline is π electron deficient and as a consequence electrophilic substitution reaction takes place at a slower rate compared to naphthalene. When isoquinoline reacts with an electrophile, an intermediate is formed in which the electrophile is bonded to nitrogen, making the pyridine ring more π deficient; as a result, further electrophilic substitution reaction takes place on the benzene ring through a high-energy doubly charged Wheland-type intermediate yielding 5-substituted as the major product.
Electrophilic substitution in isoquinoline.
Nucleophilic substitution by hydride transfer by strong nucleophilic reagents such as Grignard reagents, organolithiums, sodium amide, etc. yield an intermediate stable product, which can be oxidized to yield a substitution product.
Nucleophilic substitution reaction in isoquinoline.
Importance in Natural Products, Medicines, and Materials Isoquinoline is important because this nucleus is present in a large number of alkaloids297 like berberine and papavarine, and is also a useful template for medicinal chemistry.298 Papaverine, an opium alkaloid, finds use as a muscle relaxant and a vasodilator. Antihypertensive drugs like debrisoquine, quinalapril, and quinalaprilat all contain an isoquinoline nucleus. Quinisocaine or dimethisoquin is a topical anesthetic, which finds use as an antipruritic. Hexadecamethylenediisoquinolium dichloride, which is used as a topical antiseptic, is prepared by N-alkylation of isoquinoline with an appropriate alkyl halide.
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Natural products and drugs containing isoquinoline nucleus.
Synthesis 1. Bischler-Napieralski synthesis: This reaction is named after August Bischler and Bernard Napieralski. The reaction involves intramolecular cyclization of phenylethyl amides in the presence of POCl3 or P2O5 to give 3,4-dihydroisoquinoline, which can subsequently be oxidized to isoquinoline.299
Mechanism (by POCl3): Amide reacts with POCl3 to give imidoyl chloride (A), which on heating is converted to nitrilium salt (B). Intramolecular electrophilic aromatic substitution gives 3,4-dihydroisoquinoline.300
Mechanism (by PCl5): The amide derivative reacted with PCl5 to give the crystalline hydrochloride of benzimidoyl chloride. This salt loses hydrogen chloride at room temperature to give the cyclized product.301
Bischler-Napieralski reaction has most widely been used for the construction of dihydro- and tetrahydroisoquinoline units in the synthesis of natural products.302–304 2. Pictet-Gams reaction: This reaction named after A. Pictet and A. Gams305 is a variation of Bischler-Napieralski and involves cyclization of acylated aminomethyl phenyl carbinols or their ethers with phosphorous pentoxide in toluene or xylene. A postulated mechanism has been proposed by Fritton306 that involves the formation of oxazoline as an intermediate.
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Since the Pictet-Gams reaction requires strong acidic conditions and high temperatures to form the isoquinoline framework, a number of modifications are used such as milder reaction conditions and a mixture of trifluoroacetic anhydride and 2-chloropyridine or DMAP for electrophilic amide activation.
3. Gabriel-Colman rearrangement: This is the rearrangement of phthalimido ester in the presence of a strong base to yield substituted isoquinoline derivatives.307
The ester on hydrolysis followed by decarboxylation and hydrogenation yielded 1-hydroxyisoquinoline (isocarbostyril).
Mechanism: The base removes the acidic proton leading to the generation of ester enolate. Cycloproponation onto one of the phthalimide carbonyls yields an intermediate, which rearranges with ring expansion and subsequently aromatizes to isoquinoline.
N-Phthalimidoglycine ethyl ester have now been used to synthesize 4-hydroxyisoquinoline derivatives by adopting the Gabriel-Colman pathway.308
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4. Pictet-Spengler synthesis: This reaction named after Ame Pictet and Theodor Spengler309 is a chemical reaction in which β-arylethyl amine undergoes ring closure after condensation with an aldehyde, ketone, or 1,2-dicarbonyl compound to give corresponding tetrahydroisoquinoline.
5. Pomeranz-Fritsch reaction: A general method for the synthesis of isoquinoline named after Casar Pomeranz and Paul Fritsch is also sometimes called Pomeranz-Fritsch cyclization because it involves acid-mediated cyclization of an appropriate aminoacetal intermediate obtained by reaction of aldehyde with amine.310, 311
Mechanism: Condensation between aldehyde and amine gives the imine, which on cyclization followed by elimination yields the isoquinoline derivative.
In 1965 Bobbit et al.312 carried out modification in Pomeranz-Fritsch reaction and as a result they synthesized 1,2,3,4-tetrahydroisoquinoline in high yield. In this modification the Schiff base obtained from aromatic aldehyde and amino acetal is first hydrogenated over platinum oxide to a secondary amine, which is cyclized with 6N HCl. The resulting 1,2,3, 4-tetrahydro-4-hydroxyisoquinoline is then hydrogenolyzed over 5% platinum-carbon to 1,2,3,4-tetrahydroisoquinoline.
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A new modification was proposed by Jackson et al.313 Schiff’s bases obtained from alkoxybenzaldehydes and aminoacetaldehyde dimethyl acetal were hydrogenated to benzyamines, which were converted to N-tosylates. The latter in the presence of dilute acid was readily cyclized to isoquinoline.
According to Schlittler-Müller modification,314 diethoxyethanal reacts with benzyl amine forming the desired imine, which is then cyclized to substituted isoquinoline.
6. Aza-Wittig reaction: 1,2-Monoazabisylide prepared in situ by the reaction of 1-[[(triphenylphosphoridiene) amino]methyl]benzotriazole with diethylphosphite anion on reaction with phthalaldehyde in the presence of butyllithium produced isoquinoline.315
7. From indene: Isoquinoline in high yield is prepared by treating indene with ozone at −70°C followed by reduction of dialdehyde with dimethylsulfide in the presence of ammonium hydroxide.316
8. Beckmann rearrangement: An environmentally friendly method for the synthesis of isoquinoline involves treating E,E-cinnamaldoxime under ambient reaction conditions on zeolites and alumina. E-Z isomerization takes place followed by Beckmann rearrangement leading to the formation of isoquinoline as a major product and cinnamonitrile as a minor constituent.317
9. Metal-catalyzed synthesis: Reaction of N-tert-butylbenzaldimines with internal alkynes in the presence of copper acetate catalyst in refluxing dichloroethane yielded isoquinolines in good yield.318
Zirconocene-copper-mediated coupling of benzocyclobutanes in the presence of nitriles yields 3-substituted isoquinoline.319
Reaction of o-tolualdehyde tert-butylimine with butyllithium in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine in THF at 0°C led to the formation of benzyl anion, which reacted with benzonitrile in THF and yielded an isoquinoline derivative.320
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Palladium-catalyzed α-arylation of ketones with aryl halides containing a protected aldehyde or ketone at the o-position led to the generation of a pseudo-1,5-dicarbonyl intermediate, which on treatment with an acidic ammonium source led to concomitant acetal deprotection and aromatization and finally yielded an isoquinoline derivative.321
The Co(I)-catalyzed cycloaddition of nitrile with octa-1,7-dyne affords 5,6,7,8-tetrahydroisoquinoline.
Silver(I)-catalyzed aminofluorination of aryliminoalkynes with N-fluorobenzenesulfonimide (NFSI) led to the synthesis of 4- fluoroisoquinoline.322
A palladium-catalyzed, microwave-assisted, one-pot reaction of o-bromoarylaldehydes with terminal alkynes and ammonium acetate led to the synthesis of disubstituted isoquinolines.323
Cyclization of iminoalkynes in the presence of silver(I)-exchanged K-10 montmorillonite clay has also been used for the synthesis of isoquinoline in good yield.324
Physical Properties Isoquinoline is either a colorless crystalline, low-melting, hygroscopic solid with an mp of 26.48°C or a high- boiling liquid with a bp of 243.25°C (760 mm Hg), volatile in steam. Its density at 30°C is 1.0901 g/mL, whereas its viscosity at the same temperature is 3.2528 cP. Heat of aromatization (−∆Hn) of 85.32 eV and a resonance energy (ER)
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of 34.1 kcal/mol were calculated for isoquinoline. The dipole moment of isoquinoline at 30°C in benzene is 2.49 D. It has relatively low solubility in water but dissolves in nearly all organic solvents. Chemical Reactivity Isoquinoline is aromatic with a resonance energy of 143 kJ/mol and is considered to be a resonance hybrid of the following contributing structures. Structures I, II, and III, which are of lower energy, are the major contributors to the resonance hybrid. Additional charged structures IV–VIII are also possible, but there is disruption of the π system of both rings in these structures.
Resonance structures of isoquinoline.
1. Reaction with bases: Strong bases like Grignard reagent and organolithium tend to react like nucleophiles with isoquinoline. There are examples where isoquinoline has been converted into Grignard reagent by treatment with (iPr)2NMgCl, which has been shown to add to the variety of iodobenzenes.325 2. Reaction with acids: Isoquinoline being basic reacts with acids to form salts. Protonation usually takes place under strong acidic conditions at position 5. When isoquinoline is exposed to strong acidic conditions, reduction of the benzene ring takes place.326
3. Electrophilic substitution reaction: Electrophilic substitution reaction takes place preferably on ring carbon atoms and preferably at positions 5 and 8. (a) Nitration: Nitration of isoquinoline is better in comparison to quinoline because 5-nitroisoquinoline is obtained as the major product and 8-nitroisoquinoline as the minor constituent.
(b) Halogenation: Direct bromination takes place in the presence of strong protic acid or Lewis acid leading to the formation of 5-bromoisoquinoline as the major product.
5-Bromoisoquinoline327 is also obtained by treating isoquinoline with NBS in concentrated sulfuric acid with temperatures between −22 and −26°C.
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Reaction of isoquinoline with hydrochloric acid yields isoquinoline hydrochloride. Bromination of hydrochloride in the presence of nitrobenzene yields 4-bromoisoquinoline by the following mechanism.328
The iodination of isoquinoline takes place via α-metalation using lithium di-(tert-butyl)tetramethyl-piperidino-zincate (TMP) at room temperature using iodine. The chemoselective deprotonative zincation yielded 1-iodoisoquinoline in high yield.329
Isoquinoline is selectively brominated at the 5-position using NBS in sulfuric acid and then subsequently nitrated without isolating the 5-bromo derivative by treating it with potassium nitrate yielding 5-bromo-8-nitroisoquinoline.330
(c) Sulfonation: Sulfonation of isoquinoline takes place in the presence of oleum at temperatures up to 180°C to afford 5-sulfonic acid.
4. Nucleophilic substitution reaction: Nucleophilic substitution reaction takes place preferably in the heterocyclic ring and chiefly at the 1-position. (a) Chichibabin reaction: Amination of isoquinoline with sodium amide in liquid ammonia yields 1-aminoisoquinoline.
(b) 1-Nitroisoquinoline can be synthesized when isoquinoline is treated with a mixture of potassium nitrite, dimethylsulfoxide, and acetic anhydride. The key step of the reaction is the nucleophilic addition of nitrite to isoquinoline, which is already quaternized by reaction through nitrogen with a complex of dimethylsulfoxide and acetic anhydride.331
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(c) Ziegler reaction: Reaction of isoquinoline with butyllithium yields the 1-substitution product 1,2dihydroisoquinoline, which is dehydrogenated in the presence of nitrobenzene to yield 1-butylisoquinoline.
(d) Reissert reaction: Isoquinoline on reaction with KCN in the presence of acylating agent PhCOCl yielded 2-acyl-1-cyano-1,2-dihydroisoquinoline. Useful transformations can be carried out with this 1,2-dihydro compound, commonly called Reisseit compound. When made to react with a strong base, deprotonation takes place yielding an anion, which rearranges to 1-benzoylisoquinoline after loss of cyanide followed by 1,2-acyl shift. When made to react with an electrophilic reagent like benzyl chloride in the presence of a strong base, 1-substituted isoquinoline derivative is formed, first with the formation of anion followed by cyanide elimination.332 Similarly, methylation can also be carried out by treating the Reisseit product with methyl iodide in the presence of phenyllithium, followed by base treatment.333
A new method has been developed for adding the benzyl group at the 4-position. The reaction involves treating isoquinoline with a metallic reagent, which results in addition taking place at the 1-position generating an intermediate, which then reacts with various benzyl chlorides followed by loss of N,N-diethyl o-toluamide.334
There are several methods to add the hydroxyl group to isoquinoline. For instance, on treating isoquinoline with potassium hydroxide at high temperature, addition takes place at the 1-position, which quickly tautomerizes to amide (isocarbostyril).335
5. Oxidation: Oxidation of isoquinoline with alkaline potassium permanganate solution yields a mixture of phthalic acid and pyridine 3,4-dicarboxylic acid. However, when oxidation is carried out with neutral potassium permanganate solution, phthalimide is the exclusive product.
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6. Reduction: Isoquinoline is hydrogenated less readily in comparison to quinoline. Isoquinoline can be reduced to 1,2,3,4-tetrahydroisoquinoline by catalytic hydrogenation over platinum, by tin and hydrochloric acid, or by sodium in ethanol. Catalytic hydrogenation of isoquinoline over Raney nickel has been reported to proceed consecutively via 1,2,3,4-tetrahydroisoquinoline (A), 5,6,7,8-tetrahydroisoquinoline (B), and cisdecahydroquinoline (C) to trans-decahydroquinoline (D).
1,2,3,4-tetrahydroisoquinoline is also obtained by carrying out reduction with lithium triethylborohydride (super-hydride).336 One-pot reductive alkylation of isoquinoline was carried out by treating it with sodium borohydride in carboxylic acid media yielding N-alkyl-1,2,3,4-tetrahydroisoquinoline.337
7. Zincke’s reaction: A reaction named after Theodor Zincke is a reaction in which pyridine or its benzo derivative is transformed into pyridinium salt by reaction with 2,4-dinitrochlorobenzene.338
8. Electrocyclic reaction: Isoquinoline undergoes ring closure reactions to yield a compound in which there is an additional ring fused at nitrogen and the C-1-position. When isoquinoline is treated with DMAD, quinolizine tetracarboxylate is the product. But when in addition to DMAD phenyl isocyanate is also present, then pyrimido isoquinoline is produced in excellent yield.
Isoquinoline reacts with the oxirane ring in the presence of acetic acid yielding oxazolidine.339, 340
Isoquinoline reacts with DMAD in the presence of ethyl bromopyruvate to yield pyrrole [2,1-a]isoquinoline in high yields. The reaction is thought to proceed with the formation of a zwitterionic intermediate.341
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Isoquinoline reacts with benzyltrimethylstannanes in the presence of chloroformate to yield a 1-benzyl-1,2- dihydro derivative.342, 343
9. Nucleophilic substitution by displacement of a good leaving group: The nitrogen atom of isoquinoline by means of inductive and conjugative effects activates the halogen atom at the 1- and 3-positions toward a nucleophilic substitution reaction. 1,3-Dichloroisoquinoline under the action of red phosphorus and hydroiodic acid removes one of the halogens, which is then treated with sodium methoxide, yielding 3-methoxyisoquinoline. However, if 1,3-dichloroisoquinoline is directly treated with sodium methoxide, 1-methoxy-3-chloroisoquinoline is the product.
The bromine atom in 5-bromoquinoline undergoes replacement by cyanide by treating it with cuprous cyanide.
4-Bromoisoquinoline in the presence of palladium phosphine catalyst was carbonylated in ethanol to produce 4-carbethoxyisoquinoline.
Benzoquinolines Benzoquinolines are quinoline derivatives in which a benzene ring is fused to a quinoline molecule. All together there are five benzoquinoline derivatives, namely acridine (2,3-benzoquinoline), benzo[c]quinoline, (phenanthridine, 3,4-benzoquinoline), benzo[f]quinoline (5,6-benzoquinoline), benzo[g]quinoline (6,7-benzoquinoline), and benzo[h] quinoline (7,8-benzoquinoline).
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Benzoquinolines.
Benzoquinolines form quaternary salts with alkyl halides. These quaternary salts have been used to distinguish between the linear and angular benzoquinolines. The linear benzoquinolines form bright yellow-colored hydrochlorides, whereas angular benzoquinolines form colorless hydrochlorides. For example, 1,3-diphenylbenzo[f]quinoline is colorless and forms colorless salt, whereas 2,4-diphenylbenzo[g]quinoline is yellow in color and forms orange-red salt. Fluorescence also helps to distinguish between two types of benzoquinolines. Angular benzoquinolines have a moderately strong blue-violet fluorescence, whereas linear benzoquinolines exhibit very light blue fluorescence.
2.3.13 Benzo[c]quinoline (Phenanthridine)
Phenanthridine, also referred to as benzo[c]quinoline or 5-azaphenanthrene, is an important nitrogen-containing compound formed by replacing the carbon atom of the central ring of phenanthrene by nitrogen. It is one of the products of the destructive distillation of coal from the high-boiling anthracene oil fraction. The discovery of phenanthridine was first reported by Pictet and Ankersmit in 1889 and they synthesized it by pyrolysis of benzylideneaniline.344, 345
Structural and Reactivity Aspects346 X-ray analysis of phenanthridine shows the molecule to be planar in the solid state with a mean deviation of 0.002 Å from the mean plane of carbon and nitrogen atoms. The bond angles (in degrees) and bond length (in Å) are given in the following table.347, 348
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Bond lengths and bond angles of phenanthridine Bond length (Å)
Bond angles (o)
C(1)–C(2) 1.392
C(9)–C(10) 1.417
C(2)–C(1)–C(6) 121.58
N(14)–C(13)–C(12) 125.59
C(2)–C(3) 1.409
C(10)–C(11) 1.437
C(2)–C(1)–N(14) 118.87
C(1)–N(14)–C(13) 120.61
C(3)–C(4) 1.420
C(11)–C(12) 1.410
C(6)–C(1)–N(14) 119.48
H(15)–C(2)–C(1) 121.52
C(4)–C(5) 1.387
C(2)–H(15) 1.109
C(1)–C(2)–C(3) 119.67
H(15)–C(2)–C(3) 118.55
C(5)–C(6) 1.424
C(3)–H(16) 1.101
C(2)–C(3)–C(4) 120.03
H(16)–C(3)–C(2) 119.07
C(6)–C(1) 1.419
C(4)–H(17) 1.196
C(5)–C(4)–C(3) 119.48
H(16)–C(3)–C(4) 121.10
C(1)–N(14) 1.392
C(5)–H(18) 1.130
C(4)–C(5)–C(6) 121.63
H(17)–C(4)–C(3) 112.75
N(14)–C(13) 1.291
C(8)–H(19) 1.106
C(5)–C(6)–C(1) 117.58
H(17)–C(4)–C(5) 113.93
C(13)–C(12) 1.486
C(9)–H(20) 1.179
C(5)–C(6)–C(7) 121.49
H(18)–C(5)–C(4) 118.90
C(12)–C(7) 1.426
C(10)–H(21) 1.105
C(12)–C(7)–C(8) 116.27
H(18)–C(5)–C(6) 119.30
C(7)–C(6) 1.475
C(11)–H(22) 1.089
C(12)–C(7)–C(6) 117.59
H(19)–C(8)–C(9) 121.38
C(7)–C(8) 1.417
C(13)–H(23) 1.069
C(8)–C(7)–C(6) 125.87
H(19)–C(8)–C(7) 117.62
C(9)–C(8)–C(7) 120.72
H(20)–C(9)–C(8) 117.60
C(8)–C(9)–C(10) 124.77
H(20)–C(9)–C(10) 110.23
C(9)–C(10)–C(11) 115.78
H(21)–C(10)–C(9) 125.08
C(12)–C(11)–C(10) 119.25
H(21)–C(10)–C(11) 119.50
C(7)–C(12)–C(13) 115.57
H(22)–C(11)–C(12) 123.83
C(11)–C(12)–C(7) 122.85
H(22)–C(11)–C(10) 117.10
C(11)–C(12)–C(13) 121.58
H(23)–C(13)–N(14) 120.95
C(8)–C(9) 1.352
H(23)–C(13)–C(12) 113.50
The 1H NMR and 13C NMR chemical shifts of phenanthridine are given in the following table. In 1H NMR spectrum determination, phenanthridine was labeled with tritium. Regiospecificity and extent of labeling were also determined.349 H and 13C NMR spectral data of phenanthridine.
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1, H-10, 8.43; H-2, 7.67; H-3, H-8, 7.56; H-4, 8.17; H-6, 9.17; H-7, 7.90; H-9, 7.70
C-1, 121.0; C-2, 127.0; C-3, 128.3; C-4, 130.4; C-6, 153.1; C-7, 129.8; C-8, 128.2; C-9, 126.6; C-10, 121.3; C-1a, 126.6; C-4a, 144.1; C-7a, 142.0; C-10a, 127.7
The UV spectrum of phenanthridine (in ethanol) showed four bands at 245 nm (log ε 4.65), 289 nm (log ε 4.01), 330 nm (log ε 3.01), and 346 nm (log ε 3.01). The first two bands may be due to π→π* transition, whereas the third and fourth bands appear to be due to n→π* transition. The mass spectrum of phenanthridine shows a base peak at m/z 179. Other fragments along with appropriate metastable peaks are shown in the following diagram.
Mass fragmentation pattern of phenanthridine.
Importance in Natural Products, Medicines, and Materials Phenanthridines have been reported to possess enormous synthetic and biological activity.350 They have been reported to possess antifungal, antibacterial, antiprotozoal, and anticancer activities.351–353 Phenanthridine derivative 3,8-diamino-5-ethyl-6-phenylphenanthridinium, also known as ethidium bromide, is a trypanocidal and possible antiviral agent that has been used for decades as a standard DNA- and RNA-fluorescent marker. The phenanthridine
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nucleus is present in a number of natural products, which have been reported to possess a wide variety of biological activity. For example, trispheridine and bicolorine have been reported for trypsominiasis,354 chelerythrine for antifungal,355 sanguinarine for antibacterial,356 and nitidine and fagaronine for antitumor treatment.357 In addition, the phenanthridine nucleus is also present in phenanthriplatin, which is an improved anticancer compound.358
Natural products and drugs containing phenanthridine nucleus.
Synthesis 1. Hubert-Pictet reaction: This is one of the direct methods for the synthesis of phenanthridine. The reaction involves cyclodehydration of acyl-o-aminodiphenyl in the presence of phosphorous oxychloride. Nitrobenzene was used as a solvent in the present reaction, due to its high boiling point and good ionizing properties.359
2. Phenanthridine is also obtained by the reaction of o-aminobiphenyl with formic acid. The intermediate, formamidobiphenyl, undergoes cyclization in the presence of polyphosphoric acid to give phenanthridine.
Phenanthridine and derivatives are also synthesized by the treatment of o-phenylaniline and its homologs with cyclic ketones under hydrothermal conditions.
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3. Reaction of methyl 2-(2-nitrophenyl)phenylacetate with methanolic sodium hydroxide yields an acid, which on reductive decarboxylation yields phenanthridine.360
4. Phenanthridine is also prepared by the photolysis of benzylidenaniline.
5. Reaction of o-chlorobenzaldehyde with aniline led to the formation of Schiff’s base, which undergoes cyclization in the presence of potassium amide followed by deamination to yield phenanthridine. The reaction probably takes place via a benzyne intermediate.361
6. 3-Bromo-4-chloroquinoline reacts with lithium amalgam and furan to give phenanthridine. The reaction also takes place via a benzyne intermediate.362
7. Substituted phenanthridines are synthesized by one-pot annulations of 2-isocyanobiaryls with organoboronic acids under heating conditions. In the reaction, the isocyano group acts as a radical acceptor, which under radical cyclization yields phenanthridine.363
8. Substituted phenanthridines have been synthesized by the metal-free ion visible light-induced aerobic oxidative cyclization of 2-isocyanobiaryl.364
9. Substituted phenanthridines have also been synthesized by microwave-assisted [2+2+2] cyclotrimerization of alkynes.365
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Physical Properties Phenanthridine is a colorless crystalline compound with mp of 108°C, which gives a weak blue fluorescein in dilute alcoholic solution. It is a weak base (pKa = 3.30 in 50% alcohol) forming colorless crystalline salts with mineral acids. It is a weaker base in comparison to quinoline and acridine. It has a dipole moment of 2.39 D.366 Chemical Reactivity 1. Electrophilic substitution reaction: Phenanthridine, because of its 9 nonequivalent positions where attack of electrophiles can take place, hence it is not possible to predict the most likely position at which the electrophilic substitution reaction will. (a) Nitration: Reaction of phenanthridine with a nitrating mixture results in the formation of 1-nitrophenanthridine and 10-nitrophenanthridine.
(b) Halogenation: Fluorination of phenanthridine with a mixture of gases, fluorine, and iodine afforded 6-fluorophenanthridine.
Bromination of phenanthridine gave 2-bromophenanthridine as the only product when the reaction was carried out with NBS. However, when bromination was carried out with molecular bromine in the presence of silver sulfate in 92% sulfuric acid, a mixture of 1-bromo-, 4-bromo-, and 2-bromophenanthridines was obtained. 2. Nucleophilic substitution reaction Chichibabin reaction: Reaction of phenanthridine with sodium amide in liquid ammonia yields 6-aminophenanthridine.
3. Oxidation reaction: Ozonolysis of phenanthridine followed by treatment with alkaline hydrogen peroxide readily yields 6-phenanthridone and quinoline-3,4-dicarboxylic acid.
4. Reduction reaction: Phenanthridine is readily reduced to 5,6-dihydrophenanthridine by the action of Sn/HCl. The same compound is obtained by hydrogenation of phenanthridine over Raney nickel.367
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5. Reissert reaction: Phenanthridine readily forms Reissert compound (a compound formed by the reaction of an acyl group and a cyano group to nitrogen and carbon atoms, respectively) by reacting it with KCN/C6H5COCl.
2.3.14 Benzo[f]quinoline
Benzo[f]quinoline is one of the structural isomers of the benzoquinoline family and is also known as 5,6-benzoquinoline, naphthopyridine, and 1-azaphenanthrene. It has been isolated from the high-boiling basic fraction of coal tar.368 Structural and Reactivity Aspects369 The 1H and 13C NMR data of benzo[f]quinoline confirm it to be a 14π heteroaromatic system. 1
H and 13C spectral data of benzo[f]quinolline
H NMR (CDCl3), δ (ppm)
C NMR (CDCl3), δ (ppm)
1
13
H-2, 8.94; H-3, 7.50; H-4, 8.87; H-5, 8.55; H-6, 7.67; H-7, 7.67; H-8, 7.99; H-9, 7.99; H-10, 7.99
C-2, 130.64; C-3, 128.62; C-4, 149.55; C-5, 125.02; C-6, 127.25; C-7, 128.03; C-8, 122.49; C-9: 121.21; C-10, 130.82; C-4a, 131.58; C-4b, 125.34; C-8a, 129.52; C-10a, 148.05
Mass spectrum: The molecular ion of benzo[f]quinoline appeared at m/z 179, which was also the base peak. The molecular ion undergoes loss of HCN leading to a fragment at m/z 151. Subsequent further fragmentation yields fragments at m/z 90 and m/z 76, respectively.
Mass fragmentation pattern of benzo[f]quinoline.
Importance in Natural Products, Medicines, and Materials Benzo[f]quinoline and benzo[h]quinoline are environmental contaminants and they have been detected in automobile exhausts, urban air particulates, and cigarette smoke. Both of them have been shown to be metabolically activated to products mutagenic to Salmonella typhimurium. Benzo[f]quinoline and its derivatives find use in various fields of chemistry, including pharmaceutical chemistry. These compounds have been found to exhibit antibacterial, antimicrobial, antimalarial, antipsychotic, uridine diphosphate glucuronosyl transferase, and peripheral dopaminergic activity.370 Synthesis 1. Skraup synthesis: Synthesis of benzo[f]quinoline by Skraup’s procedure was reported earlier.371, 372 However, an improved procedure involving heating 2-naphthylamine, glycerol, and sulfuric acid in the presence of arsenic acid has been reported.369
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2. Six-Membered Heterocycles
Similarly, 5-carboxybenzo[f]quinoline has been synthesized from 2-amino-3-naphthoic acid.373 2. Reaction of 4,7-phenanthroline 7-oxide with methylsulfinyl carbanion yields benzo[f]quinolines. C-8 is probably the position of nucleophilic attack and subsequent ring opening and ring closure on to the methyl sulfinyl carbon leads to expulsion of the N-oxide group.374
3. Photolysis of trans-2-stilbazole in cyclohexane solution in the presence of oxygen was carried out, and benzo[f] quinoline along with a minor pyridine photoproduct was also obtained.375
4. Stirring a mixture of arenecarbaldehyde, naphthalene-2-amine, and acetone at 50°C in THF in the presence of 5 mol% of iodine afforded benzo[f]quinolines in good yield.376
Similarly, refluxing a mixture of arenecarbaldehyde, naphthalene-2-amine, and cyclopentanone in THF in the presence of 5 mol% iodine afforded benzo[f]cyclopenta[c]quinoline in high yield.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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5. Reaction of 2-aminonaphthalene-1-sulfonic acid with aromatic aldehyde in absolute ethanol leads to the generation of Schiff’s base. Condensation of the Schiff’s base with acetone in the presence of acid yields substituted benzo[f]quinoline derivative.377
6. Reaction of 2-naphthylamine with ethylpropiolate in toluene as solvent and trifluoroacetic acid as acid and microwave irradiation at 150°C yielded ethylbenzo[f]quinoline-2-carboxylate.378
Physical Properties 5,6-Benzoquinoline is a crystalline compound with mp of 93°C, bp 350°C/721 mm Hg, soluble in dilute acids, alcohol, ether, and benzene. It is used as a reagent for the determination of cadmium. Chemical Reactivity 1. Acetylation: The interaction of benzo[f]quinoline with ethyl alcohol and carbon tetrachloride in the presence of copper catalysts Cu(OAc)2, CuI, CuBr2, Cu(acac)2, Cu(C6H5CO2)2, or CuCl2·2H2O under optimized reaction conditions led to the formation of 2-acetylbenzo[f]quinoline. However, the highest yield was obtained when copper acetate was used as catalyst. The structure of the compound was confirmed by X-ray analysis.379
2. Alkylation: Reaction of benzo[f]quinoline with methyl sulfinyl carbanion in DMSO at 70°C using sodium hydride as a base yielded 5- and 6-methylbenzo[f]quinoline.380
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2. Six-Membered Heterocycles
3. Bromination: Reaction of benzo[f]quinoline with cyanogen bromide in methanol followed by application of bromine and sodium carbonate gave 2-bromo-4-cyano-1,3-dimethyl-1,2,3,4-tetrahydrobenzo[f]quinoline, which on hydrolysis resulted in the quantitative formation of 2-bromobenzo[f]quinoline.381
4. Nitration: Benzo[f]quinoline on reaction with fuming nitric acid and concentrated sulfuric acid at −15°C yields 7-nitrobenzo[f]quinoline. However, when the temperature was raised to 0°C, then 7,9-dinitrobenzo[f]quinoline was obtained.382
5. Fluorination: Electrochemical fluorination of benzo[f]quinoline using Et4NF.4.45HF as the electrolyte at a constant electric potential of 2.5 V was carried out. The electrolytic product was subsequently treated with aqueous alkali at room temperature whereby 7,10-difluoro- and 7,7,10,10-tetrafluorobenzo[f]quinoline were isolated383
6. Nucleophilic substitution: Positions close to the nitrogen are electrophilic and can thus undergo nucleophilic addition with alkyllithiums. Deprotonation was achieved by treating benzo[f]quinoline with a super-basic system like BuLi-LiDMAE and then quenching the reaction mixture with different electrophiles like C2Cl6, CBr4, and PhSSPh yielding 3-chloro-, 3-bromo-, and 3-phenylthiobenzo[f]quinoline.384
7. Reduction: Hydrogenation of 5,6-benzoquinoline methoiodide over Raney nickel in the presence of diethylamine yielded 1,2,3,4-tetrahydro-1-methyl-5,6-benzoquinoline.385
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
105
Catalytic hydrogenation of benzo[f]quinoline with platinum oxide in trifluoracetic acid and subsequent treatment with acetic anhydride (Eliel’s method386) yielded 4-acetyl-1,2,3,4,7,8,9,10-octahydrobenzo[f]quinoline, 7,8,9,10-tetrahydrobenzo[f]quinoline, and 5,6,6a,7.8.9.10,10a-octahydrobenzo[f]quinoline.387
Selective reduction of the heterocyclic ring of benzo[f]quinoline takes place in the presence of chlorotris(triphenylphosphine)rhodium(I) as hydrogenation catalyst.388 8. Epoxidation: The 5,6-bond of benzo[f]quinoline is the reactive site and under phase transfer conditions it reacts with sodium hypochlorite solution to yield benzo[f]quinoline-5,6-epoxide.389
9. Replacement reaction: A chlorine atom bonded to carbon adjacent to the nitrogen of the ring is a better leaving group in comparison to those in which they are away from nitrogen. Thus 1-methyl-3-chloro-benzo[f] quinoline reacted faster with hydrazine hydrate to yield a hydrazine derivative in comparison to 1-chloro-3methylbenzo[f]quinoline.390 Reaction of hydrazine derivative with nitrous acid and formic acid leads to the generation of cyclic compounds.
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2. Six-Membered Heterocycles
2.3.15 Benzo[h]quinoline
Benzo[h]quinoline is one of the structural isomers of the benzoquinoline family and is also known as 7,8-benzoquinoline and 1-naphthaquinoline. Structural and Reactivity Aspects The NMR spectrum of benzo[h]quinoline was reported by Donckt et al.,391 which was not very clear. However, a simplified 1H and 13C NMR of its acetyl derivative is reported here.392 1 H NMR (400 MHz, δ ppm from tetramethylsilane [TMS] in CDCl3) 3.00 s (3H, COCH3), 7.67 d (1H, J = 9 Hz, H-5), 7.80 t (1H, J = 8 Hz, H-9), 7.77 t (1H, J = 8 Hz, H-8), 7.88 d (1H, J = 9 Hz, H-6), 7.93 (1H, H-7), 8.23 s (2H, H-3, and 4), 9.35 d (1H, J = 8 Hz, H-10) 13 C NMR (100 MHz, δ ppm from TMS in CDCl3) 200.68 (CO), 25.77 (CO-CH3), 118.87 (C-3), 124.48 (C-10), 124.92 (C-5), 127.50 (C-9), 127.97 (C-7), 128.35 (C-4a), 128.63 (C-8), 133.71 (C-10a), 130.00 (C-6), 131.63 (C-6a), 136.49 (C-4), 151.60 (C-2) Importance in Natural Products, Medicines, and Materials A number of natural products, chiefly alkaloids, have been isolated, which possess a benzo[h]quinoline nucleus. For example, two alkaloid derivatives (A and B) have been isolated from the fruits of Macleaya cordata and they possess a benzo[h]quinoline nucleus.
Alkaloids containing benzo[h]quinoline nucleus.
A benzo[h]quinoline moiety has been recognized as a potential precursor to analogs of a number of agents with anticancer activity393 and significant antioxidant activity against various in vitro antioxidant systems. These derivatives bind DNA via intercalative modes thereby protecting DNA from harmful free radical reactions.394 Synthesis 1. Skraup synthesis: Synthesis of 7-nitrobenzo[h]quinoline has been achieved by heating 4-nitro-1-naphthylamine with glycerol and sulfuric acid in the presence of an oxidizing agent like arsenic acid.395
Synthesis of benzo[h]quinoline by the Skraup procedure is also carried out by heating 1-naphthylamine with glycerol in the presence of Sulfo-mix,396 ferrous sulfate, and boric acid.397
2. Reaction of 1-naphthylamine with ethylpropiolate in toluene as solvent and trifluoroacetic acid as acid and microwave irradiation at 150°C yielded ethylbenzo[h]quinoline-3-carboxylate.398
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
107
Chemical Reactivity 1. Acetylation: The interaction of benzo[h]quinoline with ethyl alcohol and carbon tetrachloride in the presence of copper catalysts Cu(OAc)2, CuI, CuBr2, Cu(acac)2, Cu(C6H5CO2)2, or CuCl2·2H2O under optimized reaction conditions led to the formation of 2-acetylbenzo[h]quinoline. However, the highest yield was obtained when CuI was used as catalyst.399
2. Alkylation: Reaction of benzo[h]quinoline with methyl sulfinyl carbanion in dimethylsulfoxide at 70°C using sodium hydride as a base yielded 4-, 5-, and 6-methylbenzo[h]quinoline.400
3. Chlorination: Palladium(IV) complexes have been reported to be intermediates in the functionalization of arene/alkane CH bonds. The method employs palladium(II) acetate as catalyst in conjugation with a terminal oxidant such as PhICl2 or N-halosuccinimide. Reaction kinetic reveals that palladium complex formed during the reaction is the complex from which CCl bond formation takes place during the catalysis process.401
4. Fluorination: Electrochemical fluorination of benzo[h]quinoline using Et4NF.4.45HF as the electrolyte at a constant electric potential of 2.5 V was carried out. The electrolytic product was subsequently treated with aqueous alkali at room temperature whereby 5-fluoro-, 5,6-difluoro-, and 7,10-difluorobenzo[h]quinoline were isolated.402
5. Nucleophilic substitution: Carbon adjacent to the nitrogen is electrophilic and thus undergoes nucleophilic addition of alkyllithiums. Deprotonation was achieved by treating benzo[h]quinoline with a super-basic system like BuLi-LiDMAE and then quenching the reaction mixture with different electrophiles like C2Cl6 and CBr4 yielding 2-chloro and 2-bromobenzo[h]quinoline.403
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2. Six-Membered Heterocycles
6. Amination: Direct amination of benzo[h]quinoline was achieved by treating it with p-dodecylbenzylsulfonyl azide in dichloroethane in the presence of dichloro(η5-pentamethylcyclopentadienyl)-rhodium(III) dimer and silver hexafluoroantimonate(V).404
7. Epoxidation: Reaction of benzo[h]quinoline with Fremy’s salt afforded 7,8-dione derivative, which on reduction with potassium borohydride afforded dihydro diol. Epoxidation of the dihydro diol with an excess of m-chloroperbenzoic acid afforded the antidiol epoxide.405, 406
8. Reduction: Hydrogenation of benzo[h]quinoline with platinum oxide in trifluoracetic acid yielded 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinoline, 1,2,3,4,7,8,9,10-octahydrobenzo[h]quinoline, and 7,8,9,10-tetrahydrobenzo[h]quinoline.407
Selective reduction of the heterocyclic ring of benzo[h]quinoline takes place in the presence of chlorotris(triphenylphosphine)rhodium(I) as hydrogenation catalyst.408 9. Replacement reaction: A chlorine atom in a position adjacent to the nitrogen of the ring is a better leaving group in comparison to those in which they are away from nitrogen. Thus 2-chloro-4-methylbenzo[h]quinoline reacted faster with hydrazine hydrate to yield hydrazine derivative in comparison to 4-chloro-2-methylbenzo[h] quinoline.409 Reaction of these hydrazino derivatives with nitrous acid and formic acid leads to the generation of cyclic compounds.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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2.3.16 Acridine (Dibenzo[b,e]pyridine)
Acridine, also known as bibenzo[b,e]pyridine and benzo[b]quinoline, is a linear, planar, tricyclic aromatic nitrogen heterocycle structurally related to anthracene with one of the central CH groups being replaced by nitrogen. Acridine was first isolated from the high-boiling anthracene fraction of coal tar in 1870 by Carl Grabe and Heinrich Caro. On account of its acrid smell and its irritating action on the skin and mucous membrane, this new compound was given the name “acridin” (acris meaning sharp or pungent). Acridines were first developed as dyes and then in the early 20th century they were evaluated for their pharmacological properties. Structural and Reactivity Aspects Under the influence of different solvents, acridine is known to crystallize in six different polymorphs. They differ greatly in their stability and crystal habit. Some of them have been studied in detail.410 Acridine has been classed as a π electron deficient heterocycle; as a result, it shows poor fluorescence properties. Its blue fluorescence in dilute aqueous or dilute alcoholic solution is one of its most characteristic properties. Potentiometric titration values indicate that acridine pKa 5.60 is a stronger base than quinoline pKa 4.94 or pyridine pKa 5.23. Studies have shown that the pKa value of acridine is more sensitive to the solvent effect compared to quinoline or pyridine.411 The HOMA and NICS (1) values calculated 1 Å above the ring critical point for rings A, B, and C of acridine are 0.6275, 0.7287, and 0.6271 and −16.0218, −22.4097, and −16.0185, respectively. The standard molar heat capacity Cp, m0 in the crystalline state at 0.1 MPa and 298.15 K was calculated to be 203.5 J K‑1 mol‑1 and measured at 201.5 J K‑1 mol‑1. Gas phase basicity (GB298), proton affinity, and protonation entropy (Sprot) of aciridine were determined to be 224.4, 232.5, and 0.7 kcal mol‑1.412
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2. Six-Membered Heterocycles
From the study of the different spectroscopic techniques, their spectra show the relationship of spectra to their structure. The UV and 13C NMR spectral data413 of acridine are given in the following table. UV and 13C NMR spectral data of acridine UV (ethanol) λ (nm) ε
13
C NMR (CDCl3) δ (ppm)
249 (5.22), 339 (3.81), 351 (4.0), 379 (3.44)
C-1, 129.5; C-2, 128.3; C-3, 125.5; C-4, 130.3; C-9, 135.9; C-1a, 126.6; C-4a, 149.1
Importance in Natural Products, Medicines, and Materials A number of pharmaceutical agents and dye stuffs have been found to possess an acridine nucleus like mepacrine, also called quinacrine (antimalarial, antiprotozoal, and antirheumatic agent), acriflavinium chloride (topical antiseptic), proflavine (disinfectant bacteriostatic against Gram-positive bacteria), ethacridine (antiseptic), bucricaine (anesthetic), amsacrine (antileukemic), asulacrine (anticancer), nitracrine (antitumor), tacrine (cholinesterase inhibitor for Alzheimer’s disease) acridine orange (fluorescent cationic dye), and quinacrine mustard (a fluorescent probe).
Dyes and drugs containing acridine nucleus.
Synthesis 1. Bernthsen synthesis: This reaction is named after August Bernthsen, a German chemist,414 who first reported acridine synthesis in which diphenylamine was condensed with benzoic acid in the presence of zinc chloride at higher temperatures. Thus this method is used for the synthesis of 9-substituted acridines.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
111
The yield of acridine by the Bernthsen method was low; hence in 1962 F.D. Popp reported an improved method in which polyphosphoric acid was used in lieu of zinc chloride.415
Microwave-assisted Bernthsen synthesis of a variety of 9-substituted acridines has been reported.416
Acridines are also obtained by heating o-arylaminophenylketones in the presence of strong acids like sulfuric acid or polyphosphoric acid.
All these reactions are cyclodehydration reactions with the cyclization being intramolecular SEAr in nature. 2. Ullmann reaction: This reaction is named after Fritz Ullmann, a German chemist. The reaction involves condensing o-chlorobenzoic acid with aniline or anthranilic acid in the presence of a copper catalyst, yielding N-phenylanthranilic acid, which on treatment with sulfuric acid or polyphosphoric acid undergoes cyclization to yield 9-acridone. Reduction followed by oxidation yields acridine. Alternatively, in Goldberg’s method, Nphenylanthranilic acid on reaction with phosphorous oxychloride yields 9-chloroacridine, which on reduction followed by oxidation yields acridine417
Halogen-substituted aryl ketones have also been used for the synthesis of 9-substituted acridines.
112
2. Six-Membered Heterocycles
3. Friendlander synthesis: This reaction involves heating salt of anthranilic acid with cyclohex-2-enone at 120°C, whereby 9-methylacridine is obtained
4. From acridones: A number of methods have been reported for the synthesis of acridine by reduction of acridones. Acridone on reaction with phenyllithium yields an adduct, which on acidification yields 9-phenylacridine in good yield.
Distillation of 9-acridone with zinc dust yields acridine.
Distillation of benzylaniline through a red-hot tube (700°C) yields acridine. Similarly, distillation of benzal-2- aminophenol over zinc yields acridine.
5. From 9-chloroacridine: Reaction of 9-chloroacridine with p-toluenesulfonyl hydrazine yields the corresponding acridyl derivative, which on treatment with sodium hydroxide yields acridine.
6. From acylated diphenylamines: Acylated diphenylamine when heated in the presence of I2/HI yields 9-phenylacridine.417
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113
7. From large rings: 9-Methylacridine is formed by the ring contraction of azepines.
Physical Properties Acridine, a lachrymator, causes skin irritation, is a yellow crystalline solid with mp of 114°C, and has an irritating odor. It is sparingly soluble in water, alcohol, and ether. It is aromatic in nature with a resonance energy of the order of 105 kcal/mol. It is weakly basic in nature and has a pKa value of 5.6, a slightly stronger base in comparison to pyridine. Chemical Reactivity 1. Electrophilic substitution reaction: Reaction of acridine with electrophiles often results in disubstitution at the 2- and 7-positions. (a) Nitration: Reaction of acridine with a nitrating mixture at 0°C results in the formation of 2,7-dinitroacridine.
(b) Bromination: Reaction of acridine with bromine results in the formation of di- as well monobromoacridine.
(c) Chlorosulfonation: Reaction of acridine with chlorosulfonic acid results in a mixture of 1-sulfonyl chloride and 1,8-disulfonyl chloride.418
2. Nucleophilic substitution reaction: Acridine undergoes nucleophilic substitution reaction chiefly at the 9-position and this is due to decrease in electron density at this position in comparison to the 1-, 2-, 3-, or 4-positions. Acridine reacts with nucleophiles leading to the generation of an acridane derivative, which undergoes rearomatization, depending on the stability of the acridane and reaction conditions.
Nucleophilic substitution in acridine.
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2. Six-Membered Heterocycles
Chichibabin reaction of acridine with sodium amide in liquid ammonia yields 9-aminoacridine.419
3. Reactivity of position 9: Reaction of acridine with N,N-dimethyl aniline yields 9,9′-biacridanyl (biacridane) as the major product. Biacridane along with 9-aminoacridine is also obtained when melted acridine reacts with sodamide420 under solvent-free conditions.
Reaction of acridine with reactive methylene compounds adds at the 9-position to form 9,10-dihydroacridine (acridane), which under suitable reaction conditions is rearomatized. For example, malonitrile on reaction with acridine yields an adduct, which on oxidation with MnO2 yields a 9-substituted nitrile derivative.
Similarly, nitromethane in basic medium reacts with acridine to yield 9-(nitromethyl)-9,10-dihydroacridine, whereas reaction with phenylmethylsulfone yields an adduct, which on elimination of phenylsulfinic acids yields 9-methylacridine.
Another useful reaction is the carboxylation at C-9. The process involves reaction of acridine with potassium cyanide, yielding 9-cyanoacridine, which is then hydrolyzed with H2SO4/NaNO2 to a carboxylic acid derivative.421
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115
Enolizable ketones like methyl ketones also react with acridine under Emmert reaction conditions and lead to the generation of 9-acridinyl ketones.422 The reactivity of such methyl ketones was found to be enhanced when they were used in the methyl iminium form.
Isopropyl at position 9 was introduced by the reaction of acridine with isopropyl carboxylic acid in the presence of silver nitrate.
Indole and its derivatives also react with acridine under solvent-free conditions. The heteroaromatic ring acts as a nucleophile with the conjugation taking place at position 3 of the indole ring, but if position 3 is occupied then conjugation takes place at the 2-position.
4. Oxidation: Acridine on oxidation with acidic sodium dichromate solution yields acridone, whereas oxidation with alkaline potassium permanganate solution yields quinoline-2,3-dicarboxylic acid.
5. Reduction: Acridine can be reduced by a number of methods. When reduction is carried out with an excess of lithium and ethanol in ammonia (Birch reduction), 1,4,5,8-tetrahydroacridine is the product.423
When reaction is carried out with sodium or sodium amalgam, lithium or lithium aluminum hydride, or Zn/ HCl, then reduction takes place in the pyridine ring leading to the generation of 9,10-dihydroacridine (acridane).424 However, a better yield of acridane was obtained when reduction was carried out with NiCl2-2H2O in THF and when reaction was carried out with [RuH2(η2-H2)(PCy3)2]; as a result, reduction selectively takes place in the benzene ring producing 1,2,3,4,5,6,7,8-octahydroacridine.425 When reduction was carried out with Rh/C or Rh/Al2O3, then tetradecahydroacridine was obtained.426 When reduction was carried out in μ3-oxo-trirhodium(III) acetate, then 1,2,3,4-tetrahydroacridine was the exclusive product.
116
2. Six-Membered Heterocycles
Reductive alkylation takes place when acridine reacts with n-pentanoic acid in the presence of UV light yielding 9-n-butylacridine.427
6. Electrophilic reaction at nitrogen: The pyridine-type nitrogen of the central ring of acridine is the main nucleophilic site of the molecule and thus it can easily undergo N-alkylation with methyl iodide, methyl triflate, dimethylsulfate, etc. resulting in the formation of N-methylacridinium salt.428 N-Oxidation of acridine can easily be carried out with hydrogen peroxide and m-chloroperbenzoic acid (m-CPBA).429
Ethoxycarbonylcarbene generated by thermal, photochemical, or catalytic decomposition of diazoacetate attacks the nitrogen atom of acridine yielding a stable ylide.430
7. Cycloaddition reaction: 1,3-Dipolar cycloaddition reaction of acridine with different nitrile oxides in toluene led to the synthesis of 1-substituted-3a,11b-dihydroisoxazolo[4,5-a]acridines.431
8. Photochemical reaction: Photochemical pericyclic (4π + 2σ + 2σ) addition of acridine to quadricyclane and norbornadiene in benzene solution yielded an isomeric mixture of a 1:1 Diels-Alder adduct.432
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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2.3.17 Quinolizinium Ion
The bicyclic 6-6 system with one of the bridgehead carbon atoms has been replaced by a positively charged nitrogen atom and is designated as the quinolizinium cation. It is aromatic and isoelectronic with naphthalene, quinolone, and isoquinoline. It is commonly included in the category of compounds classified as azonia aromatic heterocycles. Besides quinolizinium there are three other 6-6 systems, which carry one bridgehead nitrogen. These are classified on the basis of an additional hydrogen atom and are called 2H-quinolizine, 4H-quinolizine, and 9aH-quinolizine, but none of them have been isolated as a stable species.
Quinolizines.
Structural and Reactivity Aspects The structure of quinolizinium hexafluorophosphate has been determined by X-ray analysis.433 The quinolizinium ring is planar and the maximum deviation from the best plane for the C-1 atom is only 0.010(1) Å. In comparison to naphthalene the N5-C9a and N5/C9a-C1 have been contracted by 0.04 and 0.03 Å, respectively. The quinolizinium cation is aromatic because its delocalization energy or resonance energy (3.89) is nearly the same as that of naphthalene (3.68).434 Electron density of the quinolizinium cation has been calculated by the Hückel molecular orbital (HMO) and Pariser-Parr-Popple (PPP) methods and the results are summarized in the following table. Electron density of quinolizinium cation Method
C1
C2
C3
C4
N5
C9a
HMO
1.005
0.916
1.011
0.856
1.550
0.874
PPP
1.010
0.976
1.013
0.940
1.185
0.940
The 1H and 13C NMR data of the quinolizinium cation are given in the following table. From the spectral data, the quinolizinium ion has been proved to be aromatic. In the 1H NMR spectrum the H-4 and H-6 protons are highly deshielded due to the positive charge on the nitrogen atom. H and 13C NMR spectral data of quinolizinium ion
1
1
H NMR (DMSO-d6), δ (ppm)
H1, 8.65; H2, 8.42; H3, 8.15; H4, 9.49; H6, 9.49; H7, 8.15; H8, 8.42; H9, 8.65
13
C NMR (DMSO-d6), δ (ppm)
C1, 127.9; C2, 138; C3, 125; C4, 137; C6, 137; C7, 125; C8, 138; C9, 127.9; C9a, 143.0
The absorption spectrum of the quinolizinium cation shows a well-defined absorption bands in the near-UV and visible region at 226 (log ε 4.25), 272 (log ε 3.42), 283 (log ε 3.47), 310 (log ε 4.03), 316.5 (log ε 3.98), and 323.5 (log ε 4.23). Comparison of these values with those of naphthalene shows bathochromic shift due to the presence of cationic nitrogen. Importance in Natural Products, Medicines, and Materials Quinolizinium salts and their benzo analogs, which have been classified as azonia aromatic compounds, have in recent years gained importance and are widely studied because of their biological activities. Many alkaloids such as berberine, palmatine (used in treatment of jaundice, dysentery, hypertension, etc.), columbamine, simperverine, and flavopereurine are known to possess a quinolizinium structure. Recently, natural alkaloid semperverine has been reported to be a promising anticancer drug.435 Besides berberine a number of its derivatives were also found to affect the proliferation of human HCT116 and SW613-B3 colon carcinoma cell lines.436 Their benzo derivatives are used for the treatment of diseases linked to smooth muscle cell contraction such as hypertension and asthma.437
118
2. Six-Membered Heterocycles
Alkaloids containing quinolizinium ion nucleus.
Besides these compounds also find use as fluorescent dyes,438 antitumor agents,439 DNA intercalators,440 and nonlinear optical and ionic liquids.441 Synthesis 1. The first synthesis of the parent quinolizinium ion was reported by Woodward and Beaman.442 The reaction involved condensation of 3-isopropoxyacrolein with 2-picolyllithium. The intermediate product obtained was cyclized.
2. [3 + 3] condensation: The yield of the quinolizinium cation by the Woodward method was low. Hence improvement was introduced by involving a reaction of 2-picolyllithium with β-ethoxypropioanaldehyde yielding an alcohol, which on consecutive reaction with hydroiodic acid and potassium carbonate was converted into tetrahydroquinolizinum alcohol. The alcohol on dehydration, followed by dehydrogenation, yields the quinolizinium cation.443
Another useful method involving the [3+3] approach involves reaction of 2-cyanopyridine with 3-ethoxypropylmagnesium bromide, which after initial formation of imine and its hydrolysis yields the ketone. Cleavage of the ether by HBr leads to the formation of a bromo derivative, which cyclizes by refluxing in chloroform. Refluxing the bicyclic intermediate with acetic anhydride yields the quinolinizium cation.444
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119
Substituted quinolizinium salts are synthesized by treating 2-cyanopyridine with suitably substituted 3-ethoxypropylmagnesium bromide.
3. Cyclization of 1-(α-pyridyl)-4-ethoxy butanone in the presence of HBr and chloroform yielded 1-oxo1,2,3,4-tetrahydroquinolizinium bromide, which on dehydration with acetic anhydride containing a drop of concentrated sulfuric acid yielded quinolizinium bromide.445
4. Westphal synthesis: This reaction has proved to be a useful method for preparing polycyclic systems containing a bridgehead quaternary nitrogen.446 In this reaction, pyridinium salts, which possess an alkyl group at the 2-position and an acceptor activated with the methyl group at nitrogen, undergo a base-catalyzed cyclocondensation reaction with 1,2-dicarbonyl compounds yielding the quinolizinium ion.
A modified Westphal synthesis was introduced, which involved acylation and subsequent N-quaternization of β-(2-pyridyl)-substituted β-hydroxyketone (obtained by aldol condensation of pyridine 2-aldehyde with methylene ketones) with bromoacetate or bromoacetonitrile yielding pyridinium salt, which on treatment with Bu2NH are cyclized to quinolizinium salt by intramolecular aldol condensation followed by elimination of acetic acid.
5. [4 + 2] condensation: Reaction of 2-ethoxycarbonyl-1-methylpyridinium salt with acrylonitrile yields a heterobetaine. Removal of the cyano substituent by acid hydrolysis and decarboxylation affords the ketone, which on refluxing with acetic anhydride produces the quinolizinium cation.
6. Ring-closing metathesis: The first example of olefin ring-closing metathesis of appropriate N-(3-butenyl)-2vinylpyridinium in the presence of Grubbs catalyst led to generation of the dihydroquinolizinium cation, which can be dehydrogenated to the quinolizinium cation.447
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Ring-closing metathesis reaction of 1-butenyl-2-vinylpyridinium salts and 2-butenyl-1-vinylpyridinium salts using Grubbs second-generation and Hoveyda-Grubbs catalyst leading to the generation of 3,4-dihydro- and 1,2-dihydroquinolizinium salts has also been reported.448 Ring-closing enyne metathesis on appropriately substituted pyridinium substrates in the presence of HoveydaGrubbs catalyst to 1- and 2-vinyl-substituted 3,4-dihydroquinolizinium cations have also been reported.449
7. Quinolizinium ionic liquids or low-melting solids with an unbranched cation core have been synthesized. These ionic liquids have been found to show extremely high fluorescence quantum yields. The synthetic process involves a quaternization reaction between methylpyridine and ethyl 2-bromoacetate leading to the generation of pyridinium bromide salt. The Westphal synthetic procedure was applied by treating the pyridinium salt with 3,4-hexanedione in the presence of triethylamine. Cyclocondensation takes place leading to the generation of quinolizinium bromide salt. Anionic metathesis reaction from the bromide ion to NTf2 or BF4 or dichloroacetic acid (DCA) afforded the desired ionic liquid.450
8. A method for the synthesis of quinolizinium salts from 2-ethylpyridines and diphenylacetylene in the presence of Rh(III) catalyst along with an excess amount of copper(II) salt has been reported. Mechanistic studies suggest that 2-vinylpyridine is formed from 2-ethylpyridine in situ by copper-promoted C(sp3)-H hydroxylation, followed by dehydration. Thereafter, Rh(III)-catalyzed pyridine-directed vinylic C(sp2)-H activation and annulation with diphenylacetylene provided the substituted quinolizinium salt.451
1.1.1 Chemical Reactivity 1. Electrophilic substitution reactions: Electron localization energies calculated by Acheson and Goodall452 suggest that quinolizinium salts are unreactive toward electrophilic attack. However, bromination is an exception;
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bromine first reacts with quinolizinium bromide in a reversible process to form perbromide, which under drastic SEAr conditions leads to the generation of 1-bromoquinolizinium bromide.453
However, 1- and 2-hydroxyquinolizinium salts readily undergo bromination as well as nitration. This is because they behave as typical phenols. It is for this reason that 2-hydroxyquinolizinium salts behave as strong acids and readily lose their proton to give 2-quinolizone.
It has been observed that the hydroxyl group present at the 1-position directs the incoming group to the 2 -position, whereas the hydroxyl group present at the 2-position directs the incoming group to the 1-position. A bromo derivative in better yield is obtained when bromination is carried out with bromine in hydrobromic acid.454
Nitration with nitric acid yielded 2-nitrated betaine.
The 4-hydroxyquinolizinium ion, which exists in equilibrium with quinolizin-4-one, in its most stable tautomeric form on nitration with nitric acid in acetic acid yields a 1,3-dinitro derivative. However, when nitration is carried out with cupric nitrate in acetic anhydride, a mixture of 1-nitro and 3-nitro isomers is obtained.454b
1-Aminoquinolizinium salt on bromination gives a 2-bromo derivative as the major component and a 2,4-dibromo derivative as the minor component.
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2. Nucleophilic substitution reaction: Theoretical calculations suggest that nucleophilic substitution takes place at the 4-position with formation of an intermediate (pseudo base), which under applied reaction conditions undergoes ring opening to form the most stable product.
Reaction of the quinolizinium cation with nucleophiles like secondary amines and aminodienes has been reported. On reaction with piperidine, ring opening takes place yielding trans-1-piperidinyl-4-(2-pyridyl)butadiene.455
Reaction of methyl magnesium bromide with quinolizinium salt leads to the generation of 1-methyl-4-(2-pyridyl)1,3-butadiene in good yield. The ring-opening reaction is thought to proceed via a 4-substituted-4H-quinolizine derivative. Reaction of phenyl magnesium bromide, however, leads to the generation of cis- and trans-isomers.456
Some halogen-substituted quinolizinium ions readily undergo nucleophilic substitution reaction. 4-Chloroquinolizinium salt on reaction with sodium sulfide yields the thione derivative and with sodium malonic ester delivers an ester derivative.
3. Reaction with reducing agents: Quinolizinium iodide is completely hydrogenated in the presence of Adam’s catalyst yielding quinozilidine iodide.
Reduction of quinolizinium bromide with lithium aluminum hydride and sodium borohydride in THF causes ring-opening reactions leading to the generation of different pyridine derivatives. The hydride reduction is thought to proceed by ring-opening reaction of 4H-quinolizine.457
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However, reduction of quinolizinium bromide with sodium borohydride in ethanol resulted in formation of a mixture of reduced quinolizine derivatives.
4. Sonogashira reaction: Sonogashira is a cross-coupling reaction between aryl or vinyl halide with terminal alkyne in the presence of a palladium catalyst leading to the formation of a carbon-carbon bond.458 The first example of the Sonogashira reaction on heteroaromatic cations involves reaction between 2-bromoquinolizinium bromide and triisopropylsilylacetylene in the presence of palladium catalyst leading to the generation of a 2-ethynyl quinolizinium derivative.459
5. Stille coupling reaction: This is also known as the Migita-Kosugi-Stille reaction, and involves coupling between organotin compounds (known as organostannanes) and a variety of organic electrophiles in the presence of a palladium catalyst.460 The first application of the Stille reaction on heteroaromatic cations involves a reaction of bromoquinolizinium salts with various tributylstannyl compounds in the presence of palladium catalyst yielding different substituted quinolizinium salts.461
2.4 SIX-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH TWO AND MORE NITROGEN ATOMS 2.4.1 Diazines Diazines are six-membered, aromatic, heterocyclic compounds that contain two sp2-hybridized nitrogen atoms in the ring. There are three isomers of diazines: pyridazine (1,2-diazine), pyrimidine (1,3-diazine), and pyrazine (1,4diazine). All three isomers are colorless compounds readily soluble in water.
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There are four types of bicyclic variants of these diazenes in which a benzene ring is fused to the diazine moiety. These bicyclic diazines, commonly called the benzodiazines, are still known by their trivial names and are designated as cinnoline (benzo[c]pyridazine), phthalazine (benzo[d]pyridazine), quinazoline (benzo[d]pyrimidine), and quinoxaline (benzo[e]pyrazine).
2.4.2 Pyridazine
Pyridazine, one of the three isomeric diazines, has two nitrogen atoms present at adjacent positions to each other; hence it is also known as orthodiazine. This ring system is rarely found in any natural product and the first natural product containing this nucleus was reported only after 1970. Historically, pyridazine was first named by Knorr, while Fisher was the first to synthesize the substituted pyridazine; however, it was Tauber who first synthesized the unsubstituted pyridazine.462 Structural and Reactivity Aspects463 Pyridazine has been considered to be a resonance hybrid of two Kekulé structures (I and II). Both the structures are nonequivalent. However, structure II makes a greater contribution to the resonance hybrid.
Resonance structures of pyridazine.
Pyridazine being a 6π heteroaromatic diazine is electron deficient due to the inductive effect of nitrogen atoms that induces a partial positive charge on carbon atoms. The π electron density in pyridazine in comparison to pyridine is consistent with the observed lower reactivity toward electrophiles compared to nucleophiles.
Calculated π electron density of pyridazine as compared to pyridine.
Based on X-ray diffraction, gas-phase electron diffraction, and microwave spectroscopic studies, pyridazine has a planar slightly distorted hexagonal geometry.464 The bond length and bond angles are shown in the following figure.
Bond lengths and bond angles of pyridazine.
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The 1H and 13C NMR data of pyridazine confirm it to be a 6π heteroaromatic system. H and 13C NMR spectral data of pyridazine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-3, 9.17; H-4, 7.52; H-5, 7.52; H-6, 9.17
C-3, 153.00; C-4, 130.00; C-5, 130.3; C-6, 153.00
In comparison to pyridine, the presence of additional nitrogen in pyridazine is responsible for the downfield shift of ring protons and carbons at the 3- and 6-positions in the 1H and 13C NMR, respectively. The UV spectrum of pyridazine shows two bands at 241 nm (log ε 3.02) and 340 nm (log ε 2.26). The first band is due to π→π* transition, whereas the second band at a longer wavelength is due to n→π* transition. The n→π* transitions are usually very weak, but in pyridazine, since the two nitrogen atoms are present at two adjacent positions, this transition of pyridazine is comparatively stronger in comparison to its other two isomers. The mass spectrum of pyridazine has been reviewed. It displays the fragmentation mode of M—N2-H2.
Mass fragmentation pattern of pyridazine.
Importance in Natural Products, Medicines, and Materials465 Pyridazine has been considered by GlaxoSmithKline as one of the most developable heteroaromatic rings in drug design.466 Though examples of natural products containing the pyridazine nucleus are very few, this nucleus has proved to be a useful ligand for different targets and has a privileged structure for drug discovery. Some of the natural products containing this nucleus are quaternary salt, pyridazinomycin, an antifungal and antibiotic isolated from Streptomyces violaceoniger sp. griseofucus,467 azamerone isolated from marine sediment-derived bacterium Streptomyces sp. CNQ-766,468 antrimycin isolated from Streptomyces xanthocidicus MG-125-CF1, which shows activity in vitro against Mycobacterium smegmatis and Mycobacterium tuberculosis,469 and cirratiomycin isolated from Streptomyces cirratus 248-Sq2, which is active in vitro against a narrow range of lactobacilli and some strains of Streptococcus.470
Biologically active natural products containing pyridazine skeleton.
Pyridazine is structurally important because this nucleus is present in a large number of drugs, which offer a broad range of agrochemicals and pharmacological agents. For example, a number of herbicides like credazine, pyridafol, and pyridate contain this nucleus.
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Herbicide containing pyridazine nucleus.
In addition, this nucleus is found within the structures of a number of pharmaceuticals and clinically used drugs like cadralazine, minaprine, pipofezine, hydralazine, moxiraparine, and lodaxaprine.
Drugs containing pyridazine skeleton.
An interesting aspect of pyridazines is that they increase the water solubility of a lipophilic drug. For example, if the phenyl ring of diazepam is replaced by an isosteric pyridazine ring, about a two-unit decrease in the log P is observed.
Increase in water solubility of lipophilic drug due to presence of pyridazine.
A number of drug molecules contain basic functions and as free bases are not fit for industrial production because the free bases are often oily, low melting, not very stable, become colored on oxidation, and are also not very water soluble. However, when a pyridazine nucleus is present in the molecule, salt formation becomes possible, yielding colorless water-soluble crystalline salt.
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Synthesis 1. From maleic anhydride: Maleic anhydride or its derivative on reaction with hydrazine gives maleic hydrazide, which on reaction with phosphorous oxychloride is converted to 3,6-dichloropyridazine. The halogenated derivative on dehalogenation with hydrogen over Pd/C yields pyridazine.471
Dialkyl pyridazines were also synthesized by reaction of appropriately substituted maleic anhydride with hydrazine in benzene solution.472
2. From γ-ketoacid: γ-Ketoacid on reaction with hydrazine yields a cyclic carboxylic acid derivative, which on decarboxylation followed by reaction with phosphorous oxychloride yields 3-chloropyridazine. Dehalogenation with hydrogen over Pd/C yields pyridazine.
3. Cyclocondensation reaction of saturated 1,4-dicarbonyl compound with hydrazine, semicarbazide, or similar hydrazine derivative in the presence of mineral acid yields pyridazines.
6-Substituted pyridazine-3-(2H)-one was synthesized by cyclocondensation of γ-ketocarboxylic acid with hydrazine followed by dehydrogenation of the dihydrocompound.473
Unsaturated 1,4-dicarbonyls also undergo cyclization with hydrazine to yield alkylated/arylated pyridazine.474 The (Z) alkenyl diketone reacts readily with ethanolic hydrazine hydrate at room temperature to yield a pyridazine derivative; however, reaction with (E) isomer produces pyridazine at elevated temperatures.475
4. Schmidt-Druey synthesis: A one-pot synthetic procedure that allows condensation of 1,2-diketones, α-methylene ester, and hydrazine led to the formation of pyridazin-3(2H)-one.476
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5. [4 + 2] cycloaddition reaction of tetrazines with alkynes: Tetrazines due to the presence of four electronwithdrawing nitrogen atoms in the ring are commonly used as azadiene in [4+2] cycloaddition reactions. 1,2,4,5-Tetrazine reacts with electron-rich dienophile to produce the pyridazine derivative. This inverse electrondemanding Diels-Alder reaction proceeds via a bridged intermediate, which after loss of nitrogen yields the desired pyridazine.477
Similarly, cycloaddition reaction of 1,2,4,5-tetrazine with alkynylboronate ester yielded boronic ester, which undergoes a Suzuki coupling reaction to generate a pyridazine derivative.478, 479
Thiophene S,S-dioxides substituted with bulky groups at the 3- and 4-positions undergo Diels-Alder addition with N-phenyltriazolinedione to give an adduct, which on hydrolysis is converted to a 4,5-substituted pyridazine derivative.480
6. Ring enlargement reaction: Furan derivatives are transformed into pyridazines in two steps. In the first step, furan is converted to 2,5-dialkoxy-2,5-dihydrofuran by oxidative addition of 2 mol of alcohol, followed by acidpromoted ring expansion in the presence of hydrazine.481
7. From ketazine dianion: The dianions of alkyl aryl ketazines generated by treating alkyl aryl ketazines with 2 equivalents of lithium diisopropylamide rearrange to pyrrole/tetrahydropyridazine/pyrazole depending on the type of ketazine. Ketazine dianions without substituents on the carbon termini (acetophenone azine) or with electron-withdrawing substituents rearrange to tetrahydropyridazine.482
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Dibromocyclopropene undergoes a 1,3-dipolar cycloaddition reaction with α-diazoester leading to the formation of unstable cyclopropane-fused pyrazolines, which after loss of hydrogen halide readily rearranges to pyridazines.483
8. From 1,2-diazepines: Pyridazines can be obtained by contraction of 1,2-diazepines. The C-5 carbon of diazepine on halogenation followed by dehydrohalogenation leads to the generation of a diazonorcaradiene intermediate, which rearranges to pyridazine.484
9. Diaza-Wittig reaction: A simple and safe method for the synthesis of substituted pyridazine from 1,3-diketones involving a diaza-Wittig reaction as the key step has been reported. The process involves reaction of methyl acetoacetate with p-acetamidobenzene- sulfonyl azide (p-ABSA) in acetonitrile to yield α-diazo-β-ketoester, which in the presence of titanium tetrachloride is converted to aldol on reaction with aldehyde. Mild oxidation of aldol with 1-hydroxy-1,2-benziodoxol-3(1H)-one-1-oxide (IBX) followed by diaza-Wittig reaction with hexamethyl phosphorous triamide (HMPT) affords pyridazine in good yield.485
Physical Properties At room temperature, pyridazine is a colorless liquid with a pyridine-like odor, bp of 208°C (mp ‑8°C), density d423.5= 1.1035, and surface tension 50.15 dynes/cm2 at 0°C. A high boiling point indicates the involvement of intermolecular association. Pyridazine possesses a high dipole moment (3.9 D). This abnormal high dipole moment is because the two nitrogen lone pairs are located on the same side of the ring. As a result, there is a greater pull of electrons on that side, resulting in high dipole moment. Chemical Reactivity 1. Quaternization: Pyridazine reacts with alkyl halide or dialkyl sulfates in the presence of a base to yield monoquaternary salt. The position of alkylation is determined by the presence of the alkyl group on the ring. For example, in 3-methylpyridazine the alkylation takes place mainly at N-1, although N-2 is more electron rich. Similarly, in 3-methoxy-6-methylpyridazine the N-1 is alkylated.486
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Pyridazine functionalized at the nitrogen position to form NO, NN, and NC bonds results in activation of the C-3-position, which reacts further to yield more complex heterocycles. Thus pyridazine on reaction with an aqueous solution of hydroxylamine sulfonic acid (HOSA), potassium iodide, and potassium hydrogen carbonate yields the aminated pyridazine. Subsequent [3+2] cycloaddition with butyne-2-one generates pyrazolol[1,5-b]pyridazine in two steps. This compound has been used as a cyclin-dependent kinase inhibitor for the treatment of solid tumors.487
2. Reaction with nucleophilic reagents: The introduction of the second nitrogen into the pyridine results in diazines reacting with alkyl- and aryllithium compounds to form a stable dihydro adduct. These dihydro adducts can readily be transformed into corresponding substitution products. Pyridazine readily reacts with butyllithium to give a C-3 substitution product.
3-Substituted pyridazine-1-oxide adds cyanide (as KCN or (CH3)3SiCN) in the 6-position in the presence of acylating agent (Reissert reaction).
Direct introduction of organic perfluoro moiety in pyridazine involves nucleophilic addition of perfluoroalkyllithium reagent (generated in situ from perfluoroalkyl iodides, methyllithium, and lithium bromide complex) leading to the formation of dihydropyridazine adduct (tetrahydropyridazine is also formed as a by-product), which is quantitatively oxidized in air to corresponding 3-perfluoroalkylpyridazine.488
Reaction of pyridazine with lithium 2,2,6,6-tetramethylpiperidinide (LTMP) metalates the C-3-position. Coupling of benzaldehyde with the lithiated pyridazine yields the pyridazine benzyl alcohol derivative.489
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Reaction of Weinreb amide with lithiated pyridazine led to the synthesis of long chain α-ketopyridazines, a class of potent inhibitors of fatty acid amide hydrolyase.489
Other metals like zinc, aluminum, copper, and manganese have been used for metalation but it was observed that deprotonative cadmium leads to improved regioselectivity and efficiency.489
C-4 of pyridazine can also be functionalized by using a nonmetallic phosphagene base in place of LTMP. This reaction is highly C-4 regioselective and efficient. The process involves reaction of pyridazine with benzophenone in the presence of a phosphagene base and zinc iodide.
C-4 regioselective arylation of pyridazine is achieved by using a copper catalytic system (copper iodide/phenanthroline in a 1:1 ratio) in combination with hindered lithium triethylcarboxide in dimethylformamide (DMF).
Chichibabin reaction of diazines is quite uncommon due to reduced aromaticity of the diazine π system. However, the initial step is quite easy leading to the generation of a dihydro product, which can be oxidized in situ with potassium permanganate yielding 4-aminopyridazine.490
3. Oxidation: Nitrogen of the pyridazine is oxidized by reaction with m-CPBA in dichloromethane. This oxidation product, which is activated at C-3, reacts with excess aryl bromide to undergo regioselective CH arylation in the presence of palladium acetate and tri-tert-butylphosphine.489
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2. Six-Membered Heterocycles
Pyridazine on reaction with peracid forms 1-oxide, which can then be made to undergo different substitution reactions.
4. Reduction: Pyridazine on reduction under pressure in the presence of a catalytic amount of platinum(IV) oxide in ethanol followed by treatment with ethanolic-HCl led to yield 1,2-dihydropyridazine salt.489
3,6-Dimethylpyridazine is reduced to a hexahydro derivative on reaction with sodium and alcohol.
Pyridazine is also reduced by nickel-aluminum alloy in sodium hydroxide/potassium solution to diamines.491
Partial reduction of pyridazine was achieved by treating it with benzylchloroformate and sodium cyanoborohydride in methanol at room temperature, which gave a mixture of products.492
5. Free radical reaction: 4-Isopropylpyridazine is formed predominantly in 10:1 regioselective ratio when pyridazine is stirred in the presence of tert-butylperoxide and bis(((isopropyl)sulfinyl)oxy)zinc (IPS) that act as an i-Pr radical donor.
6. Carboxylation: C-4 Carboxylation of pyridazine is achieved by treating it with carbon dioxide in the presence of [(I-t-Bu)AuOH] (I-t-Bu = 1,3-(di-tert-butylimidazol-2-ylidene) and potassium hydroxide in THF.
7. Cycloaddition: Pyridazine underwent a cycloaddition reaction with resublimed maleic anhydride in dry chloroform to yield a 1:2 adduct, which was assigned the analogous structure 1,2,3,4-tetrahydro-[1,2-b]pyridopyridazine-1,2,3,4-tetracarboxylic bis anhydride.493
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Benzonitrile oxide generated in situ undergoes a cycloaddition reaction with pyridazine to yield monocyclo adduct (A), which on standing in solvent in the presence of air undergoes slow autoxidation to afford pyridazinone. The monocyclo adduct (A), which is still reactive toward benzonitrile oxide on exposure to excess benzonitrile oxide, affords the bis-cycloadduct (B).494
Pyridazine undergoes Diels-Alder reaction with 2-methylene-imadazolidine. The Diels-Alder product loses nitrogen followed by ring aromatization to yield N,N′dimethyl-N-phenyl-1,2-ethanediamine.
8. Thermal and photochemical reaction: Pyridazine is converted to pyrimidine on heating to 300°C probably via a diazabenzvalene intermediate. However, photolysis of pyridazine yields mainly pyrazine probably via a transient intermediate similar to Dewar benzene.
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2. Six-Membered Heterocycles
2.4.3 Pyrimidine
Pyrimidine is one of the three diazines containing two nitrogen atoms at 1- and 3-positions of the six-memebered aromatic heterocycle, hence it is also known as 1,3-diazabenzene, but pyrimidine is still the accepted IUPAC name. Structural and Reactivity Aspects495a In comparison to pyridine (pKa 5.2), pyrimidine is weakly basic (pKa 1.3). The decreased basicity of pyrimidine is due to the electron-withdrawing effect of the second nitrogen atom present in the ring. Pyrimidine being an aromatic compound can be represented as a resonance hybrid of a number of canonical structures.
Resonating structures of pyrimidine.
Pyrimidine is less aromatic compared to pyridine and benzene and this is because the resonance energy of pyrimidine (26 kcal/mol, 110 kJ mol−1) is comparatively less than benzene (36 kcal/mol, 150 kJ mol−1) and pyridine (31 kcal/mol, 117 kJ mol−1). The structure of pyrimidine has been determined by X-ray crystallography. It has a planar, slightly distorted hexagonal geometry. The crystal is orthorhombic P n a 21, with each unit cell consisting of four pyrimidine molecules. Pyrimidine is aromatic in character, and based on X-ray diffraction, gas-phase electron diffraction, and microwave studies the bond length and bond angles are very close to those of benzene.
Bond lengths and bond angles of pyrimidine.
The 1H and 13C NMR spectrum of pyrimidine is similar to pyridine, except that the presence of additional nitrogen in pyrimidine is responsible for the downfield shift of ring protons and carbon atoms at the 2-, 4-, and 6-positions. H and 13C NMR spectral data of pyrimidine
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 9.26; H-4, 8.78; H-5, 7.35; H-6, 8.78
C-2, 158.4; C-4, 156.9; C-5, 121.9; C-6, 156.9
The UV spectrum of pyrimidine shows three bands at 228 nm (log ε 3.48), 243 nm (log ε 3.50), and 272 nm (log ε 2.62). The first two bands are due to π→π* transition, whereas the third band at a longer wavelength is due to n→π* transition. Importance in Natural Products, Medicines, and Materials Heterocycles containing pyrimidine are of great interest because they constitute an important class of natural as well as synthetic products because many of their derivatives not only exhibit useful biological activities but are clinically very important. The three nucleobases, thymine, cytosine, and uracil, which are essential building blocks of nucleic acids DNA and RNA, all contain pyrimidine derivatives. The pyrimidine ring is also present in vitamins like riboflavin, thiamine, and folic acid, which are important growth factors for the human body.
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Nucleobases and vitamins containing pyrimidine nucleus.
In medicinal chemistry, pyrimidine derivatives are well known for their therapeutic importance. Many pyrimidine derivatives have been developed as chemotherapeutic agents and are being widely used. The barbituric acid derivative veranal is used as a hypnotic. The most potent drug Viagra, which has been used for male impotence, is precisely a pyrimidine derivative. It is the drug used to treat erectile dysfunction and pulmonary arterial hypertension. Zidovudine, also known as azidothymidine, a nucleoside analog, is an antiretroviral drug used for the successful treatment of HIV/ AIDS infections. Imatinib is a chemotherapeutic drug that is used to slow down or stop the growth of cancer cells.
Drugs containing pyrimidine nucleus.
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2. Six-Membered Heterocycles
Synthesis 1. From malonic esters: Condensation between malonic esters and urea in the presence of a base led to the formation of barbituric acid.495b
Barbituric acid on treatment with phosphorous oxychloride yields 2,4,6-trichloropyrimidine, which on reduction with zinc dust and water yields pyrimidine.496
The yield of pyrimidine from the foregoing method was not very successful. However, pyrimidine in better yield was obtained by carrying out reduction of 2,5-dichloropyrimidine with hydrogen and palladium barium sulfate in the presence of magnesium oxide.
If the reaction is stopped after 2 mol of hydrogen have been absorbed, then pyrimidine can be isolated. However, if the reduction process is allowed to proceed, then 1,2,3,4-tetrahydropyrimidine is isolated.497 Instead of malonic ester, malic acid has also been used for the synthesis of pyrimidine. Decarboxylation of malic acid with concentrated sulfuric acid yields α-formyl acetic acid, which on reaction with urea gives uracil.498 This on reaction with phosphorous oxychloride in dimethylaniline results in the formation of dichloropyrimidine, which is reduced to pyrimidine.
A convenient synthesis of pyrimidine is by the reaction of 1,1,3,3-tetraethoxypropane with formamide.
2. Bredereck synthesis: Bredereck first synthesized 4,6-disubstituted pyrimidines by reacting β-diketones or βiminoketones with formamide.499
A few years later a more direct route to pyrimidine 4-carbaldehyde was put forth by Bredereck et al.500. In this method, vinylogous amide obtained by a reaction of pyruvaldehyde-dimethylacetal and dimethylformamide acetal
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137
was treated with formamidine to give pyrimidine acetal, which on treatment with dilute sulfuric acid afforded pyrimidine 4-aldehyde.
Bredereck improved upon his own procedure and synthesized pyrimidine in one step. The one-step procedure is simpler and easier than the three-step procedure used in the past. The process involves heating formamide at higher temperatures with 4,4-dimethoxyl-2-butanone.501
3. Pinner pyrimidine synthesis: This reaction involves the condensation of 1,3-dicarbonyl compounds with amidines in the presence of acid or base to yield pyrimidine derivatives.502
The mechanism of the reaction was studied by Katritzky et al. and they proposed the following mechanism for the condensation of methyl acetoacetate with acetamidine.503
4. Remfry-Hull synthesis: This is the condensation of α-butylmalondiamide with ethyl formate in ethanolic sodium hydroxide to yield 5-butyl-6-hydroxypyrimidin-4(3H)-one.504
The Remfry-Hull synthesis of 4,6-dihydroxypyrimidine from malondiamides and esters is modified to permit inclusion of an alkylamino group in position 5 or an alkyl group in position 2. Malondiamide reacts with formamide to give 4,6-dihydroxypyrimidine.505
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2. Six-Membered Heterocycles
5. Traube synthesis: The reaction named after Wilhelm Traube is in fact used for the synthesis of purines. The first step of the reaction involves the synthesis of pyrimidine, which is then converted to purine. Pyrimidine synthesis involves a reaction between guanidine hydrochloride with cyanoacetic ester in the presence of sodium ethoxide.506
A modification of Traube’s procedure was carried out and instead of 2,6-diamino-4-oxopyrimidine, 2,4-diamino- 6-hydroxypyrimidine was obtained.507
Hydroxy derivatives of pyrimidine were also synthesized by treating ethyl acetoacetate with thiourea yielding 2-thio-6-methyluracil, which was desulfurized with aqueous ammonia and Raney nickel catalyst to yield 4-methyl-6-hydroxypyrimidine.508
6. Biginelli synthesis: This is a multicomponent reaction between ethyl acetoacetate, aryl aldehyde, and urea leading to the formation of 3,4-dihydropyrimidin-2-(1H)-one.509 The reaction is catalyzed by Brönsted acid or Lewis acid.
A new one-pot synthesis of Biginelli 3,4-dihydropyrimidine derivatives under planetary ball milling, solvent-free and catalyst-free conditions has been reported.510 There are number of modifications that have been proposed for the traditional Biginelli reaction, but most of them lack the experimental and conceptual simplicity of the Biginelli reaction. However, there is one noticeable exception, called the Atwal modification of the Biginelli reaction.511
7. 4,5-Disubstituted pyrimidines are biologically active and they have been used as precious intermediates in drug discovery. Zinc chloride-catalyzed, three-component coupling reaction between variety of functionalized enamines, triethylorthoformate and ammonium acetate, led to the generation of mono- and disubstituted pyrimidines.512
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8. A simple high-yielding synthesis of pyrimidines from ketones in the presence of hexamethyldisilazane (HMDS) and formamide under microwave conditions has been described.513
9. Intermolecular cycloaddition reaction of alkynes (terminal or internal) with aryl nitriles in the presence of an NbCl5 complex yielded substituted pyrimidine with excellent chemo- and regioselectivity.514
Trimerization of acetonitrile in the presence of potassium methoxide yields 4-amino-2.6-dimethylpyrimidine.515
1,3,5-Triazines on reaction with electron-rich dienophiles yield pyrimidines.516
10. A novel three-component condensation reaction between functionalized enamine, triethylorthoformate and ammonium acetate in the presence of zinc chloride produces 4,5-disubstituted pyrimidine in moderate yield in a single step.517
A novel three-component condensation reaction between an aromatic aldehyde, ketone, and guanidine carbonate under solvent-free conditions led to the synthesis of 2-amino-4,6-diarylpyrimidine in good yield.518
11. Reaction of triflic anhydride with ketones in the presence of nitriles offers an improved method for the synthesis of pyrimidines. The reaction between ketone and tiflic anhydride generated (triflyloxy)carbonium ion, which is easily trapped by the nitrile by nucleophilic attack to give pyrimidines.519
140
2. Six-Membered Heterocycles
12. Reaction of α,β-unsaturated trifluoromethyl ketones with amidines in acetonitrile gave the corresponding 4-hydroxy-4-(trifluoromethyl)-3,5,6-trihydroxypyrimidines, followed by successive dehydration with phosphorous oxychloride-pyridine-silica gel, and oxidation with manganese(IV) oxide yielded 2,6-disubstituted 4-(trifluoromethyl)pyrimidines in excellent yield.520
Physical Properties Pyrimidine is a colorless, low-melting, hygroscopic solid with mp of 21°C (bp 123°C) and density d423.5= 1.529 g/cc. It is easily soluble in water. Chemical Reactivity 1. Quaternization: Pyrimidine reacts with alkyl halide to yield monoquaternary salt. Dialkylation is carried out with reactive electrophiles like Meerwein’s salt ([Et3O]BF4).521
2. Electrophilic substitution reaction: Due to the presence of two nitrogen atoms, electron density on all carbon atoms is reduced; as a result, electrophilic substitution reaction on pyrimidine takes place only under drastic conditions. However, the presence of an electron-donating group facilitates substitution reaction, probably by the addition-elimination pathway. Monoquaternary salt of pyrimidine undergoes bromination by heating it in nitrobenzene at 130°C.522, 523
Unsubstituted pyrimidine is unable to undergo nitration; however, the presence of two electron-releasing groups makes nitration of pyrimidine relatively easier. Thus 2,4-dihydroxy-6-methylpyrimidine undergoes nitration quite easily.
Similarly, halogenation is also carried out in the presence of electron-donating groups. However, sometimes a dihalo product is also formed.
3. Oxidation: Pyrimidine on reaction with peracid gives a poor yield of N-oxide.524 However, alkylpyrimidines give a satisfactory yield of an N-oxide derivative.
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4. Nucleophilic reaction: In pyrimidine, nucleophilic attack may take place at 2-, 4-, or 6-positions forming a dihydro product, which on oxidation yields the substituted pyrimidine derivative.
Nucleophilic attack in pyrimidines with organolithium compounds takes place at C-4 to give an adduct, which is readily aromatized on treatment with potassium permanganate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.525, 526
Phenylmagnesium bromide readily adds to the C-4 carbon of pyrimidine to form an intermediate, which on hydrolysis yields dihydropyrimidine. Oxidation of dihydropyrimidine with KMnO4 in acetone yields 4-phenylpyrimidine.527
Nucleophilic substitution reaction at the C-2 position is rare, but when the C-4 position is occupied, then reaction takes place at C-2. For example, reaction of 4,6-dichloropyrimidine with allyllithium yields 2-allyl-substituted pyrimidine as the exclusive product.528
Similarly, 2-chloropyrimidine does not undergo nucleophilic substitution at the halogenated carbon, instead a halogen-retained product is obtained with the new substituent at position C-4.529
5-Bromopyrimidine reacts with lithium diisopropylamide to yield 5-bromo-4-lithiopyrimidine, which reacts with the second molecule of 5-bromopyrimidine to give a dimer, which undergoes aromatization to form bipyrimidine.530
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2. Six-Membered Heterocycles
An amination reaction of 2-chloro-4-phenylpyrimidine with potassium amide in liquid ammonia gives 4-amino- 4-phenylpyrimidine. Although it appears to be an addition-elimination process, isotopic labeling experiments revealed that nucleophilic ring-opening/ring-closure mechanism was involved.531
Pyrimidine on reaction with hydrazine is rearranged to pyrazole by the following mechanism.532
5. Gomberg-Hey reaction: Reaction of pyrimidine with diazotized p-nitroaniline yielded 2-p-nitrophenylpyrimidine and 4-p-nitrophenylpyrimidine. The reaction was thought to proceed by a free radical mechanism.533
6. Reduction: Pyrimidine is reduced by nickel-aluminum alloy in sodium hydroxide-potassium hydroxide solution to diamines.534
Partial reduction of pyrimidine was achieved by treating it with benzylchloroformate and sodium cyanoborohydride in methanol at room temperature.535
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7. Cycloaddition: [4+2] Cycloaddition reaction of pyrimidine with electron-rich alkynes takes place to yield regioselective-substituted pyridine products via loss of hydrogen cyanide.536
Benzonitrile oxide generated in situ undergoes a cycloaddition reaction with pyrimidine to yield biscyclo adduct (A) and triscyclo adduct (B).537
8. Dimroth rearrangement: A rearrangement reaction takes place in certain 1-alkyl-2-iminopyrimidines, where endocyclic and exocyclic nitrogen atoms switch places.
9. Hilbert-Johnson reaction: Reaction of 2,4-dialkoxypyrimidines with protected glycosyl halides yields pyrimidine nucleosides.
2.4.4 Pyrazine
Pyrazine, also known as 1,4-diazine, is a symmetrical six-membered aromatic heterocyclic compound that contains two nitrogen atoms at the 1- and 4-positions.
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2. Six-Membered Heterocycles
Structural and Reactivity Aspects The complete structure of pyrazine has been determined by X-ray analysis and electron diffraction studies.538 From X-ray analysis it has been proved that the ring is a planar hexagon with D2h symmetry. The CC bond length being similar to those of benzene (1.378 Å) is larger in comparison to the CN bond length. The ring angle at the heteroatom is smaller than that at the carbon atom. The other bond lengths and bond angles are shown in the following diagram.
Bond lengths and bond angles of pyrazine.
The symmetrical structure of 1,4-diazine is reflected in the 1H and 13C NMR spectra (in CDCl3) with one signal for the ring proton (δ 8.590) and one for the ring carbon atom (δ 145.9). The UV spectrum of pyrazine shows three bands at 261 nm (log ε 3.87), 267 nm (log ε 3.72), and 301 nm (log ε 2.88). The first two bands are due to π→π* transition, whereas the third band at a longer wavelength is due to n→π* transition. Importance in Natural Products, Medicines, and Materials Pyrazines are present in heat-processed food such as beef products, toasted barley, cocoa, coffee, peanuts, potato chips as well as in fresh foods like tomatoes, peas, green bell peppers, etc. Pyrazines are thought to arise by spontaneous heat-induced condensation between amino acids and sugars through Strecker’s degradation. A number of natural products containing this nucleus have been isolated. For instance, clavulazine isolated from Okinawa soft coral Clauvlaria viridis, botryllazine A from the red ascidian Botryllus leachi, and barrenazine from unidentified tunicate collected from Madagascar.539–541
Natural products containing pyrazine nucleus.
This nucleus is responsible for the flavor and pleasant aroma of a number of foodstuffs.542 Pyrazines have also shown interesting anti-HIV, antitubercular, and antibacterial activities. Pyrazines have also been used as pharmaceutical intermediates, for example, 2-methylpyrazine has been used for the synthesis of the antitubercular drug pyrazinamide. Pyrazinamide, itself a pyrazine derivative, along with rifampin and ethambutol, constitute first-line drugs for tuberculosis therapy. Besides pyrazinamide, a number of other pharmaceuticals with a pyrazine nucleus have shown numerous physiological effects, such as anti-HIV (oltipraz), proteasome inhibitor (bortezomib), narcotic addiction (varenceline), fungal antibiotic (aspergillic acid), pulmonary heart disease (ligustrazine), hypnotic (eszopiclone [Lunesta]), and eye drops for glaucoma or ocular hypertension (brimonidine).
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Food additive and drugs containing pyrazine nucleus.
Synthesis 1. Staedel-Rugheimer synthesis: The first synthesis of pyrazine from aminoketone was reported in 1876 by StaedelRugheimer. The process involves self-condensation of amino ketones followed by oxidation, which yields pyrazine.543 Amino ketone was, however, synthesized by the heating of 2-chloroacetophenonone and ammonia in an autoclave.
2. Gutknecht pyrazine synthesis: This reaction is a variation of Staedel-Rugheimer synthesis. The reaction involves treatment of ketone with nitrous acid from an oximino ketone followed by reduction to α-amino ketone, which dimerizes to dihydropyrazine via a pinacol-type process. The dihydropyrazine is then oxidized to pyrazine. The overall process of conversion of ketone to pyrazine is referred to as Gutknecht condensation.544
3. Catalytic dehydrogenation of ethanolamine in the presence copper, copper and zinc oxide, or zinc oxide and sodium carbonate at 250–300°C yields pyrazine.545
4. Deaminocyclization of ethylenediamine followed by dehydrogenation over copper chromite results in the formation of pyrazine.546
5. [4 + 2] condensation: Pyrazine is manufactured by the condensation of glyoxal and ethylenediamine at high temperatures on a copper-chromium oxide catalyst.
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2. Six-Membered Heterocycles
Similarly, alkyl derivatives of pyrazine are synthesized by condensation of ethylenediamine with a 1,2-diketo derivative to yield the intermediate dihydropyrazine. Oxidation to pyrazine is carried out over copper chromite at 300°C.547
6. 2-Methylpyrazine is synthesized by the reaction of ethylenediamine and propylene glycol in the presence of a catalyst system such as copper-chromium, copper-zinc chromium, or zinc-phosphoric acid-manganese.548–550
The reaction is thought to proceed by the following mechanism.551
7. A condensation reaction between ethylene diamine and epoxide in the presence of a copper-chromium oxide catalyst yields pyrazine.552
Pyrazine has been conveniently synthesized by the reaction of ethylenediamine and ethylene oxide in the presence of aluminum oxide and nickel at 400°C.
8. Synthesis of unsubstituted pyrazine was also reported by Wolff and Marburg.553 The process involves heating chloroacetal and ammonia in a sealed tube, whereby diacetylamine was obtained, which on heating with hydrochloric acid yielded 2,6-dihydroxymorpholine. The oxygen of morpholine could be replaced by heating it with hydrazine or hydroxylamine under pressure.
9. Dehydrogenation of piperazine in the presence of a palladium-magnesium chloride-aluminum oxide catalyst yields pyrazine.
10. A simple, cost-effective, and environmentally friendly method for the synthesis of pyrazine derivatives has been reported. The process involves direct condensation between respective 1,2-diketo compounds and 1,2-diamines in aqueous methanol and catalyzed by potassium tert-butoxide at room temperature.554
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11. A novel regioselective method for the synthesis of alkylpyrazines involves condensation of α-oximido carbonyl compound with allylamine. The resulting imine is isomerized in the presence of potassium tert-butoxide to 1-hydroxy-1,4-diazahexatriene. Thermal electrocyclization-aromatization to pyrazine is achieved after O-acylation of the oxime with methyl chloroformate.555
12. Photolysis of vinyl azide in methanol gave a good yield of pyrazine probably via an azirine derivative.556
13. Synthesis of highly substituted pyrazine involving reaction of α-diazo oxime ethers with 2H-azirines in the presence of copper complexes has been reported.557
Physical Properties Pyrazine is a colorless, stable compound mp 54°C, bp 115°C and a zero dipole moment. It is readily soluble in water and sparingly soluble in alcohol and ether. It is a weaker base in comparison to pyridazine or pyrimidine. Chemical Reactivity Pyrazine being an aromatic compound can be represented as a resonance hybrid of a number of canonical structures. Due to the symmetrical nature of the molecule the dipole moment of pyrazine is zero.
Resonating structures of pyrazine.
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2. Six-Membered Heterocycles
From the canonical structures it can be seen that in pyrazine there are electron deficiencies at 2, 3, 5, and 6. Thus these positions can be attacked by nucleophilic reagents. Studies have shown that nucleophilic reagents could attack the ring if there is at least one electron-releasing group like CH3, NH2, OH, etc. already bonded to the ring. 1. Electrophilic substitution reaction: Due to the presence of two nitrogen atoms, electron density on all carbon atoms is reduced; as a result, electrophilic substitution reaction on pyrazine takes place only under drastic conditions. However, the presence of an electron-donating group facilitates substitution reaction, probably by an addition-elimination pathway. Chlorination of 2-methylpyrazine could be carried out under milder conditions.558
Similarly, bromination of 2-aminopyrazine can also be carried out to yield 2-amino-3,5-dibromopyrazine.
Direct bromination of pyrazine is carried out by heating it with HBr and bromine.
2. Nucleophilic substitution reaction: Although pyrazine is more reactive than pyridine toward nucleophiles but Chichibabin reaction is unsatisfactory. However, 2-chloropyrazine on reaction with sodamide in liquid ammonia yields 2-aminopyrazine not by the addition-elimination mechanism but by the ANRORC mechanism.
Due to inductive and resonance effects of nitrogen atoms, the protons bonded to methyl carbon atoms are acidic and thus can easily be removed by a strong base. The resultant carbanion can undergo condensation and alkylation reactions.559, 560
2,3 and 2,6-dichloropyrazines on treatment with lithiodithiane react in the usual manner to yield 2-substituted pyrazine derivatives.561
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3. Reduction: Reduction of pyrazine with sodium and ethanol give piperazine.
Electrochemical reduction of pyrazine on silver electrodes from 1.0 M KBr solution yielded a 1,4-dihydropyrazine cation as the major product.562
Pyrazines are also reduced by nickel-aluminum alloy in sodium hydroxide solution.563 Partial reduction of pyrazine was achieved by treating it with benzylchloroformate and sodium cyanoborohydride in methanol at room temperature, whereby a mixture of products was obtained.564
4. Oxidation: Oxidation of pyrazine with hydrogen peroxide in acetic acid gives pyrazine N-oxide. The monoxide is formed first; however, on heating at higher temperature for a longer period of time with excess hydrogen peroxide, di-N-oxide is obtained.
Alkyl derivatives of pyrazine on reaction with hydrogen peroxide in acetic acid are converted to both mono-Noxide and di-N-oxide, with mono being the major product.565
Besides chemical oxidation, enzymatic oxidation of the alkyl group of pyrazine with bacteria such as Pseudomonas putida has been helpful in the oxidation of 2,5-dimethylpyrazine to its monocarboxylic acid derivative.566
5. Metalation: Ortho-halogen-substituted pyrazine derivatives have been synthesized by treating pyrazine with iodine in the presence of lithium-2,2,6,6-tetramethylpiperidide.
The 2-iodopyridazine formed reacts in the presence of palladium acetate to form a bipyridazine derivative.567
150
2. Six-Membered Heterocycles
6. Replacement of leaving group: Halogen and methoxy-substituted pyrazines react with soft nucleophiles such as amines, thiolate, and malonate anions to give substituted products.568
7. Hydroxycarbonylation: The reaction of pyrazine with oxalic acid monoesters under oxidative conditions led to hydroxycarbonylation.569
8. Cycloaddition: Benzonitrile oxide generated in situ undergoes a cycloaddition reaction with pyrazine to yield two isomeric biscyclo adduct products (A and B) with monocycloadduct as an intermediate.570
2.4.5 Piperazine
Piperazine, also known as 1,4-diazacyclohexane or hexahydro-1,4-diazine, is a six-membered heterocycle with two nitrogen atoms located at the 1- and 4-positions of the ring. Structural and Reactivity Aspects571 Like cyclohexane, piperazine prefers the chair conformation. In the stable chair conformation the NH bond favors the equatorial conformation.572
Conformations of piperazine.
The CC and CN bond lengths are 154.0 and 146.7 ppm, respectively. The CCN and CNC bond angles are 110 and 109 degrees, respectively.
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151
The 1H and 13C NMR spectral data of piperazine are given in the following table. H and 13C NMR spectral data of piperazine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3, 5, 6; 2.84
C-2, 3, 5, 6; 47.9
Importance in Natural Products, Medicine, and Materials Piperazine is an important scaffold that is found in a large number of biologically active compounds. Its amino and alcohol derivatives have considerable application in the preparation of hardeners of epoxy resins, insecticides, urethane catalysts, and antioxidants. Piperazine derivatives have also been developed as carbon dioxide capturing materials.573 A number of drugs available in the market have a piperazine skeleton. For example, cyclizine is used to treat nausea, vomiting, and dizziness, citrizine is a second-generation antihistamine, amoxapine is an antidepressant, and trimetazidine and ranolazine are used to treat angina pectoris.
Drugs containing piperazine nucleus.
Synthesis 1. Self-condensation of ethanolamine in the presence of ammonia at 150–200°C and 100–200 bar pressure yields piperazine.
2. Reaction of oxirane with ethylenediamine yields an intermediate, which cyclizes to piperazine.
3. Piperazine has been synthesized by heating diethylene triamine574 with Raney nickel at 150°C.
4. Selective reduction of pyrazine with isopropanol in the presence of the catalyst [Ir(COD)(NHC)PPh3]BF4 yields piperazine.575
152
2. Six-Membered Heterocycles
5. 2-Phenylpiperazine576 is synthesized by condensation of bromophenyl acetic acid ethyl ester with ethylenediamine followed by reduction of 3-phenylpiperazine-2-one obtained as intermediate with LiAlH4.
Synthesis of 2-phenylpiperazine has also been reported by reaction of oxirane derivative with ethylenediamine.577 6. 1,1-Dimethylpiperazinium salt: Reaction of dimethylamine with N-bis(2-chloroethyl)amine in methanol solution yields 1,1-dimethylpiperazinium chloride.578
7. Diastereoselective carboamination of N1-allyl-N2-aryl-N1-vinyl-propane-1,3-diamine with aryl bromide in the presence of palladium catalyst yields cis-piperazine.579
8. Reaction of N,N′-dimethylethylenediamine with tosylbis(2-(toxyloxy)ethyl)amine in the presence of potassium carbonate yields 1-methyl-4-tosylpiperazine.580
9. Reaction of diethanolamine and methylamine over zeolite yields N-methylpiperazine.581
Physical Properties Piperazine is a white crystalline solid with mp of 106oC, and behaves as a secondary amine. It is freely soluble in water and other protic polar solvents but sparingly soluble in diethyl ether and other nonpolar solvents. Chemical Reactivity 1. Acetylation: Synthesis of 1-acetylpiprazine: Piperazine reacts with acetyl chloride in glacial acetic acid under ultrasonic irradiation in a microreactor at 60°C for 4 min to give 1-acetylpiperazine in excellent yield.582
2. N-Formylation: Reaction of piperazine with chloroform and potassium fluoride on basic alumina in acetonitrile at room temperature for 24 h yields symmetrically 1,4-disubstituted as the major product and Nmonoformylated as the minor product.583
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153
3. Reaction of piperazine with benzyl chloride in ethanol at 65°C yields piperazine dihydrochloride, which on treatment with absolute ethanol and dry hydrogen chloride followed by a reaction with aqueous sodium hydroxide yields 1-benzylpiperazine.584
4. Aroylation: One-step aroylation of piperazine is achieved by treating it with aroyl chloride in glacial acetic acid leading to the synthesis of 1-aroylpiperazine.585
5. Reaction of piperazine with ethyl chlorocarbonate under controlled conditions in aqueous solution gave 1-carbethoxypiperazine, which reacted with alcoholic methyl tosylate to yield 1-carbethoxy-4methylpiperazine.586 The title compound was found useful in the chemotherapy of filariasis.
6. Refluxing piperazine with phthalic anhydride in the presence of 4-dimethylaminopyridine as catalyst in dichloromethane as solvent yields 2-(piperazine-1-yl-carbonyl)benzoic acid.587
7. 1-(Phenylsulfonyl)piperazine was synthesized by the reaction of piperazine with arylsulfonyl chloride588 in dichloromethane at 0°C.
8. The reaction of piperazine with acrylonitrile in a molar ratio of 1:1.2 in the presence of recyclable inexpensive ionic liquid triethylammonium acetate at 25°C yields 3-(piperazine-1-yl)propanenitrile.589
Aza-Michael addition of piperazine onto methyl 2-propenoate in the presence of copper(II) acetylacetonate immobilized in recyclable ionic liquid [(bmim)BF4] afforded 1-(2-methoxycarbonylethyl)piperazine in high yields. However, disubstituted piperazine was also obtained as a minor component.590
154
2. Six-Membered Heterocycles
9. 6-Aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles on reaction with piperazine or substituted piperazine in refluxing ethanol afforded 6-aryl-4-piperazinyl-2H-pyran-2-one-3-carbonitriles, which are used as versatile precursors for ring transformation reactions to construct a variety of heterocycles.591
2.4.6 Cinnoline
Cinnoline is also known as 1,2-diazanaphthalene. It is a benzo-fused derivative of pyridazine. As benzene ring is fused to the 5,6-position of the pyridazine ring, hence it is known as benzo[c]pyridazine. Cinnoline as the parent molecule does not occur in nature; however, this ring system was first discovered by von Richter. Structural and Reactivity Aspects The UV spectrum of cinnoline in ethanol displayed six absorption maxima at λmax 276 nm (log ε 3.45), 286 (log ε 3.42), 308.5 (log ε 3.29), 317 (log ε 3.25), 322.5 (log ε 3.32), and 390 (log ε 2.42). All the absorption maxima are attributed to π→π* transition except for the one at 390 nm, which is due to n→π* transition, due to nonbonding electrons of the ring nitrogen atoms.592 The 1H and 13C NMR data of cinnoline confirm it to be a benzo derivative of pyridazine.593 H and 13C NMR spectal data of cinnoline
1
1 H NMR (acetone d6) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-3, 9.32; H-4, 8.08; H-5, 8.01; H-6, 7.84; H-7, 7.93; H-8, 8.49
C-3, 146.1; C-4, 124.6; C-5, 127.9; C-6, 132.3; C-7, 132.1; C-8, 129.5; C-4a, 126.8, C-8a, 151.0
The 15N NMR chemical shifts of cinnoline (referenced against neat nitromethane) in dimethyl sulfoxide-d6 are 44.6 (N1) and 41.2 (N2), respectively.
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155
Importance in Natural Products, Medicines, and Materials Cinnoline represents a developing branch of organic compounds, which exhibit a wide range of biological activity. These compounds have been reported to possess anticancer,594 fungicidal and bactericidal,595, 596 antituberclular,597 and sedative598 activities. Previously, it was considered that no cinnoline derivative occurs in nature. However, very recently, natural products containing the cinnoline nucleus have been isolated. Schizocommunin has been isolated from cultures of Schizophyllum commune, a basidiomycetous fungus collected from the bronchus of patients suffering from allergenic bronchopulmonary mycosis. Schizocommunin was found to exhibit strong cytotoxicity against murine lymphoma cells. Symmetrical cinnoline 4849F was isolated from the cultures of Streptomyces sp. 4849. Cinnoline 4849F exhibited cytotoxicity against human breast cancer MCF-7 and human ovarian cancer A2780 cell lines. 3-Methylcinnoline and 4-methylcinnoline were analyzed to be present in the volatile fraction of Hibiscus esculentus.599
Natural products containing cinnoline nucleus.
This nucleus is found as a substructure in a number of drugs like cinoxacin and cintazone.
Drugs containing cinnoline nucleus.
Synthesis 1. From cinnoline derivatives: Thermal decarboxylation of cinnoline 4-carboxylic acid in benzophenone at 155– 165°C yields cinnoline as the major product along with 4,4′-dicinnolinyl as the minor constituent.600
Reduction of 4-chlorocinnoline with iron and 15% sulfuric acid yields 1,4-dihydrocinnoline, which on oxidation with mercuric oxide gave cinnoline.
Reduction of 4-hydroxycinnoline with lithium aluminum hydride in refluxing THF, followed by oxidation of partially reduced cinnoline with mercuric oxide, yields cinnoline.601
156
2. Six-Membered Heterocycles
2. From carbohydrates: When d-glucose is heated with an excess of phenylhydrazine in the presence of hydrochloric acid, d-glucose phenylosazone and 1-(3-cinnolinyl)-d-arabinotetritol are obtained. Treatment of a cinnonyl derivative with UV light in aqueous sodium hydroxide solution for 8 h gives cinnoline.602
3. From cyclooctatetraene: Cyclooctatetraene on reaction with bromine gave dibromide derivative, which on reaction with ethyl azodicarboxylate gives an adduct (A), which is debrominated with a Zn/Cu couple to give another adduct (B). Adduct B when heated to 350°C rearranges to 1,2-diethoxycarbonyl-1,2-4a,8atetrahydrocinnoline, which is dehydrogenated by o-chloranil to 1,2-diethoxycarbonyl-1,2-dihydrocinnoline. This dihydro product on alkaline hydrolysis in the presence of activated manganese dioxide yields cinnoline.603, 604
4. Diazotization of amines: Diazotization of o-aminobenzaldehyde followed by coupling with nitromethane in dilute solution gave nitroformaldehyde o-formylphenyl hydrazone, which on cyclization yielded 3-nitrocinnoline.605
5. Von Richter cinnoline synthesis: The reaction named after Von Richter involves thermal cyclization of 2-alkynylbenzenediazonium salts to a 4-hydroxycinnoline derivative.606
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
157
Von Richter transformed diazonium chloride derived from o-aminophenylpropiolic acid into a nitrogenous derivative. This nitrogenous derivative was named cinnoline because of its analogy with quinoline.
The 4-hydroxycinnoline-3-carboxylic acid obtained by the foregoing process can be easily converted to cinnoline. The process involves heating 4-hydroxycinnoline-3-carboxylic acid above its melting point, where carbon dioxide is liberated and 4-hydroxycinnoline is obtained. Distillation of 4-hydroxycinnoline with zinc dust yields cinnoline.
The foregoing synthesized 4-hydroxycinnoline synthesized can also be converted to cinnoline via 4-chlorocinnoline.607
Mechanism: Earlier papers suggested that von Richter reaction proceeds through A pathway.608, 609 However, recent studies suggest that during the reaction, simultaneous attack of the triple bond on the diazo group followed by attack of the halide ion affords halocinnoline, which is then hydrolyzed to yield a 4-hydroxycinnoline derivative (B pathway).610
6. Widman-Stoermer synthesis: Synthesis of 3- and/or 4-alkyl, aryl-substituted cinnolines by cyclization of diazotized o-aminoarylethylenes is accomplished by this method.611, 612
Esters of anthranilic acid on reaction with Grignard reagent followed by dehydration yields o-aminoarylethylenes, which on diazotization followed by cyclization yield 4-methylcinnoline.
158
2. Six-Membered Heterocycles
7. Borsche’s synthesis: Cinnoline has been prepared by standing a diazotized solution of 2-amino-5nitroacetophenone at room temperature overnight, which slowly cyclized to 4-hydroxy-6-nitrocinnoline.613
A modification of the Borsche-Herbert reaction was proposed, where phosphorous ylides of o-aminoacetophenones were used for cyclization.614 8. Stolle-Becker synthesis: The conversion of N-benzylideneaminoisatin in the presence of a base to 3-phenyl-4cinnolinecarboxylic acid is known as Stolle-Becker synthesis.615
However, no chemical/experimental evidence was provided regarding the reaction. Detailed experimental evidence supporting the validity of the Stolle-Becker reaction was provided by Baumgarten et al.616 The process involves reaction of benzaldehyde phenylhydrazone with 100% excess of oxalyl chloride yielding N-benzylideneamino-Nphenyloxamyl chloride, which on treatment with aluminum chloride in chloroform gave N-benzylideneaminoisatin. Treatment of the latter with hot 20% aqueous sodium hydroxide gave 3-phenyl-4-cinnolinecarboxylic acid.
9. Baumgarten synthesis: The yield of a cinnoline derivative by Stolle-Becker synthesis was not very successful. Hence Baumgarten developed a method in which 3-substituted cinnoline was synthesized in good yield. Reaction of a diazotized solution of 2-aminobenzaldehyde with nitromethane yielded nitroformaldehyde 2-formylphenylhydrazone as an intermediate, which cyclized in alkali to produce 3-nitrocinnoline.617
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159
10. Barber’s synthesis: The synthetic approach to cinnoline was described in a British patent by Barber et al.618, 619 The process involves the reaction of benzenediazonium chloride with diethyl malonate and subsequent hydrolysis of the resulting condensation product followed by conversion to acid chloride. The acid chloride cyclized in the presence of titanium tetrachloride yielding 4-hydroxycinnoline-3-carboxylic acid, which was thermally decarboxylated at 205–215°C to hydroxyl cinnoline.
11. Neber-Bossel synthesis: This is a classical method for the formation of 3-hydroxycinnoline via N(2)C(3) bond formation. The process involves diazotization of (2-aminophenyl)hydroxyacetate followed by reduction of the diazonium salt obtained. The reduced product is then cyclized to 3-hydroxycinnoline on boiling with hydrochloric acid.620, 621
Physical Properties Cinnoline crystallizes out from ether as a solvate of colorless needles with mp of 24°C and from ligroin as a pale-yellow crystal with mp of 39°C. It has a quinoline-like odor and is soluble in water and most organic solvents. On exposure to air it liquefies and rapidly turns green. Cinnoline with a pKa value of 2.70 in water at 20°C is a weaker base in comparison to quinoline and isoquinoline. The dipole moment of cinnoline is 4.14 D, slightly lower in comparison to pyridazine (4.32 D). Chemical Reactivity 1. Salt formation: Cinnoline is a strong base and forms stable salts with hydrochloric acid and picric acid. It forms an addition compound with methyl iodide.622 2. Electrophilic substitution reaction: Diazines do not undergo an electrophilic substitution reaction unless electron-donating substituents are present. However, their benzo derivative undergo electrophilic substitution reaction chiefly at 5- and 8-positions. Cinnoline undergoes nitration in the presence of concentrated sulfuric acid yielding a mixture of 5- and 8-nitrocinnoline.623, 624
160
2. Six-Membered Heterocycles
3. Oxidation: When cinnoline is treated with hydrogen peroxide in acetic acid, a mixture of cinnoline 1-oxide and cinnoline 2-oxide are obtained, of which 2-oxide is the major component.625
The nitrogen-containing ring in cinnoline is stable to oxidation. Potassium permanganate oxidation of 4-phenylcinnoline yielded 5-phenylpyridazine-3,4-dicarboxylic acid, which was stepwise decarboxylated to 4-phenylpyridazine.622
4. Free radical reaction: Reaction of cinnoline with N-nitrosoacetanilide at 50–60°C for 3 h gave a mixture of products, of which 4,4′-dicinnolinyl was the major product. Formation of 4,4′-cinnolinyl is thought to take place by a free radical mechanism by two different paths.626
5. Reduction: On refluxing with lithium aluminum hydride in ether solution, cinnoline is reduced to 1,4-dihydrocinnoline.627 However, when cinnoline is refluxed with amalgamated zinc in 33% acetic acid for 2 h, indole is the product. It was observed that when the reduction process is stopped as soon as a yellow color of the reaction mixture is discharged, then the 1,4-dihydro derivative can be isolated at this stage, which on further reaction with amalgamated zinc in acetic acid yields indole.628
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Cinnoline when heated with formic acid and formamide undergoes reductive formylation to yield 1-formamidoindole.629
4-Phenylcinnoline on reaction with zinc and acetic acid was converted to 3-phenylindole.622
6. Reaction with ketene: Cinnoline reacts with 2 equivalents of dimethylketene in ether to give an adduct (4-isopropilidene-1,1-dimethyl-4H[1,3,4]oxadiazino[4,3-a]cinnolin-2(1H)-one), which on alkaline hydrolysis yields amido acid.630
7. Replacement reaction: The chloro group of 4-chlorocinnoline has been replaced by different nucleophiles. 4-Chlorocinnoline on reaction with sodium ethoxide in ethanol, the chloro group is replaced by ethoxy group. Similarly the chloro group has been replaced by hydroxyl and aromatic amino group.622
2.4.7 Phthalazine
Phthalazine, like cinnoline, is also a 6,6-benzo-fused derivative of pyridazine, but unlike cinnoline, which has two nitrogen atoms at the 1- and 2-positions, phthalazine has nitrogen atoms at the 2- and 3-positions, hence it is known as benzo[d]pyridazine. Structural and Reactivity Aspects632 Phthalazine is isomeric with cinnoline because both contain nitrogen atoms at the ortho-position. However, cinnoline is 1,2-diazanaphthalene, whereas phthalazine is 2,3-diazanaphthalene. In contrast to cinnoline, which has a double bond between two nitrogen atoms, phthalazine has a single bond between them and is well confirmed by theoretical and experimental studies. Phthalazine is thus exclusively represented by the Kekulé structure.
162
2. Six-Membered Heterocycles
The exact structure of phthalazine has been determined by X-ray analysis. Bond lengths (in Å) are depicted in the following figure.
The UV spectrum of phthalazine in methyl cyclohexane shows five bands at 252 nm (log ε 3.629), 259 nm (log ε 3.668), 267 nm (log ε 3.587), 290 nm (log ε 1.108), and 296.5 nm (log ε 1.061). The first three bands are due to π→π* transition, whereas the fourth and fifth bands at longer wavelengths are due to n→π* transition.631 The structure of phthalazine was further confirmed by its 1H and 13C NMR data. The aromatic protons of the benzenoid ring appeared as a AA′BB′ system. 1 H NMR (acetone d6) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1/H-4, 9.60; H-5/H-8, 8.13; H-6/H-7, 8.00
C-1/C-4, 152.0; C-5/C-8, 126.7; C-6/C-7, 133.2; C-4a/C-8a, 126.7
The 15N NMR chemical shift632 of phthalazine (referenced against neat nitromethane) in dimethyl sulfoxide-d6 is δ 10.3. Importance in Natural Products, Medicines, and Materials Heterocycles containing phthalazine moiety are important targets in synthetic organic chemistry because this moiety is present in a number of biologically active compounds. Phthalazine derivatives have been reported to possess cytotoxic,633 antimicrobial,634 anticonvulsant,635 antifungal,636 anticancer,637 and antiinflammatory activities.638 Isolation of natural products containing phthalazine nucleus have recently been reported. Azamerone was isolated from marine-derived species of Streptomyces, while 6-asidotetrazolo[5.1-a]phthalazine was obtained from Gymnodinium breve, a toxic red tide dinoflagellate.639
Natural products containing phthalazine nucleus.
Besides, this nucleus is found within the structures of a number of drugs like hydralazine, budralazine, azelastine, and zopolrestat.
Drugs containing phthalazine nucleus.
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163
Chemical Synthesis640 1. Dehalogenation of phthalazines: Halogen atoms present at the 1- or 1- and 4-positions of phthalazine are easily removed by reduction. 1-Chlorophthalazine on catalytic reduction with 5% palladium on charcoal and 1,4-dichlorophathalazine on chemical reduction with phosphorous and hydroiodic acid yielded phthalazine.
1-Hydrazinophthalazine, when oxidized at room temperature by oxygen in ethanolic alkali or by heating with copper sulfate at pH 8, yielded phthalazine.
2. Reaction involving hydrazines: Phthalazine was first prepared by Gabriel and Pinkus641 in 1893 by treating tetrachloro-o-xylene with hydrazine.
Phthalazines are conveniently synthesized by condensation reaction between o-diaroylbenzenes or o-acylbenzoic acid and hydrazine.
Phthalazine has also been prepared by reaction of o-phthaldehyde with aqueous hydrazine sulfate.
This method has limited utility because it depends on the availability of o-phthaldehyde. However, a two-step convenient synthesis of phthalazine from phthalonitrile has been reported. The process involves reaction of dinitrile with hydrazine hydrate in dioxane and acetic acid yielding 1,4-dihydrazlnaphthalazine, which is oxidized with molecular oxygen to phthalazine.642
164
2. Six-Membered Heterocycles
The reaction of hydrazine with an appropriately substituted aromatic aldehyde, followed by cyclodehydration of acylhydrazone, yields phthalazine.
3. From tetrazines: Symmetrical tetrazines react with olefins to yield phthalazine derivatives.643
A new method has been reported for the synthesis of 4-imino-3,4-dihydrophthalazine from 2-(2-phenylhydrazono) acetaldehyde using 2-ethylidenemalononitrile and benzylidenemalonitrile via formation of a number of intermediates, which cyclizes in the presence of zinc chloride to yield phthalazine.644
A novel one-step synthesis of phthalazine from aromatic aldehydes has also been reported. The key step of the reaction is the transformation of aromatic aldehyde into a directed ortho-metalation group (DMG). This is achieved by reacting it with lithium amide derivatives to form R-aminoalkoxides. Commonly, N,N,N′-trimethylethylenediamine or bis(2-methoxyethyl)amine are used for the formation of R-aminoalkoxides. After the in situ formation of Raminoalkoxide or DMG, the dianion is formed by o-lithiation with n-BuLi. The dianion on reaction with dimethylformamide gives o-bis(aminoalkoxide), which after hydrolysis with aqueous ammonium chloride and hydrazine yields phthalazine.645
4. From phthalic anhydride: Reaction of phthalic anhydride with malonic acid in pyridine gave 2-acetylbenzoic acid, which was esterified with dimethyl sulfate. The acetyl group was brominated with phenyltrimethylammonium tribromide (PTT). The bromo derivative was treated with thiophenol or
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165
3,4-difluorothiophenol using K2CO3 as a base yielding the thio derivative, which was cyclized by treating with hydrazine hydrate to yield a phthalazine derivative.646
5. From aldazines: Synthesis of 1-arylphthalazine is achieved by heating aromatic aldazines with aluminum chloride/triethylamine at 170–200°C. However, when reaction is carried out with aluminum chloride alone, phthalazine is obtained.647
Physical Properties At atmospheric pressure phthalazine forms white hard prism with mp of 90–91°C, which slowly turns yellow. It is readily soluble in water and all organic solvents except ligroin. The pKa value of phthalazine is 3.47 in water at 20°C. This higher base strength value in comparison to pyridazine (pKa 2.3) is explained on the basis of the single NN bond in phthalazine. Chemical Reactivity640 1. Salt formation: Phthalazine on reaction with various acids like hydrochloric, hydrobromic, hydroiodic, and picric acids forms salts. 2. Nitration: Phthalazine on nitration with potassium nitrate and concentrated sulfuric acid yielded 5-nitrophthalazine as the main product and 5-nitro-1(2H)-phthalazone as the by-product.648
3. Oxidation: Phthalazine on oxidation with alkaline potassium permanganate undergoes ring opening to generate pyridazine-4,5-dicarboxylic acid.
However, when there is an oxidizable group bonded to the carbon of the azine ring, oxidation of the attached group takes place first.
166
2. Six-Membered Heterocycles
4. Reduction: Phthalazine on reaction with sodium amalgam yields tetrahydrophthalazine, which on reaction with nitrous acid is transformed into dioxime of o-phthalaldehyde.
On reaction with zinc and hydrochloric acid, phthalazine yields α,α-diamino-o-xylene, which on warming with hydrochloric acid is transformed into dihydroisoindole.
Reductive acylation of phthalazine on reaction with benzyl chloroformate in the presence of sodium cyanoborohydride gave a separable mixture of 2-benzyloxycarbonyl-1,2,3,4-tetrahydrophthalazine and 2,3-dibenzyloxycarbonyl-1,2,3,4-tetrahydrophthalazine.649
5. N-Alkylation: Treatment of phthalazine with methyl iodide yields N-methylphthalazinium iodide, which on treatment with potassium hydroxide solution 2-methyl-1,2-dihydrophthalazine.
6. C-Alkylation/Arylation: Phthalazine on reaction with phenyl magnesium bromide gave 1-phenyl-1,2dihydrophthalazine, which on oxidation gave 1-phenyl phthalazine.
7. Photochemical reaction: Phthalazine dissolved in methanol containing HCl gas on irradiation yields 1-methylphthalazine.
Phthalazine on UV light irradiation in 2-propanol under nitrogen undergoes dual photoreduction to yield simultaneously two photo products, 1,2-dihydrophthalazine and 1,1′, 2,2′-tetrahydro-1,1′bisphthalazine.650
Irradiation of phthalazine in acidified methanol and ethanol yielded 2-methylphthalazine and 2-ethylphthalazine, respectively. The reaction is thought to proceed by a pathway involving electron transfer from the solvent to an excited state of protonated phthalazine.651
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8. Reissert reaction: Phthalazine on reaction with benzoyl chloride and potassium cyanide in a methylene dichloride water solvent system yields a phthalazine Reissert compound.652
9. Replacement reaction: The halogen group of 4-halophthalazine has been replaced by different nucleophiles. For example, when 4-chlorophthalazine reacts with sodium alkoxide in alcohol, the chloro group is replaced by nucleophiles such as alkoxy group. Similarly chloro group has been replaced by hydroxyl and aromatic amino group.
10. 1,3-Dipolar cycloaddition reaction: Cycloaddition reaction of 2-[2-(3-nitrophenyl-2-oxoethyl)]phthalazinium with DMAD in the presence of an excess of triethylamine gave dimethyl cis-3-(3-nitrobenzoyl)-1-10bdihydropyrrola[2,1-a]phthalazine-1,2-dicarboxylate, which on reaction with tetrakis-pyridino Co(II)dichromate (TPCD) yielded dimethyl 3-(3-nitrobenzoyl)-pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate.653
168
2. Six-Membered Heterocycles
2.4.8 Quinolizine
Quinazoline is also known as 1,3-diazanaphthalene. It is derived by fusion of the benzene ring to the 5,6-position of pyrimidine, hence it is also known as benzo[d]pyrimidine. Quinazoline has also been called phenmiazine, benzyleneamidine, benzo-1,3-diazine, and 5,6-benzopyrimidine. The name quinazoline was first proposed by Weddige because he observed that this compound was isomeric with cinnoline and quinoxaline, the two benzodiazines known at that time. Structural and Reactivity Aspects654 Quinazoline is a cyclic-conjugated 10π electron system with a resonance energy value of 127.2 kJ mol−1 and an aromaticity index of 143. The observed dipole moment of quinazoline in benzene is 2.2 D and this value is in good agreement with the calculated value (2.55 D). Quinazoline behaves chemically like its pyrimidine counterpart with the exception that quinazoline is more basic due to electrophilicity of the C-4-position. N
N N pKa 1.1
N pKa 3.3
pKa values of pyrimidine and quinazoline.
Fusion of the benzene ring with the pyrimidine rings results in altered reactivity of both the rings in quinazoline. The benzene ring is deactivated toward electrophilic attack due to the electron-withdrawing effect of the pyrimidine ring. There is significant electron depletion at C-2 and C-4 but only minor depletion at C-5, C-6, C-7, and C-8. Thus nucleophilic attack can take place at C-2 and C-4, whereas electrophilic attack can take place at C-5, C-6, C-7, and C-8. The structure of quinazoline was solved in 1976 by X-ray diffraction. The bond lengths and bond angles are given in the following table. Bond lengths and bond angles of quinazoline Bond
Bond length (nm)
Position
Interbond angle (o)
N(1)C(2)
0.1307
C(2)N(1)C(8a)
115.9
C(2)N(3)
0.1355
N(3)C(2)N(1)
128.3
N(3)C(4)
0.1307
C(4a)C(4)N(3)
123.5
C(4)C(4a)
0.1407
C(4)N(3)C(2)
115.2
C(4a)C(8a)
0.1400
C(8a)C(4a)C(4)
116.3
N(1)C(8a)
0.1372
N(1)C(8a)C(4a)
120.8
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169
The UV spectrum of quinazoline in water showed three bands at 222 nm (log ε 4.57), 271 nm (log ε 3.40), and 305 nm (log ε 3.38). All three bands are due to π→π* transition. However, when the UV spectrum of quinazoline vapors was carried out an additional band was observed at 365 nm (log ε 0.200), and this was probably due to n→π* transition.655 In the 1H NMR spectrum of quinazoline the H-2 and H-4 protons are deshielded due to nitrogen atoms of the diazine ring and are observed at 9.23 and 9.29 ppm, with H-4 being most deshielded due to the resonance effect. Corresponding H-5 and H-8 are less shielded with H-8 being the least and observed at 7.01 ppm. In the 13C NMR spectrum of quinazoline the C-2 and C-4 carbon atoms were observed at 156.1 and 161.1 ppm, respectively. This downfield shifting is observed due to deshielding effect of the heteroatoms. 1
H and 13C spectral data of quinazoline
1
H NMR (CCl4) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 9.23; H-4, 9.29; H-5, 7.84; H-6, 7.58; H-7, 7.83; H-8, 7.01
C-2, 156.1; C-4, 161.1; C-5, 128.1; C-6, 128.8; C-7, 135.1; C-8, 129.3; C-4a, 126.0; C-8a, 151.3
The 15N NMR chemical shifts of quinazoline (referenced against neat nitromethane) in dimethyl sulfoxide-d6 showed two sharp signals at 97.8 (N1) and 86.5 ppm. Under electron impact, quinazoline fragments by consecutive loss of two molecules of hydrogen cyanide from molecular ion to give a benzyne radical.
Mass fragmentation pattern of quinazoline.
Importance in Natural Products, Medicines, and Materials Quinazolines are one of the most important nitrogen benzodiazenes and are found in a number of natural products: pharmaceuticals, pesticides, and functional organic materials. As main building blocks, the quinazoline nucleus is present in a number of natural alkaloids isolated from plants, animals, and microorganisms. The first quinazoline alkaloid to be isolated was vasicine in 1888. Later on, a number of quinazoline natural products were isolated and characterized.
Natural products containing quinazoline nucleus.
The structural diversity of quinazolines was broadened with isolation of asperlicins from Aspergillus alliaceus, which is a potent cholecystokinin antagonist, and benzomalvin from the fungus culture of Pencillium sp.
Natural products containing quinazoline nucleus.
170
2. Six-Membered Heterocycles
Quinazolines are found in a diverse array of synthetic and naturally occurring compounds and they have shown to possess diverse biological activities like sedative, analgesic, anticonvulsant, antitussive, antirheumatic, antidiabetic, anticancer, and antimicrobial. Besides, this nucleus is found within the structures of a number of drugs like prazosin, gefitinib, erlotinib, lapatinib, and vantetanib.
Drugs containing quinazoline nucleus.
Synthesis 1. From quinazoline derivatives: Unsubstituted quinazoline was first synthesized by Gabriel in 1903 by mild alkaline potassium ferricyanide oxidation of 3,4-dihydroquinazoline.
Oxidation of 4-hydrazinoquinazoline with a stream of oxygen through alkaline ethanolic solution for 2 h yielded quinazoline. Reaction of quinazoline-3-oxide with 2-butanone also yields quinazoline.
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171
2. From anilines: Protection of amino group with ethyl chloroformate followed by reaction with hexamethylenetetramine (HMTA) in TFA resulted in the formation of the cyclized product dihydrobenzoquinazoline, which on oxidation with K3Fe(CN)6 without separation of the intermediate yielded the quinazoline derivative.656
4-Arylaminoquinazolines have been synthesized by reaction of 2-aminobenzonitrile with anilines in the presence of aluminum chloride forming amidine as intermediate, which on heating with 85% formic acid at 90°C yielded 4-arylaminoquinazoline derivative.657
4-Arylquinazolines have also been synthesized by heating 5-nitroanthranilonitrile with dimethyl formamide acetal yielding an imine derivative, which on heating with 3-bromoaniline yielded the desired quinazoline derivative in excellent yield.658
Synthesis of 2,4-dihydroxyquinazolines has been reported. The process involves reaction of 2-aminobenzonitrile with carbon dioxide in the presence of a base to generate carbamate salt, which undergoes nucleophilic cyclization with attack of carbamate oxygen on nitrile functionality. Rearrangement takes place to yield an intermediate, which is protonated to yield 2,4-dihydroxyquinazolines.659
3. Microwave-promoted reaction: A microwave-promoted synthesis of 4-aminoquinazoline has been reported. The process involves heating anthranilonitrile, 2-thiophenenitrile, and potassium tert-butoxide in a domestic microwave oven for 3 min.660
172
2. Six-Membered Heterocycles
Reaction of an amino-protected derivative under microwave activation not only increased the yield of quinazoline but also reduced reaction time and the ratio of reagents used.661
4. Niementowski quinazoline synthesis: A chemical reaction between anthranilic acid and amide to form 4-oxo-3,4dihydroquinazolines is known as the Niementowski reaction, named after its discoverer Stefan Niementowski.662
5. Bischler synthesis: The process of heating 2-(acetamido)benzaldehyde with alcoholic ammonia or primary amine at 100°C to yield 2-methylquinazoline is known as Bischler synthesis. Initially, a 3,4-dihydro derivative is formed, which spontaneously undergoes dehydrogenation to quinazoline.
6. Riedel synthesis: This is a method for the direct synthesis of quinazoline by reaction between onitrobenzaldehyde and formamide. In the first step, o-nitrobenzylidene diformamide is formed, which on reduction with zinc and acetic acid gave quinazoline in good yield.663
7. Transition metal-mediated approach: Quinazoline is synthesized by the reaction of 2-nitrobenzaldehyde with formamide to give corresponding N-[1-formylamino-1-(2-nitrophenyl)-methyl]-formamide, which when treated with a palladium(II) and molybdenum(II) complex as catalyst in the presence of carbon monoxide under high pressure produced quinazoline.664
The Cu2O-catalyzed reaction between o-bromobenzylbromide and benzamidines using CsCO3 as a base and N,N′dimethylethylenediamine (DMEDA) as additive in solvent yields substituted quinazoline in one step.665
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173
A one-pot synthesis of quinazoline involving a three-component reaction between 2-aminoaryl ketone, an aldehyde, and ammonium acetate in the presence of a low-melting, inexpensive, nontoxic, easily biodegradable mixture of maltose-dimethylurea (DMU)-NH4Cl has been reported.666
8. [2 + 2 + 2] condensation: A one-pot synthesis of multiple substituted quinazoline by [2+2+2] cascade annulation of diaryliodonium salts and two nitriles has been reported. The reaction is also applicable for two different nitriles to give a regioselective product.667
9. Ring enlargement reaction: 2-Substituted quinazoline can be synthesized by the treatment of dihydrotriazolines with ammonia. The process involves the opening of five-membered rings to an amidine derivative, which undergoes cyclocondensation to yield a quinazoline derivative.668 Initially, triazoline is formed by a reaction of aldehyde with morpholine and subsequent reaction with aryl azide.
10. Ring contraction reaction: 3H-1,4-Benzodiazepines669 are used as a substrate for the construction of 4-substituted quinazolines by thermal ring contraction.
11. From o-fluorobenzaldehyde: Reaction of cyano- or nitro-substituted o-fluorobenzaldehyde with amidine resulted in the formation of an imine derivative, followed by intramolecular aromatic substitution at the fluorine-substituted carbon center yielding a quinazoline derivative.670
174
2. Six-Membered Heterocycles
Physical Properties Quinazoline is a solid, which crystallizes from petroleum ether and melts at 48–48.5°C. It is steam volatile and readily sublimes under vacuum. It has a characteristic pleasant odor and bitter taste. It is soluble in water and nearly all organic solvents. In a legal color test it gives a red color in acidic as well as basic medium. Chemical Reactivity 1. Quaternization: Methylation of quinazoline with methyl iodide and been demonstrated to produce 1-methylquanzolium iodide and 3-methylquanzolium iodide in a ratio of 1:5 in favor of the latter isomer.671
2. Electrophilic substitution reaction: Because quinazoline is π electron deficient, no electrophilic substitution takes place in the pyrimidine ring. However, under forcing conditions, an electrophilic substitution reaction can take place in the benzene ring. Nitration of quinazoline takes place, yielding 6-nitroquinazoline. Bromination of quinazoline with NBS in concentrated sulfuric acid at room temperature has been reported to yield 6-bromoquinazoline. In addition to a monosubstituted product, tri- and tetrabrominated products are also obtained.672
3. Nucleophilic substitution reaction: Quinazoline reacting with acetophenone at room temperature afforded 2-(3,4-dihydro-4-quinazolin)acetophenone. This reactivity is possibly due to -M and -E effects of the ring nitrogen atom and the effect of the fused benzene ring at the 4-position.673
Reaction of quinazoline with a reactive methylene compound like phenylacetonitrile in the presence of methoxide afforded 4,4'-biquinazoline and α-phenyl-4-quinazolineacetonitrile.674
The reaction is thought to proceed by the following mechanism.
Reaction of reactive methylene compound in the absence of a base catalyst yields quinoline derivatives. Quinazoline on reaction with malononitrile yields 2-aminoquinoline-3-carbonitrile and 2-hydroxyquinoline-3-carbonitrile.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
175
Reaction of quinazoline with alkylmagnesium bromide yields a 3,4-dihydro derivative, which without isolation is oxidized with potassium ferricyanide to 4-alkylquinazoline.
Reaction of quinazoline with excess 3,3-dimethylbutene in the presence of rhodium catalyst and tri(cyclohexyl) phosphine gave 2-alkylquinazoline in excellent yield.675
4. Amination (Chichibabin reaction): Reaction of quinazoline with sodium amide in DMA yielded 4-aminoquinazoline. However, when the amination reaction is carried out in the potassium amide/ liquid ammonia/potassium permanganate van der Plas system, in addition to 4-aminoquinazoline, 2% of 4,4′-diquinazolyamine is also obtained.
5. Oxidation: Quinazoline is oxidized in dilute acid with 2 equivalents of hydrogen peroxide at room temperature to quinazolin-4(3H)-one.
Quinazoline is stable to oxidation but on reaction with alkaline potassium permanganate under drastic conditions, the benzene ring is ruptured to yield 4,5-pyrimidinedicarboxylic acid.
Oxidation of quinazoline by a mutant strain of the bacterium Pseudomonas putida gives cis-5,6-dihydroquinazoline- 5,6-diol, cis-5,6,7,8-tetrahydroquinazoline-5,6-diol, and quinazolin-4(3H)-one.
6. Reduction: Quinazoline is reduced to 3,4-dihydroquinazolines effectively in the presence of Adam's platinum oxide676 catalyst.
However, reduction to 1,2,3,4-tetrahydroquinazoline takes place under forcing conditions. Reductive acylation of quinazoline on reaction with benzyl chloroformate in the presence of sodium cyanoborohydride gave 1,3-dibenzyloxycarbonyl-1,2,3,4-tetrahydroquinazoline.677
176
2. Six-Membered Heterocycles
7. Suzuki reaction: Microwave-promoted Suzuki reaction of quinazoline halide with boronic acid was carried out in the presence of stable catalyst tetrakis triphenylphosphine palladium and cesium carbonate afforded 4-substituted quinazoline in high yield.678
8. Ring-opening reaction: Quinazoline on reaction with hydroxylamine undergoes ring cleavage between C-2 and C-3 to yield N-(hydroxyiminomethyl)anthraniloaldehydeoxime.679
9. Replacement reaction: 4-Chloroquinazolines are important synthetic intermediates, which can undergo nucleophilic attack at C-4 to yield new quinazoline derivatives. The reaction is thought to proceed with activation of benzaldehyde by cyanide addition and activation of quinazoline as a 4-toluenesylfonyl derivative.680
Synthesis of an important intermediate is reported, which has been used in the synthesis of AX7593, a quinazoline- derived photoaffinity probe for epithelial growth factor receptor.681
2.4.9 Purine 6 1N 2
5
N7
4
N9 H
8
N 3
Purines are a group of cyclic diureides, aromatic in nature and consisting of a pyrimidine ring fused to an imidazole ring. The word purine (pure urine) was coined by Emil Fischer in 1884 for this naturally occurring derivative.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
177
Structural and Reactivity Aspects682a Purine exists in four tautomeric forms, 1H- (a), 3H- (b), 7H- (c), and 9H-tautomer (d), depending on the site of attachment of the proton to the ring nitrogen atoms. The 1H- and 3H-tautomers are much less stable in comparison to the 7H- and 9H-tautomers, which are present in equal concentration in the concentrated aqueous solution. However, in the solid state, 7H-purine is the dominant tautomer.
(A)
(B)
(C)
(D)
Different tautomers of purine.
The structure of purine was confirmed by X-ray, which shows that the imidazole ring is planar. However, the fused pyrimidine ring deviates from the coplanar arrangement. The bond lengths (in pm) and bond angles (in degrees) are shown in the following diagram.
Bond length and bond angles in purine.
The 1H and 13C NMR spectra of purine are comparable to the two fused rings of pyrimidine and imidazole, except that the protons in the imidazole ring are shifted downfield in comparison to the parent ring. H and 13C NMR spectral data of purine
1
1
H NMR (DMSO-d6) δ (ppm)
13
C NMR (DMSO-d6) δ (ppm)
H-2, 8.99; H-6, 9.19; H-88.68
C-2, 152.1; C-4, 154.8; C-5, 130.5; C-6, 145.5; C-8, 146.1
The mass spectrum of purine shows two consecutive losses of hydrogen cyanide, a pattern that is often observed in heterocyclic compounds containing two nitrogen atoms in one ring.
Mass fragmentation of purine.
Importance in Natural Products, Medicines, and Materials Purine is important because this skeleton is present in a number of natural products like saxitoxin, microxine, aplidiamine, and many others. A number of structures possessing the purine nucleus have been reported to show diverse biological activities. They have been reported to possess antitumor,682b anti-HIV,683 antiviral,684 anticonvulsant,685 and bronchodilator activity.686
178
2. Six-Membered Heterocycles
Saxitoxin
Microxine
Aplidiamine
Natural products containing purine skeleton.
A number of drugs have been shown to possess the purine skeleton. For example, 6-mercaptopurine, sold under the brand name Purinethol, is used for the treatment of leukemia and autoimmune diseases. Fludarabine, sold under the brand name Fludara, is used for the treatment of leukemia and lymphoma. Aciclovir, also known as acyclovir, is an antiviral agent used primarily for the treatment of herpes infection. Abacavir is used for the treatment of HIV/ AIDS. Dideoxyinosine (didanosine), sold under the brand name Videx, is used for the treatment of HIV/AIDS. Allopurinol, sold under the brand name Zyloprim, is used to decrease uric acid levels in blood.
Drugs containing purine nucleus.
Purines are important because some of their derivatives, particularly adenine and guanine, are monomeric building blocks of DNA and RNA nucleic acid poly chains. In addition to being building blocks of DNA and RNA, purines are also found in a number of other important biomolecules such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. Besides adenine and guanidine, other notable purine derivatives are xanthine, hypoxanthine, theobromine, caffeine, and uric acid.
Important purine derivatives.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
179
Synthesis 1. Fischer synthesis: Fischer first synthesized687 purine from uric acid isolated from kidney stones. Uric acid reacted with PCl5 to give 2,6,8-trichloropurine, which on treatment with HI and PH4I gave 2,6-diiodopurine. The diiodo product on reduction with zinc dust yields purine.
Adenine is synthesized by treating 2,6,8-trichloropurine with aqueous ammonia followed by treatment with HI.
2. Traube synthesis: Purine has also been synthesized by heating 4,5-diaminopyrimidine688 with formic acid at 100°C under carbon dioxide and then slowly raising the temperature to 210°C. This method has been used for the synthesis of a number of purines unsubstituted at the 8-position.
Reaction between guanidine and cyanoacetic acid ester leads to the synthesis of pyrimidine derivative. An amino group is introduced at the 5-position by nitrosation followed by ammonium sulfide reduction yielding 4,5-diaminopyrimidine. The diamino derivative on treatment with formic acid yields purine.689 Formamide690 and formamidine691 have also been used in place of formic acid.
Reaction of 4-amino-5-nitrosopyrimidine with formic acid in the presence of Raney nickel yields purine.
A slight modification of this method includes heating 4,5-diaminopyrimidine with dithioformic acid in sodium hydroxide solution and heating the product obtained with sodium methoxide.
Adenine has also been synthesized by this method. The process involves reaction of 6-chloro-4,5-diaminopyrimidine with diethoxymethyl acetate furnishes 6-chloropurine, which on amination with ammonia yields adenine.
180
2. Six-Membered Heterocycles
3. 8-Substituted purine has been synthesized by treating 4,5-diaminopyrimidine with acetic anhydride.
8-Substituted purines are synthesized by treating 2,4,5,6-tetraaminopyrimidine with 4-methoxy benzoyl chloride followed by cyclization with phosphorous oxychloride.
4. Bergmann synthesis: 4,5-Diaminopyrimidine condenses with amidine salts to yield 8-substituted purine in high yield.692
5. Suzuki reaction: Disubstituted purines have been synthesized by Suzuki cross-coupling reaction. 2,4-Dichloropurine on reaction with MeZnBr yielded monosubstituted purine, which underwent a Suzuki crosscoupling reaction with phenylboronic acid yielding disubstituted purine.693
6. Domino Heck-Negishi reaction: A three-component domino Heck-Negishi coupling reaction for the synthesis of purine derivative with a carbon substituent at C-6 has been reported. The process involves organozinc reagent for the first time to trap an alkylpalladium intermediate of olefins in the domino Heck reaction.694
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
181
7. Purine in good yield is obtained by heating formamide in an oil bath at 160–200°C in an open vessel for 28 h.695
Synthesis of adenine has also been achieved in one step by heating formamide with phosphoryl chloride at 120°C in a sealed tube or by reaction of aminomalonimidamide with triethyl orthoformate.
8. Desulfurization: Desulfurization of sulfanyl-substituted purine leads to the generation of pure purine.
9. Reaction of alkylaminoacetonitriles with formimidamide acetate gives 7-substituted purine in good yield.
10. Diels-Alder reaction: Based on inverse electron demand, Diels-Alder cycloaddition reaction of 1,3,5-triazine and 2,4,6-tri(trifluoromethyl)-1,3,5-triazine with in situ-generated 1-substituted 5-amino-1H-imidazole separately produced functionalized purines.696
11. 7-Substituted purines have efficiently been synthesized from 4-amino-1H-imidazole-5-carbaldehyde oxime (prepared from 4-nitroimidazole697). Condensation of the amino group with orthoesters resulted in the formation of iminoethers. Cyclocondensation of the ortho groups with ammonia resulted in the formation of the purine ring system.698
Physical Properties Purine is slightly yellow to cream crystalline powder with mp of 214°C and is soluble in water.
182
2. Six-Membered Heterocycles
Chemical Reactivity 1. Protonation at nitrogen: Purine is a weak base and protonation of all the four nitrogen atoms is possible, but the most prominent cation is formed by protonation699 of N-1. 2. N-Alkylation: N-Alkylation of purine takes place at N-7 and/or N-9. Purine reacts with iodomethane to yield 7,9-dimethylpurinium salt.700 However, on reaction with dimethysulfate and vinyl acetate, alkylation takes place at N-7.
Base-induced coupling is the most popular method for carrying out N-alkylation reactions. The process involves generating a purinyl cation in the presence of a base such as metal carbonates like K2CO3 or Cs2CO3 or hydrides like NaH in a polar solvent.701
N-Alkylation of 6-chloropurine was carried out using Mitsunobu reaction. The process involved reacting purine with alcohol in the presence of diethylazodicarboxylate (DEAD). N-9-Alkylated product was the major product in comparison to the N-7-alkylated product.702
N-Alkylation of purines was also achieved under solid-liquid-phase transfer catalysis by use of 18-crown-6 or tetraglyme in the presence of potassium tert-butoxide as base.703
N-Alkylation of adenine with alkyl esters of phosphorous oxyacid takes place at the 3-position yielding 3-alkyladenine.704
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
183
3. Electrophilic substitution reaction: Nitration of 6-substituted purine with tetrabutylammonium nitrate/ trifluoroacetic anhydride (TBAN/TFAA) has been studied. The nitrating mixture selectively nitrates at the C-2 position.705
The reaction has been proved to take place in three steps. Electrophilic attack by trifluoroacetyl nitrate on the N-7 position results in nitroammonium species that are trapped by trifluoroacetate anions furnishing an N 7-nitramine intermediate, which undergoes a nitramine rearrangement, producing 2-nitro-4-chloropurine706 with elimination of TFA.
4. Nucleophilic substitution reaction (a) Chichibabin reaction: Reaction of purine with KNH2 in ammonia leads to the formation of 6-aminopurine (adenine).
(b) Halopurines, thiols, or sulfides react with organometallic compounds in the presence of a phosphine-nickel complex or palladium catalyst (Negishi reaction) to yield alkylated purines.
184
2. Six-Membered Heterocycles
(c) Nucleophilic addition of 2-thiobarbituric acid to 1,6-double bond of purine takes place to yield 1,6-dihydro-6(4,6-dioxo-2-thiohexahydropyrimidin-5-yl)purine.707
5. Deuteration: Purine is rapidly deuterated at C-8 in neutral water at 100°C. The reaction probably involves 8-deprotonation of purinium cation to give a transient ylide.
6. Oxidation: Direct oxidation of purines with peracid is the most favored method for the synthesis of purine-1 and -3-oxides. When an electron-donating substitute is present at C-6, then N-1 nitrogen is oxidized first. Adenine 1-oxide is synthesized in 84% yield by reacting adenine with hydrogen peroxide in the presence of acetic acid.
7. Reduction: Electrochemical reduction of purine takes place in two stages. In the first stage, 1,6-dihydropurine is formed, which on further reduction yields 1,2,3,6-tetrahydropurine. Hydrolysis of tetrahydropurine yields 4-aminoimidazole.708, 709
8. Photochemical reaction: Purine, which is relatively stable under the influence of UV light, undergoes photochemical alkylation on reaction with 1-propylamine yielding 6-propyl-9H-purine.710
Photoirradiation of adenine with isopropyl alcohol results in substitution of C(8) hydrogen with alcohol.711
9. Glycosylation: Synthesis of 2-deoxyribonucleoside was achieved by reaction of 1-α-chloro-2-deoxy-3,5di(ptoluyl)-erythro-pentofuranose with sodium salt of purine in acetonitrile.712 The two isomers formed, 9-β and 7-β, were in the ratio of 4:1.
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185
Efficient synthesis of purines and purine nucleosides, via an inverse electron-demand Diels-Alder reaction, has also been reported.713 10. Ring transformation: The imidazole ring of purines undergoes a ring-opening process leading to the generation of a pteridine derivative. Purine 2(1H)-one on reaction with glyoxal in aqueous sulfuric acid solution afforded pteridine 2(1H)-one monohydrate. Similarly, purine 2(1H)-one reacting with glyoxylic acid yielded pteridine 2,6(1H,5H)-dione.
3,9-Dimethyluric acid on chlorination-reductive dechlorination undergoes oxidative ring transformation to imidazo[1,5-c]imidazole.714
2.4.10 Pteridine
Pteridine is an aromatic heterocyclic compound formed by the fusion of pyrimidine and pyrazine. The word pteridine is derived from the Greek word pteron meaning wings, because most of the pteridine derivatives have been isolated from the wings of insects. Pteridines are normally colored compounds with the parent compound being yellow in color. Structural and Reactivity Aspects715 The structure of pteridine was confirmed by X-ray analysis, which not only confirmed the composition of the structure but also the point of fusion. Hence pteridine is also called pyrazino[2,3-d]pyrimidine. The bond length and bond angles as determined by X-ray are comparable with those of pyrimidine and pyrazine. Bond lengths (in pm) and bond angles (in degrees) are shown in the following diagram. 135
140 139 N
131
N 137
139
140
N
N 116120 129
130
Bond lengths and bond angles of pteridine.
N 136 136N 129
115
N
114 119 122 121 120
123 116
N
128
186
2. Six-Membered Heterocycles
The 1H and 13C NMR spectra of pteridine suggest it to be a π-deficient heteroaromatic system. The 1H and 13C NMR spectral data of pteridine are given in the following table. H and 13C NMR spectral data of pteridine
1
1
H NMR(CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 9.55; H-4, 9.80; H-6, 9.15; H-7, 9.33
C-2, 159.2; C-4, 164.1; C-6, 148.4; C-7, 153.0; C-9, 154.4; C-10, 135.3
The UV spectrum of pteridine in cyclohexane gave four absorption bands at 263 (log ε 3.10), 296 (log ε 3.85), 302 (log ε 3.87), and 396 nm (log ε 1.88). The first three bands are due to π→π* transition, whereas the fourth band is due to n→π* transition. Importance in Natural Products, Medicines, and Materials Pteridines have been isolated from natural sources where they are present as pteridinones or aminopteridones. They are present as pigments in the wings and eyes of insects and in the skin of fish and amphibians. For example, xanthopterin, a yellow pigment, was isolated from the English brimstone butterfly; leucopterin, a white pigment, was isolated from the cabbage white butterfly; and erythropterin was isolated from rub kip butterfly.
Pteridine isolated from natural source.
Folic acid and riboflavin, the essential metabolites of living organisms, possess a pteridine skeleton.
A number of pteridine-based compounds are of commercial interest because they are easily available in the market as drugs. For example, methotrexate is used clinically as an antineoplastic agent for several common acute leukemias. Folinic acid or leucovorin finds use as an adjuvant in cancer chemotherapy involving methotrexate and triamterene, a potassium-sparing diuretic that inhibits both the excretion of potassium ions and the reabsorption of sodium ions.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
187
Synthesis 1. Gabriel-Isay (Gabriel-Colman) synthesis: This reaction involves cyclocondensation of 5,6-diaminopyrimidine with symmetrical 1,2-dicarbonyl compounds like benzil or glyoxal to yield pteridines. The original reaction involved reaction of 6-methylpyrimidine-4,5-diamine with benzil to yield 4-methyl-6,7-diphenylpteridine.716
However, the parent pteridine is synthesized by reaction of pyrimidine 4,5-diamine with glyoxal or some other equivalent synthon.
The method works with symmetrical diketones; however, reaction of diaminopyrimidine with unsymmetrical diketones, α-keto aldehydes, α-keto acids, or their esters led to a mixture of pteridine derivatives. 2. Polonovski-Boon reaction: A general method for the synthesis of 7,8-dihydropteridine developed by Boon, Ramage, and their collaborators and independently by Polonovski is known as Polonovski-Boon reaction. The reaction involves condensation of 6-chloro-5-nitropyrimidine with an α-aminocarbonyl compound yielding an intermediate, which on reduction followed by cyclization yields a pteridine derivative.
3. Viscontini reaction: This efficient synthetic method involves condensation of sugar phenylhydrazones with 5,6-diaminopyrimidines under slightly acidic conditions to provide regioselectively 6-substituted pterins.
By this method, neopterin has been synthesized in much higher yield.717 4. Timmis synthesis: Base-catalyzed condensation of 4-amino-5-nitrosopyrimidines with compounds containing an activated methylene group like ketones, aldehydes, nitriles, and cyano acetic acid affords pteridines.718, 719
188
2. Six-Membered Heterocycles
Condensation of α-methylenenitrile with 2,4,6-triaminopyrimidine yielded triamterene, a potassium-sparing diuretic.
5. Pachter synthesis: This is a modification of Timmis reaction and involves reaction of 4,6-diamino-5-nitroso-2phenyl pyrimidine with a reactive methylene compound like benzyl methyl ketone in the presence of potassium acetate to yield 4-amino-7-methyl-2,6-diphenylpteridine.720
6. Blicke synthesis: Condensation of aminopyrimidines with aldehydes and HCN followed by cyclization using NaOMe as a base produced pteridine via cyanoamines.721
7. From pyrazines: Reaction of 3-(aminomethyl)pyrazin-2-amine with orthoformates followed by oxidative aromatization yields 6-substituted pteridine.
Taylor’s method for the synthesis of pteridines from pyrazines is a valuable alternative method to commonly apply a condensation reaction of diaminopyrimidines with dicarbonyl compounds. The process involves condensation of α-aminonitrile with α-ketoaldoximes to give 2-amino-3,5-disubstituted pyrazine-1-oxide, which is subsequently cyclized and deoxygenated to give 6-substituted pteridines.722
Degradation of tolualloxaine by oxidative methods yields 2,6-dihydroxypteridine.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
189
Reaction of 2,3-diamide of 2,3-pyrazinedicarboxylic acid with 2 mol of potassium hypobromite yields the potassium salt of 2,6-dihydroxypteridine, which on hydrolysis with acid yields 2,6-dihydroxypteridine.723
Physical Properties Pteridine is a yellow-colored solid with mp of 139.5°C. It is insoluble in water. Chemical Reactivity 1. Action of acid and base: Under appropriate conditions the pyrimidine ring of pteridine undergoes degradation with acid and alkali. 2,6-Dihydroxypteridine on heating with 100% sulfuric acid at 240°C gave 2-aminopyrazine. The same compound on heating with 2–3 equivalents of 12% alkali for 2 h at 170°C gave 2-amino-3-carboxylic acid. Both compounds were obtained in high yield.724
2. Nucleophilic addition: Pteridine readily undergoes nucleophilic addition with water, alcohol, and amines to form covalent adducts chiefly at the C-4- and C-7-positions. Nucleophilic addition of water to pteridine affords covalent hydrates. Under acidic conditions, 3,4-hydrated cation is initially formed, which slowly equilibrates with dehydrated 5,6,7,8-cation.
Pteridine undergoes nucleophilic addition reaction with methanol to yield an equilibrium mixture of 3,4-dihydro- 4-methoxypteridine (1:1 adduct) and 5,6,7,8-tetrahydro-6,7-dimethoxypteridine725 (2:1 adduct).
Amination of pteridine is achieved by a combination of nucleophilic addition and oxidation reaction. Thus pteridine on reaction with potassium permanganate in liquid ammonia yields 4-aminopteridine.
190
2. Six-Membered Heterocycles
3. Nucleophilic substitution reaction: Reaction of pteridine with Grignard reagent followed by oxidation led to the formation of a new carbon-carbon bond on the pyrazine ring, regioselectively at the C-7-position.
4. Oxidation: Pteridine derivatives like xanthopterin on treatment with molecular oxygen over platinum or on treatment with hydrogen peroxide are converted to leucopterin.724
5. Reduction: Tetrahydropteridine derivatives are highly reactive toward oxidation; as a result, it is difficult to isolate them. However, when electron-withdrawing groups are present on the ring they are stable and can easily be isolated. Thus 5,6,7,8-tetrahydropteridine-4-carboxylate can be isolated on reaction of suitably substituted pteridine with sodium borohydride.726
6. Heck reaction: Palladium-catalyzed coupling reaction of 6-chloropteridine with acetylenes yields alkynylsubstituted pteridines.727
7. Reaction with PCl5 and POCl3: Leucopterin on reaction with phosphorous pentachloride and phosphorous oxychloride yields a monochloro derivative, which is reduced by hydroiodic acid to 6-deoxyleucopterin.
8. Ring fission: Pteridines are thermally stable; however, in hot solutions they are unstable. They undergo fission of the pyrimidine ring in aqueous acid to yield 3-aminopyrazine-2-carbaldehyde.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
191
2.5 SIX-MEMBERED HETEROCYCLES WITH THREE AND MORE NITROGEN ATOMS Triazines are six-membered heterocycles analogous to benzene in which three carbon atoms have been replaced by three consecutive nitrogen atoms. There are three important isomers of triazines, which are distinguished from each other on the basis of the position of the nitrogen atoms, and are referred to as 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine.
2.5.1 1,2,3-Triazine
1,2,3-Triazine is the systematic name for one of the three isomers of triazines. However, in some literature the term v-triazine has been used. The letter v denotes that the nitrogen atoms are vicinal. A less satisfactory name, β-triazine, has also been used. Structural and Reactivity Aspects728 The structure of 1,2,3-triazine was elucidated by X-ray crystallographic analysis, which shows that the molecule is planar in nature. The bond lengths (in Å) are shown in the following figure.729 Bond angles (in degrees) were, however, derived from X-ray studies of 4,5,6-tris(4-methoxyphenyl)-1,2,3-triazine.
Bond lengths and bond angles of 1,2,3-triazine.
The UV spectrum of 1,2,3-triazine (in ethanol) shows a medium intensity band at 288 nm (log ε 2.93) and this may be due to n→π* transition. There is another band that appears as a shoulder in the short region at 232 nm and is due to π→π* transition. In the 1H NMR spectrum of triazine in CDCl3 the protons adjacent to the nitrogen, i.e., 4-H and 6-H, appear downfield as a doublet at δ 9.06 (2-H). The 5-H proton also appears as a doublet at δ 7.45. In the 13C NMR spectrum the 4-C and 6-C appear at δ 149.7, whereas 5-C appears at δ 117.9. The mass spectrum of triazine showed a strong peak at m/z 53, attributed to nitrogen elimination from the parent ion.
Mass fragmentation pattern of 1,2,3-triazine.
192
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials There has been no evidence of the occurrence of natural products containing the 1,2,3-triazine nucleus. A number of substituted 1,2,3-benzotriazines have been reported to have the ability of inhibiting VEGFR-2 kinase activity.730 However, there are reports that this nucleus is present in some pesticides, e.g., guthion.
Guthion, a pesticide containing 1,2,3-triazine skeleton.
Synthesis 1. Unsubstituted monocyclic 1,2,3-triazine is synthesized by oxidation of N-aminopyrazole with freshly prepared nickel peroxide with acetic acid.728 1-Aminopyrazole was, however, obtained by deprotonation with sodium hydride followed by amination with (O-mesitylenesulfonyl) hydroxylamine (MSH).
A number of alkyl- as well aryl-substituted monocyclic 1,2,3-triazines have also been synthesized from suitably substituted 1-aminopyrazoles.728 2. Deprotonation and lithium-halogen exchange of 4-bromopyrazole and subsequent trapping of C-lithiate by dimethylsulfide afforded thio-substituted pyrazole, which on N-amination with monochloroamine yielded N-aminopyrazole. Treatment of N-aminopyrazole with NaIO4 under biphasic ring expansion conditions yields 5-methylthio-1,2,3-triazine.731
Similarly, 5-methoxy-1,2,3-triazine and 5-(N-acetylamino)-1,2,3-triazine have been synthesized from 4-methoxypyrazole and 4-nitropyrazole, respectively.730
3. Thermal rearrangement of cyclopropenylazides yields substituted 1,2,3-triazines.
Physical Properties 1,2,3-Triazine is obtained as a colorless crystalline solid by crystallized with ether; it has mp of 70–71°C and sublimes readily.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
193
Chemical Reactivity 1. Cycloaddition reaction: The inverse electron demand Diels-Alder (IED-DA) reaction of parent 1,2,3-triazine that undergoes [4+2] cycloaddition reaction with different heterodineophiles has been reported. 1,2,3-Triazine underwent [4+2] cycloaddition with aliphatic amidine and imidate to give a pyrimidine derivative. Similarly, ynamines react with 1,2,3-triazine to yield pyridine derivatives.732
It was believed that electron-donating substituents would not only decrease the overall reactivity of 1,2,3- triazine but would also prevent cycloaddition reaction. It has been observed that though the rate of reaction was decreased on reaction with amidines but was quite effective for the synthesis of pyrimidine in excellent yield.732 To prove that the cycloaddition reaction takes place in a single step, 1,2,3-triazine substituted with electron donating group was treated with amidine 15N-20g doubly labelled with 15N, pyrimidine derivative incorporated with a single 15N label was obtained in high yield.
2. Oxidation: Oxidation of 4-methyl-1,2,3-triazine with m-CPBA in dichloromethane at room temperature yielded a mixture of 6-methyl-1,2,3-triazine-1-oxides and 4-methyl-1,2,3-triazine-2-oxides, whose structures were confirmed on the basis of NMR data.733
3. Reduction: Catalytic hydrogenation of 4,6-dimethyl-1,2,3-triazine on Pd/C yielded the 2,5-dihydro derivative.732
4. Hydrolysis: 1,2,3-Triazine is a stable molecule. However, when heated at higher temperatures in the presence of aqueous acid it undergoes ring fission to yield 1,3-dicarbonyl compounds.
194
2. Six-Membered Heterocycles
2.5.2 1,2,3-Benzotriazine 8 7
1
N
6 5
N2 N3
4
Structural and Reactivity Aspects The 1H NMR spectrum734 of parent 1,2,3-benzotriazine was recorded in [(CD3)2SO] showing one proton doublet at τ 0.15 and four proton multiplets from τ 1.45–1.86. Importance in Natural Products, Medicines, and Materials A number of substituted 1,2,3-benzotriazines have been reported to have the ability of inhibiting VEGFR-2 kinase activity, for example, CTZ12, a potent VEGFR-2 inhibitor used for the treatment of various cancers.735 There are reports that this nucleus is present in pesticide, guthion.
Synthesis 1. Stirring a solution of 1H-indaziol-1-amine in methylene chloride with a mixture of lead tetraacetate (LTA), calcium oxide, and dry methylene chloride yields the parent 1,2,3-benzotriazine.734
2. Oxidation of azidohydrazone with mercury(II) oxide gave diazo-azide, which on refluxing in benzene yields 4-methyl-1,2,3-benzotriazine.734
3. Oxidative cyclization of the hydrazones of o-aminophenyl ketones gave 4-substituted benzotriazine.734
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
195
4. Reaction of 4-cyano-2-methoxyphenol with different alkyl halides in the presence of potassium carbonate in DMF afforded 4-substituted-3-methoxybenzonitrile, which on selective nitration with nitric acid gave the nitro compound. The nitro compound was reduced to amine, diazotized with substituted aniline at 0°C to afford benzotriazine.735
5. Reaction of 1-o-chlorophenyl-3-cyanophenyltriazene with 70% aqueous ethanol gave 3-substituted 3,4-dihydro4-imino-1,2,3-benzotriazine, which rearranges to 4-anilino-1,2,3-benzotriazine.736
Physical Properties 1,2,3-Benzotriazine is a pale yellow crystalline solid with mp of 119–120°C. Chemical Reactivity 1. Vacuum pyrolysis of 1,2,3-benzotriazine and its methyl derivative with continuous wave CO2 laser yielded 1-azabenzocyclobutene and 2-methylbenzazete, respectively.737
Pyrolysis of 1,2,3-benzotriazine above 450°C resulted in fragmentation of the triazine ring to afford benzyne, which then dimerizes to biphenylene.738
2. Nucleophilic addition: Treatment of 4-phenyl-1,2,3-triazine with ethyl magnesium bromide in ether, followed by quenching of the resulting anion with methyl iodide, gave indazole.739
3. The C-4-position in 1,2,3-benzotriazine is very electrophilic and undergoes covalent hydration across the N3C4 bond to give 2-aminophenyl ketones.
196
2. Six-Membered Heterocycles
4. 4-Phenyl-1,2,3-benxotriazine on reaction with hydrazine forms hydrazone of 2-aminodiphenyl ketone.
5. Diels-Alder reaction: Heating a mixture of 1,2,3-benzotriazine (prepared by oxidation of indazol amine) and cyclohexanone enamine in dry chloroform in the presence of zinc bromide in a sealed tube at 90–100°C gave 1,2,3,4-tetrahydroacridine.740
Benzotriazine undergoes cyclization with enamines to produce a bicyclic intermediate, which eliminates nitrogen to produce quinolines. Benzotriazine in good yield is generated in situ from 1H-indazol-1-amine through LTA oxidation.
6. Heating a mixture of 1,2,3-benzotriazine and pyrrolidine-enamine of acetophenone in dry chloroform in the presence of zinc bromide in a sealed tube at 100°C gave 2-phenylquinoline.741
7. Oxidation: Reaction of 4-Methoxy-1,2,3-benzotriazine with m-CPBA at 20°C yields 4-methoxy-1,2,3-benzotriazine-2-oxide.742
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
197
8. Cycloaddition reaction: Reaction of 1,2,3-benzotriazine derivative with diphenylcyclopropenone gave pyrazolo[1,2-a] [1,2,3]benzotriazene-1-one, pyrazolo[1,2-a][1,2,3]benzotriazene-3-one, and pyrazolo[2,3-a]quinazoline-3-one adducts.
2.5.3 1,2,4-Triazine 4
3 2
N
N N
5 6
1
1,2,4-Triazine is the systematic name for one of the three isomers of triazines. However, in some literature the term as-triazine has been used because of asymmetry in the arrangement of nitrogen atoms in the ring. In older literature, less satisfactory names, α-triazine and isotriazine, have also been used. Structural and Reactivity Aspects743 1,2,4-Traizine is a π electron deficient heterocyclic system and is represented by two canonical structures I and II. Theoretical calculations have shown that structure I contributes more to the ground state of the molecule.
Resonating structures of 1,2,4-triazine.
The structure of 3-amino-1,2,4-triazine, determined by X-ray crystallographic analysis,744 revealed that the 1,2,4-triazine ring is planar but slightly distorted due to the presence of electronegative nitrogen atoms in the ring. The shorter bonds between C2N2 (1.319 Å) and between C3N3 (1.312 Å) suggest that the ring has an appreciable double bond character. The bond distances C1N1, C1N3, and C1N4 possess partial double bond character. The bond distances (Å) and bond angles (degrees) are depicted in the following table.
Bond lengths and bond angles of 1,2,4-triazine Bond lengths (Å)
Bond angles (o)
N(1)N(2) 1.334(2)
N(2)N(1)C(1) 118.06(12)
N(1)C(1) 1.351(2)
C(2)N(2)N(1) 119.48(12)
N(2)C(2) 1.319(2)
C(3)N(3)C(1) 114.73(12)
N(3)C(3) 1.312(2)
N(4)C(1)N(1) 117.04(12)
N(3)C(1) 1.358(2)
N(4)C(1)N(3) 117.87(12)
N(4)C(1) 1.330(2)
N(1)C(1)N(3) 125.08(12)
C(2)C(3) 1.394(2)
N(2)C(2)C(3) 120.59(14) N(3)C(3)C(2) 122.0(13)
198
2. Six-Membered Heterocycles
The UV spectrum of 1,2,4-triazine in methanol shows two absorption bands at 374 and 247.8 nm. The band at 374 is due to n→π* transition, whereas the band at 247.8 is due to π→π* transition. The 1H and 13C NMR spectral data of 1,2,4-triazine are given in the following table. H and 13C spectral data of 1, 2,4-triazine
1
1
H NMR (δ values in ppm)
13
C NMR (δ values in ppm)
H-3, 9.66; H-5, 8.84; H-6, 9.48
C-3, 158.1; C-5, 149.6; C-6, 150.8
The mass spectrum of 1,2,4-triazine shows the following fragmentation pattern, which has been confirmed by mass spectrum of 1,2,4-triazine 3d.745, 746
Mass fragmentation pattern of 1,2,4-triazine.
Importance in Natural Products, Medicines, and Materials 1,2,4-Triazine has occupied a unique position in medicinal chemistry because a number of these derivatives have been reported to possess promising biological activity. 1,2,4-Triazines have been reported to possess antifungal,747 anti-HIV,748 antiinflammatory,749 and antihypertensive activity.750 Besides these, they are used as herbicides and pesticides. 4-Amino-6-tert-butyl-3-(methylmercapto)-1,2,4-triazine (sencor, metribuzin, BAY 94337) is the best and most widely used herbicide. A number of clinically used drugs available in the market contain the 12,4-triazine nucleus. For example, azaribine is an antineoplastic and antipsoriatic drug, lamotrigine is an anticonvulsant drug used in the treatment of epilepsy,751, 752 tirapazamine is an anticancer agent, and furalazine is an antimicrobial agent.
Drugs possessing 1,2,4-triazine skeleton.
Synthesis 1. The first synthesis of unsubstituted 1,2,4-triazine was reported by Paudler and Barton in 1966. The process involves condensation of glyoxal with ethoxycarbonyl amidrazone and yields ethyl 1,2,4-triazine-3-carboxylate, which was converted to unsubstituted triazine by saponification followed by decarboxylation.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
199
Preparative synthesis of 1,2,4-triazine involves reaction of monomeric glyoxal with formamidazone hydrochloride in absolute methanol at −50°C.753
Unsubstituted triazine is also synthesized by oxidation of hydrazine-1,2,4-triazine with manganese(IV) oxide or silver(I) oxide.754
2. Desulfurization of 3-mercapto-1,2,4-triazine yielded 5,6-disubstituted 1,2,4-triazine.755
3. Condensation of amidrazone with diethyl dioxosuccinate resulted in the formation 5,6-disubstituted 1,2,4-triazine derivative. Cyclization as well as decarboxylation takes place simultaneously.756
4. Condensation of S-methylthiosemicarbazide with glyoxal or another α,β-dicarbonyl compound readily affords the 3-methylthio 1,2,4-triazine, which on reaction with hydrazine was easily converted to its 3-hydrazino derivative. Oxidation with activated manganese dioxide yielded 1,2,4-triazine. The yield of triazine was, however, low. This shortcoming was overcome by converting the 3-methythio-1,2,4-triazine to its 3-methoxy derivative, which is then converted to its 3-hydrazino derivative in high yield. Oxidation with activated manganese dioxide yielded the parent compound.757
5. [4 + 2] Domino annulation: Simple and efficient [4+2] domino annulations in one pot for the synthesis of 1,2,4-triazines have been reported. The process involves reaction of benzimidohydrazide with acetophenone,
200
2. Six-Membered Heterocycles
styrene, 1-phenylethanol, 1,2-diphenylethyne, and phenylacetaldehyde in the presence of oxidants like selenium dioxide, iodine, copper oxide, etc. yielding 1,2,4-triazine derivatives.758
6. Cyclization of acylhydrazones of 1,2-dicarbonyl compounds with ammonia yields 1,2,4-triazines.759, 760
7. Reaction of phenacyl bromide/chloride with acylhydrazide yields 1,2,4-triazine. The reaction is proposed to take place by the following mechanism.761
8. Substituted 1,2,4-triazines were conveniently synthesized in one step by condensation of amides with 1,2-diketones in the presence of a base, followed by cyclization with hydrazine hydrate.762
The reaction was also carried out under microwave irradiation without using solvent and better yields of triazines were obtained compared to the conventional process. 1,2,4-Triazines are also obtained by refluxing acylhydrazones with ammonium acetate in acetic acid. Acylhydrazone required as substrate was prepared by reaction of ethyl 3-oxobutanoate with p-toluenesulfonyl azide and triethylamine, which produced ethyl 2-diaza-3-oxobutanoate. This on treatment with triphenylphosphine followed by hydrolysis and acylation in the presence of pyridine763 afforded acylhydrazone. This on treatment with ammonium acetate in acetic acid delivered substituted 12,4-trazines.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
201
9. By ring enlargement: Heating 1-benzohydrazonyl-1,2,3-triazoles with a slight excess of sodium hydride in dry benzene gave 1,2,4-triazines. The reaction proceeds by the formation and decomposition of aryl(1,2,3-triazol1-yl)diazomethanes by Bamford-Stevens reaction, followed by ring enlargement of the resulting carbene.
Physical Properties 1,2,4-Triazine has a low mp of 16–17.5°C, and is a yellow-colored liquid with a bp of 158°C. It is soluble in nearly all organic solvents. It is stable to acid, less stable to base, and is hygroscopic. It is stable and can be stored at temperatures below 0°C. When stored in a refrigerator for a longer period of time, it becomes an amber-like solid, whose constitution has 1 mol of 1,2,4-triazine and 1 mol of water. Chemical Reactivity 1. Quaternization: 1,2,4-Triazines are weak bases because they are unable to form salts with dilute mineral acids. However, 3-methyl-5,6-dimethyl-1,2,4-triazine gave a good yield of colorless monomethiodide when quaternized in methanol.764 Reaction of 1,2,5-triazin-3-one with concentrated nitric acid, the ring is ruptured and 1,2-dicarbonyl compounds are isolated.
2. Cycloaddition reaction: 1,2,4-Triazine is a classical example of a synthetically accessible moiety capable of diene 4π participation in an IED-DA (Inverse Electron Demand-Diels Alder) reaction with electron-rich dienophiles. Cycloaddition reaction between 1,2,4-triazine and enamines is regioselective and takes place with [4+2] addition exclusively across C-3/C-6 of the triazine moiety with more nucleophilic carbon of the dienophile bonding to the C-3. The cycloaddition reaction is followed by in situ retro-Diels-Alder reaction with loss of nitrogen and in situ elimination of pyrroline yielding 3,4-disubstituted pyridines.765, 766
202
2. Six-Membered Heterocycles
3-Phenyl-1,2,4-triazine reacts with enamine first to form the 3,4-dihydropyridine derivative, which on oxidation followed by Cope elimination affords 2-phenydihydrocyclopenta[c]pyridine. Similarly, 6-phenyl-1,2,4-triazine initially forms the 3,4-dihydropyridine derivative, which after the elimination of amine yields 5-phenyldihydrocyclopenta[c] pyridine.
The IED-DA reaction of 1,2,4-triazines with electron-rich olefins has been used for the synthesis of natural products. For example, four members of the louisianin family (A, B, C, and D) are simple pyridine derivatives displaying both antibacterial and anticancer activity and have been synthesized from 1,2,4-triazine from a common tetrasubstituted pyridine intermediate.767
3. Covalent hydration: Addition of water to a solution of 1,2,4-triazine in TFA yields the hydrated compound, which is stabilized by protonation.
4. Nucleophilic substitution reaction: The most reactive position in 1,2,4-triazine where nucleophilic substitution reaction can take place is C-5 and the least reactive site is C-3.768 Reaction of 1,2,4-triazine with methylmagnesium iodide at room temperature yielded 5,6-dimethyl-3-phenyl- 2,5-dihydro-as-triazine, which on oxidation with potassium permanganate aromatized to 5,6-dimethyl-3-phenyl-1, 2,4-triazine. Similarly, in the presence of sodium hydride, reactive methylene compounds, phenylacetonitrile and acetophenone, add smoothly at position 5 to yield an adduct, which on oxidation yields the aromatic triazine derivative.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
203
Reaction of 1,2,4-triazine derivative with hydrazine and hydrogen peroxide separately yields 5-hydrazino-6- methyl-3-phenyl-1,2,4-triazine and 6-methyl-5-oxo-3-phenyl-2,5-dihydro-as-triazine.
Direct nucleophilic acylation of 1,2,4-triazine in which a nitronate anion serves as a nucleophilic acyl group has been reported. 1,2,4-Triazine reacts with nitromethane and other primary nitroalkanes in the presence of an excess of powdered KOH in DMSO to yield the oxime derivative, which is then cleaved by sodium dithionite to yield the carbonyl derivative.769
5. Reduction: 1,2,4-Triazines are reduced with zinc in glacial acetic acid/alcohol to the dihydro derivative along with the imidazole derivative.770
Reduction of 3-(methythio)-5-phenyl-1,2,4-triazine and 3-methoxy-5-phenyl-1,2,4-triazine with sodium borohydride separately gave 3-(methylthio)-5-phenyl-2,5-dihydro-1,2,4-triazine and 3-methoxy-5-phenyl-2,5-dihydro1,2,4-triazine respectively in good yield.771
Electrochemical reduction of 1,2,4-triazine leads to the unstable 1,4-dihydro derivative, which rearranges to 1,2- or 4.5-dihydro derivative. These derivatives are further reduced to imidazole or tetrahydro-1,2,4-triazine.772
204
2. Six-Membered Heterocycles
6. Suzuki reaction: Bromination of 3-amino-1,2,4-triazine followed by Suzuki coupling with a variety of boronic acids and subsequent deamination yielded substituted triazines. These triazines then react with trans-cyclooctene.773
7. Oxidation: Oxidation of 1,2,4-triazines with peracids yielded 1,2,4-triazin-5-ones.774
2.5.4 1,3,5-Triazine 5
4
N
6
N3 N
2
1
1,3,5-Triazine is the systematic name for one of the three isomers of triazines. However, in some literature the term s-triazine has been used, where s denotes symmetrical due to symmetry in the arrangements of all three nitrogen atoms in the ring. Structural and Reactivity Aspects775a X-ray studies suggest that the symmetrical 1,3,5-triazine molecule is planar but deviates quite markedly from regular hexagon. The CN bond distance is 131.9 pm and the CH bond distance is 100.0 pm. The NCN and CNC bond angles were found to be 126.8 and 113.2 degrees, respectively.775b The 1H and 13C NMR confirmed the symmetrical nature of the molecule with H- and C-atoms being highly deshielded (due to the presence of the alternating N-atom in the ring) and appearing as a singlet at δ 9.25 and δ 166.1, respectively. The UV spectrum of 1,3,5-triazine in cyclohexane shows two absorption bands at 218 (2.13) and 272 (2.89) nm. Importance in Natural Products, Medicines, and Materials In recent years, the 1,3,5-triazine skeleton has been one of the most interesting chemical cores and has been subjected to extensive studies. This scaffold has provided the basis for the design of compounds that have useful agricultural and medicinal applications. An important application of 1,3,5-triazine derivatives or compounds containing this skeleton is as herbicides, fungicides, and insecticides. Anilazine finds use as a fungicide, menazon as an insecticide, and simazine, atrazine, cyanazine, and prometon as herbicides.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
205
Fungicide, insecticide and herbicides containing 1,3,5-triazine skeleton.
Cyanuric acid is a disinfectant and herbicide used as a chlorine stabilizer in swimming pools. Cyanuryl chloride or cyanuric chloride is an important triazine derivative, which has been used as a starting material for the synthesis of herbicides, optical brighteners and reactive dyes. Melamine is used to produce melamine resin, a durable thermosetting plastic.
Important 1,3,5-triazine derivatives.
Molecules possessing a 1,3,5-triazine nucleus have been found to display a wide range of interesting biological activities and many are in use as drugs. For example, 5-azacytidine (trade name Vidaza) is used for the treatment of myelodysplastic syndrome and as an anticancer agent, tretamine, dioxadet, and altreamine are used as anticancer agents, hydramitrazine as an antispasmodic, and chlorazanil as a diuretic.
Drugs containing 1,3,5-triazine skeleton.
Chemical Synthesis 1. Unsubstituted 1,3,5-triazine is synthesized by thermal cyclocondensation of formamidine acetate and triethyl orthoformate.776
206
2. Six-Membered Heterocycles
2. Nef method: The method involves treating hydrogen cyanide with ethanol in ether saturated with hydrogen chloride. The resulting iminoethyl formate hydrochloride, on neutralization with sodium hydroxide, followed by distillation, yields s-triazine.777
3. A more satisfactory method for the synthesis of unsubstituted s-triazine is via so-called sesquihydrochloride of hydrocyanic acid (prepared from hydrogen cyanide and hydrogen chloride), which loses two-thirds of its hydrogen chloride and splits off one-third on reaction with a basic acceptor.
4. Trimerization of imidates in the presence of sodium acetate yielded trisubstituted s-triazine.778
5. Reaction of N′-acyl-N,N-dimethylamidine with amidine forms trisubstituted 1,3,5-triazines.779
6. Benzoguanamine, which is an intermediate for pharmaceuticals and is used to increase the thermoset properties of alkyd, acrylic, and formaldehyde resin, is synthesized by heating benzonitrile and dicyandiamide in the presence of potassium hydroxide and methyl cellosolve.780
7. Cyanuric acid,781 an important 1,3,5-triazine derivative, is synthesized by heating free cyanic acid at 150°C.
8. Cyanuric chloride (2,4,6-trichloro-s-triazine) is prepared by the action of chlorine on hydrocyanic acid in direct sunlight.782
9. Reaction between N-cyanoamidines and chloromethylene iminium salt yields the s-triazine derivative.783
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
207
10. Pinner triazine synthesis: This reaction, first reported by Adolf Pinner in 1890, involves reaction of arylamidines with phosgene yielding s-triazines.
11. Ostrogovich synthesis: The synthesis of s-triazine784 involves the reaction of thioacids with cyanoguanidine leading to the formation of an intermediate, which was cyclized to 2-thio-4-amino-6-methyl-s-triazine.
Physical Properties 1,3,5-Triazine is a white crystalline solid with mp of 85–86°C, a bp of 114°C, and is very volatile and hygroscopic. It is easily soluble in most organic solvents. Chemical Reactivity 1. Electrophilic substitution reaction: 1,3,5-Triazines under the influence of the inductive effect of the three nitrogen atoms do not undergo electrophilic substitution reaction. However, bromination reaction takes place probably via nucleophilic addition reaction.785
Similarly, chlorination of s-triazine takes place at higher temperature (200°C) yielding cyanuric chloride as the major product and dichlorotriazine as the minor product.
Reaction of s-triazine with dinitrogen pentoxide and quenched with methanol produces 1,3,5-trinitro-2, 4,6-trimethoxyhexahydrotriazine, which on chromatography yields cis- and trans-2,4,6-trimethoxy-1,3,5- trinitrohexahydrotriazine in equimolar ratio.786
2. Nucleophilic substitution reaction: 1,3,5-Triazines are susceptible to nucleophilic attack and the reaction probably takes place via a ring-opening process leading to the generation of important heterocycles like triazoles and benzimidazoles.787,788
208
2. Six-Membered Heterocycles
Due to symmetrical arrangement of nitrogen atoms in s-triazine, each carbon is susceptible to nucleophilic attack by alkyllithium to give a 1,4-adduct, which on hydrolysis yields 1,4-dihydrotriazine. However, on reaction with LiNR2, the triazine ring is opened leading to the formation of crystalline 3-lithio-1,3,5,7-tetraazaheptratriene.789, 790
The formation of lithium salt has been proposed to take place by the following mechanism.
Reaction of 1,3,5-triazine with amines takes place with the opening of the triazine ring forming corresponding amidines.791
s-Triazine reacts with sodium amide in xylene at 160°C (in an autoclave) forming disodium salt of cyanamide, which was confirmed by its transformation to dibutylcyanamide.791
s-Triazine reacts with hydroxylamine forming N,N′-dihydroxyformimidamide.
Nucleophilic attack of cyanamide on s-triazine in the presence of secondary amine leads to the formation of a dehydro-N-Mannich base. The reaction takes place with the formation of two intermediates with the following proposed792 mechanism.
Reaction of 1,3,5-triazine with dimethyl 1,3-acetonedicarboxylate produced dimethyl 4-hydroxypyridine-3,5- dicarboxylate.793
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
209
3. Formylating reagent: In Gatterman’s aldehyde synthesis, hydrogen cyanide can be substituted by 1,3,5-triazine. In the presence of hydrogen chloride, triazine undergoes electrophilic attack on aromatic compounds like furans, pyrroles, and polyhydroxybenzenes yielding an intermediate aldimine hydrochloride, which is hydrolyzed to aldehyde.794, 795
Formylation of 1-(2-hydroxyphenyl)-2-(4-hydroxyphenyl)ethan-1-one with 1,3,5-triazine, followed by cyclocondensation with boron trifluoride etherate, afforded isoflavones.796, 797
4. Methylating agent: 1,3,5-Triazine is very susceptible to nucleophilic attack. Two molecules of a primary amine can be added to each carbon atom leading to ring cleavage, release of ammonia gas, and 3 equivalents of disubstituted formamidine. Thus reaction of aliphatic or aromatic diamines with s-triazine yields heterocyclic derivatives.798
Electron-rich nitrogen of s-triazine can abstract a proton from the reactive methylene compounds like malonic acid derivatives yielding a carbanion, which can then be added to the triazine carbon. The intermediate aminomethyl recyclizes to produce 4,5-disubstituted pyrimidines.799
5. 1,3,5-Triazine functions as an azadiene in an IED-DA reaction, producing pyrimidine or a fused pyrimidine ring system. For example, 1,3,5-triazines on reaction with electron-rich alkyne dienophiles yield pyrimidines.800, 801
Under mild thermal conditions, 1,3,5-triazines also react with cyclic as well as acyclic enamines, which are electron- rich dienophiles, to give pyrimidines.
210
2. Six-Membered Heterocycles
5-Aminopyrazoles react with electron-deficient 1,3,5-triazines to give various pyrazolopyrimidines. This new type of IDA reaction is highly regioselective with the 5-amino group being the determining factor.802, 803
This new type of IDA reaction has been useful in the synthesis of the natural product nebularine in one step.
Tetrazine Tetrazines are thought to be benzene derivatives in which the four CH units of benzene have been replaced by four electronegative nitrogen atoms. There are three important possible isomers of tetrazines, namely 1,2,3,5-tetrazine, 1,2,3,4-tetrazine, and 1,2,4,5-tetrazine.
2.5.5 1,2,3,4-Tetrazine 1 6 5
N N
N2 N3
4
1,2,3,4-Tetrazine is one of the isomers of tetrazines, and is more commonly referred to as ν-tetrazine or osotetrazine. The parent 1,2,3,4-tetrazine is unstable and its stability is increased by fusion with five- and six-membered rings and also by making their oxides. Structural and Reactivity Aspects804 An X-ray of 5,7-di-tert-butyl-2-R-2H-cyclopenta[e]-1,2,3,4-tetrazine has been recorded. The X-ray reveals that the molecule is planar and CC bond lengths are in good accordance with the aromatic ring bonded to a five-membered ring. The NN bond lengths are of typical value due to resonance as depicted by the following resonance structures.
Resonating structures of 1,2,3,4-tetrazine derivative.
The selected bond lengths (Å) are given in the following table. Selected bond lengths of 1,2,3,4-triazine CN1
N1N2
N2N3
N3N4
CN4
1.312
1.328
1.358
1.300
1.344
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
211
The 1H and 13C NMR of benzotetrazine 1,3-dioxide in acetone-d6 have been recorded.
1
H and 13C NMR spectral data of benzotetrazine 1,3-dioxide
1
H NMR δ (ppm)
13 C NMR δ (ppm)
H-5, 7.92; H-6, 8.18; H-7, 7.91; H-8, 8.35
C-4a, 144.7; C-5, 125.2; C-6, 139.2; C-7, 132.3; C-8, 119.9; C-8a, 129.0
The 15N NMR spectrum of benzotetrazine 1,3-dioxide was quite helpful in ascertaining the tetrazine structure. The spectrum in acetone d6 showed four signals. N NMR spectral data of benzotetrazine 1,3-dioxide
15
N1
N2
N3
N4
−41.0
−23.9
−48.7
−81.9
The UV spectrum of benzotetrazine-1,3-dioxide shows two strong absorption bands at 310 and 420 nm. The first band is due to π→π* transition, whereas the second one is due to n→π* transition. Importance in Natural Products, Medicines, and Materials804 So far there have been no reports of the synthesis of the parent monocyclic 1,2,3,4-tetrazine. However, 1,2,3,4-benzotetrazine-1,3-dioxide is a stable compound, hence the biological activity of this compound is discussed here. 1,2,3,4-Benzotetrazine-1,3-dioxide is biologically active due to its ability to release nitrosating species during their reduction.805 Thus they are considered to be nitric oxide donors,806 which make them a promising drug molecule for treating cardiovascular, inflammatory, bacterial, and other viral diseases. 5-Nitro and 7-nitro derivatives of benzotetrazine 1,3-dioxide are effective thiol-dependent activators of cyclase. They exhibit hypotensive as well as reduced caspase activity. 1,2,3,4-Benzotetrazine-1,3-dioxide and its 6- and 7-bromo derivatives are inhibitors of ADP-induced aggregation of human platelets. Besides, they also showed antimetastatic properties.807 Synthesis808 There is no published work or evidence for the synthesis of the parent monocyclic 1,2,3,4-tetrazine. The first example of an aromatic 1,2,3,4-tetrazine-6-phenyl[1,2,3]triazolo[4,5-e]-1,2,3,4-tetrazine was reported in 1988. Otherwise, all others are either their substituted dihydro derivatives or their benzo oxide/dioxide derivatives. 1. The first synthesis of 1,2,3,4-tetrazine derivative was reported in 1972. The process involves nitrosation and reduction of sym-dimethylethylenediamine to yield N,N′-dimethyl-N,N′-diaminoethylenediamine, which on oxidation with sodium hypochlorite yields 1,4-dimethyl-1,4,5,6-hexahydro-1,2,3,4-tetrazine.809
Synthesis of the alkyl/aryl derivatives of dihydrotetrazine was also reported by oxidation of N,N′-dialkyl/diaryl-N,N′- diaminoethylenediamine with potassium ferricyanide in the presence of potassium permanganate.810 2. Azoxyanilines on diazotization yield the diazonium salt. The chloroform solution of diazonium salt at 40°C, when passed through a pad of silica gel, gave the 1,2,3,4-benzotetrazine-1-oxide derivative.
212
2. Six-Membered Heterocycles
1,2,3,4-Benzotetrazine-1,3-dioxide is obtained when the diazonium salt is treated with peroxybenzoic acid in aqueous acetonitrile at 0°C.
1,2,3,4-Benzotetrazine-1,3-dioxide was also obtained in high yield when appropriate N-nitroanilines were treated with phosphoric anhydride or PCl5 in acetonitrile at ambient temperature.811
3. The first example of synthesis of an aromatic 1,2,3,4-tetrazine, 6-phenyl[1,2,3]-triazolo[4,5-e]-1,2,3,4-tetrazine, was reported in 1988, and was obtained by oxidation of 4-amino-2,4-dihydro-2-phenyl[1,2,3]triazolo[4,5-d][1,2,3] triazole.812
4. (6R) and (6S) stereoisomers of 1,2,3,6-tetrahydro-1,2,3,4-tetrazine have been synthesized by stereoselective DielsAlder reaction of chiral 1,2-diazo-1,3-butadiene with diethylazodicarboxylate. Initially, the reaction was slow at room temperature but on microwave irradiation it was greatly accelerated.813
Chemical Reactivity814 1. Electrophilic substitution reactions: Nitration of 1,2,3,4-benzotetrazine 1,3-dioxide with a mixture of sulfuric acid and nitric acid gave a mixture of 5-nitro- and 7-nitro-1,2,3,4-benzotetrazine-1,3-dioxides815 in a ratio of 1:2.
However, heating 1,2,3,4-benzotetrazine 1,3-dioxide with an HNO3/oleum mixture afforded a 5,7-dinitro derivative without opening the tetrazine ring. Bromination of 1,2,3,4-benzotetrazine 1,3-dioxide with dibromoisocyanuric acid in trifluoroacetic acid containing a little amount of sulfuric acid gave a mixture of 5-bromo- and 7-bromo products in equal ratio.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
213
2. Nucleophilic displacement reactions: Reaction of nitro- and bromo-1,2,3,4-benzotetrazine 1,3-dioxide with KOH/MeOH, NaN3/DMF, Me2NH/DMF, and MeNH2/DMSO resulted in the displacement of the bromo and nitro groups by methoxy, azido, dimethylamino, and methylamino groups without opening the tetrazine ring.816
3. Reduction: Reduction of 1,2,3,4-benzotetrazine 1,3-dioxide with Na2S2O4 or SnCl2 afforded benzotriazole.817
The reduction was suggested to proceed with the formation of benzotetrazine 2-oxide, which underwent a ring- opening process. The open chain tautomer is then cyclized to thermodynamically more stable N-nitrosobenzotriazole, which on hydrolysis gave benzotriazole.
4. Photochemical reaction: Photochemical reaction of 1,4-dimethyl-1,4,5,6-tetrahydro-1,2,3,4-tetrazine at room temperature yields 1,3,5-trimethyl-1,3,5-triazinane. The triazinane product is formed probably due to trimerization of formaldehyde N-methylimine, obtained from the diradical formed after evolution of nitrogen from tetrazine.818
Degradation of 6-phenyl[1,2,3]triazolo[4,5-e]-1,2,3,4-tetrazine in solution gave a mixture of triazole and tetrazole. The reaction probably takes place with the stepwise elimination of nitrogen.819
214
2. Six-Membered Heterocycles
2.5.6 1,2,3,5-Tetrazine 1 6
N
5N
N2 N3
4
1,2,3,5-Tetrazine is one of the isomers of tetrazine, which is more commonly referred as as-tetrazine. In this isomeric tetrazine, three nitrogen atoms are adjacently present, while the fourth nitrogen is present at position 5 of the ring. So far, there is no published work on the synthesis of the parent monocyclic 1,2,3,5-tetrazine. However, few biologically active compounds are known in which the tetrazine moiety is fused to the pyrazole ring. The two most important compounds of this category are temozolomide and mitozolomide. Both the compounds have been reported to exhibit antitumor activity.
Biologically active compounds with 1,2,3,5-tetrazine skeleton.
Synthesis 1. as-Tetrazine derivatives, along with some known compounds, have been synthesized by electrochemical oxidation of cyanamide with a platinum anode in aqueous potassium hydroxide solution followed by treatment of the anolyte with hydrochloric acid or carbon dioxide. The tetrazine derivatives obtained were 4-amino-6-cyanoamino-1,2,3,5-tetrazine, 4-amino-6-cyanoguanidino-1,2,3,5-tetrazine, and 4-ureido-6-cyanoguanidino-1,2,3,5-tetrazine.820
2. 5-Amino-4-cyano-3-methylpyrazole obtained from benzyl alcohol in four steps via a solid phase synthesis is converted to pyrazolo[5,1-d]-[1.2.3.5]tetrazine-4(3H)-one under one-pot sequential reaction conditions.821
3. Reaction of nitrilimine with 2-aminopyrimidine in the presence of triethylamine yielded pyrimido[2,1-d]1,2,3,5-tetrazine.822
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
215
Chemical Reactivity820,823 1. 4-Amino-6-cyanoamino-1,2,3,5-tetrazine when warmed at 40°C with dilute sulfuric acid or dilute hydrochloric acid gave amidinobiuret and nitrogen.
2. When hydrogen chloride gas was introduced into the dry acetone solution of potassium salt of 4-amino-6cyanoamino-1,2,3,5-tetrazine, hydrochloride of the base was the initial product, which on treatment with water gave 2,4-diamino-6-chloro-1,3,5-triazine.
3. When 4-amino-6-cyanoguanidino-1,2,3,5-tetrazine is heated with dilute mineral acid, it decomposes to melamine, carbon dioxide, ammonia, and nitrogen.
4. When 4-ureido-6-cyanoguanidino-1,2,3,5-tetrazine is heated with dilute mineral acid, it decomposes to melamine, carbon dioxide, ammonia, and nitrogen.
2.5.7 1,2,4,5-Tetrazine 4
5
N 6
N N
3
N2
1
1,2,4,5-Tetrazine is a six-membered planar and symmetrical nitrogen heterocycle with four nitrogen atoms present at the 1,2,4,5-positions of the ring. Of the three possible tetrazine isomers, 1,2,4,5-tetrazine is most commonly known as sym-tetrazine or s-tetrazine. Structural and Reactivity Aspects823 s-Tetrazine, which was first synthesized by Pinner in 1893, can best be represented by two degenerate Kekulé’s structures.
Kekule structure of s-tetrazine.
216
2. Six-Membered Heterocycles
The structure of 1,2,4,5-tetrazine has been determined by X-ray crystallography and the molecule was found to be almost planar and symmetrical. The experimental bond lengths and bond angles are in good agreement with the values calculated by semiempirical methods. Bond lengths and bonds angles of s-tetarzine Bond lengths (Å)
Bond angles (o)
NN
CN
NNC
NCN
1.321
1.334
115.6
127.2
The UV spectrum of 1,2,4,5-tetrazine in ethanol shows two strong bands at 274 (log ε 3.56) and 538 nm (log ε 2.75). The first band is due to π→π* transition, whereas the second band is due to n→π* transition. The symmetrical structure of 1,2,4,5-tetrazine is reflected in the 1H and 13C NMR spectra (in acetone d6) with one signal for the ring proton (δ 11.05) and one for the ring carbon atom (δ 161.2). The mass spectrum of s-tetrazine is found to be very simple and it fragments as follows.
Mass fragmentation pattern of s-tetrazine derivative.
Importance in Natural Products, Medicines, and Materials The most important feature regarding tetrazine is its high electron affinity, resulting in electrochemical reversible reduction potential, and its low-lying characteristic, which results in n→π* transition in the visible region, thereby making tetrazines deeply colored molecules. Because of these features, tetrazines display unique photochemical and electrochemical properties,824 which find use in a number of applications. 3,6-Disubstituted tetrazines find use in the development of sensors, optical switches, and solar cells. s-Tetrazines substituted with heteroatoms display fluorescent properties. Some are even fluorescent in a crystalline state, which makes them the smallest organic fluorophore fit for sensing applications. Dipyridyl-s-tetrazine and related molecules have frequently been used as bridging ligands in metallo-organic compounds.825 They are particularly useful in organic chemistry as synthetic intermediates for the synthesis of a number of natural products.826 New nanocomposite materials have also been obtained by reaction of s-tetrazine827 with C60 or carbon nanotubes.828 Tetrazine-N-hydro(di, tetra, hexa) derivatives exhibit numerous biological activities and some of them have been tested positive for antitumor activity.829 Besides, they are also used for intracellular small molecule imaging, postsynthetic DNA labeling, and in vivo imaging. Synthesis 1. Oxidation: There is no direct method for the synthesis of s-tetrazine. It is always obtained by oxidation of its 1,2-dihydro or 1,4-dihydro derivatives using a variety of oxidizing agents.
The most commonly used oxidizing agents are nitrous acid, halogens, ferric chloride, nitric acid, hydrogen peroxide, chromic oxide, and isoamyl nitrite.830 2. Pinner synthesis831: There are several methods for the synthesis of s-tetrazine derivatives. However, the first synthesis was reported by Pinner. The method involves reaction of hydrazine with benzonitrile forming a dihydrotetrazine derivative, which on oxidation yields the aromatic 3,6-diphenyl-1,2,4,5-tetrazine.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
217
However, Pinner method was applicable for aromatic nitriles that are not sterically hindered. This protocol was not suitable for aliphatic nitriles and the process was modified by replacing nitriles by aldehydes to obtain hexahydro-s-triazines, which on oxidation delivered volatile alkyl-substituted s-tetrazines.832, 833
The yields of the 1,2-dihydro derivatives in all reactions were not good but these have been improved by using sulfur as catalyst.834
The improved synthesis of the 1,2-dihydro derivative with the addition of sulfur is proposed to take place by the following mechanism.835
Recently, one-pot synthesis of s-tetrazines directly from aliphatic nitriles and hydrazines has been reported. The method involves reaction of benzyl cyanide with hydrazine in the presence of Lewis acid metal salts like ZnBr2, ZnCl2, Zn(OTf)2, Cu(OTf)2, MgBr2, MnBr2, CuBr2, etc., without involving isolation of the 1,2-dihydro derivative, which is oxidized by NaNO2 in the presence of HCl.836
3. Hantzsch and Lehmann synthesis: Base-catalyzed dimerization of ethyl diazoacetate afforded 1,2-dihydro1,2,4,5-tetrazine salt, which was neutralized, oxidized, and subsequently decarboxylated to yield s-tetrazine.837
218
2. Six-Membered Heterocycles
4. [4 + 2] condensation reaction: Dichloromethylhydrazines have also been used for the synthesis of tetrazines. The method involves reaction of dichloromethylhydrazines with hydrazine forming the dihydro derivative, which was oxidized to 1,2,4,5-tetrazine.
Dichloromethylhydrazines can be prepared by reaction of 1,2-diacylhydrazines with PCl5 or chlorination of 2-acylhydrazones with thionyl chloride and chlorine.838 5. One-pot synthesis of unsubstituted s-tetrazine was reported for the first time in 1980 by reaction between commercially available formamidine acetate and hydrazine acetate.839, 840
6. Many carboxylic acid derivatives like imidates, hydrazides, thioamides, and thiohydrazides also react with hydrazine to afford 1,2-dihydrotetrazine, which on oxidation yields tetrazine.841, 842
7. Green chemistry: An efficient green procedure was used for the synthesis of both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazine in moderate yield by the reaction of gem-difluoroalkenes with hydrazine under aerobic conditions at room temperature.843
8. Substituted hydrazines like 1-benzylidine-2-alkylhydrazine have also been employed for the synthesis of 1,2,4,5-tetrazine derivatives. The process involves treating the substituted hydrazine derivative with iodine and sodium hypochlorite.844
9. Synthesis by ring enlargement: On heating 3-azido-5-substituted 1,2,4-triazol-4-amine in chlorobenzene at 110°C liberates nitrogen to yield 6-substituted 1,2,4,5-tetrazine-3-amine.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
219
10. Dichlorotetrazine is a versatile synthon obtained by the sequence of reaction of guanidine with hydrazine followed by reaction with 1,3-dicarbonyl compounds and chlorine. It is used for the synthesis of a wide variety of tetrazine derivatives by nucleophilic displacement of chlorine by various nucleophiles like alcohols, thiols, and amines. Monosubstitution takes place readily at room temperature, whereas disubstitution requires forcing conditions. The method involves synthesis of bis(3,5-dimethyl-1H-pyrazol-1-yl)-s-tetrazine, which can subsequently be converted to 3,6-dichloro-s-tetrazine in two steps.
Physical Properties 1,2,4,5-Tetrazines are usually red, bluish red, or violet-red in color. They are quite unstable and can be stored only out of contact with air or at reduced temperatures. 1,2,4,5-Tetrazine itself is soluble in water and in most organic solvents. Chemical Reactivity 1. Aromatic nucleophilic substitution reaction: Due to the presence of four electron-withdrawing groups in the tetrazine core, it reflects a high degree of electrophilicity. Thus the groups present at positions 3 and 6 are capable of leaving as anions, and opening a new pathway by which modifications can be made in the s-tetrazine core by means of aromatic nucleophilic substitution reactions. The most common groups that are capable of leaving as anions are halogens, the methylsulfanyl group, and the 3,5-dimethylpyrazolyl group. The aromatic nucleophilic substitution reaction in s-tetrazine takes place by the following pathway.
Aromatic nucleophilic substitution in s-tetrazine.
Butan-1,4-diol reacts with 3,6-dichloro-1,2,4,5-tetrazine in the presence of 2,4,6-collidine at room temperature to give the monosubstituted derivative. Similarly, unsymmetrical-substituted tetrazine was synthesized by reacting 3,6-dichloro-1,2,4,5-tetrazine with excess ammonia.845
220
2. Six-Membered Heterocycles
3,6-Dichloro-1,2,4,5-tetrazine condenses with 2 equivalents of sodium salt of 5-aminotetrazole to yield the disubstituted 3,6-bis(1H-1,2,3,4-tetrazol-5-ylamino)-1,2,4,5- tetrazine.846
1,2,4-Trizole in acetone reacts with 3,6-dichloro-1,2,4,5-tetrazine to yield 3,6-bis-(1,2,4-triazol-1-yl)-1,2,4,5- tetrazine. Similarly, 3,5-diamino-1,2,4-triazole in DMF reacts with a solution of dichlorotetrazine in acetonitrile to yield 3,6-bis-(3,5-diamino-1,2,4-triazolyl-1-yl)-1,2,4,5-tetrazine.847
2. N-oxidation: Oxidation of 1,2,4,5-tetrazine-3,6-diamine with performic acid affords 1,4-dioxide as the major product with 1-oxide as the minor product. However, oxidation with trifluoroperoxyacetic acid yields 1-oxide as the major product and 1,5-dioxide as the by-product.
3. Reduction: s-Tetrazine can easily be reduced by 1,2-dihydrotetrazines or dihydropyridazines to 1,4-dihydro-1,2,4,5-tetrazine.
Reduction of 3,6-diphenyl-1,2,4,5-tetrazine with lithium aluminum hydride leads to isolation of benzalazine.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
221
However, reduction with sodium borohydride yields 1,6-dihydro-1,2,4,5-tetrazine as the product.
4. Amination: Reaction of 3-alkyl/aryl-1,2,4,5-tetrazine derivative with liquid ammonia between −45 and −35°C affords homoaromatic σ adducts, which are ionic and this has been confirmed on the basis of 1H and 13C NMR spectroscopy.848
5. Cycloaddition reaction: Tetrazines due to the presence of four electron-withdrawing nitrogen atoms in the ring are commonly used as azadiene in a [4+2] cycloaddition reaction. 3,6-Bis-(polyfluoroalkyl)-s-tetrazine reacts with a variety of unsaturated compounds like styrene, acetylene, aliphatic and alicyclic olefin, and allene with ease to yield pyridazines. However, 3,6-diphenyl and 3,6-dimethyl-s-tetrazine reacts similarly but less readily.849
s-Tetrazine undergoes [4+2] cycloaddition reaction with open chain alkenes like ethylene to initially form 4,5-dihydropyridazine, which undergoes trimerization to give a mixture of stereoisomers with respect to the central triazine ring system.
An inverse demand Diels-Alder reaction of unsubstituted s-tetrazine was reported for the first time in 1987. The method involves reaction of s-tetrazine with 4,5-dihydro-1-methyl-2-(methythio)pyrrole yielding 2,3-dihydro-1methylpyrrolo[2,3-d]pyridazine.850
1,2,4,5-Tetrazine reacts with electron-rich dienophile to produce the pyridazine derivative. This IED-DA reaction proceeded via a bridged intermediate, which after loss of nitrogen yields the desired pyridazine.851
222
2. Six-Membered Heterocycles
Similarly, a cycloaddition reaction of 1,2,4,5-tetrazine with alkynylboronate ester yielded boronic ester, which undergoes a Suzuki coupling reaction to generate the pyridazine derivative.852, 853
s-Tetrazine undergoes an electron demand Diels-Alder process with simple alkenes to dihydropyridazine, which on oxidation forms the pyridazine derivatives.
This method has been used for the synthesis of a derivative of the natural isolate epibatidine.854 The reaction commences with the cycloaddition of tetrazine with enol ether forming an intermediate, loss of nitrogen, and subsequent methanol elimination yields the product.
s-Tetrazine on reaction with thietanone undergoes a series of condensations-fragmentations and cyclization to yield pyrazol-4-ol.
2.6 Six-Membered Heterocycles With One Oxygen Atom
223
Tetrazine undergoes a [4+2] cycloaddition reaction with epoxy naphthalene derivative yielding an intermediate, which undergoes a retro[4+2] reaction to yield isobenzofuran, which rapidly reacts with a C60 molecule to yield a [4+2] cycloaddition product.855
2.6 SIX-MEMBERED HETEROCYCLES WITH ONE OXYGEN ATOM 2.6.1 Pyrans Pyrans or oxines are monocyclic six-membered oxygen heterocycles with two double bonds. There are two isomeric forms of pyran designated as 2H- and 4H-pyran, which differ only in the location of the double bonds. 2HPyran has a saturated carbon at the C-2-position, whereas 4H-pyran has a saturated carbon at C-4. Since both of them lack the conjugated double bond characteristic of benzene and pyridine, as a consequence both pyrans are unsaturated closed chain compounds lacking aromatic properties.
2.6.2 2H-Pyran 3
4
2 O 1
5 6
Structural and Reactivity Aspects856 The IR spectrum of 2H-pyran shows typical CC stretching bands at 1600–1650 cm−1. In the 1H NMR spectrum of a 2H-pyran derivative in CCl4, 3H and 4H olefinic protons were observed at δ 4.89 and δ 5.60, respectively. Importance in Natural Products, Medicines, and Materials 2H-Pyran derivatives constitute a class of rare compounds and there are only a few examples in which this nucleus is present in a natural product. Among them is versicolin, an antibiotic that has been isolated from Aspergillus versicolor.857
Synthesis So far there has been no evidence for the existence of parent 2H-pyran. However, due to the importance of this nucleus, a number of its polyfunctionalized derivatives have been synthesized.
224
2. Six-Membered Heterocycles
1. Palladium-catalyzed cycloisomerization of enynols through a 6-endo-dig cyclization leads to 2H-pyran derivative.
2. Methylmagnesium bromide when added to pyrylium ion forms the 2H-pyran derivative, which on heating tautomerizes to dienones.
3. Addition of metal hydride complexes such as sodium borohydride to pyrylium salt takes place at the C-2position leading to the generation of 2H-pyran derivative.
4. An efficient and divergent one-pot synthesis of substituted 2H-pyran involving intermolecular cyclization of βoxo amides was mediated by N,N,N′,N′-tetramethylchloroformamidinium chloride (TMC).858
5. Reaction of α-halo carbonyl compound with dimethyl aceylenedicarboxylate (DMAD) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalyst at room temperature yields a furan derivative (minor product) and highly functionalized 2H-pyran as the major product.859
6. One-pot synthesis of highly stable 2H-pyran from propargyl vinyl ethers has been reported. The process proceeds via an Ag(I)-catalyzed propargyl-Claisen rearrangement, followed by base-catalyzed isomerization and 6π-oxaelectrocyclization leading to the formation of the 2H-pyran derivative.860
Chemical Reactivity 1. It has been observed that 2H-pyran undergoes electrocyclic ring opening to dienone.861
2.6 Six-Membered Heterocycles With One Oxygen Atom
225
2. 2,2,4,6-Tetramethyl-2H-pyran undergoes regioselective Diels-Alder reaction with propiolic ester to give a bicyclo adduct, which on cycloreconversion and acetone elimination yields 2,4-dimethylbenzoate.
3. 2,4,6-Triphenylpyrylium ion on reaction with butylamine, cyclohexylamine, etc. yields corresponding ringopened divinylogous amides. This reaction is thought to proceed with the formation of a charged 2H-pyran reaction intermediate.862
Similarly, on heating 2,2,4,6-tetramethyl 2H-pyran the heterocyclic ring is opened yielding a product that on reaction with LiAlH4 yields a reduced product.
4. Polyfunctionalized 2H-pyrans, which in aqueous solution are in equilibrium with their pyrylium cation, readily undergo a ring-opening process leading to the generation of diketones.863, 864
2.6.3 3,4-Dihydro-2H-Pyran 4 3
5 6
O
2
1
3,4-Dihydro-2H-pyran, also known as 2,3-dihydro-4H-pyran, is a six-membered nonaromatic heterocycle with one oxygen atom and one double bond in the ring. It is chiefly used as a protecting agent.
226
2. Six-Membered Heterocycles
Structural and Reactivity Aspects865 The 1H and 13C NMR spectra of 3,4-dihydro-2H-pyran suggest it to be a cyclic enolic ether. H and 13C NMR spectral data of 3,4-dihydro-2H-Pyran
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.97; H-3/4, 1.90; H-5, 4.65; H-6, 6.37
C-2, 65.8; C-3, 22.9; C-4, 19.6; C-5, 100.7; C-6, 144.2
Examination of the Raman spectra suggests that the dihydropyran moiety exists predominantly in the half chair conformation with a twist angle of 23 degrees. Groups present at the 2-position may be either equatorially or axially oriented, but out of the two the conformer in which the group is axially oriented predominates due to an anomeric effect. OR H
O
RO
O H
Conformations of dihydropyran.
Importance in Natural Products, Medicines, and Materials A 3,4-dihydro-2H-pyran skeleton is present in a number of natural products like carbohydrates, iridoid alkaloids, and antibiotics. A number of drugs containing this skeleton have been reported. For example, zanamivir and laninamivir, the two drugs that are recommended for the treatment of influenza caused by influenza A and B viruses, contain this skeleton.
Drugs containing 3,4-dihydro-2H-Pyran skeleton.
Synthesis 1. 3,4-Dihydro-2H-pyran is synthesized by catalytic dehydration of tetrahydrofuryl alcohol with alumina at higher temperatures.866
2. [4 + 2] cycloaddition reaction: This is a reaction of synthetic importance because substituted dihydropyran derivatives are synthesized by this method. The reaction involves heating crotonaldehyde with methyl vinyl ether at 200°C in an autoclave in the presence of a catalytic amount of hydroquinone.867
3. 4-Acyloxylbutylphosphonium salt obtained by reaction of 1,4-dibromobutane with triphenylphosphine undergoes intramolecular Wittig reaction yielding 6-methyl-3,4-dihydro-2H-pyran.868
2.6 Six-Membered Heterocycles With One Oxygen Atom
227
4. Substituted dihydropyran derivatives were synthesized by the reaction of Baylis-Hillman acetate with 2,4-pentanedione869 in the presence of DABCO in aqueous THF at 42–50°C.
Physical Properties 3,4-Dihydro-2H-pyran, a cyclic vinyl ether, is a colorless, flammable liquid with a bp of 86°C. It is soluble in water and ethanol. Chemical Reactivity 1. Addition of hydrogen: 3,4-Dihydro-2H-pyran on hydrogenation in the presence of nickel yields tetrahydro-2H-pyran.870
2. Addition of halogen acid: Hydrochloric and hydrobromic acid adds across the reactive double bond forming corresponding 2-halotetrahydro-2H-pyran, which readily undergoes dehydrohalogenation. This property has thus been used for the synthesis of 2-substituted tetrahydro-2H-pyran. For example, 3,4-dihydro-2H-pyran on reaction with hydrogen bromide forms 2-bromotetrahydro-2H-pyran, while on reaction with mercuric cyanide or silver cyanide 2-cyanotetrahydro-2H-pyran is the product.871
3. Addition of halogen: Halogens adds across the reactive double bond forming the 2,3-dihalo derivative. Halogen at the 2-position can easily be substituted by a reactive group. 3,4-Dihydro-2H-pyran reacts with bromine to form 2,3-dibromotetrahydro-2H-pyran, which on reaction with silver cyanate yielded 3-bromo-2isocyanatotetrahydro-2H-pyran .872
4. Addition of bromine fluoride: Bromine fluoride generated in situ by reaction of bromine with silver fluoride added across the reactive double bond yielded a trans-derivative as the major product.873
228
2. Six-Membered Heterocycles
5. Hydroboration: Hydroboration takes place regioselectively leading to the generation of tetrahydro-2H-pyran-3-ol.874
6. Reaction of 3,4-dihydro-2H-pyran with diethyl hydroxymethylphosphonate and phosphorous oxychloride yields diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate.
7. Cycloaddition reaction: The addition of carbene to alkene to give a cyclopropane derivative is one of the characteristic reactions of carbene. Carbene generated by reaction of methylene iodide with a zinc-copper couple reacts with 3,4-dihydro-2H-pyran to yield the cyclopropane derivative.875
Dichlorocarbene, the halogen derivative of carbene, has been generated by a variety of methods by the use of chloroform and alkali metal alkoxide, sodium trichloroacetate, butyllithium, and bromotrichloromethane. However, dichlorocarbene generated by using trichloroacetic acid and an alkali metal alkoxide gives a higher yield of adduct.876 The adduct on dehydrohalogenation results in opening of the cyclopropane ring to give a 2,3-dihydrooxepine system.
Diphenylketene undergoes cycloaddition reaction with 2,3-dihydropyran to yield the cyclobutanone derivative.877
Diphenylacetylene on reaction with an excess of 3,4-dihydro-2H-pyran yielded the cyclobutene derivative878 on irradiation at 2537 Å.
8. When 3,4-dihydro-2H-pyran is stirred with dilute hydrochloric acid, ring opening takes place leading to the generation of 5-hydroxypentanal.879
2.6 Six-Membered Heterocycles With One Oxygen Atom
229
9. As protecting group: In organic synthesis, in the presence of acid catalyst, 3,4-dihydro-2H-pyran is used as a protecting group for alcohols. Reaction of alcohols with dihydropyran forms dihydropyranyl ether. These ethers are stable to alkali, organolithium, Grignard reagent, LiAlH4, and acetic anhydride, yet they undergo hydrolysis with dilute acid to regenerate the alcohol.
A mixture of camphorsulfonic acid, propargyl alcohol, and 3,4-dihydro-2H-pyran in dichloromethane when stirred for 2 h yields 2-propargyloxytetrahydropyran.880
In addition, 3,4-dihydro-2H-pyran has also been effectively used for the protection of the carboxylic group, secondary amines, and amides.
10. Hypohalogenation of3,4-dihydro-2H-pyran was effected by the use of trichloroisocyanuric acid in the presence of water. In addition to trans-2-hydroxy-3-chlorotetrahydro-2H-pyran,2,2'-oxybis(3-chlorotetrahydro-2H-pyran) was also formed.881
11. A stereoselective synthesis of (E)-4-hexen-1-ol involves chlorination of 3,4-dihydro-2H-pyran to yield 2,3-dichlorotetrahydro-2H-pyran, which underwent coupling with methylmagnesium bromide and afforded 3-chloro-2-methyltetrahydro-2H-pyran, which on treatment with an ethereal suspension of sodium, followed by hydrolysis of the sodium salt solution with water.882
12. Oxidation: Oxidation of 3,4-dihydro-2H-pyran with nitric acid yields glutaric acid while oxidation with osmium tetraoxide provided tetrahydro-2H-pyran-2,3-diol.Ozonolysis of 3,4-dihydro-2H-pyran yielded hydroperoxide which on treatment with tributoxyphosphine yields aldehyde while reaction with toluenesulfonyl chloride provided methyl 4-(formyloxy)butanoate.
230
2. Six-Membered Heterocycles
2.6.4 Tetrahydropyran 4 3
5 6
O
2
1
Tetrahydropyran is a saturated six-membered heterocyclic compound composed of five sp3-hybridized carbon atoms and one sp3-hybridized oxygen atom. In fact, it is considered to be a cyclohexane derivative in which one of the carbon atoms of cyclohexane has been replaced by oxygen, hence it is also known as oxacyclohexane. Structural and Reactivity Aspects883a The structure of tetrahydropyran was determined in the gaseous state by electron diffraction and microwave spectroscopy. These studies suggest that this six-membered oxygen heterocyclic compound like cyclohexane exists in chair conformation with Cs symmetry. In chair conformation, tetrahydropyran exits in two isomeric forms, specified as 1C4 and 4C1. The letter C stands for chair and the number indicates the carbon atoms, which are located above or below the reference plane of the chair conformation. The energy barrier for this ring flipping is about 10 kcal/mol. 1
4
O
O 4
4
C1
1
C4
1
Conformations of tetrahydropyran.
The free energy of activation for ring inversion was calculated to be 42.3 kJ mol−1 (at 212 K) and this value was quite similar to cyclohexane (43.0 kJ mol−1) but lower than that of piperidine (46.1 kJ mol−1). The bond angles and bond lengths of tetrahydropyran in the gas phase as determined by electron diffraction and microwave spectroscopy are given in the following diagram.
Bond lengths and bond angles of tetrahydropyran.
The 1H and 13C NMR spectra of tetrahydropyran are quite similar to that of a cyclic ether. H and 13C spectral data of tetrahydropyran
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2/H-6, 3.65; H-3/H-4/H-5, 1.65
C-2/C-6, 68.6; C-3/C-5, 27.4; C-4, 24.3
231
2.6 Six-Membered Heterocycles With One Oxygen Atom
Importance in Natural Products, Medicines, and Materials The tetrahydropyran nucleus has been found to be present in a number of natural products that have shown significant biological and pharmacological activities, for example, antifungal, cytotoxic macrolides, Phorboxazole A and B,883b antileishmanial agent, (−)-centrolobine,884 microbial product with antitumor activity, and GEX1A (herboxidiene).885 R1
O
R2
N OMe OMe
O
O N
Br
O OH
OH
O
O
O
O
Phorboxazole A,
R1= H, R2 = OH
Phorboxazole B,
R1= OH, R2 = H Me
OH
MeO (-)-Centrolobine
OMe
O
O
Me
O COOH
Me
Me
Me
Me
OH
GEX1A (herboxidiene)
Natural products containing tetrahydropyan nucleus.
A number of tetrahydropyran derivatives have been used as materials in photographic films886 and host-guest chemistry.887 Synthesis 1. Hydrogenation: 3,4-Dihydro-2H-pyran on hydrogenation in the presence of nickel yields tetrahydropyran.888
2. Intramolecular Williamson synthesis: When hydroxy and halogen groups are part of the same molecule they undergo cyclization on heating in the presence of NaH in THF. 5-Bromopentan-1-ol on heating with NaH in THF cyclized to afford tetrahydro-2H-pyran.
Similarly, heating a mixture of pentane-1,5-diol with sulfuric acid yields tetrahydro-2H-pyran.
3. Acid-catalyzed cyclization of δ-substituted aldehydes leads to the generation of tetrahydro-2H-pyran derivatives.889
The reaction is thought to proceed with the protonation of aldehyde to form carbocation I. This carbocation undergoes intramolecular exchange to give a more stable carbocation II, followed by cyclization leading to the generation of tetrahydropyran derivative.
232
2. Six-Membered Heterocycles
4. Prins reaction890: Tetrahydro-2H-pyran derivatives have been synthesized by the reaction of alkenes with aldehydes. Buten-1-ol reacts with a variety of aldehydes or ketones in the presence of acid to yield a variety of tetrahydro-2H-pyran derivatives.891
Prins-cyclization reaction has been used in the synthesis of tetrahydro-2H-pyran odorants, including commercial Florol and Clarycet, by grinding an aldehyde and a homoallylic alcohol in the presence of a catalytic amount of p- toluenesulfonic acid (p-TSA) on silica under solvent-free conditions.892
5. 3-Hydroxy-3,7-dimethyloct-6-enoic acid in the presence of an acid catalyst such as boron trifluoride diethyl etherate, or iodine underwent cyclization to yield a tetrahydro-2H-pyran derivative.893
6. [4 + 2] cycloaddition reaction: Reaction of triethylsilylaldehyde with allyl silane in the presence of BF3-etherate afforded a tetrahydropyran derivative as a single diastereoisomer.894
2.6 Six-Membered Heterocycles With One Oxygen Atom
233
7. Reaction of hex-5-en-1-ol with peracid leads to the generation of 4-hydroxybutyloxirane, which on acidcatalyzed cyclization leads to the generation of 2-hydroxymethyltetrahydro-2H-pyran.
Physical Properties Tetrahydropyran is a colorless, volatile, mobile liquid with a pungent sweetish odor with a bp of 88°C. It is highly flammable and irritating to eyes and skin. It is soluble in water but miscible with alcohol and ether. Chemical Reactivity 1. Reaction with aryl amines: Tetrahydropyran when heated with aniline and toluidines over activated alumina at higher temperatures yielded N-phenylpiperidine and N-tolylpiperidine in excellent yield. However, yields with o-toluidine were much lower.895, 896
2. Ring-opening reactions (a) Heating tetrahydropyran with trimethylbromosilane and trimethylchlorosilane separately at higher temperature yields 1-bromo-5-trimethylsilyoxypentane and 1-chloro-5-trimethylsilyoxypentane, respectively.897
(b) Reaction with HBr: Tetrahydropyran when heated with hydrobromic acid and concentrated sulfuric acid underwent ring opening to yield 1,5-dibromopentane.898
(c) Reaction with nitric acid: Oxidation takes place leading to the generation of glutaric acid.
(d) Reaction of tetrahydropyran with acetyl chloride in presence of zinc chloride yields 5-chloropentyl acetate.
(e) When heated in the vapor phase with carbon monoxide in the presence of nickel catalyst, pimelic acid is obtained.
234
2. Six-Membered Heterocycles
(f) Reaction of tetrahydropyran with ethyl iodide and mercury(II) acetate result in the ring opening and yields of 5-ethoxypentyl acetate.899
3. Photolysis: Photolysis of liquid tetrahydropyran at 185 nm yields 2-(5′hydroxypentyl)tetrahydropyran, valeraldehyde, pent-4-en-1-ol, and pentan-1-ol as the major products. These products are thought to be formed via biradical (I) and through intramolecular and intermolecular photoreaction.900
2.6.5 4H-Pyran
4H-Pyran is a six-membered, unsaturated, nonconjugated, nonaromatic oxygen heterocycle with two double bonds and an sp3-hybridized carbon at position 4 of the ring. Structural and Reactivity Aspects901 The IR spectrum of 4H-pyran, in contrast to 2H-pyran, shows typical CC stretching bands at ≈ 1700 and ≈1600 cm−1. The 1H and 13C NMR of 4H-pyran (in CCl4) are given the following table. H and 13C NMR spectral data of 4H-pyran
1
1
H NMR (δ values in ppm)
13
C NMR (δ values in ppm)
H-2/H-6, 6.16; H-3/H-5, 4.63; H-4, 2.65
C-2/C-6, 141.1; C-3/C-5, 101.1
Importance in Natural Products, Medicines, and Materials The chemistry of 4H-pyran has been a subject of research for centuries902a because of its biological and pharmacological activities. They constitute a structural unit of a number of natural products. Compounds containing this nucleus have been reported to possess a wide range of biodynamic properties such as antimicrobial,902b antiviral,903 antiallergic, antibacterial, diuretic, anticoagulant, antianaphylactic,904 and antitumor.905 Synthesis 1. A Diels-Alder adduct formed by reaction of acrolein with vinyl acetate is decomposed on a column of glass beads at 350°C leading to the generation of 4H-pyran and acetic acid.906 This compound was unstable in air and hence disproportionate to dihydropyran and pyrylium ion.
2.6 Six-Membered Heterocycles With One Oxygen Atom
235
Synthesis of 4H-pyran has also been reported by heating a mixture of glutaraldehyde and hydrochloric acid in methylene dichloride at 90°C and 40 mm Hg.907 2. Stable polyfunctionalized 4H-pyrans are synthesized by the reaction of formaldehyde with ethyl acetoacetate in the presence of piperidine, yielding diketone, which on reaction with zinc chloride cyclized to a 4H-pyran derivative.908
3. Mesityl oxide condenses with ethyl acetoacetate to yield 4H-pyran.
4. Stable and polyfunctionalized 4H-pyran derivative was synthesized by one-pot condensation of an active methylene diketo compound with an aldehyde and malononitrile using basic Mg/La mixed oxide as catalyst.909
5. Polyfunctionalized 4H-pyrans have also been synthesized by cyclocondensation of aryl aldehydes with malononitrile and β-dicarbonyls in dimethylacetamide in the presence of baker’s yeast.910
6. An efficient method has been developed for the synthesis of 4H-pyran derivatives by cyclocondensation of aldehydes, malononitrile, and ethyl acetoacetate using silica-supported ammonium acetate as recyclable catalyst, promoted by ultrasonic irradiation.911
7. Benzylmagnesium chloride on reaction with pyrylium ion forms a 4H-pyran derivative.
236
2. Six-Membered Heterocycles
8. Neutral alkynes in the presence of a nickel catalyst undergo a [4+2] cycloaddition reaction with α,β-unsaturated carbonyl compound to yield a 4H-pyran derivative.912
9. One-pot, three-component coupling of an aldehyde, malononitrile, and reactive methylene compound in the presence of Amberlyst A21, an ion exchange polystyrene resin led to the synthesis of polyfunctionalized 4Hpyrans. The process is simple, requires no chromatographic purification, and no hazardous solvent has been used.913
10. 2H-Pyrans could be converted into substituted 4H-pyrans by treating them with sodium hydroxide in ethanol at room temperature.914
Physical Properties 4H-Pyran has a bp of 80°C and an nD20 of 1.4559. Chemical Reactivity 1. Pyrylium tetraborate is obtained as a crystalline solid by reaction of 4H-pyran with triphenylmethane tetrafluoroborate.
2. Lithium aluminum hydride reduction of 3-carbethoxy-2,4,4,6-tetramethyl-4H-pyran afforded 3-hydroxymethyl2,4,4,6-tetramethyl-4H-pyran. Reaction of this alcohol with chromic trioxide oxidizes it to an aldehyde. Basecatalyzed aldol condensation of the aldehyde with acetone yields an unsaturated ketone.915
2.6 Six-Membered Heterocycles With One Oxygen Atom
237
3. When 2,4-dinitrophenylhydrazine (DNP) reacts with 4H-pyrans, a ring-opening reaction takes place leading to the generation of bis-2,4-dinitrophenylhydrazone derivatives.
4. Reaction of 2,4,6-trimethylpyrylium perchlorate with sodium borohydride yields 2,4,6-trimethyl-4H-pyran and 4-methyl-cis-3-trans-5-heptadien-2-one. It was experimentally proved that the open chain structure formation takes place with the intermediate formation of a 2H-pyran derivative.916
5. Photochemical reaction: On UV irradiation, 2,4,6-triphenyl-4-benzyl-4H-pyran isomerizes to 2-benzyl-2H-pyran, which on further reaction with hydrochloric acid yields 1,2,3,5-tetraphenylbenzene in quantitative yield.
4-Benzyl-2,4-diphenyl-6-alkyl-4H-pyran on reaction with perchloric acid yields 1,3-diphenylnaphthalene. The reaction is thought to proceed by the following mechanism.
2.6.6 Pyrylium Salt
Pyrylium cation is a six-membered heterocyclic compound consisting of five carbon atoms and one positively charged oxygen atom.
238
2. Six-Membered Heterocycles
Structural and Reactivity Aspects917 The X-ray analysis of 3-acetyl-2,4,6-trimethylpyrylium salt shows that the molecule is a planar, slightly distorted hexagon with CC and CO bonds of almost equal length. The bond length (in pm) and bond angles (in degrees) are shown in the following diagram.
Bond lengths and bond angles of a derivative of pyrylium salt.
The 1H and 13C NMR spectral data of pyrylium ion are given in the following table. H and 13C NMR spectral data of pyrylium ion
1
1 H NMR (CF3COOD) δ (ppm)
13
C NMR (CD3CN) δ (ppm)
H-2/6, 9.22; H-3/5, 8.08; H-4, 8.91
C-2/6, 169.2; C-3/5, 127.7; C-4, 161.2
The 1H NMR of unsubstituted pyrylium salt was also recorded. The most deshielded were the α-protons at δ 8.6 followed by γ-protons at δ 7.5, and the least deshielded protons were at δ 7.1. The pyrylium ion is represented by a number of resonating structures with the positive charge delocalized over the whole ring.
Resonationg structures of pyrylium ion.
Importance in Natural Products, Medicines, and Materials The most important application of pyrylium salts is in the photographic industry where they are used as photosensitive layers in films and papers. Pyrylium salts, because of their fluorescent properties, are used as internal labeling agents for photographic films. These films are identified by the fluorescence of specific pyrylium salts and their respective color when they are exposed to UV light.918 Besides, pyrylium salts are also used as fluorescent dyes and dye lasers. Some pyrylium salts have been reported to function as plant growth stimulants and as anticorrosion agents.918 Synthesis 1. Pyryliumtetrafluoroborate has been prepared by hydride abstraction from the corresponding 4H-pyran using triphenylcarbeniumtetrafluoroborate.919
2. 2,6-Di-tert-butyl-4-methylpyrylium trifluoromethanesulfonate was synthesized by heating pivaloyl chloride, anhydrous tert-butyl alcohol, and trifluoromethanesulfonic acid920 at 95–105°C.
3. 2,4,6-Triphenylpyrylium tetrafluoroborate, a versatile, useful, stable starting material for the synthesis of substituted nitrobenzene derivatives, has been prepared by heating benzalacetophenone and acetophenone in dichloroethane with a 52% ethereal solution of fluoroboric acid.921
2.6 Six-Membered Heterocycles With One Oxygen Atom
239
4. 2,4,6-Trimethylpyrylium tetrafluoroborate, 2,4,6-trimethylpyrylium perchlorate, and 2,4,6-trimethylpyrylium trifluoromethanesulfonate were synthesized by reaction of acetic anhydride and tert-butyl alcohol with 40% fluoroboric acid, 70% perchloric acid, and trifluoromethanesulfonic acid, respectively.922–924
5. Balaban-Nenitzescu-Praill reaction: Diacylation of alkenes that have three or more carbon atoms in the presence of strong acids afforded pyrylium salts.
Electrophilic diacylation of isobutene or α-methylstyrene with acetic anhydride in the presence of sulfuric acid affords 2,4,6-trimethylpyrylium or 2,6-dimethyl-4-phenylpyrylium sulfoacetates, respectively.925
6. Hantzsch-type synthesis: This process involves the reaction of an aldehyde with 2 moles of aryl methyl ketone in acetic anhydride affording a 1,5-diketone, which cyclizes to pyran. Oxidation of pyran yielded pyrylium salt.926, 927
Chemical Reactivity 1. Reaction with ammonia and other amines: Pyrylium salt reacts with ammonia and other amines to give pyridine or pyridinium derivatives. This is one of the best methods for preparing nitrogen heterocycles.
Reaction of 2,6-di-tert-butyl-4-methylpyrylium trifluoromethanesulfonate with ammonium hydroxide yields 2,6-di-tert-butyl-4-methylpyridine.928
240
2. Six-Membered Heterocycles
2. 2,4,6-Trimethylpyrylium salt reacts with warm alkali resulting in the formation of 2-hydroxypyran, which immediately undergoes a ring-opening process. The acyclic intermediate undergoes aldol-type condensation to form 3,5-dimethylphenol.
3. 2,4,6-Triphenylpyrylium ion reacts with methoxide to produce methoxy-substituted 2H- and 4H-pyrans.
4. Reaction of 2,4,6-triphenylpyrylium tetrafluoroborate with nitromethane in the presence of triethylamine in absolute ethanol yields triphenylnitrobenzene.929
5. Reaction of 2,4,6-trimethylpyrylium salt with sodium cyanide afforded a conjugated acyclic 5-cyano-2,4-dienone by α-addition of the cyanide anion to the pyrylium cation followed by electrocyclic ring opening of 2H-pyran. Dienone on reaction with HCl afforded 5-cyanosorbic acid.930
The same reaction has been reinvestigated by reacting 2,4,6-trimethylpyrylium perchlorate with sodium cyanide at room temperature in a stirred mixture of water and ethyl ether. The major product was 2-Z,4-Z,2,4-dimethyl6-oxo-2,4-heptadienonitrile and 2-E,4-Z,2,4-dimethyl-6-oxo-2,4-heptadienonitrile was the minor product. When treated with concentrated hydrochloric acid under similar reaction conditions, 2-Z,4-E,2,4-dimethyl-6-oxo-2,4heptadienonitrile and 2-E,4-E,2,4-dimethyl-6-oxo-2,4-heptadienonitrile, respectively,931 were formed.
2.6 Six-Membered Heterocycles With One Oxygen Atom
241
6. Reaction with organometallics: The addition of organometallic compounds normally takes place at the α-position, whereby ring opening takes place leading to the formation of dienones or aldehydes. However, reaction with benzylmagnesium chloride is an exception because it leads to the formation of a 4H-pyran derivative.
2,4,6-Trimethylpyrylium ion reacts with methylmagnesium bromide leading to the generation of a pyran derivative, which undergoes a ring-opening process to give 4,6-dimethylhepta-3,5-dien-2-one.
Pyrylium perchlorate undergoes reaction with butyllithium at −78°C, and ring opening takes place leading to the formation of nona-2,4-dienal.932
7. Photochemical reaction: Photolysis of pyrylium perchlorate in acetic acid containing acetic anhydride yields triacetates in a 5:2 ratio.933
However, when photolysis is carried out in wet acetonitrile, a single oxazoline derivative was obtained, which was identified by X-ray crystallography. Oxazoline formation takes place by hydration of initially formed nitrilium ion, followed by cyclization and opening of the epoxide.
8. Reaction of 2,4,6-triphenylpyrylium with hydroxylamine affords the monoxide of a pseudobase. It readily isomerizes into 3,5-diphenyl-5-phenacyl-2-isoxazoline, which on reaction with mineral acid splits into acetophenone and 1,3-diphenylisoxazole.934
242
2. Six-Membered Heterocycles
9. Azulene: A simple and general method of azulene synthesis involves reaction of 2,4,6-trimethylpyrylium perchlorate with cyclopentadienyl sodium. 4,6,8-Trimethylazulene formed during the reaction is crystallized935 from ethanol with mp of 80–81°C.
Pyranones Pyrones or pyranones are unsaturated, six-membered, oxygen heterocycles comprised of one oxygen atom and a carbonyl group in the ring. They exist in two isomeric forms, 2-pyrone or α-pyrone and 4-pyrone or γ-pyrone, assigned on the basis of the position of the carbonyl group relative to the oxygen atom within the ring system. They are also known as 2H-pyran-2-one and 4H-pyran-4-one, respectively.
2.6.7 2H-Pyran-2-One (2-Pyranone)
2-Pyranone, also known as α-pyrone, 2H-pyran-2-one, or pyran-2-one, is an unsaturated lactone that exhibits aromatic as well as aliphatic characters. The 2-pyrone skeleton is more readily found in nature as part of coumarin, the benzo derivative of 2-pyrone. Structural and Reactivity Aspects936 2-Pyrone is well presented as a resonance hybrid between two structures, an enol lactone (1) and a betaine (2). From IR spectrum studies, the presence of an absorption band around 1730 cm−1, which is characteristic for ketonic groups, suggested that structure (2) does not play an important part in the description of the 2-pyran-2-one system.
Resonance structures of 2-Pyrone.
Microwave spectroscopic studies further suggest that 2-pyrone possesses bond parameters of an enol-lactone system with a localized CC double bond and single bonds.
Bond lengths and bond angles in 2-pyrone.
2.6 Six-Membered Heterocycles With One Oxygen Atom
243
The 1H and 13C NMR spectral data of 2-pyrone are given in the following table. H and 13C NMR spectral data of 2-pyrone
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H3, 6.38; H-4, 7.58; H-5, 6.43; H-6, 7.77
C-2, 162.0; C-3, 116.7; C-4, 144.3; C-5, 106.8; C-6, 153.3
The IR spectrum for 2-pyran-2-one shows carbonyl group stretching vibration at ≈1730 cm−1 and suggests that betaine structure (2) has a minor role to play in describing the 2-pyran-2-one ring system. In the mass fragmentation pattern of the 2-pyran-2-one system, furan and cyclopropenylium ion are the main fragments.
Mass fragmentation pattern of 2-pyran-2-one.
Importance in Natural Products, Medicines, and Materials The 2-pyrone nucleus is present in a wide variety of natural products isolated from animals, plants, bacteria, fungi, etc. and they are reported to possess a wide spectrum of biological activity such as antibacterial, antifungal, anti-Alzheimer’s disease, anticancer, cholesterol lowering, and cardiotonic.937–939 The diverse biological activity expressed by 2-pyranone is thought to be as a result of enzyme inhibition.940–942 In July 2013, α-pyrones were identified as a new class of signaling molecule in bacterial communication, similar to quorum sensing.
Natural products containing 2-pyranone skeleton.
Synthesis 1. 2-Pyrone in good yield is obtained by heating coumalic acid at higher temperature over fine copper turnings.943 2-Pyrone in low yield have earlier been obtained by pyrolysis of heavy metal salts of coumalic acid944 and pyrolysis of its carboxylic acid derivative of coumalic acid over copper.945
Coumalic acid has been prepared by heating cheap and easily available malic acid with oleum. The reaction is believed to proceed by initial dehydration/decarboxylation of malic acid, yielding an aldehyde acid enol (A), which then condenses by Michael addition to the enol of the corresponding enone yielding product B, which after dehydration and lactonization yields coumalic acid.946, 947
244
2. Six-Membered Heterocycles
2. 2-Pyrone is also synthesized by a reaction of formaldehyde with 3-butenoic acid.
3. Condensation of 3,3-dichloropropenal with a reactive methylene compound like methyl ethyl ketone afforded 2-pyrone.
4. Claisen condensation between diethyl oxalate and α,β-unsaturated ester results in the formation of an intermediate, which undergoes ring closure via keto enol to produce 2-pyrone.948
5. 5,6-Difunctionalized 2-pyrones were easily synthesized by reaction of ene-ynoic acid with iodine followed by either a Stille or Negishi cross-coupling reaction.949, 950
6. Improvements were made in the use of the Stille reaction for the synthesis of 2-pyrones, which could be formed in one step by reaction of acyl chloride with a distannane.951
2.6 Six-Membered Heterocycles With One Oxygen Atom
245
7. Sonogashira coupling reaction between iodo-substituted unsaturated ester and terminal alkyne leads to the generation of (Z)-2-alken-4-ynoate, which undergoes electrophilic cyclization in the presence of ICl or I2 affording 2-pyrone.952
Fluorinated 2-pyrone derivative was synthesized by the reaction of (2E)-2,3-difluoro-3-iodoacrylic acid with terminal alkynes under Sonogashira alkynylation conditions using PdCl2(PPh3)2 in combination with CuI as a co-catalyst.953
8. Palladium-catalyzed coupling of terminal alkyne with haloacrylic acid leads to the formation of (Z)-5-alkyl-2-en4-ynoic acid, which undergoes lactonization in the presence of zinc bromide to form 2-pyrones.954a
9. Highly functionalized 2-pyrones have been synthesized by stirring an equimolar mixture of ketenedithioacetals such as methyl 2-cyano-3,3-(dimethylthio)acrylate or dimethyl 2-(bis(methylthio)methylene)malonate and aliphatic or arylmethyl ketone using more than 1 equivalent of powdered KOH in dry DMF/DMSO at room temperature for 4–5 h. Usual workup provided 6-aryl-4-methylthio-2H-pyran-3-carbonitrile/carboxylate in moderate yield.954b, c
Physical Properties 2-Pyrone is a colorless liquid with a bp of 208°C, miscible with water. Chemical Reactivity 1. Electrophilic substitution reaction: 2-Pyrone has an aromatic character, which is reflected by its reactions toward electrophilic substitution reaction. The substitution preferably takes place at either the 3- or 5-position, i.e., ortho or para to the carbonyl group. (a) 2-Pyrone on reaction with bromine in carbon tetrachloride initially forms an unstable adduct, which on warming yields 3-bromo-2-pyrone. The reaction takes place by addition-elimination sequence rather than by direct electrophilic substitution.955
246
2. Six-Membered Heterocycles
However, when photobromination is carried out at a lower temperature than the addition product, trans-dibromide is obtained, which in the presence of base undergoes dehydrobromination. (b) Nitration with nitronium tetrafloroborate, initially attacks the carbonyl oxygen forming o-nitro salt (pyrylium salt), which slowly rearranges to 5-nitro-2-pyrone.956
However, with an electrophilic reagent like trimethyloxonium tetrafluoroborate (Meerwein’s reagent) the attack takes place only at the carbonyl oxygen forming pyrylium salts.
2. Nucleophilic substitution reaction: 2-Pyrone can readily be attacked by nucleophilic reagents at the C-4- and C-6-positions. The intermediates formed during the process are readily stabilized by resonance.
(a) 2-Pyrone, which possesses an unsaturated lactone ring system on reaction with the base, underwent a ringopening process.
(b) Depending on the type of nucleophile, 2-pyrone can easily be attacked by nucleophilic reagents. Weak nucleophiles attack at the C-2-position, whereas strong nucleophiles attack at the C-6-position. 2-Pyrone reacts with ammonia with the initial attack at C-6, followed by rearrangement to yield pyridin-2(1H)-one.
2.6 Six-Membered Heterocycles With One Oxygen Atom
247
(c) 2-Pyrone reacts with sodium cyanide in DMF to yield a product that on acidification yields 5-trans-cyano-2-cis4-pentadienoic acid.957
The mechanism of the reaction involves the attack of the cyanide ion at position C-6 of pyrone, leading to the generation of resonance-stabilized carbanion intermediate A, which cleaves to give the stable carboxylate anion B.
(d) Grignard reagent is first added to the carbonyl group followed by ring opening of the 2-pyrone. The second molecule of the Grignard reagent reacts with either of the two carbonyl groups in the intermediate. Protonation and dehydration lead to the generation of an aldehyde and ketone.
3. Cycloaddition reactions: 2-Pyrone has some aromatic character, hence it undergoes Diels-Alder [4+2] cycloaddition reaction less readily in comparison to cyclic-conjugated dienes. 2-Pyrone undergoes cycloaddition reaction with maleic anhydride. The adduct formed undergoes thermal decarboxylation to 1,2-dihydrophthalic anhydride.
2-Pyrone undergoes cycloaddition reaction with bis(trimethylsilyl)acetylene with 2-pyrone acting as diene and alkyne as dienophile. Initially, a highly strained bicyclooctadiene is formed, from which expulsion of a two-atom bridge takes place to yield the aromatic compound. The presence of a trace amount of acid was responsible for isomerization of the product.958
Similarly, reaction of 2-pyrone diene with bis(pentamethyldisilanyl)acetylene and diphosphyrylacetylene dienophile yielded the desired 1,2-bis(pentamethyldisilanyl)benzene959 and 1,2-diphosphorylbenzene,960 respectively.
248
2. Six-Membered Heterocycles
Tetrasilyl diyne dienophile undergoes cycloaddition with 2 equivalents of 2-pyrone in toluene (containing triethylamine) to afford [2.2] orthocyclophane (1). When the reaction was carried out in bromobenzene, [2.2] metacyclophane (2) was isolated.961
In the foregoing cycloaddition reactions, elimination of carbon dioxide from the initially formed bicyclo product led to aromatization; however, if the olefin contains such groups, which are unable to be eliminated after the formation of the bicyclo product, then this would lead to the formation of dihydrobenzenes. Dihydrobenzene (A) as a single product was obtained by cycloaddition of 2-pyrone with the endocyclic double bond of the tricyclic diene (B).962
The cycloaddition of 1,2,3-triphenylcyclopropene with 2-pyrone leads to the generation of cycloadduct product (A). Elimination of a molecule of carbon dioxide with the spontaneous ring enlargement led to the generation of 1,6,7-triphenylcyclohepta-1,3,5-triene.963
Reaction of 2-pyrone with the reactive 1,4-dihydronaphthalene-1,4-endo-oxide resulted in the formation of a regioisomeric mixture of Diels-Alder cycloadduct, which after a few transformations resulted in the formation of biologically active anthracycline 7-deoxydaunomycinone.964
A number of complex natural products were synthesized involving tandem pericyclic reactions. The reaction involves intermolecular Diels-Alder cycloaddition reaction of 2-pyrone with α,ω-diene followed by expulsion of carbon dioxide from bicyclic lactone (A) and intramolecular Diels-Alder reaction of cyclohexadiene (B) to afford the polycyclic structure.965
2.6 Six-Membered Heterocycles With One Oxygen Atom
249
4. Photochemical Reaction (a) When a cold solution of 2-pyrone in methylene chloride is irradiated by visible light, photobromination takes place possibly by an ionic mechanism as well as by a radical pathway yielding dl-trans-5,6-dibromo-5,6dihydro-2-pyrone as the exclusive product.955
(b) Photochemical reactions of 2-pyrone have been widely investigated and have been found to give interesting products. Direct photolysis of an ethereal solution of 2-pyrone leads to the generation of bicyclic β-lactone (A) as the exclusive product. However, when photolysis is carried out in the presence of 10% added methanol, methyl trans-4-formyl-3-butenoate is the product.966 Continued irradiation of bicyclic β-lactone (A) yields cyclobutadiene.967
Irradiation of 2-pyrone in the presence of a triplet sensitizer results in dimerization, leading to the formation of a tricyclic structure. (c) Photodimerization: Pressurization of a 50% solution of 2-pyrone in toluene or nitromethane at 7 kbar at 70°C in the presence of 1% hydroquinone yields dimer 1. However, photosensitization of 2-pyrone968 leads to a mixture of dimers 2 and 3.
Ring transformation by nitrogen nucleophiles: Suitably functionalized 2H-pyran-2-ones such as 6-ary-4-methylthio2H-pyran-3-carbonitriles/carboxylates smoothly undergo ring transformation reactions by different nitrogen
250
2. Six-Membered Heterocycles
nucleophiles such as ammonia, heterocyclic primary and sec.amine, hydrazine, cyanamide, and generated molecular diversity by stirring a mixture of 2-pyranone with different nitrogen nucleophiles in DMF at room temperature or by heating neat or in different solvents.969
Ring transformation reactions by carbanion: Numerous aromatic and heterocyclic compounds have been prepared by ring transformation reactions of 6-aryl-4-methylthio-2H-pyran-3-carbonitriles by carbanion generated from acetophenone, 1-substituted 4-piperidone, terahydrothiophene-3-one, 2-ethoxycarbonyl-4-cyclopentan-4-one, nitromethane, and 1-aryl-3-methylpyrazol-5-one in DMF using powdered KOH as a base at room temperature. Usually, reaction is initiated with carbanion attack at C-6 followed by cyclization. Usual workup and purification yielded a variety of compounds.969
2.6 Six-Membered Heterocycles With One Oxygen Atom
251
2.6.8 4H-Pyran-4-One (4-Pyranone)
4-Pyranone, also known as γ-pyrone or pyran-4-one or simply 4-pyrone, is an unsaturated, nonconjugated, nonaromatic, six-membered oxygen heterocycle. This skeleton is more readily found in naturally occurring compounds such as chromone, maltol, and kojic acid. Structural and Reactivity Aspects970 4-Pyrone is well presented as a resonance hybrid of two structures. However, the dipole moment of 4-pyran-4-one is ≈4 D and its greater basicity (pKa = 0.1) suggests that the betaine canonical structure (2) makes little contribution to the resonance hybrid.
Resonating structures of 4-pyrone.
The structure of 4-pyrone as a cross-conjugated, localized cycloenone system on the basis of its bond parameters has been established on the basis of microwave spectroscopy.
Bond length and bond angles of 4-pyrone.
The 1H and 13C NMR spectral data of 4-pyrone suggest it to be an α,β-unsaturated carbonyl system. H and 13C NMR spectral data of 4-pyrone
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H2, 7.88; H-3, 6.38
C-2, 155.6; C-3, 118.3; C-4, 179.9
Importance in Natural Products, Medicines, and Materials 4-Pyrone is of great value because this structural subunit is present in a number of natural products like onchitriols I and II, and verticipyrone.971 Besides, a number of natural products and synthetic molecules possessing this skeleton have been reported to display various biological activities such as flavoring agents in the food industry, skin whitening agent, treatment of melismas, alixinas as an antitumor agent, and phenoxan as an anti-HIV agent.
252
2. Six-Membered Heterocycles
Natural products and drugs containing 4-pyrone nucleus.
Synthesis 1. Decarboxylation of chelidonic acid and orcomanic acid yields 4-pyrone. Decarboxylation, however, takes place smoothly in the presence of copper powder. Chelidonic acid is, however, prepared by reaction of acetone with ethyl oxalate.
2. From Meldrum’s acid: Meldrum’s acid on reaction with acetyl chloride in the presence of pyridine yields the acylated product, which on reaction with butyl vinyl ether yields pyrandione as intermediate. On treatment of pyrandione with p-toluenesulfonic acid, decarboxylation and loss of butanol led to the formation of 4-pyrone.972
2.6 Six-Membered Heterocycles With One Oxygen Atom
253
3. A new environmentally friendly (metal-free) synthetic strategy for the synthesis of 4-pyrones with high efficacy has been reported.973 The process involves heating 1,5-diphenylpenta-1,4-diyn-3-one with Brønsted acid like pTsOH in methanol at 90°C.
4. Benzoylation of acetyl and benzoylacetones at the terminal methyl group leads to the formation of 1,3,5-triketones, which in the presence of sulfuric acid is cyclized to 4-pyrones.974
5. Synthesis of aryl- and alkyl-disubstituted 4-pyrones from β-keto acids in the presence of trifluoromethanesulfonic anhydride has been reported. The reaction proceeds via decarboxylative autocondensation of β-keto acids.971
6. Symmetrically substituted 4-pyrones are synthesized by heating alkanoic acids or their anhydrides with polyphosphoric acid975 at 200°C.
7. Dehydroacetic acid, an important 4-pyrone derivative, is synthesized by Claisen condensation of two molecules of ethyl acetoacetate followed by cyclization.
Physical Properties 4-Pyrone is a low-melting colorless crystalline solid mp 32°C. Chemical Reactivity 1. 4-Pyrone reacts with Grignard reagent with the attack preferentially at carbonyl carbon (C-2), forming tertiary alcohol, which undergoes dehydration with acid to form 4-substituted pyrylium salt.976
254
2. Six-Membered Heterocycles
2. 4-Pyrone, which possesses an unsaturated lactone ring system on reaction with the base, undergoes a ringopening process leading to the generation of oxopentanedial.
3. 4-Pyrone in comparison to 2-pyrone is more basic and on alkylation with dimethyl sulfate gave 4-methoxypyrylium salt.
4-Pyrone also reacts with trialkyl derivatives of silyltrifluoromethanesulfonate forming 4-silyloxypyrylium triflate.
4. Formylation: 4H-Pyrones are formylated by using a carbon monoxide-hydrochloric acid mixture in the presence of trifluoroacetic acid as a catalyst.977
5. Reaction with hydroxylamine: 4-Pyrone reacts with hydroxylamine hydrochloride to afford 1-hydroxy-4pyridone or 4-hydroxyaminopyridine-N-oxide.978
6. Reaction with amino acid: 4-Pyrone reacts with 3-aminopropanoic acid to yield N-carboxyethyl-4-pyridone. The reaction is proposed to take place by a ring-opening and ring-closure process.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
255
7. Photochemical reaction: Irradiation of a trifluoroethanol solution of 3,5-dimethyl-4-pyrone at 254 nm yields 3,6-dimethyl-2-pyrone. The reaction takes place with the intermediate formation of 2,5-dimethylcyclopentadienone epoxide.979
8. Cycloaddition reaction: 2,6-Diethyl-4-pyrone on reaction with tosylisocyanate undergoes [2+2] cycloaddition reaction followed by loss of carbon dioxide to afford a 4-imine derivative, which on reaction with aqueous ammonia at 60°C gave a 1,4-dihydropyridine derivative. The pyridine derivative on reaction with sulfuric acid yielded 4-amino-4,6-diethylpyridine.980, 981
2.7 SIX-MEMBERED BENZO-FUSED OXYGEN HETEROCYCLES 2.7.1 Benzopyrans Benzopyrans are bicyclic oxygen-containing heterocycles in which the benzene ring is fused to the pyran ring. However, in older literature such compounds are called chromenes and according to the latest IUPAC nomenclature this name is retained. There are two isomers of benzopyran: 1-benzopyran (chromene) and 2-benzopyran (isochromene).
2.7.2 2H-1-Benzopyran (2H-Chromene)
2H-1-Benzopyran is a bicyclic-conjugated oxygen heterocycle constituted by fusion of the “b” site of the pyran ring with the benzene ring. All the carbons except C-2 (sp3) are sp2 hybridized and an oxygen atom at position 1 is part of the chromene ring.
256
2. Six-Membered Heterocycles
Structural and Reactivity Aspects The ultraviolet spectrum of 2H-1-benzopyran in hexane shows two bands at λmax (hexane) 266.5 and 314 nm due to π→π* transition. The IR spectrum of 2H-1-benzopyran showed the following peaks: 3040, 2970, 2840, 1644, 1610, 1613, 1570, 1495, 1480, 1360, 1230, 1110, 930, and 750 cm−1. The peaks at 1644 and 1230 cm−1 are for the carbon-carbon double bond of the pyran ring and CO stretching of the cyclic ether. The most reliable and characteristic information regarding the structure of 2H-1-benzopyran is provided by 1H NMR. The assignment is as follows: δ 4.53 (q, 2H, 2-H), 5.38 (m, 1H, 3-H), 6.20 (m, 1H, 4-H), 6.60–7.13 (m, 4H, Ar-H). The pyran ring protons exhibited the following coupling: J1,2 = 3Hz; J4,2 = 2 Hz; J3,4 = 10 Hz. The 13C NMR data of 3,3-dimethyl-2H-chromene are as follows.982 13
C NMR (CDCl3) δ (ppm)
C-2, 76.05; C-3, 130.66; C-4, 122.29; C-5, 126.26; C-6, 120.65; C-7, 129.01; C-8, 116.28; C8a, 152.91; C4a, 121.24; 2CH3, 27.98
The mass spectrometry of 2H-1-benzopyran along with its fragmentation pattern is depicted in the following diagram. The base peak is the benzopyrylium cation, formed by loss of the hydrogen radical.
Mass fragmentation of 2H-1-benzopyran.
Importance in Natural Products, Medicines, and Materials A number of natural products like acetovanillochromene, ageratochromene, alloevodione, alloevodionol, euproeioxheomwnw, evodione, arahypin, xanthyletin, calanone, etc., isolated from plants, are 2H-chromene derivatives. The 2H-chromene nucleus, which is also present in a number of natural products like tannins and polyphenols,983 has been reported to possess antitumor984 and antibacterial activity.985 Although a large number of natural products with a 2H-chromene nucleus have been isolated and various synthetic derivatives have been prepared, this bicyclic heterocyclic received significant attention when two important 2H-chromene derivatives, precocene I and precocene II, isolated from Ageratum houstonianum were reported to induce precocious metamorphosis in a variety of insects.986 Since then a large number of natural products having a 2Hchromene nucleus have been isolated and identified. For example, acronycine is an antitumor drug,987 inophyllum B36 is an HIV-1 reverse transcriptase inibibitor,988 and robustic acid is a c-AMP inhibitor.989
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
257
Natural products containing 2H-Chromene nucleus.
A number of pharmaceuticals and some newly synthesized biologically active compounds have been reported to possess a 2H-chromene nucleus. For example, icaprim, an antibiotic used for skin infection,990 daurichromenic acid, a highly potent anti-HIV agent,991 and 6-fluoro-2H-chromene, exhibited the highest 5-HT1A receptor affinity among a series of 6-chromane derivatives.992 Similarly, a 4′-dehydroxyphlorizin derivative with a 6-substituted-2H-chromene unit was tested for potential antidiabetic activity as a Nac-glucose cotransported inhibitor.
Drugs containing 2H-chromene nucleus.
Synthesis993 1. Reaction of salicylaldehyde with triphenylvinylphosphonium yields 2H-chromene. The reaction involves Michael addition followed by Wittig reaction.994, 995
Reaction of sodium salt of salicylaldehyde with substituted allyltriphenylphosphonium bromide yielded 2H-1benzopyran derivative.996 The reaction involves the initial formation of a butadienyl phenolic product by Wittig reaction. This phenolic product undergoes nonreversible sigmatropic shift of phenolic hydrogen to give an intermediate methylene quinonoid compound, which undergoes instantaneous ring closure to give a benzopyran derivative.
258
2. Six-Membered Heterocycles
Ortho-formylation of p-hydroxybenzaldehyde after acetalization of the aldehyde followed by reaction with triphenylvinylphosphonium bromide yielded 2H-1-benzopyran-6-carboxyaldehyde.997
2. Petasis condensation: This reaction involves condensation of vinylic or aromatic boronic acid, aromatic aldehydes, and amines in the presence of a resin-bound amine yielding 2H-chromenes.998
3. Reaction of Grignard reagent with coumarin: Synthesis of 2,2-disubstituted 2H-1-benzopyran derivatives was reported by reaction of alkyl magnesium halide with coumarin. The reaction is thought to proceed by following the reaction pathway.999
The formation of pyrylium salt during the course of reaction was proved by reacting coumarin with 1 equivalent of Grignard reagent; pyrylium chloride was isolated after neutralization with hydrochloric acid.1000 However, the normal Grignard path was disapproved and a new mechanism was proposed, according to which reaction of Grignard reagent with coumarin led to opening of the ring, yielding an intermediate that undergo 1,4-addition before ring closure to chromene.1001
4. Dehydrohalogenation of 3,4-dihalochromans by treatment with sodium alkoxide in solvent under reflux condition yields 4-halo-2H-1-benzopyran.1002
Halogenation of chroman is accomplished with bromine in carbon tetrachloride or N-bromosuccinimide. Dehydrohalogenation is accomplished by heating of halochroman over sodium alkoxide or by treating with alkoxide in benzene under reflux conditions yielding 2H-1-benzopyran.1003, 1004
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
259
5. Dehydration: 4-Chromanones on reaction with Grignard reagent yields an alcoholic compound, which on dehydration with anhydrous copper acetate yields 2H-1-benzopyran along with alkylidene chroman as a side product.1005, 1006
6. Condensation reaction: Isobutylene and 2-chloro-2-methylpentane react with salicylaldehyde in the presence of silica-alumina (150°C) or zinc chloride (75°C) to yield 2H-1-benzopyran derivative. The reaction is thought to proceed with the formation of chromanol, which is then dehydrated.1007
7. Thermal rearrangement: Thermal cyclization of aryl propargyl ethers (prepared by alkylation of appropriate phenol with halogenated alkyne) effected regioselective orthocyclization yielding 2H-chromene derivatives.1008
8. 1,3-Michael-Claisen annulation reaction: Precocene II, a molecule showing antijuvenile activity was synthesized from α-methylene-δ,δ-dimethyl-δ-valerolactone. Michael addition of thioacetal anion to lactone followed by cyclization of the resulting adduct with ZnCl2 afforded tetrahydrochroman. Transacetalization was carried out using Fujita’s condition, yielding a product that was aromatized with p-TsOH. Methylation of the resulting phenol with methylsulfate and dehydrogenation with DDQ yielded precocene II.1009
260
2. Six-Membered Heterocycles
9. Ring-closing metathesis: Substituted phenol was initially converted to its corresponding aryl allyl ether which undergoes thermal Claisen rearrangement to afford o-allylphenol. In the next step, terminal alkene was isomerized to internal alkene in the presence of ruthenium-based catalyst yielding a mixture of E and Z isomers, in which the E isomer predominates. O-Allylation afforded the 1-alloyloxy-2-(prop-1-enyl)benzene. This compound underwent ring-closing metathesis in the presence of Grubbs second-generation catalyst yielding the 2H-chromene derivative.1010
An atom-economical and environmentally friendly FeCl3-catalyzed intramolecular alkyne-aldehyde metathesis process for the synthesis of functionalized 2H-chromene derivatives from readily available alkynyl ethers of salicylaldehyde derivatives has been reported.1011
A Novel cobalt-catalyzed reaction between salicyl-N-tosylhydrazones and terminal alkynes that led to the generation of 2H chromenes has been reported.1012
An efficient gold-catalyzed method for the synthesis of 2H-chromene has been reported. Monoallylic diols (prepared from salicylaldehyde) undergo exo-cyclization in the presence of Au(I) catalyst yielding the title compound.1013
Gold-catalyzed cycloisomerization of substituted aryl propargyl ethers yields substituted 2H-chromenes. According to the proposed mechanism, a hydroarylation reaction is initiated by addition of gold(I) catalyst. As a result of high aurophicity of alkyne moiety the aryl propargyl ether is activated by gold(I) metal to form the auropropargyl complex (I), which undergoes endo-selective hydroarylation to form the Wheland-type intermediate (II). Release of gold (I) catalyst affords the 2H-chromene derivative.1014–1016
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
261
An aldol-type condensation reaction between 3-methoxyphenol, 3,3-dimethylacrylaldehyde, and phenylboronic acid afforded cyclic borate, which on heating undergoes elimination reaction to yield o-quinone methide, which undergoes electrocyclization reaction to produce 2H-chromene derivative.1017, 1018
10. Enantioselective organocatalytic 2H-chromene synthesis: The first organocatalytic asymmetric synthesis of benzopyrans via one-pot oxa-Michael addition followed by intramolecular aldol condensation between salicylaldehyde and α,β-unsaturated aldehyde was reported by Ardidsson et al. The reaction used diphenylprolinol trimethylsilyl ether as catalyst.1019
Synthesis of 2-substituted 2H-chromene-3-carbaldehyde was carried out by adopting a domino oxa-Michael/ aldol condensation reaction using diphenylprolinol trimethylsilyl ether as catalyst.1020 Synthesis of chiral chromenes employing (S)-diphenylprolinol triethylsilyl ether as chiral organocatalyst and benzoic acid as co-catalyst works well with salicylaldehyde and trans-cinnamaldehyde.1021 The nitrochromenes were synthesized by one-pot enantioselective oxa-Michael/aza-Henry condensation between salicylaldehyde and nitro-olefins using chiral secondary amine as organocatalyst and salicylic acid as co-catalyst.1022
Palladium-catalyzed asymmetric allylic alkylation of phenol allyl carbonates in an intermolecular fashion led to enantioselctive formation of the allylic CO bond, followed by cyclization to provide chiral chromans, which on subsequent oxidation yield chiral chromene.1023
262
2. Six-Membered Heterocycles
Synthesis of 3-nitro-2H-chromene via enantioselective tandem oxa-Michael/Henry reaction using chiral amine is established1024 Another effective method for synthesis of optically active 2H-chromene derivative involving kinetic resolution has been reported.1025 The reaction involves the use of chiral thiourea-derived Takemoto’s catalyst, which undergoes selective asymmetric formal [2+2] cycloaddition of azomethine ylide with one enantiomer of nitrochromene leaving behind the other enantiomer.
Physical Properties 2H-1-Benzopyran is a liquid with a bp of 92°C/15 mm and nD251.5551, d4161.0993. Chemical Reactivity 1. Oxidation: Treatment of 2H-chromene with [hydroxyl(toxyloxy)iodo]benzene (HTIB) in methanol introduced a methoxy group at the C-4-position yielding a 4H-chromene derivative.1026
Reaction of 2H-chromene with osmium tetroxide and peroxide in anhydrous ether or cold (−15 to −20°C) dilute potassium permanganate afforded cis-glycol,1027, 1028 while treatment with hydrogen peroxide in formic acid produced trans-glycol.1029
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
263
Reaction of 2H-chromene derivative with 5% perbenzoic acid in chloroform over a period of 4 h causes epoxidation.1030
Epoxidation of 2H-1-benzopyran can be achieved in chloroform by using perbenzoic acid.1031–1033
2. Reduction: Hydrogenation of a nonaromatic double bond of the pyran ring has been accomplished with a variety of reagents. The most commonly used catalysts are palladium on charcoal, platinum, and Raney nickel. Palladium on charcoal has been used with methanol, ethanol, acetic acid, and ethyl acetate as solvent. When hydrogenation is carried out with palladium on charcoal in ethanol, debenzylation of the ether group also takes place.1034
Lithium aluminum hydride in tetrahydropyran reduces the pyran double bond as well as amide group of 2H-1-benzopyran-3-carboxamide.1035
Reaction of 3-nitrochromene with sodium borohydride and hydrazine hydrate in the presence of Raney nickel and propyl iodide yielded 3-N,N-dipropylaminochromane, which showed anxiolytic activity.1036
Birch reduction of a 2H-chromene derivative by series of single electron transfer processes led to opening of the ring to yield o-prenylated phenols.1037
3. Addition reactions: Addition of chlorine is accomplished by bubbling chlorine gas through an ice-cold solution of 2H-chromene derivative in chloroform.1038
264
2. Six-Membered Heterocycles
Treating 2,2-dimethyl 2H-1-chromene with saturated bromine water solution led to the synthesis of bromo derivative 4-bromo-3-hydroxy-2,2-dimethyl chroman.1039
Addition of MeOBr also takes place when methyl 2H-1-benzopyran-3-carboxylate is treated with a methanolic solution of N-bromosuccinimide.1040
Isobutyraldehyde added to 3-nitrochromene in the presence of racemic proline and sodium acetate yielded trans-chromanes.1041
The addition of benzyl-2-ketopentanoate to 2H-1-chromene in the presence of Takemoto’s chiral catalyst yields an antiisomer of keto ester with 97% enantiomeric excess.1042
The asymmetric nucleophilic addition of dimethylmalonate to 2H-chromene in the presence of Takemoto’s chiral reagent provides trans-diastereomer in high yield and in high enantiomeric excess.1043, 1044
Carbene addition: When 2-methyl-2H-1-benzopyran is treated with sodium methoxide and ethyl trichloroacetate, addition of dichlorocarbene from a less hindered side takes place leading to the generation of a dichlorocyclopropane derivative of benzopyran.1045, 1046
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
265
4. Nitration: Selective nitration of the double bond in 2H-chromene is achieved by successive treatment with nitrogen monoxide at room temperature, followed by dehydration of the intermediate nitrochromanol by boiling over acidic alumina for 30 minutes in dichloroethane.1047
5. Photochemical reaction: Irradiation of 2,2-dimethyl-2H-1-benzopyran in methanol yielded o-quinoneallide, which is unstable and decomposes to give different phenolic products depending on the reaction conditions.1048
2.7.3 4H-1-Benzopyran (4H-Chromene)
4H-Benzo[b]pyran is a bicyclic, nonconjugated, unsaturated oxygen heterocycle, constituted by fusion of the benzene ring with the “b” site of the 4H-pyran ring. Because the benzene ring is not in conjugation with the pyran ring and does not meet the criteria of Hückel’s rule of the (4n+2π) electron system for aromaticity it is neither a true aromatic nor aliphatic. Structural and Reactivity Aspects Since the carbon-carbon double bond of the pyran ring of 4H-1-benzopyran is not in conjugation with the benzene ring, its ultraviolet spectrum should be similar to that of substituted benzenes. The ultraviolet spectrum of substituted 4H-1-benzopyran showed three absorptions at 212, 278, and 284 nm. All these bands are due to π→π* transition.1049 The infrared spectrum of 4H-1-benzopyran showed absorptions at 1665, 1580, 1490, 1273, 1050, and 755 cm−1. The carbon-carbon double bond stretching at 1665 cm−1 is observed at a higher frequency in comparison to 2H-1benzopyran. Pyran aromatic ether1050 CO stretching is also observed at higher frequencies of 1273 and 1050 cm−1. The most reliable and characteristic information on the structure of 4H-1-benzopyran is provided by the 1H NMR spectrum.1051 The assignment is as follows: δ 3.36 (q, 2H, 4-H, J4,4 = 0.6 Hz), 4.83 (sextet, 1H, 3-H, J3,4 = 2.0 Hz, J2,3 = 6.4 Hz), 6.44 (sextet, 1H, 2-H, J2,4 = 3.6 Hz), and 6.90 (4H, Ar-H).
266
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials A large number of natural products with a 4H-chromene nucleus have been isolated and a large number of their synthetic derivatives have been prepared. For example, 7-hydroxy-6-methoxy-4H-chromene, which was isolated from the plant Wisteria sinensis along with related compound 6,7-dimethoxy-4H-chromene, was reported to be having interesting organoleptic properties.1052 This compound has also been efficiently synthesized.
Natural products containing 4H-chromene nucleus.
Another naturally occurring 4H-chromene is uvafzlelin, isolated from the stems of Uvaria ufielii, which show broad-spectrum antimicrobial activity against Gram-positive and acid-fast bacteria.1053 In recent years a number of 4H-chromenes and their derivatives have attracted great interest because a number of these compounds have exhibited diverse pharmacological properties such as antimicrobial, antiangiogenesis, antioxidant, antitumor, and anticancer activities.1054–1059
Different biological activity exhibited by differently functionalized 4H-chromene skeleton.
Synthesis 1. When 2-hydroxymethylcoumaran is heated at 300–400°C, 4H-chromene is obtained along with 2-methylcoumarone.1060
2. Chromone-2-carboxylic acid on boiling with an excess of thionyl chloride gives 4,4-dichloro-4H-chromene.1061
3. From phenols: o-Allyl phenol was initially obtained from its corresponding aryl allyl ether by thermal Claisen rearrangement. This compound in the presence of copper acetate was then converted to its respective aryl vinyl ether. Then ruthenium-mediated ring-closing metathesis yielded the 4H-chromene derivative.1062
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
267
Phenols substituted with a 3-keto substituent on heating with a catalytic amount of acid catalyst in acetic anhydride yield 4H-chromene derivative.1063, 1064
Reaction of resorcinol with acetylacetone in the presence of concentrated hydrochloric acid or sulfuric acid yields 4-methylene-4H-1-benzopyran.1065, 1066
4. 2-Amino-3-cyano-4H-chromene scaffold has received increasing attention during the last few years due to diverse biological activities. One-pot, three-component reaction of aromatic aldehyde, malononitrile, and resorcinol in refluxing ethanol in the presence of Rochelle salt as a novel green heterogeneous and reusable catalyst led to the synthesis of 4H-chromene derivative. This compound has also been synthesized by using modified mesolite-type natural zeolite as green catalyst.1067
Atom-efficient condensation reaction between malononitrile and 2-hydroxybenzaldehyde in the presence of triethylamine or indium chloride yields an imine intermediate, which can be trapped with thiophenol to yield 2-amino-4-(phenylsulfanyl)-4H-chromene-3-carbonitrile or reduced with Hantzsch dihydropyridine ester to yield unsubstituted 2-amino-3-cyano-4H-chromene.
Enantioselective synthesis of a 4-substituted chromene derivative has been reported. The process involves treating E-2-(2-nitrovinyl)phenol with malononitrile in diethyl ether at room temperature in the presence of thiourea-based catalyst, which yields the 4H-chromene derivative in moderate enantiomeric excess.1068
268
2. Six-Membered Heterocycles
A number of methods have been reported for increasing the yield of the title compound.1069–1072 5. Reduction of the double bond and carbonyl group of coumarin with H2/Pd-C followed by DIBAL-H yielded an alcoholic derivative, which on dehydration with oxalic acid yielded a 4H-chromene derivative.1073
Reaction of coumarin with sodium ethoxide yields 2-hydroxycinnamate. Conjugate addition of ethyl cyanoacetate generates an intermediate that undergoes cyclization to ethyl 2-amino-3-ethoxycarbonyl-4H-4-chromenylacetate.
Heating acetyloxychromans in a vacuum at high temperature (450–700°C) yields 4H-1-benzopyran.1074
Similarly, pyrolysis of acetate ester of 2- or 3-chromanol yielded 4H-1-benzopyran.1050, 1051
Heating 3-chromanol or its methyl ester with a catalytic amount of polyphosphoric acid yields 4H-1-benzopyran.1075
Physical Properties 4H-1-Benzopyran is a liquid with a bp of 77°C/9 mm, 44°C/1.3 mm, and nD25 1.5551. Chemical Reactivity 1. Addition reaction (a) Addition of halogen: Addition of bromine to 4H-chromene takes place to yield dibromo derivative, but this product could not be isolated because it decomposes spontaneously to yield halobenzopyran.1060, 1076, 1077
(b) Addition of alcohol: By treatment of a solution of 4H-chromene in alcohol with a trace of acid, carbocation is formed as an intermediate, which reacts further with alcohol to yield an ether derivative.1060, 1076
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
269
(c) Addition of water takes place by treating 4H-chromene derivative with 1N H2SO4 solution. The addition takes place according to the Markovnikov rule.1076
(d) Reaction of 4H-chromene with diborane followed by alkaline oxidation led to the addition of water by following the anti-Markovnikov rule.1078
(e) Addition of carbene: Reaction of 4H-chromene with dichlorocarbene affords 1,1-dichloro-1a,7a-dihydro-4Hbenzo[b]cyclopropa[e]pyran in good yield.
2. Reaction with Grignard reagent: 4H-Chromene on reaction with bromine followed by treatment with phenyl magnesium bromide yields 2-bromo-1-(2-hydroxyphenyl)-3-phenylpropan-3-ol, which on heating with p-toluenesulfonic acid yielded trans-3-bromo-flavan. This on treatment with methanolic KOH afforded 2H-chromene.1079
3. Oxidation: Reaction of 2-phenyl-4H-chromene with potassium permanganate in acetone affords 2-phenyl-4H-chromone.
2.7.4 Benzopyrylium Salts Benzopyrylium salts are pyrylium salt derivatives in which a benzene ring is fused to a pyrylium cation. All together there are two benzopyrylium derivatives, namely benzo[b]pyrylium (chromylium or 1-benzopyrylium) and benzo[c]pyrylium (isochromylium or 2-benzopyrylium) salts.
270
2. Six-Membered Heterocycles
Structural and Reactivity Aspects1080a The positive charge of the 1-benzopyrylium salt is distributed unevenly over the heterocyclic ring. As a result, the following resonance structures are possible.
Resonanting structures of 1-benzopyrylium salt.
2-Benzopyrylium salt is represented by the following two mesomeric structures.
Resonanting structure of 2-benzopyrylium salt.
The 1H NMR data of 1-benzopyrylium trifluoromethanesulfonate are given in the following table. H spectral data of 1-benzopyrylium salt
1
1-Benzopyrylium H-1, 9.87; H-3, 8.13; H-4, 9.72
The 13C NMR data of 2-phenyl 1-benzopyrylium perchlorate and 2-benzopyrylium salt are given in the following table. C NMR spectral data of 1- and 2-benzopyrylium salt
13
1-Benzopyrylium
2-Benzopyrylium
C-2, 176.8; C-3, 118.6; C-4, 150.0; C-4a, 127.5; C-8a, 157.7
C-1, 174.0; C-3, 149.7; C-4, 116.4; C-4a, 140.7; C-8a, 118.0
Because 1-benzopyrylium salts are colored, their UV/Vis maxima are usually quite intense and observed around >350 nm. Importance in Natural Products, Medicines, and Materials 1-Benzopyrylium is of great value because this structural subunit is the aglycon part (commonly called anthocyanidins) of the anthocyanins—the plant pigments responsible for the large variety of colors of flowers, fruits, and leaves. The most common 1-benzopyrylium derivative present in plants is its 2-phenyl derivative commonly called flavylium chloride. Some selected anthocyanidins and the color they impart to flowers/fruits are shown in the following table. Anthocycnidins and the colour they impart Anthocyanidin
Color
Cyanidin
Magenta
Delphinidin
Purple, blue
Pelargonidin
Orange
Malvidin
Purple
Peonidin
Magenta
Structures of some common 1-benzopyrylium salts.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
271
2-Benzopyrylium salts are not found in nature. However, their application lies in their transformation to isoquinoline derivatives. Synthesis 1. Unsubstituted 2-benzopyrylium cation was synthesized in two steps. In the first step, oxidation of indene affords homophthalic dialdehyde. In the second step, the dialdehyde is cyclized to 2-benzopyrylium tetrachloroferrate by treating it with hydrochloric acid and ferric chloride.1080b
2. Reaction of dialkoxycarbocation (formed by reaction of acetals with triphenylmethyl perchlorate) with benzyl ketone leads to the generation of 2-benzopyrylium salt.1081
3. Reaction of resorcinol with acetylacetone in the presence of hydrochloric acid affords 1-benzopyrylium ion.1082
4. Condensation of o-hydroxybenzaldehyde with reactive methylene compounds such as acetophenone in ethyl acetate solution, which is saturated with hydrogen chloride, affords an important benzopyrylium ion-flavylium chloride.1083 The reaction is thought to proceed with the formation of o-hydroxychalcone as intermediate.
5. Condensation of resorcinol with α,β-ethylenic ketone like cinnamyl phenyl ketone in the presence of oxidizing agent such as chloranil affords 1-benzopyrylium salt.
1-Benzopyrylium salts are also synthesized by condensation of resorcinol with phenyl ethynyl ketone in the presence of hydrochloric acid.1084
272
2. Six-Membered Heterocycles
6. Refluxing 1,1,3,3-tetraethoxypropane (bis-acetal of malondialdehyde) with o-cresol in the presence of stannic chloride in toluene affords acetal ether, which in the presence of acetic acid and perchloric acid yields hetero ring-unsubstituted benzopyrylium salt.
7. Addition to carbonyl oxygen: Carbonyl oxygen of chromone undergoes protonation to produce hydroxybenzopyrilium salt. Thus reaction of chromone in ether with hydrogen chloride leads to the precipitation of chromone hydrochloride (4-hydroxy-1-benzopyrilium chloride).
In comparison to chromone the carbonyl oxygen of coumarin is less readily protonated. However, reactive electrophiles like Meerwein’s salt ([Et3O]BF4) attack carbonyl oxygen of coumarin, yielding 2-alkylated benzopyrylium ion.
Coumarin reacts with aromatic compounds in the presence of phosphoryl chloride alone or with zinc chloride to yield benzopyrylium ion.1085, 1086
Coumarin reacts with Grignard reagent to form benzopyrylium ion.
Chemical Reactivity 1. Ring-opening reaction: Benzopyrylium salt on heating in aqueous alkali resulted in the ring opening of the heterocyclic ring followed by carbon-carbon bond cleavage.
2. Reaction with amines: 2-Benzopyrylium salt reacts with ammonia to afford isoquinoline derivative or isoquinolium salts.1087
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
273
Reaction of 2-benzopyrylium ion with aniline resulted in the formation of 2-phenyl-3-methyl-6,7- dimethoxyisoquinolinium perchlorate. However, on reaction with ethylenediamine, bis-cations are formed.1088
1-Benzopyrylium salts on reaction with amines form C-2 and C-4 derivatives. For example, 1-benzopyrylium salt reacts with piperidine to form 2H and 4H adducts. This reaction is, however, reversible in acidic medium.
1-Benzopyrylium salt reacts with an ethereal solution of dimethylaniline to afford a colorless compound N,Ndimethyl-4-(2-phenyl-4H-chromen-4-yl)aniline, which on oxidation yielded carbinol.1089
3. Reduction: Catalytic reduction of 1-benzopyrylium salts results in saturation of the double bond in the heterocyclic ring.
4. Oxidation: Ozonolysis of 3-methoxy-4′-bromoflavylium chloride in glacial acetic acid followed by decomposition of the ozonide with water and zinc dust afforded salicylaldehyde, p-bromobenzoic acid, and methyl 2-(2-methoxy-2-oxoethyl)phenyl 4-bromobenzoate.1090
274
2. Six-Membered Heterocycles
5. Benzopyrylium salt on reaction with tertiary benzenoid amine forms flavylium salts, which on warming with pyridine forms flavones.
6. Reaction with carbon nucleophiles: Malononitrile adds to 1-benzopyrylium salts in the presence of triethylamine affording 4-substituted chromene derivatives.
When benzopyrylium salt is generated by O-silylation of chromone on reaction with silyl enol ethers or allylsilanes, addition takes place at the C-2-position.
2-Benzopyrylium perchlorate on reaction with aqueous sodium cyanide in the presence of diethyl ether yielded stable, colorless cyanoisochromene derivatives.1091
2.7.5 Chroman (2,3-Dihydro-2H-1-Benzopyran)
Chroman or 3,4-dihydro-2H-1-benzopyran or benzodihydropyran is a bicyclic oxygen heterocycle resulting from the fusion of the benzene ring with the “b” (2,3) site of dihydropyran. Structural and Reactivity Aspects1092 The 1H and 13C NMR spectral data of chroman are given in the following table.1092 H and 13C NMR spectral data of chroman
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.82; H-3, 1.70; H-4, 2.28
C-2, 74.0; C-3, 32.8; C-4, 22.6; C-5a, 121.7; C-8a, 147.5
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
275
Importance in Natural Products, Medicines, and Materials Though chroman as an independent unit it is not found in nature; however, this important scaffold is present in many natural products like vitamin E (all tocopherol, tocotrienol, and tocomonoenol derivatives). This nucleus is also present in many clinically used drugs like troglitazone, nebivolol, Trolox, and ormiloxifene.
Vitamin and drugs containing chroman nucleus.
Chromans are also important synthons that are associated with a wide variety of biological activities like neuroprotective,1093 antiestrogen,1094 antioxidant,1095 anti-HIV,1096 and antibreast cancer agents.1097 Synthesis1098a 1. Chroman was first prepared by warming an alkaline solution of 2-(3-chloropropyl) phenol.1098b However, chroman in high yield and in purified form by distillation from sodium was obtained by cyclization of 1-phenyl-3-chloropropoxybenzene.1099
2. Heating coumarin over copper chromate at 250°C yields 2-(3-hydroxypropyl)phenol, which on reaction with phosphorous tribromide in benzene yields 2-(3-bromopropyl)phenol. Warming an aqueous sodium hydroxide solution of 2-(3-bromopropyl)phenol yields chroman.1100
3. Freshly prepared 1,3-diphenoxypropane, when heated with aluminum chloride in boiling benzene, gives chroman.
Similarly, 6-methylchroman was also obtained by reaction of appropriate 1,3-di(p-tolyloxy)propane with aluminum chloride in boiling benzene.1101
276
2. Six-Membered Heterocycles
4. Reaction of an acetyl derivative of allyl phenol with hydrogen bromide in the presence of benzoyl peroxide yields chroman.
5. Grignard reagent on reaction with 3,4-dihydrocoumarin afforded tert-alcohol through ring fission, which underwent ring closure to generate 2,2-dialkyl chroman.1102
6. Domino reaction: The synthesis of chroman derivative involves a reaction of salicyl N-thiophosphinylimines and ethyl 2,3-pentadionate in the presence of triphenylphosphine or (2′-hydroxylbiphenyl-2-yl)diethylphosphane (LBBA) as catalyst. The reaction is the first example of ϒ-CH3 of allenoate undergoing cyclization to chroman derivatives.1103a
7. Allenylidene-ene process: A novel method for the synthesis of chiral chromanes has been reported.1103b The process involves heating propargylic alcohol bearing an (E)-alkene moiety in 1,2-dichloroethane in the presence of an optically active thiolate-bridged diruthenium complex and NH4BF4 yielding 4-ethynyl-3-(1-phenylethenyl) chromane as a mixture of two diastereomers, the syn-isomer with 93% enantiomeric excess being the major and the anti-isomer being the minor.
8. A new method for the synthesis of 2-substituted and 2,2-disubstituted chromans using a Pd-catalyzed carboetherification reaction between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols has been reported. In this reaction, formation of a new CO and CC bond takes place leading to the generation of chroman in good yield.1104a
Palladium-catalyzed asymmetric allylic alkylation of phenol allyl carbonates in an intermolecular fashion led to enantioselective formation of the allylic CO bond, which was followed by cyclization to provide chiral chromans.1104b
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277
9. A novel method for direct access to chromans has been accomplished by carrying out allylic oxidation of phenols with terminal olefins in the presence of a combination of Pd(II)/bis-sulfoxide CH activation and Lewis acid co-catalysis.1105
Physical Properties Chroman is a colorless, steam volatile, oily liquid with a bp of 214°C/742 mm, d20 1.0610, and nD20 1.544, with a peppermint-like odor. It is soluble in nearly all organic solvents. Chroman gives a red color with sulfuric acid. Chemical Reactivity 1. Alkylation: A number of 4-alkylchromans have been synthesized by reacting 4-bromochroman with appropriate Grignard reagent. 4-Bromochroman is, however, prepared by treating chroman with N-bromosuccinimide.
2. Friedel-Crafts acylation: Reaction of chroman with veratroyl chloride (3,4-dimethoxybenzoyl chloride) in the presence of Lewis acid catalyst yields 6-veratroyl chroman.1106
3. Reduction: Chroman is reduced with lithium in 1:1 (by volume) of dry ethylamine and dimethylamine to 3,4,5,6,7,8-hexahydrochroman in 85% yield, which reacts with perphthalic acid in moist ether to give trans diol, which is cleaved with lead tetraacetate to yield 6-oxononanolide.1107
4. Gas-phase pyrolysis of chroman at 413°C gave a mixture of o-cresol, benzofuran, and styrene in a ratio of 4:2:1.1108
278
2. Six-Membered Heterocycles
However, pyrolysis of chroman over alumina at 250°C gave only 2,3-dihydro-2-methylbenzo[b]furan in 10% yield.
5. Thermal decomposition: Gas-phase thermal decomposition of chroman has been studied between 760 and 1110 K. Decomposition starts with the elimination of ethene leading to the formation of 6-methylene-2,4-cyclohexadien1-one (o-quinone methide). Quinone methides are important intermediates in the chemistry of lignin. At high temperature (860–980 K) quinone methide decomposes into CO, benzene, and a small amount of fulvene.1109
2.7.6 Coumarin
Coumarin is a fragrant chemical compound belonging to the benzopyrone family. The term coumarin comes from the French term coumarou meaning tonka beans, from which it was first isolated. Structural and Reactivity Aspects1110a X-ray analysis of coumarin suggests it to be a planar compound. The bond angles (in degrees) and bond lengths (in pm) of coumarin as derived from X-ray analysis are given in the following diagram.
Bond lengths and bond angles of coumarin.
The UV absorption spectrum of coumarin is quite helpful in distinguishing it from other chromones. Chromones show one strong absorption band at 240–250 nm (log ε 3.8), whereas coumarins show two strong absorption bands at 274 and 311 nm (log ε 4.03 and 3.72), which are attributed to the benzene and pyrone rings.1110b The δ-lactone carbonyl stretching frequency of coumarin is usually observed in the region 1720–1750 cm−1. In contrast to other isomeric chromones, the IR spectrum of coumarin normally shows three strong absorption bands in the region 1600–1660 cm−1, due to CC stretching.1111, 1112
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
279
The 1H and 13C NMR data of coumarin confirm it to be a 2H-pyran-2-one derivative. The 1H NMR data further suggest that coumarin has an enol lactone character rather than that of heteroarene. The 1H and 13C NMR data of coumarin are given in the following table. H and 13C NMR spectral data of coumarin
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-3, 6.43; H-4, 7.80; H-5, 7.36; H-6, 7.22; H-7, 7.45; H-8, 7.20
C-2, 159.6; C-3, 115.7; C-4, 142.7; C-4a, 118.8; C-8a, 153.1
The mass fragmentation pattern of coumarin is shown in the following diagram. It involves loss of CO from the carbonyl group, a characteristic feature of coumarins. The benzofuran ion is further decomposed by consecutive loss of CO and the hydrogen atom.1113
Mass fragmentation pattern of coumarin.
Importance in Natural Products, Medicines, and Materials Coumarins constitute a class of naturally occurring oxygen ring compounds that are structural subunits of a number of more complex natural products. Coumarin itself was first isolated in 1822 from tonka beans, coumarins, which have been found to play an important role in plant biochemistry and are also involved in the actions of plant growth hormones and growth regulators, control of respiration, photosynthesis, as well as defense against infections.1114 A number of naturally occurring organic compounds containing coumarin moiety have been found to exhibit useful applications. Calanolide A1115, 1116 is a novel nonnucleoside reverse transcriptase inhibitor with potent activity against HIV-1. Inophyllum B has also been found to be an active component for inhibition against HIV-reverse transcriptase.1117 (+)-Cordatolide A is also a novel coumarin, and its structure and properties are similar to (+)-calanolide.1118Ayapin, also a coumarin derivative, has been reported to have pronounced blood thinning or anticoagulant property.1119
Biologically active natural products containing coumarin nucleus.
Molecules possessing the coumarin nucleus have been found to display a wide range of interesting properties—a number of them are highly colored, strongly absorbing in the UV region and exhibiting potent fluorescence and luminescence.1120–1122 Besides, a number of biological activities have been attributed to this nucleus and it is thus considered an attractive drug scaffold used in the treatment of viral infection,1123 neurodegenerative diseases,1124, 1125 edema,1126 inflammation, and as a hepatoprotective and antioxidant agent.1127 A number of coumarin derivatives are already being used as drugs, for example, vitamin K antagonists (warfarin), anticoagulants (phenprocoumon), antibiotics (novobiocin), antispasmodics (hymecromone), and coronary vasodilators (carbochromen).
280
2. Six-Membered Heterocycles
Drugs containing coumarin nucleus.
Synthesis1128 1. Perkin reaction: Coumarin was synthesized by the Perkin method by heating salicylaldehyde with acetic anhydride and anhydrous sodium acetate.
2. Pechmann coumarin synthesis: Pechmann reaction involves condensation of phenol with β-keto ester in the presence of sulfuric acid or Lewis acid yielding coumarin.1129, 1130
The reaction proceeds by the following mechanism.
A method has been developed for the synthesis of coumarin via Pechmann reaction catalyzed by montmorillonite K-10 or KSF in yields up to 96%. The advantage of this procedure is that it is environmentally friendly and inexpensive, with easy separation of the product and recyclability of the catalyst.1131
The use of cation exchange resins Zeokarb 225 and Amberlite IR 120 as condensing agents in the synthesis of coumarins has been reported. The reaction takes place in the following steps: (1) addition across the double bond of the enolic form of β-keto ester, (2) ring closure, and (3) dehydration.1132, 1133
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
281
Microwave-assisted Pechmann reaction has been developed for the synthesis of coumarins from substituted phenols and methylacetate in the presence of sulfuric acid. This protocol reduced the reaction period from several hours to a few minutes.1134 A convenient microwave-assisted one-pot synthesis of coumarin under Pechmann reaction conditions using different catalysts like FeF3, Sm(NO3)3, and TiCl4 under solvent-free conditions has also been reported.1135–1137 3. Claisen rearrangement: To overcome the difficulties encountered with Pechmann synthesis, a new application of Claisen rearrangement was developed using allyl or propargyl aryl ethers, in which allylic or propargylic αcarbon was oxygenated. This method has been applied in cases where coumarin synthesis could not be achieved by Pechmann reaction. The reaction involves rearrangement of α-oxygenated allyl aryl ethers. The intermediate alkoxychroman obtained was then oxidized to coumarin.1138
4. Knoevenagel reaction: Condensation of 2-hydroxybenzaldehyde with compounds having active methylene groups (like malonic acid, malonic ester, cyanoacetic ester) in the presence of amine resulted in the formation of coumarins.1139, 1140
Two different mechanisms have been proposed for this reaction.1141 According to first mechanism, the formation of imine or iminium salt with amine, followed by reaction with the enolate of a reactive methylene compound and elimination of amine, followed by ring closure, yields coumarin.
In the second mechanism, carbanion produced by deprotonation of the reactive methylene compound by amine attacks the carbonyl group to yield an intermediate. Proton transfer and ring closure via acyl substitution, followed by dehydration, yields coumarin.
282
2. Six-Membered Heterocycles
The yield of coumarin derivatives by Knoevenagel condensation reaction is low. Attempts have been made by increasing the yield up to 94% by carrying out Knoevenagel condensation under microwave conditions.1142 A procedure for preparing coumarin-3-carboxylic acid by stirring salicyladehyde and Meldrum’s acid using a catalytic amount of potassium phosphate has been reported.1143 Coumarin-3-carboxylic acid has also been synthesized by reacting malononitrile with an aldehyde or ketone in the presence of piperidine.1144
A solid-phase synthesis of coumarin-3-carboxylic acid derivatives using Knoevenagel condensation between ethyl malonate bound to Wang resin and o-hydroxybenzaldehydes in the presence of pyridine and piperidine at room temperature has been discovered.1145
Iodocoumarin derivatives were synthesized by condensation of 3,5-diiodosalicylaldehyde with active methylene compounds (ethyl acetoacetate, malononitrile, ethyl cyanoacetate) in the presence of piperidine as catalyst. In this reaction, 3-substituted coumarins were obtained in excellent yield. When acetic acid was used as an active methylene compound in the presence of sodium acetate, unsubstituted coumarin was obtained.1146
Ultrasound-promoted synthesis of coumarin-3-carboxylic acid by reaction of substituted o-hydroxybenzaldehyde with Meldrum’s acid has also been reported.1147 5. Wittig reaction: A novel one-pot synthesis of coumarins via intramolecular Wittig cyclization involving reaction of o-hydroxybenzaldehydes with phosphonium ylides [phosphorane, (ethoxycarbonymethylene)triphenylphosphorane] has been reported. The reaction primarily takes place through a betaine and/or oxyphosphetane intermediate.1148, 1149
A novel Wittig reaction involving an ortho-carbonyl compound and triphenyl(α-carboxymethylene)phosphorane imidazolide has also been reported.1150
A novel route to the synthesis of 4-carboxymethylcoumarin involving electrophilic substitution reaction between the conjugate base of a substituted phenol and the betaine formed by the addition of triphenylphospine to dimethyl acetylenedicarboxylate (DMAD) has also been reported.1151 Coumarins have also been synthesized by involving a one-pot reaction of o-hydroxy- benzaldehyde, ethyl 2-bromoacetate, and triphenylphosphine in the presence of a catalytic amount of triethylamine in ethyl acetate, water, or under solvent-free conditions.1152 A simple, efficient, and inexpensive method involving intramolecular
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
283
Wittig reaction of substituted 2-formylphenyl 2-bromoacetate with triphenylphosphine in saturated aqueous sodium bicarbonate at ambient temperature has been developed.1153
6. Reformatsky reaction: Condensation of aldehydes or ketones with an organozinc derivative of α-halo esters yielding β-hydroxy esters is known as Reformatsky reaction. However, under appropriate conditions, lactonization could take place leading to the formation of coumarins.
Sodium telluride-triggered cyclization of the bromoacetate of salicylaldehyde to coumarin via modified Reformatsky reaction has been achieved. The cyclization proceeds by formation of the phenolate ester enolate, which attacks the ortho-carbonyl group leading to cyclization.1154
7. Palladium-catalyzed synthesis: Reaction between substituted phenol and an alkyne in the presence of palladium(0) complex as catalyst has been reported. In the presence of formic acid, palladium(II) acetate is reduced to Pd(0), which then catalyzes the reaction. Cis addition initially affords (E)-cinnamic ester, and E-Z isomerization accounts for the isolation of coumarin rather than E-cinnamete.1155
3-Substituted coumarins have been synthesized by adopting Heck’s reaction conditions. The reaction involves treating 3-bromocoumarin with alkenes and alkynes in the presence of palladium catalyst.1156
284
2. Six-Membered Heterocycles
Physical Properties Coumarin is a colorless or white crystalline solid with a vanilla beanlike odor, mp 71°C. It is soluble in chloroform, ethanol, and ether. Chemical Reactivity 1. Compared to chromone the carbonyl oxygen of coumarin is less readily protonated. However, reactive electrophiles like Meerwein’s salt ([Et3O]BF4) attack the carbonyl oxygen of coumarin, yielding benzopyrylium ion.
Coumarin reacts with aromatics containing electron-withdrawing groups in the presence of phosphoryl chloride alone or with zinc chloride to yield benzopyrylium ion.1157, 1158
2. Coumarin on reaction with bromine undergoes addition reaction to give 3,4-dibromo-3,4-dihydrocoumarin, which on reaction with KOH undergoes Perkin-type rearrangement to give benzo[f]furan. Treating coumarin dibromide with alcoholic potassium hydroxide followed by acidification with hydrochloric acid yielded coumarilic acid.1159 The dibromo derivative also undergoes elimination of HBr by the action of a base leading to the formation of 3-bromocoumarin.1159
Chloromethylation of coumarin, carried out by treating it with a solution of coumarin in acetic acid with formaldehyde and hydrogen chloride, produced 3-chloromethyl coumarin.1160
3. Electrophilic substitution (a) Sulfonation: Coumarin on reaction with hot chlorosulfonyl chloride yields 6-sulfonyl chloride.1161 This sulfonyl derivative on reaction with N,N-dimethylhydrazine and hydrazine hydrate-triethylamine yielded hydrazone derivatives.
(b) Nitration: Coumarin on reaction with 1 equivalent of ceric ammonium nitrate (CAN) gave 6-nitrocoumarin as the sole product in excellent yield.1162
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
285
4. Reaction with nucleophilic reagents: Coumarin, being a lactone on reaction with aqueous alkali solution, is readily hydrolyzed to give yellow solutions of the corresponding salts of cis-cinammic acid, which cannot be isolated (because the acid reverts immediately to coumarin) and on prolonged alkali treatment leads to isomerization and formation of a stable trans-acid (coumaric acid) salt.
A simple and effective synthetic route to various coumarin-fused heterocycles like pyrazoles, isoxazoles, and pyrimidine, adhering to the green chemistry principle has been reported. The process involves microwave irradiation of α,β-unsaturated ketone of the coumarin ring with different nucleophiles in aqueous medium in the presence of a green catalyst.1163
5. Reaction with Grignard reagent: Coumarin reacts with methyl magnesium iodide affording tertiary alcohol and 2,2-alkylchromenes giving a mixture of products.1164, 1165
Coumarin on reaction with phenyl magnesium bromide yields 3-(2-hydroxyphenyl)-1,1-diphenylprop-2-en-1-ol and 3-(2-hydroxyphenyl)-1,3-diphenylprop-1-one. Both the compounds on boiling with acetic acid yield 2,2-diphenyl2H-chromene and 2,4-diphenyl-4H-chromene, respectively.1166
286
2. Six-Membered Heterocycles
However, a new protocol for the Cu-catalyzed asymmetric conjugate addition of Grignard reagent to coumarin has been developed. The corresponding products are formed in high yield and enantioselectively. The process involves copper-catalyzed asymmetric conjugate addition of Grignard reagent to coumarin in the presence of ferrocenyl- based biphosphine ligand leading to the generation of 4-alkylchroman-2-ones.1167
Asymmetric 1,4-addition of alkylboronic acid to coumarins takes place with high enantioselectivity in the presence of rhodium catalyst generated from Rh(acac)(C2H4)2 and (R)-SEGPHOS to yield (R)-4-arylchroman-2-ones in over 99% enantiomeric excess. This reaction has been applied for the synthesis of (R)-tolterodine, an antimuscarinic drug.1168
6. Fries rearrangement: 4-Methyl-7-hydroxycoumarin on reaction with acetic anhydride yields 4-methyl7-acetoxycoumarin. This esterified derivative in the presence of aluminum chloride undergoes Fries rearrangement to yield 4-methyl-7-hydroxy-8-acetylcoumarin.1169
7. Claisen rearrangement: 4-Methyl-7-allyloxy coumarin undergoes Claisen rearrangement to yield 8-allyl-7-hydroxy-4-methylcoumarin.1170
8. Heterocyclic ring fission: Heating 4-methyl-7-hydroxy-8-acetylcoumarin with sodium hydroxide followed by acidification led to ring opening to yield 2,6-dihydroxyacetophenone.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
287
9. Reduction: Lithium aluminum hydride not only saturates the CC double bond, it also attacks the carbonyl carbon giving a mixture of products.
10. Cycloaddition reaction: Under forcing conditions, coumarin serves as a dienophile in Diels-Alder reaction and undergoes cycloaddition reaction with 2,3-dimethyl-1,3-butadiene at 260°C to give a tetrahydrobenzocoumarin derivative.1171, 1172
11. Photochemical reaction: Coumarin on prolonged illumination in the solid state or in solution is converted to its dimer, with head-to-head cis-cyclobutane structure. The trans-head-to-head dimer is obtained by irradiating coumarin in ethanol in the presence of photosensitizer benzophenone.1173–1175
Photodimerization of coumarin was also carried out in solid inclusion complexes with β- and ϒ-cyclodextrins.1176 [2+2] Photodimerization of coumarin to an optically active antihead-to-head dimer in the presence of an optically active host compound in cyclohexane solution has been found to proceed with high enantioselectivity.1177
12. Transformation to other heterocycles: Coumarin can be transformed to 4H-chromene by sequential reduction of the double bond and carbonyl group by H2, Pd/C, and DIBAL-H, respectively, yielding a hydroxyl chroman derivative, which on dehydration with oxalic acid yields a 4H-chromene derivative.
288
2. Six-Membered Heterocycles
Coumarin on reaction with sodium ethoxide yields 2-hydroxycinnamate, which on conjugate addition with ethyl cyanoacetate undergoes cyclization to yield a 4H-chromene derivative.
Coumarin on reaction with phosphorous pentasulfide gives thiocoumarin.1178
2.7.7 Isocoumarin
Isocoumarin, also known as 1H-2-benzopyran or 3,4-benzopyrone, is an isomer of coumarin in which the orientation of lactone is reversed. Thus isocoumarin is an unsaturated, nonconjugated oxygen heterocycle constituted by fusion of the benzene ring with the 3,4-position (“c” site) of the 2-pyrone ring. It is neither a true aromatic nor a true aliphatic compound because it shows the properties of aliphatic and aromatic compounds. Structural and Reactivity Aspects The structure of unsubstituted isocoumarin has been proved on the basis of 1H NMR spectroscopy.1179 1
H NMR spectral data of isocoumarin
1
H NMR (CDCl3)
δ 8.31 (br d, J = 7.5 Hz Ar-H), 7.28–8.0 (m 3H, Ar-Hs); 7.28 (d 1H, J = 5.7 Hz); 6.49 (d 1H, J = 5.7 Hz, vinylic H)
The IR spectrum shows two prominent bands at 1728 and 1638 cm−1 for CO and CC stretching vibrations. Importance in Natural Products, Medicines, and Materials Isocoumarin represents an important class of compound that exhibits a wide range of pharmacological activities. A large number of isocoumarins have been isolated from plants and have been explored for antifungal, antimicrobial, anticancer, antiallergic, antiinflammatory, anti-HIV, and anticoagulant activities.1180 Some of the promising isocoumarin derivatives are capillarin and artemidin, which have potential antifungal activity. Thunberginol A and B exhibit antiallergic and antimicrobial activity. Ruticulol and cytogenin are known for their antitumor activity.
Natural products containing isocoumarin skeleton.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
289
Synthesis1181a 1. One of the most convenient synthetic methods of isocoumarin involves ozonization of indene in ethyl alcohol followed by decomposition of cyclic ester to 2-carboxyphenylacetaldehyde, which on treatment with mineral acid yields isocoumarin.1181b
2. Claisen condensation: Condensation of diethyl homophthalate with methyl formate in the presence of sodium ethoxide affords isocoumarin-5-carboxylic acid, which on decarboxylation with phosphoric acid yields isocoumarin.1182
Condensation of diethyl homophthalate with diethyl oxalate in the presence of sodium metal affords triester, which when heated loses ethanol to give diethyl isocoumarin-3,4-dicarboxylate. Heating the dicarboxylate with hydrochloric acid in a sealed tube at 180–190°C, yields isocoumarin-3-carboxylic acid.1183
3. Heating homophthalic acid with aryl or acyl chlorides yields isocoumarins.1184
4. Condensation of phthalaldehydic acid with nitromethane in the presence of sodium hydroxide in methanol gave (nitromethyl)isobenzofuranone, which on treatment with sodium borohydride in dimethylsulfoxide afforded 2-(2-nitroethyl)benzoic acid. Nitro acid was converted to keto acid by applying Nef procedures. Keto acid on intramolecular cyclization followed by dehydration yielded isocoumarin.1179
290
2. Six-Membered Heterocycles
5. Acid-catalyzed selective intramolecular cyclization of enynecarboxylic acid to isocoumarin derivative has been reported.1185
6. Reaction of o-iodobenzoic acid with 1-hexyne in the presence of Pd(PPh3)4, Et3N, and ZnCl2 in DMF at 100°C gave isocoumarin.1186
7. Tandem Stille reaction: Reaction of 2-iodobenzoic acid with allenyltributyltin reagent in the presence of palladium acetate, triphenylphosphine, and tetrabutylammonium bromide in dimethylformamide afforded 3-substituted isocoumarins via tandem Stille reaction and 6-endo-dig oxacyclization.1187
8. Cross-coupling reaction of o-bromobenzoate with n-tributyl vinyl tin in the presence of palladium catalyst affords isocoumarin.1188
9. The reaction between 4-hydroxycoumarin and a benzyne precursor in the presence of CsF as fluoride source in acetonitrile at room temperature affords isocoumarin.1180
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
291
10. A multicomponent reaction between terminal alkynes, arynes, and carbon dioxide yields isocoumarin.
Physical Properties Isocoumarin is a low-melting solid with mp of 45–46°C. Chemical Reactivity1189 1. Hydrolysis: Isocoumarin on alkaline hydrolysis undergoes a ring-opening process to give homophthaldehydic acid. However, isocoumarin containing alkyl group at position 3 provides ketone under same reaction conditions.
2. Reaction with nitrogen nucleophiles: Ammonia and its derivatives add to isocoumarins to yield isocarbostyrils.1190
This process has been used in the synthesis of indole alkaloid yobyrine. The process involves treating isocoumarin with tryptamine and the product obtained is converted to yobyrine.
3. Reaction with Phosphorous pentasulphide: Isocoumarin on reaction with phosphorous pentasulfide affords 1-thioisocoumarin, which on treatment with ammonium sulfide or aniline yields isoquinoline.
4. Reaction with Grignard reagent: Reaction of isocoumarins with Grignard reagent yields an alcoholic derivative, which on dehydration with strong acid affords 1-substituted 2-benzopyrylium salt.
292
2. Six-Membered Heterocycles
5. Reduction: Reduction of isocoumarin was carried out with sodium borohydride, leading to the generation of 3,4-dihydroisocoumarin. On reaction with alkali the heterocyclic ring was opened yielding 2-(2-oxoalkyl) benzoic acid, which was reduced by sodium borohydride to a corresponding alcohol. The intermediate alcohol was cyclized to 3,4-dihydroisocoumarin1191 in the presence of acidic reagents (sulfuric acid solution, acetic anhydride).
6. Oxidation: Oxidation of 3,4,6,7-tetraphenyl isocoumarin with chromium trioxide affords 2-benzoyl-4,5diphenylbenzoic acid.
7. Photocycloaddition reaction1192: Irradiation of isocoumarin (λ = 350 nm) in the presence of 10-fold molar excess of tetrachloroethene in acetonitrile afforded a cis-fused cyclobutane derivative.
However, irradiation of isocoumarin (λ = 350 nm) in the presence of 10-fold molar excess of 2,3-dimethyl-but-2ene in acetonitrile afforded a mixture of cis- and trans-fused cyclobutane derivative.
Benzopyrones Benzo[b]pyrone is a bicyclic, unsaturated, nonconjugated oxygen heterocycle constituted by fusion of the benzene ring with the 2,3-position (“b” site) of the pyran-4-one ring. It is neither a true aliphatic nor a true aromatic compound because it exhibits the properties of aliphatic as well as aromatic compounds. There are two structural isomers: (1) α-benzopyrone, commonly referred to as coumarin and (2) γ-benzopyrone, commonly referred to as chromone.
2.7.8 Chromone
Chromone, also known as 4-chromone, 1-benzopyran-4-one, 4H-chromen-4-one, or 4H-benzo[b]pyran-4-one, is an isomer of coumarin and consists of a substituted keto group at the 4-position of the 4H-pyran ring. The word chromone is derived from the Greek word chroma meaning color. The word chromone was first used by Bloch and Kostanecki for several naturally occurring colored compounds like brazilin and hydroxyflavones that contained a benzopyran-4-one structure. Some important chromone derivatives are flavone, flavanol, and isoflavone.
293
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
Some important chromone derivatives.
Structural and Reactivity Aspects Chromones can be identified on the basis of their color tests. Chromones in ethanol produced a crimson to blue color when an aqueous 0.001 N iodine solution was added to them.1193 2-Methylchromone gave a red to violet color when an aqueous solution of chromone was poured over pellets of potassium hydroxide on a watch glass.1194 2-Methychromones are also identified by adding sodium nitroprusside in ethanol to an ethanolic solution of chromone. A drop of 30% sodium hydroxide solution is added followed by acidification with two drops of acetic acid. 2-Methylchromone if present produces a reddish violet coloration.1195 Synthetic methods often lead to a mixture of chromones and coumarins which can be separated by a chemical method. To a mixture of chromone and coumarin was added a solution of sodium ethoxide in ethanol, whereby the 2- and 4-pyranone rings were opened to give phenolic diketone and carboxylic acid, respectively. The carboxylic acid was recyclized by acid at 18°C to yield coumarin, while the β-ketoester was extracted with aqueous sodium hydroxide and cyclized to the chromone in the presence of acid.1196
Another method of differentiation between chromone and coumarin is their behavior toward bromine. Chromone, when treated with bromine in chloroform or glacial acetic acid, forms perbromide, whose solubility is very low in solvent. Coumarin under similar reaction conditions forms a 3-bromo derivative.1197 Spectral methods are quite helpful in distinguishing chromones from coumarins. The chemical shifts of 1H NMR of chromone1198 and coumarin are given in the following table (δ ppm from TMS in CDCl3). Comparative 1H NMR spectral data of chromone and coumarin C-2
C-3
C-4
C-5
C-6
C-7
C-8
Chromone
7.88
6.34
-
8.21
7.42
7.68
7.47
Coumarin
-
6.45
7.80
7.63
7.22
7.45
7.20
One of the major differences between the two benzopyrans is the paramagnetic shift suffered by the C-5 proton of chromone because of the effect of the adjacent carbonyl group. The 13C NMR spectral data of chromone is given in the following table.1199 The NMR was taken in a 50:50 (v/v) mixture of CDCl3 and (CD3)2SO. C NMR spectral data of chromone
13
Chromone
C-2
C-3
C-4
C-5
C-6
C-7
C-8
8a
4a
145.5
113.0
177.6
125.3
125.8
133.8
118.3
156.6
125.0
294
2. Six-Membered Heterocycles
The structure of chromone is well established on the basis of its mass fragmentation pattern.1200–1202
Mass fragmentation pattern of chromone.
Importance in Natural Products, Medicines, and Materials The bicyclic rigid chromone fragment has been a privileged scaffold in drug discovery processes because several biological properties have been attributed to some of its derivatives, namely antiallergic, antiinflammatory, antioxidant, anticancer, antiviral, and antifungal activities.1203, 1204 Besides this, a number of chromone derivatives are found highly effective in the treatment of cystic fibrosis.1205–1207 There are numerous chromone derivatives that have been used as therapeutic agents. Khellin extracted from the seeds of the plant Ammi visnaga has previously been used as a diuretic to relieve renal colic,1208 and in the treatment of angina pectoris and asthma. However, the present use of khellin focuses on the treatment of vitiligo, a pigmentation disorder.1209 Nevertheless, due to the secondary effects of khellin like headaches or intestinal disorders, sodium chromoglycate (Lomudal), a derivative of khellin was developed, which finds use as a mast cell stabilizer in allergic rhinitis, asthma, and allergic conjunctivitis. Diosmin (Daflon) is used for the treatment of venous diseases, whereas flavoxate is used as a muscle relaxant to treat urge incontinence.1210, 1211
Therapeutic agents containing chromone skeleton.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
295
Taking into account the therapeutic potential of chromone derivatives, researchers have tried to elucidate the possible structure-activity relationship that might lead to new drug discovery. Structural modification along with biochemical activity is listed in the following diagram.1212
Structure activity potential of chromone.
Synthesis 1. The first synthesis of chromone was reported in 1900 and it involved heating 4-oxo-4H-1-benzopyran-2carboxylic acid in a vacuum.1213
2. Under heating conditions, 2-hydroxy-benzoylpyruvic acid in acetic anhydride undergoes decarboxylation followed by cyclization yields chromone.
3. Claisen condensation: Claisen condensation between o-hydroxyaryl allyl ketone with a carboxylic acid ester in the presence of a strong base delivered diketones, which on heating in acidic medium cyclized to chromones.
The first example was reported by Kostanecki et al., who synthesized 7-ethoxy-4H-1-benzopyran-2-carboxylic acid from 2′ethoxy-4′-hydroxyacetophenone via diketone intermediate which cyclized in the presence of HCl.1214
The ester group of the Claisen condensation product obtained by reaction of 2-hydroxyacetophenone with diethyloxalate is susceptible to transesterification. When the sodium salt of this compound is suspended in methanol at 0°C and acidified with dilute sulfuric acid, the methyl ester formed is cyclized to chromone methyl ester. However, cyclization in acidic ethanol yields a chromone ethyl ester derivative.1215
296
2. Six-Membered Heterocycles
Claisen condensation of o-hydroxyacetophenone with an ester in the presence of sodium hydride yielded 1,3-dione, which was cyclized to 2-(2-phenylethyl)chromone.1216
4. Kostanecki reaction: The reaction of o-hydroxyaryl ketones with aliphatic acid anhydride in the presence of sodium or potassium salt of corresponding acid provides chromones is known as the Kostanecki reaction.1217
This reaction was further elaborated by Allan and Robinson1218 who synthesized flavones by reacting 2,4-dihydroxyacetophenone with benzoic anhydride in the presence of sodium benzoate. Thus synthesis of chromones is known as the Kostanecki reaction, whereas synthesis of flavones is known as the Allan-Robinson reaction.
Mechanism: The most likely mechanism of Kostanecki reaction is one proposed by Baker.1219–1221 According to the mechanism hydroxyaryl ketone is first acylated to yield an ester, which undergoes enolization followed by acylation of the enolate to yield enolacetate. Cyclization followed by loss of water yields the chromone.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
297
To increase the yield of the product, a number of modifications in the Kostanecki reaction were introduced. The process involves reacting o-hydroxyacetophenone with ester (ethyl propionate) in the presence of metallic sodium. The resulting sodium enolate was quenched with acetic acid to give the diketone, which on heating with acetic acid and hydrochloric acid yielded ethylchromone in 75% yield.1222
Usually, the Kostanecki reaction is carried out at high temperatures (>160°C), and modifications were developed where acetic formic anhydride was used at room temperature instead of acetic anhydride.1223, 1224
Another variation adopted for the Kostanecki reaction was the use of a stoichiometric amount of 1,8-diazabicyclo[5.4.0]undec-7-ene instead of sodium acetate.1225 Calanolide A, a potent nonnucleosidal-specific reverse transcriptase inhibitor, was synthesized first by converting propiophenone to a chromone derivative by the Kostanecki reaction, which after several steps was converted to (+)-calanolide.1226
298
2. Six-Membered Heterocycles
5. Baker-Venkataraman rearrangement: The dione prepared by Claisen condensation can also be prepared from o-acyloxy ketones. The base-catalyzed rearrangement of o-acyloxy ketones to β-diketones is known as the BakerVenkataraman rearrangement.1227, 1228
The diacetate of resacetophenone reacts with sodium to afford dioxophenol, which cyclized to form 7-hydroxy-2methylchromone under acidic conditions.1229
2′-Acyloxyacetophenone in the presence of potassium tert-butoxide underwent Baker-Venkataraman rearrangement to yield 1-(2-hydroxyaryl)-1,3-diketone. The diketone was subsequently cyclized in methanol or trifluoroethanol containing a cobalt (salen) complex [CoIII(salpr)OH] at 60°C to chromone in good yield.1230, 1231
6. Simonis reaction: The reaction of a phenol with 3-oxoester in the presence of sulfuric acid yields coumarin. The reaction is known as Pechmann condensation. However, cyclization by phosphorous pentoxide afforded chromone, which is called the Simonis reaction.1232
7. One-pot synthesis of 2-methylchromone by condensation of 3,5-dimethoxyphenol with 5-(1-methoxyalkylidene), Meldrum’s acid, in the presence of Yb(OTf)3 catalyst has also been reported.1233
8. Vilsmeier-Haack reaction1234: This one-pot synthesis has chiefly been used for the synthesis of chromone-3carbaldehyde by reaction between o-hydroxyalkylarylketone and a formylating agent known as Vilsmeier-Haack reagent.1235, 1236
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
299
The reaction, however, suffered from a number of drawbacks like long reaction time, unexpected side reactions, and unsatisfactory yield. The problem was overcome by using boron trifluoride etherate with formation of an intermediate1237–1239 and making a variation in the Vilsmeier-Haack reagent like triphosgene (bistrichloromethyl)carbonate/DMF, phosgene iminium chlorides, or DMF-dimethylacetal.1240
Vilsmeier reagent prepared from phthaloyl chloride and DMF was very helpful in converting 2-hydroxyacetophenone to chromone. Ready availability and low cost of phthaloyl dichloride and DMF, high activity of Vilsmeier reagent, shorter reaction time, and mild reaction conditions are some of the advantages of this new method.1241
The first step of the mechanism involves reaction of boron trifluoride complex with o-hydroxyacetophenone, which is then attacked by Vilsmeier reagent, followed by nucleophilic attack of the hydroxyl group; finally, deamination takes place to form chromone.
9. Ruhemann reaction: The reaction of phenol with chlorofumaric acid or acetylenic dicarboxylic acid esters under basic conditions yields an intermediate, which undergoes cyclization in the presence of sulfuric acid, perchloric acid, or hydrogen fluoride to afford chromones. This method has largely been used for the synthesis of chromone-2-carboxylic acid derivatives.1242
300
2. Six-Membered Heterocycles
10. Nucleophilic displacement of ethyl salicylate by anion derived from DMSO produced sulfinylketone, which on cyclization with formaldehyde yielded chromanone, which after thermal elimination of MeSOH gave chromone.1243, 1244
Salicylic acid or its substituted derivative was converted to its O-acyl(aroyl) by reaction with corresponding acid chloride or anhydride, which when treated with tert-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole furnished the corresponding silyl ester. The silyl derivative and (trimethylsilyl)-methylenetriphenylphosphorane when heated in refluxing THF undergoes intramolecular Wittig cyclization to yield the desired chromone.1245
Reaction of activated salicylic acid derivative with diethyl malonate yields an intermediate, which after hydrolysis and decarboxylation yields 2-methylchromone.1246
2-Methylchromone is also obtained by reaction of methylsalicylate with dimethylpentan-2,3-dienedionate1247 in the presence of KOtBu/BuOH. 11. 2-Hydroxyacetophenone on reaction with triethyl formate in the presence of perchloric acid was converted to benzopyrylium salt, which on heating with water yielded 7-hydroxychromone.1248, 1249
12. A transition metal-catalyzed reaction provides one of the most attractive methodologies for the synthesis of chromone derivatives. A one-pot Sonogashira carbonylation-annulation reaction has been developed that involves a reaction of o-iodophenol with terminal alkynes under a carbon monoxide atmosphere in the presence of secondary amine and a catalytic amount of palladium complex and yields 2-substituted chromone.1250
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
301
Use of a microwave has been found to speed up the reaction process and the yield of the chromone derivative.1251 Synthesis of 2-substituted chromone by a Sonogashira coupling reaction by palladium catalysis was also carried out by reaction of o-methoxybenzoyl chloride with terminal alkyne and o-methoxybenzaldehyde with lithium acetylide.1252 Direct palladium-catalyzed aerobic dehydrogenation of chroman-4-one using O2 as oxidant yields chromone.1253
13. Treatment of a benzofuran derivative with osmium tetroxide followed by hydrolysis yields chromone. The reaction involves oxidation of a double bond, followed by opening of the furan ring and recyclization yielded chromone.
14. The 3-formyl chromone synthesized previously has been used for the synthesis of other chromones. Reduction of the formyl group of chromone with a suspension of basic alumina in isopropanol,1254 and oxidation with sodium chlorite in the presence of aminosulfonic acid,1255 led to the formation of 3-hydroxymethylchromone and chromone-3-carboxylic acid, respectively.
Physical Properties Chromone is a colorless crystalline compound with mp of 59°C. Chemical Reactivity 1. Carbonyl oxygen of chromone undergoes protonation to produce hydroxyl benzopyrylium salt. Thus treatment of chromone in ethereal HCl produced 4-hydroxy-1-benzopyrylium chloride.1256
Benzopyrylium salts have been converted into important derivatives. Benzopyrylium salt on reaction with tertiary benzenoid amine forms flavylium salts, which on warming with pyridine forms flavones.
302
2. Six-Membered Heterocycles
Benzopyrylium salt generated by silylation of chromone reacts with silyl enol ethers or allylsilanes. The addition takes place at the C-2-position.1257
2. Electrophilic substitution reaction (a) Nitration: Chromone readily undergoes a substitution reaction in acidic medium via hydroxyl benzopyrylium cation, which is then attacked by the electrophile yielding a 6-nitro derivative.1258,1259
(b) Bromination: Chromone also undergoes bromination at the 6-position by treating it with dibromoisocyanuric acid (1,3-dibromo-1,3,5-triazine-2,4,6-trione) in the presence of sulfuric acid.
3. Substitution in the heterocyclic ring: Substitution at position 3 of the pyran ring takes place when chromone is refluxed in ethanol with dimethylamine, formaldehyde, and hydrochloric acid, aminomethylation takes place under Mannich conditions.1260
4. Reaction with nucleophiles: The chromone nucleus behaves as a Michael acceptor toward nucleophiles. The pyran ring is opened by alkali due to addition of water, leading to the generation of o-hydroxyphenyl-1,3diketone, which on reaction with acid produced o-hydroxyphenyl ketone and carboxylic acid or salicylic acid and ketone.
Chromone reacts with cold sodium hydroxide solution. The attack takes place at C-2 leading to a ring-opening process.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
303
Secondary amines also attack chromones at the C-2-position leading to a ring-opening process.
In some cases, chromone reacts with secondary amines to yield enamines.1261, 1262
3-Iodo chromone reacts with imidazole to yield a 2-substituted product probably via addition-elimination sequence.1263
5. The carbonyl group of the pyran ring of chromone does not react with hydroxylamine or hydrazine to form oxime or hydrazone; instead the products were isoxazole and pyrazole, respectively.1264, 1265
However, reaction of phenylhydrazine with chromone at 0°C formed phenylhydrazone in good yield along with enamine as the minor component. The unstable enamine was readily transformed into 5-(2-hydroxyphenyl)-1-phenylpyrazole.
Reaction of chromone with anthrone leads to the generation of an anthraquinone derivative.1266
304
2. Six-Membered Heterocycles
When chromone was refluxed with thionyl chloride in an atmosphere of carbon dioxide or with dichloromethyl methyl ether, the carbonyl group was substituted by two chlorine atoms yielding 4,4-dichlorochromen.1267, 1268 On addition of a small amount of benzoyl peroxide to this reaction a mixture of chromone and thionyl chloride, trichlorochromen, was obtained.
6. Addition reaction: Reaction of chromone with sulfuryl chloride yielded an addition product, 2,3-dichlorochromanone.
Reaction of chromone with NBS in aqueous dimethyl sulfoxide leads to the addition of hypobromite across the C-2 and C-3 double bond. However, when reaction of NBS is carried out in methanolic dimethyl sulfoxide, then 3-bromo-2-methoxy chromanone is obtained.1269
A novel and readily prepared C2-symmetric chiral bis-sulfoxide ligand and its successful use in the rhodium- catalyzed asymmetric 1,4-addition of tetraarylborate acid to chromone is reported1270 with high enantioselectivity.
7. Cycloaddition reaction: Heating chromone with tert-butyldimethylsilyl trifluoromethane sulfonate (TBDMSOTf) at 80°C results in the formation of 4-tert-butyldimethylsilyloxy-1-benzopyrylium triflate. The silylated chromone derivative undergoes cycloaddition reaction with α,β-unsaturated ketone in the presence of TBDMS triflate and 2,6-lutidine.1271, 1272
3-Acylchromones, chiefly 3-formyl chromone, undergo hetero Diels-Alder reaction with vinyl ethyl ether to provide a cycloaddition product, which on reaction with sulfuric acid undergoes a ring-opening process to yield 4-oxo-4H- chromen-3-yl-acrolein.1273, 1274
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
305
Chromone-3-ester also undergoes a cycloaddition reaction but serves as a dienophile under Diels-Alder reaction conditions.1275
Chromone on reaction with trimethylsilyl triflate yields benzopyrylium salt, which on reaction with ethyl diazoacetate yields a cycloproponation adduct. On acidification the cyclopropane ring is opened leading to a benzoxepine derivative.1276
8. Photocycloaddition reaction: Chromones undergo [3+2] and [2+2]π cycloaddition reaction quite readily.1277 The photoaddition reaction involves electrophilic attack by C-3 of chromone involving n→π* triplet excitation.
Irradiation of a solution of chromone with 1,1-dimethoxyethylene1278, 1279 gave two products: A and B. Studies revealed that product B was a secondary photolysis product of A.
9. Reaction with Grignard reagent: Enantioselective copper-catalyzed conjugate addition of dialkylzinc reagent to chromone led to the synthesis of optically active 2-alkylchromanones.1280
306
2. Six-Membered Heterocycles
However, a direct enantioselective synthesis of chiral 2-alkylchromanones has been reported. The process involves copper-catalyzed asymmetric conjugate addition of Grignard reagent to chromone in the presence of ferrocenyl-based biphosphine ligand.1281
10. Alkenylation of chromone: A general method for introducing the vinyl group into chromone involves a reaction between 3-halochromone and alkene. However, a direct alkenylation method has also been reported. The process involves a cross-coupling reaction of chromone with alkene in the presence of Cu(OAc)2/Ag2CO3 associated with the use of pivalic acid.1282
2.8 SIX-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH MIXED HETEROATOMS 2.8.1 Oxazines Six-membered heterocycles containing one oxygen and one nitrogen in a doubly unsaturated ring have systematically been named as oxazines. Depending on the relative position of the heteroatom and double bonds, there are number of isomers of oxazines.
2.8.2 1,2-Oxazine Monocyclic 1,2-oxazines with two double bonds can exist in three 4H, 2H, and 6H isomeric forms. Besides the three isomers, several oxo, thioxo, imino, di, and tetrahydro derivatives are also known.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
307
Structural and Reactivity Aspects1283 X-ray crystal analysis of tetramethyl-1,2-oxazinium cation has been helpful in confirming the 1,2-oxazine s tructure. The bond lengths (in Å) are shown in the following figure.
The 13C NMR spectral data of tetramethyl-1,2-oxazinium salt and 5-methyl-3-phenyl-1 and 2-oxazine are given in the following table. 13
C NMR spectral data of two 1,2-oxazine derivatives Tetramethyl-1,2-oxazinium salt
5-Methyl-3-phenyl-1,2-oxazine
C-3
165.1
156.8
C-4
157.3
110.9
C-5
139.7
141.4
C-6
197.5
66.5
Importance in Natural Products, Medicines, and Materials 1,2-Oxazines constitute a versatile class of N and O heterocycles, which are useful intermediates in the synthesis of γ-lactams, γ-amino acids, amino alcohols, aziridines, pyrrolizidines, and pyrrolidine derivatives. Synthesis 1. Reaction of arylmethylketoxime with ethyl magnesium bromide yields aryl-substituted 6H-1,2-oxazine.1284
2. Action of weak acid on the monoxime of 1,3,4-triphenylbutane-1,2,4-trione yields 5-hydroxy- 6-methoxy-3,4,6-triphenyl-6H-1,2-oxazine.
The reaction is reversible and on boiling with water the oxime is regenerated. 3. Refluxing 1,4-diphenyl-3-nitro-3-buten-1-one with hydroxylamine in pyridine-ethanol yields 3,6-diphenyl-6H-1,2-oxazine.1285
308
2. Six-Membered Heterocycles
4. Cycloaddition reaction of 2-chloro-2-nitrosopropane with butadiene affords an adduct, which on reaction with aqueous alkali yields 3,6-dihydro-2H-1,2-oxazine.1286
5. Reaction of ketones with hydroxylamine hydrochloride in the presence of sodium acetate afforded oximes, which on treatment with chloramine-T gave α-nitrosoolefins, which subsequently underwent hetero-Diels-Alder reaction with terminal acetylenes to give 6H-1,2-oxazines in excellent yield.1287
6. Hydroboration of 2,3-dimethylbuta-1,3-diene afforded 2,3-dimethylbutane-1,4-diol, which on bromination is subsequently converted to 1,4-dibromobutane. Cyclization to N-methyloxazines is affected on treatment of 1,4-dibromobutane with N-hydroxyurethane under basic conditions.1288
7. On reaction of lithiated methoxy allenes with D-glyceraldehyde-derived nitrones, [3+3] cyclization takes place leading to the generation of enantiopure 1,2-oxazine derivatives.1289
Chemical Reactivity 1. During reaction of 5-hydroxy-6-methoxy-3,4,6-triphenyl-6H-1,2-oxazine with phenyl magnesium bromide the methoxy group is substituted by the phenyl group yielding 5-hydroxy-3,4,6,6-tetraphenyl-6H-1,2-oxazine, which on alkylation with ethyl bromide yields 2-ethyl-5-oxo-3,4,6,6-tetraphenyl-5,6-dihydro-6H-1,2-oxazine.1290
2. 6H-1,2-Oxazine derivatives in concentrated halogen acid rearrange to form 2,4-diarylpyrroles.1291
3. When 3-phenyl-6H-1,2-oxazine reacts with benzyl alcohol in the presence of hydrochloric acid, conjugate addition takes place leading to the generation of a 5-ether derivative.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
309
4. Reduction of 3,6-dihydro-2H-1,2-oxazine normally takes place with the NO bond. Depending on the type of reducing agent used, a variety of products are formed.
5. The enantiomeric pure 1,2-oxazine derivatives have been converted to highly functionalized compounds, most of them being similar to carbohydrates. The process involves acid treatment of 1,2-oxazine whereby cleavage of the acetonide ring takes place. Subsequent reaction with enol ether forms bicyclic ketal, which on exhaustive hydrogenolysis provides furan derivatives, which are equivalent to the depicted ulose.1289
6. The enol ether double bond of 1,2-oxazines has been employed to react with other electrophiles. Hydroboration proceeds regio- and stereoselectively leading to the introduction of the hydroxyl group at C-5. This hydroxyl derivative is then used for the preparation of aza sugars, amino sugars, azetidine, or pyrrolidine (imino sugar derivatives). Polyhydroxylated pyrrolidines are moderately strong α-l-fucosidase inhibitors.1292
310
2. Six-Membered Heterocycles
7. The NO bond of 5,6-dihydro-3-phenyl-4H-1,2-oxazine is readily cleaved by retro-Diels-Alder process under mild conditions to give 2-phenyl pyrrole.
8. 5,6-Dihydro derivatives possessing a substituent at C-6 capable of stabilizing a positive charge are readily cleaved under acidic conditions. Thus 6-ethoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine is readily converted to pyrroline N-oxide on reaction with HCl in methanol.
2.8.3 1,3-Oxazine Monocyclic 1,3-oxazines are also known as metoxazine (or mazoxin). The 1,3-oxazines with two double bonds can exist in three 4H, 2H, and 6H isomeric forms. Besides three isomeric forms, several oxo, thioxo, imino, di, and tetrahydro derivatives are also known.
Structural and Reactivity Aspects The 1H and 13C NMR data of 2-ethoxycarbonyl-4,6-diphenyl-2H-1,3-oxazine are given in the following table.1293 H and 13C NMR spectral data of 1,3-oxazine derivative
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 6.1; H-5, 6.6
C-2, 86.6; C-5, 95.5; C-4, 161.4; C-6, 163.6
UV absorption spectra of 1,3-oxazine shows absorption maxima in the range of 210–260 nm due to the presence of CC and CN chromophoric groups. On the basis of NMR spectral data it has been proved that various dihydro derivatives of 1,3-oxazines exist in half chair conformations and tetrahydro derivatives as chair conformations as depicted in the following diagram.1294–1297
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
311
Importance in Natural Products, Medicines, and Materials Because of their biological and pharmaceutical activities the chemistry of 1,3-oxazines has been a subject of research. They constitute a structural unit of a number of natural products. For example, geissospermine was found to contain this ring. A number of derivatives were also evaluated for their analgesic, antibacterial,1298 and anticonvulsant activities. Numerous 1,3-oxazine derivatives are drugs. Efavirenz, an antiretroviral drug used for the treatment and prevention of HIV/AIDS, 3-oxauracil, an antimetabolite for its activity against E. coli and L121 leukemia cells, and oxazinomycin, an antibiotic.
Drugs containing 1,3-oxazine nucleus.
Synthesis1296 1. The first synthesis of the 1,3-oxazine derivative was reported by Kohn1299 and consisted of cyclizing 3-aminopropan-1-ol derivative with aldehyde.
2. The first example of the synthesis of 1,3-4H-oxazine was reported by Wohl1300 by the reaction of an aqueous solution of oxalic acid with diethyl acetal of γ-benzoylamino propionaldehyde.
3. A general method for the synthesis 1,3-4H-oxazine was reported by Gabriel and Miyamichi1301 by the reaction of β-(N-acylamine) derivatives of ketones and carboxylic acid esters with PCl5 or P2O5, respectively.
312
2. Six-Membered Heterocycles
4. Reaction of an acetylenic compound with Schiff’s base and acyl chloride in the presence of stannous chloride yielded a 4H-1,3-oxazine derivative.1302
5. 2H-1,3-Oxazine is synthesized by the action of alkali on isoxazolium salts.1303
6. When 4-amino-1-azadienes were treated with esters of glyoxylic acid at 20–50°C, substituted 2H-1,3-oxazines were isolated in excellent yields.1304
7. 1,4-Cycloaddition of unactivated olefins with N-acyliminiums (obtained from benzotriazole precursors) afforded polysubstituted 5,6-dihydro-4H-1,3-oxazines.1305
8. Treating 3-aminopropan-1-ol with acetylene under pressure yields 2-methyl tetrahydro-1,3-oxazine.1306
9. 3-Aminopropan-1-ol also undergoes cyclization with vinylbutoxyethyl ether in the presence of mercuric salts to yield 2-methyl tetrahydro-1,3-oxazine.1306
10. Reacting vinyl ether of 3-aminopropanol with N,N-dimethylcarbamyl chloride in the presence of potassium carbonate yields a 1,3-oxazine derivative.1307
11. Benzoylation of 3-bromopropylamine in the presence of a base yields 2-phenyl-5,6-dihydro-4H-1,3-oxazine. The reaction is proposed to take place with the intermediate formation of N-benzoyl-3-propylamine.1308
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
313
12. Reaction of 3-aminopropanol with tert-butylisocyanide in the presence of silver cyanide leads to the formation of 5,6-dihydro-4H-1,3-oxazine.1309
13. 3-Propanolamines on reaction with acetylenic ethers afford 1,3-oxazines.1310
14. A novel method for the synthesis of oxazines involves reaction of 3-azidopropanol with aromatic aldehydes.1311
Chemical Reactivity 1. 1,3-Oxazines act as bases and react with acids to form salts, which vary with regard to their solubility in water and their stability. 4H-1,3-Oxazine on reaction with trityl perchlorate in acetonitrile forms 3-azapyrylium salts.1300
2. Ring-opening reaction: A common reaction of 1,3-oxazines is their ability to be hydrolyzed with a ring-opening process. This process takes place in the presence of dilute mineral acids. (a) 5-Nitrotetrahydro-1,3-oxazine is readily hydrolyzed to a 3-amino-2-nitropropanol derivative.1312, 1313
(b) Hydrobromide of 2-phenyl-5,6-dihydro-1,3-oxazine is hydrolyzed in water to form 3-aminopropylbenzoate, which is rearranged to 3-benzamidopropanol.1314
(c) 1,3-4H-Oxazine is also hydrolyzed by water particularly in the presence of acids.1314
3. 6-Aryl-6-alkyltetrahydro-1,3-oxazines when warmed with concentrated hydrochloric acid undergo rearrangement to piperidinols.1315, 1316
4. In basic medium, 5-nitro-5-hydroxymethyltetrahydro-1,3-oxazine couples with aryl diazonium salt to afford an arylazo compound with elimination of a molecule of formaldehyde.
314
2. Six-Membered Heterocycles
5. Catalytic hydrogenation of oxazine in the presence of Adam’s catalyst in ethanol at atmospheric pressure led to an amide.1317
Reduction of 2H-1,3-oxazine derivative with NaBH3CN in THF/AcOH at 20–50°C after basic hydrolysis yielded 1,3-aminoalcohol as a single stereoisomer, which on further reduction with LiAlH4 yielded an aminodiol derivative. Cyclocondensation of aminoalcohol with aqueous formaldehyde afforded tetrahydroxazine.1318
6. 1,3-Oxazines by hydride abstraction are readily converted to oxazinium cations, which are stable species and can readily be attacked by nucleophiles to yield a variety of products.1319–1321 By reacting oxazinium cation with ammonia and benzyl magnesium bromide, ring opening takes place followed by cyclization.
2.8.4 1,4-Oxazine
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
315
In the 1,4-oxazine series, only the 4H and 2H isomers are known and they are in equilibrium with each other. Besides the two isomers there are several other oxo, thioxo, imino, di, and tetrahydro derivatives, which are known. 1,4-Oxazines are not aromatic and they exist in boat conformation. Structural and Reactivity Aspects1322 X-ray crystal analysis of tert-butylmethyl 4H-1,4-oxazine-3,4-dicarboxylate suggests the flat boat conformation of this original antiaromatic system. The bond lengths of tert-butylmethyl 4H-1,4-oxazine-3,4-dicarboxylate and tert- butyl 4H-1,4-oxazine-4-carboxylate are shown in the following figure confirming the structure of the molecule.
Bond lengths of 1,4-oxazine derivatives.
The 1H and 13C NMR of the parent 4H-1,4-oxazine were recorded, which further proved the complete structure. H and 13C NMR spectral data of 4H-1,4-oxazine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-2, 5.29; H-3, 5.19; N-H, 2.9
C-2, 126.4; C-3, 114.5
Importance in Natural Products, Medicines, and Materials The 1,4-oxazine scaffold is a structural unit of a number of naturally occurring and synthetic compounds and they have been reported to have diverse biological activities like antiulcer, antihypertensive, antifungal, and a nticancer.1323 A number of tricyclic 1,4-oxazines have been evaluated as dopamine agonists with selectivity for D2 receptors thereby making them therapeutically important candidates for the treatment of Parkinson’s disease.1324 A number of drugs are available in the market with the presence of the 1,4-oxazine skeleton. Reboxetine is a drug used as an antidepressant,; timolol, as an eye drop, is used to treat high pressure inside the eye during ocular hypertension and glaucoma, and when taken orally it is used to treat high blood pressure; aprepitant is used to treat nausea and vomiting associated with highly emetogenic cancer chemotheraphy; phendimetrazine is used as an appetite suppressant; and dextromoramide is a powerful opioid analgesic.
Drugs containing 1,4-oxazine skeleton.
316
2. Six-Membered Heterocycles
Synthesis 1. Synthesis of the parent 1,4-4H-oxazine was reported for the first time by Aitken et al. The monosubstituted oxazine synthesized by Coudert et al. was subjected to flash vacuum pyrolysis (FVP) at 450°C yielding the parent 4H-1,4-oxazine.1322
2. Fusing diglycolic acid with ammonium carbonate yields morpholine 3,5-dione, which was converted to an N-protected derivative, the N-Boc morpholine 3,5-dione. Treatment of N-Boc derivative with potassium bis(trimethylsilyl)amide (KHDMS) in the presence of hexamethylphosphoramide (HMPA) at −78°C afforded the bisvinylphosphate derivative, which on reduction in the presence of palladium acetate yielded 4-(tert-butoxycarbonyl)-[1,4]-oxazine.1325
3. A metal- as well as solvent-free protocol for hydroalkoxylation of alkynyl alcohols with sodium hydride leads to stereospecific synthesis of 1,4-oxazines with one as well as two chiral carbon centers. The desired alkynyl alcohol was obtained by reaction of aldehyde with Grignard reagent by following Cram’s rule.1326
4. Partial hydrogenation of N-phenacylideneaniline in the presence of palladium on carbon afforded N-3,4,6-tetraphenyl-4H-1,4-oxazin-2-amine.
5. Cyclodehydration of N,N-diphenacylaniline with excess phosphoryl chloride affords 2,4,6-triphenyl- 4H-1,4-oxazine.
6. Diphenacyl ether reacts with ammonia in ethanol to form 3,5-diphenyl-2H-1,4-oxazine.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
317
Chemical Reactivity 1. Tautomerism: Heating 3,5-diphenyl-2H-1,4-oxazine with acetic anhydride in pyridine at 100°C results in tautomerization to the 4H- form, which is trapped by N-acetylation to yield 3,5-diphenyl-4H-1,4-oxazine.1327
2. Metalation: Treatment of 4-substituted 4H-1,4-oxazine with butyllithium at −78°C leads to regioselective deprotonation at C-3, resulting in the formation of a 3-lithio derivative, which subsequently reacts with different electrophiles to form 3,4-disubstituted-4H-1,4-oxazines.1325
3. Stille or Suzuki reaction: Bisvinylphosphate was subjected to Stille or Suzuki reaction with a tin reagent in the presence of catalytic Pd-(PPh3)4 and anhydrous LiCl in refluxing THF yielding the 3,5-disubstituted vinyl derivative.1325
4. tert-Butyl 2-formyl-3,5-diphenyl-4H-1,4-oxazine-4-carboxylate was subjected to Wittig reaction, which resulted in the formation of conjugated diene in good yield.1325
5. tert-Butyl 2-iodo-3,5-diphenyl-4H-1,4-oxazine-4-carboxylate undergoes a Sonogashira coupling reaction with prop-2-yn-1-ol in the presence of palladium catalyst to yield an alkynyl derivative.
6. Michael addition reaction: 1,4-Oxazine underwent a Michael-type nucleophilic addition reaction with 4-methoxyphenol and thiophenol, resulting in the formation of a single diastereomeric product in good yield. The 2,3-trans-stereochemistry was confirmed on the basis of NMR spectroscopy.1328
318
2. Six-Membered Heterocycles
7. Nucleophilic addition: A secondary amine on reaction with α,β-unsaturated methyl ester resulted in the opening of the heterocyclic ring via an addition-elimination process and delivered enamines as a mixture of Z- and Eisomers in good yield.
Nucleophilic addition of benzylamine to α,β-unsaturated methyl ester afforded the tetrahydropyrazinol in quantitative yield. The structure of tetrahydropyrazinol was confirmed by X-ray analysis.
8. William-Ben Ishai Amino acid synthesis: Synthesis of α-amino acid takes place through the intermediate formation of 1,4-oxazine-2-one. The process involves nucleophilic addition of tert-butyldimethylsilylketene acetal followed by hydrogenolysis to afford the amino acid.1329
2.8.5 Morpholine
Morpholine also referred to as 1-oxa-4-aza-cyclohexane, tetrahydro-1,4-oxazine, or diethylenimide oxide and is thought to be derived from tetrahydropyran by replacing one methylene group by NH. Structural and Reactivity Aspects1330 Like cyclohexane, morpholine prefers the chair conformation. In the stable chair conformation the hydrogen atom bonded to nitrogen can occupy either the axial or equatorial position. However, on the basis of X-ray analysis the H-atom bonded to nitrogen preferably exists in equatorial conformation.1331
Conformations of morpholine.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
319
Primary bond distances (in Å) and angles (in degrees) are given in the following table. Bond length
Bond angle
O1C2: 1.432
C6O1C2: 110.32
C2C3: 1.516
O1C2C3: 111.31
C3N4: 1.466
C2C3N4: 108.69
N4H: 0.89
C3N4C5: 109.25
N4C5: 1.468
N4C5C6: 108.43
C5C6: 1.510
C5C6O1: 111.41
O1C6: 1.424
The 1H and 13C NMR spectral data of morpholine are given in the following table. H and 13C NMR spectral data of morpholine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H2, 3.65; H-3, 2.80; N-H, 1.92
C-2, 68.1; C-3, 46.7
Importance in Natural Products, Medicines, and Materials Morpholine and its derivatives have received worldwide attention due to their remarkable and wide variety of applications. The morpholine nucleus is present in a wide variety of natural products.1332 For example, alkaloid polygonapholine isolated from the rhizome of Polygonatum altelobatum is used as a tonic by the Taiwanese.1333 Two alkaloids, chelonin A and chelonin C, were isolated from the marine sponge Chelonaplysilla sp., while chelonin A was found to exhibit antimicrobial activity against Bacillius subtilis and also has antiinflammatory effects.1334 Two spiroalkaloids, acortatarin A and acortatarin B, isolated from the rhizome of Acorus tatarinowii were presumed to be valuable starting compounds for designing new antidiabetic and anticancer drugs.1335
Natural products containing morpholine skeleton.
A number of morpholine-based compounds are of commercial interest because they are easily available in the market as drugs and fungicides. For example, viloxazine and reboxetine are effective antidepressants, linezolid is an antibiotic for the treatment of Gram-positive bacteria, gefitinib is used for the treatment of breast and lung cancer, and dextromoramide is an analgesic.
320
2. Six-Membered Heterocycles
Drugs containing morpholine skeleton.
A number of morpholine derivatives like amorolfine, fenpropimorph, and tridemorph find use as agricultural fungicides.
Agricultural fungicides possessing morpholine skeleton.
Synthesis 1. On an industrial scale, morpholine is produced by dehydration of diethanolamine with sulfuric acid. It is also prepared by reaction of dichlorodiethyl ether with ammonia at 50°C and 1750 psi pressure.1336
2. Disubstituted morpholines are prepared by reaction of N-benzyl-2-aminoethanol with oxirane in the presence of 70% sulfuric acid followed by catalytic debenzylation.
3. (R)-2-Benzylmorpholine, an appetite suppressant agent, was synthesized from 2-bromo-3-phenylacrylaldehyde. The process involves reduction of 2-bromo-3-phenylacrylaldehyde with baker’s yeast to 2-bromo-3phenylpropanol. Bromo alcohol on treatment with a base gave 2-benzyl oxirane, which on treatment with ethanolamine sulfonate under basic conditions resulted in the opening of the oxirane ring to sulfate ester. Sodium hydroxide treatment of sulfate ester afforded (R)-2-benzylmorpholine.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
321
An alternate method for the synthesis of (R)-2-benzylmorpholine employing Sharpless asymmetric epoxidation has also been reported.1337 4. Enantiomerically pure morpholine-3,4-dimethyl-2-phenylmorphine has been synthesized by reaction of 2-methylamino-1-phenyl-propan-1-ol (L-ephedrine) with chloroethanol.1338
5. Synthesis of cis-3,5-disubstituted morpholines from enantiomerically pure amino alcohols has been reported. The key step of the reaction is generation of the substrate by a Pd-catalyzed carboamination reaction between N-protected amino alcohol with NaH and allyl bromide; cleavage of the Boc group followed by Pd-catalyzed Narylation of the resulting amine trifluoroacetate salt provided the substrate. The desired morpholine heterocycle is obtained through Pd-catalyzed coupling with an aryl or alkenyl halide.1339
6. Petasis coupling reaction: A three-component coupling reaction between protected amino alcohol with glyoxal and phenyl boronic acid afforded 2-hydroxymorpholines.1340
7. A one-step protocol for the synthesis of morpholine involving reaction of diphenyl vinyl sulfonium salts with protected amino alcohols has been reported.1341
Physical Properties Morpholine is a colorless, hygroscopic liquid with a bp of 128.3°C. It is soluble in water in all proportions but not in strong alkali. Chemical Reactivity 1. Enamine formation: A general method for the synthesis of enamines from secondary amine involves refluxing morpholine with cyclohexanone and p-toluenesulfonic acid in toluene yielding 1-morpholino-1-cyclohexene.1342
322
2. Six-Membered Heterocycles
The enamines formed have been utilized for carrying out acylation, for example, acylation of cyclopentanone through enamine formation.1343
2. N-alkylation and arylation: Morpholine can be alkylated and arylated by several methods. Dialkyl sulfates, trialkyl phosphates, alkyl halide, and aryl halide are the effective reagents.
3. Morpholine undergoes Michael-type nucleophilic addition across α,β-unsaturated compounds (1) in the presence of a catalytic amount of silica-supported aluminum chloride at 60°C under solvent-free conditions or (2) under solvent- and catalyst-free conditions to afford β-amino compounds in excellent yield.1344, 1345
4. Reaction with epoxides: Morpholine reacts with oxirane rings to give corresponding β-4-morpholine alkanols.
Regio- and stereoselective epoxide ring opening of N,N-disubstituted-1,2-epoxy-3-aminocyclopentane using Lewis acid catalyst resulted in the formation of diaminocyclopentanols.1346
5. Nitration: N-Nitromorpholine is prepared by heating morpholine with acetone cyanohydrin nitrate.1347
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
323
6. Willgerodt-Kindler reaction: The reaction of aryl alkyl ketone with elemental sulfur and an amine like morpholine yields a thioacetamide, which on hydrolysis yields amide.1348, 1349
7. Mannich reaction: Morpholine like other secondary amines reacts with aldehydes to give Mannich-type condensation reactions.1350
8. Morpholine on reaction with sodium hypochlorite yields N-chloromorpholine, which on reaction with 2-chloromethoxybenzene in the presence of 80% sulfuric acid gave 2,4-dichloromethoxybenzene.1351
9. Leuckart-Wallach reaction: Addition of formic acid to a mixture of aldehyde and morpholine results in reductive alkylation of morpholine.
10. 4-Nitrophenyltriflate under high pressure undergoes an addition elimination reaction with morpholine.1352
11. Excess of morpholine on treatment with glyoxal or its monohydrate produced 1,1,2,2-tetramorpholine.1353 It is an exothermic reaction.
12. 6-Aryl-methylthio-2H-pyran-2-one-3-carbonitrile on reaction with morpholine in refluxing ethanol provided 6-aryl-4-morpholino-2H-pyran-3-carbonitrile.1354
324
2. Six-Membered Heterocycles
Thiazines Thiazine is a six-membered, unsaturated, nonconjugated heterocycle containing four carbons, one sulfur, and one nitrogen atom with two olefinic bonds in the ring. There are three isomeric thiazines: 1,2-thiazine, 1,3-thiazine, and 1,4-thiazine, which differ by the arrangement of sulfur and nitrogen atoms in the ring.
2.8.6 1,3-Thiazine
Structural and Reactivity Aspects The 1H and 13C NMR spectral data of thiasporin A, a 1,3-thiazine derivative are given in the following table.1355 1 H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-3, 6.79 (d); H-4, 7.10 (t); H-5, 6.56 (t); H-6,7.51 (d)
C-1, 114.4; C-2, 146.5; C-3, 116.1; C-4, 130.2; C-5, 115.2; C-6, 128.4; C-7, 166.4; C-9, 118.7; C-10, 164.2; C-11, 157.7
Importance in Natural Products, Medicines, and Materials 1,3-Thiazine is an unsaturated heterocyclic compound with sulfur and nitrogen at the 1- and 3-positions of the ring. Because an NCS linkage is present in the molecule, it has been reported to be useful in the field of pharmaceutical and medicinal chemistry. Recently, a natural product, thiasporine A, containing this nucleus, isolated from a marine-derived Actinomycetospora chlora, showed cytotoxicity1355 against the nonsmall-cell lung cancer cell line H2122 with an IC50 value of 5.4 μM. 1,3-Thiazine is also part of the framework of cephalosporins—an important class of β-lactam antibiotics, xylazine-agonist at the α-2 class of adrenergic receptor, which is used for sedation, anesthesia, and as a muscle relaxant. Chlormezanone-marketed as trancopal, used as anxiolytic and a muscle relaxant.
Drugs containing 1,3-thiazine nucleus.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
325
Synthesis 1. From thiourea or thioamides: Acetophenone on Claisen-Schmidt condensation reaction with aryl aldehydes yields chalcones, which on treatment with thiourea undergo cyclocondensation in a basic medium to yield a 1,3-thiazine derivative.
Heating 2-nitropropane-1,3-diol with thiourea yields 5-nitro-2H-1,3-thiazine-2-imine.
Reaction of 4-methylpent-3-en-2-one with thiourea in the presence of hydrogen bromide yields 4,6,6-trimethyl-3H-1,3-thiazine-2(6H)-imine.
Reaction between thiourea and acetylene monocarboxylates in methanol yields 1,3-thiazin-4-one in good yield.1356
Thioacetamide reacts with aromatic aldehyde to form a N-thiacyl imine heterodyne derivative, which undergoes hetero Diels-Alder reaction with alkenes to form a 1,3-thiazine derivative.
2. Hetero-Diels-Alder reaction: Reaction of 3-aza-4-dimethylamino-1-thiabutadienes with acrylates by heating or under high pressure results in the formation of substituted 5,6-dihydro-4H-1,3-thiazine.
326
2. Six-Membered Heterocycles
Thiazines are also obtained by reaction of alkynes with heterodienes.1357–1359
3. Allylamine derivatives react with arylisothiocyanate to form an allyl thiourea derivative, which undergoes intramolecular cyclization by Sulfa-Michael reaction to yield 2-amino substituted-5,6-dihydro-4H-1,3-thiazine.
4. 5,6-Dihydro-4H-1,3-thiazines were synthesized by a boron trifluoride etherate-catalyzed reaction of α,β-unsaturated ketones with thiobenzamide. The synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv(ATCC 27294) using Alamar blue susceptibility assay.1360
5. A three-component reaction involving thiobenzamide, benzaldehyde and 1-hexene resulted in the formation of 1,3-thiazine derivatives. The reaction takes place via a hetero-Diels-Alder reaction affording two diastereoisomers—endo- and exo-1,3-thiazines.1361
Chemical Reactivity 1. Rearrangement: By heating 2-amino-1,3-thaizine to 145°C, it rearranges to 3,4-dihydropyrimidine-2-thione.1362
2. Dimroth rearrangement: 2-Amino-6H-1,3-thiazines with an ester group at C-5 undergo Dimroth rearrangement to 3,4-dihydropyrimidine-2-thiones. The rearrangement was carried out under microwave conditions employing either toluene or 1-methyl-2-pyrrolidone as solvent.1363
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
327
3. Staudinger reaction: The diastereoisomeric endo- and exo-1,3-thiazines on reaction with chloroacetyl chloride in the presence of triethylamine in refluxing toluene were transformed by stereoselective Staudinger reaction into corresponding chloro-β-lactam-condensed-1,3-thiazine. However, the endo-chloro-β-lactam-condensed-1, 3-thiazine was obtained under basic conditions.1361
2.8.7 1,4-Thiazine
1,4-Thiazine is an unsaturated, six-membered, nonconjugated heterocyclic compound with four carbon atoms, one nitrogen atom and one sulfur atom at the 1,4-position (opposite corners) of the ring. Structural and Reactivity Aspects Conformational studies of tetrahydro-1,4-thiazine-1,1-dioxides using 1H and 13C NMR studies suggest that the molecule exists in chair conformation with equatorial orientation of the substituents.1364
The 1H and 13C NMR spectral data of 5-acetyl-2,3-dihydro-1,4-thiazine is given in the following table. 1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.01; H-3, 3.51; H-6, 6.19
C-2, 26.6; C-3, 40.9; C-5, 135.6; C-6, 106.5
Importance in Natural Products, Medicines, and Materials The 1,4-thiazine derivative chondrine and 1,4-thiazine-1,1-dioxide have been isolated from the red alga Chondria crassiacaulis and marine sponge Anchinoe tenacior, respectively. Besides a novel thiazine derivative, 5-acetyl-2,3- dihydro-1,4-thiazine with an intense popcorn-like odor has been isolated from an aqueous ribose/cysteine solution.
Natural products containing 1,4-thiazine skeleton.
328
2. Six-Membered Heterocycles
Synthesis 1. Heating ammonium 2,2′-thiodiacetate affords 3,5-dihydroxy-2H-1,4-thiazine, which is passed over alumina on pumice at 450°C to yield 2H-1,4-thiazine.1365
2. L-1,4-Thiazine-3-carboxylic acid has also been synthesized. The process involves reaction of bromoethanol and l-cysteine in the presence of sodium in liquid ammonia to give S-(2-hydroxyethyl)-l-cysteine, which on heating with hydrochloric acid gave S-(2-hydroxyethyl)-l-cysteine hydrochloride. Cyclization in the presence of dimethylformamide-triethylamine afforded the thiazine derivative.1366
3. When benzyl (S)-N-benzyloxycarbonyl-2-aziridine carboxylate is reacted with 2-chloroethanol in dichloromethane in the presence of a catalytic amount of BF3-etherate, ring opening takes place and the intermediate N-benzyloxycarbonyl-O-(2-chloroethyl)cysteine benzyl ester was obtained. The benzyloxycarbonyl and benzyl ester group were removed by catalytic hydrogenation followed by cyclization in the presence of triethylamine to afford tetrahydro-2H-1,4-thiazine-3-carboxylic acid.1367
4. Reaction of substituted 3-aminoacrylates with S2Cl2 or SCl2 affords bis(2-aminovinyl)sulfides, which on cyclization forms diethyl 3-amino-3,5-bis(trifluoromethyl)-2H-1,4-thiazine-2,6-dicarboxylate. Loss of ammonia yields diethyl 3,5-bis(trifluoromethyl)-2H-1,4-thiazine-2,6-dicarboxylate.1368
5. Reaction of a solution of chloroacetone in methyl ethyl ketone with thioglycolamide in the presence of triethylamine affords 5-methyl-2,3-dihydro-4H-1,4-thiazine-3-one, which on reaction with phosphorous pentasulfide in pyridine afforded thiolactam. Alkylation of thiolactam with triethyloxonium tetrafluoroborate afforded 3-ethylthio-5-methyl-2H-1,4-thiazine.1369
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
329
Chemical Reactivity 1. 3,5-Disubstituted-2H-1,4-thiazine, when heated in ethanol solution containing picric acid or nitrobenzene, underwent oxidative coupling at the 2-position giving 2,2′-bithiazines.1370
2. Treatment of diethyl 3,5-bis(trifluoromethyl)-2H-1,4-thiazine-2,6-dicarboxylate with triethylamine provided corresponding pyrroles in good yield.
3. Reaction of 3-ethylthio-5-methyl-2H-1,4-thiazine with p-toluidine in the presence of a trace of acid afforded 3-p-tolylamino-5-methyl-2H-1,4-thiazine.1369
4. Reaction of 4,5-dimethyl-2,3-dihydro-1,4-thiazine-4-one with methyl iodide in anhydrous acetone afforded 3-methylthio-4,5-dimethyl-2H-1,4-thiazinium iodide, which on treatment with potassium tert-butoxide followed by reaction with an excess of methyl iodide resulted in the formation of 3-methylthio-4,4,5-trimethyl-1,4thiazinium iodide.1369
+
330
2. Six-Membered Heterocycles
2.8.8 Phenoxazine
Phenoxazine or 10H-phenoxazine is a tricyclic heterocyclic compound in which oxazine is fused on each side by the benzene ring. Structural and Reactivity Aspects1371a Pheoxazine in not planar but slightly folded along the axis, which passes through the two central heteroatoms. The hydrogen atom bonded to the nitrogen may be placed either between or out of the planes of the two rings, producing two molecular geometries, which may be called H-intra and H-extra.
The 1H NMR spectrum of phenoxazine showed aromatic proton signals from δ 6.7 to 7 (m) and a singlet for the NH proton at δ 8.2. The UV spectra of phenoxazine shows bands at λmax 239 (log ε 4.66), which is due to π→π* transition, and at λmax 318 (log ε 3.93), which is due to n→π* transition. The IR spectrum of phenoxazine, besides the ring stretching modes from 1450 to 1630 cm−1, also reveals a strong NH stretching frequency at 3342 cm−1. Importance in Natural Products, Medicines, and Materials Phenoxazine is important because this nucleus is present in a large number of naturally occurring compounds like dactinomycin or actinomycin D, which is used to treat a number of types of cancer. Phenoxazine derivatives find use as drugs, sedatives, tranquilizers, central nervous system depressants, and antitumor agents. They are also used as colorants in the textile industry and as laser dyes. Synthesis 1. The classical method for the synthesis of phenoxazine is based on Bernthensen’s synthesis, which involves pyrolytic condensation of o-aminophenols with catechols.
2. Phenoxazine was synthesized in good yield by heating an equimolar mixture of o-aminophenol and its hydrochloride.1371b
The reaction was proposed to proceed through formation of o,o'-dihydroxydiphenylamine as intermediate, which was isolated and characterized.1372A better procedure for the synthesis of unsubstituted phenoxazines involves autocondensation of o-aminophenol in the presence of iodine with the elimination of ammonia and water.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
331
3. Turpin reaction: Originally the reaction is based on the condensation of 2-aminophenol with picryl chloride to give 2-nitrophenoxazine.1373 The reaction takes place with the intramolecular displacement of the 2-nitro group by the phenoxide group at the 2-position.
Turpin’s reaction has been widely used for the synthesis of substituted phenoxazines.1374–1376 4. 2-Chloronitrobenzenes react with phenols containing nitro or methoxy groups at the ortho-position to yield 2,2′-disubstituted diphenyl ethers, which were catalytically reduced and demethylated to yield phenoxazines.1377, 1378
In place of 2-methoxy phenol, 2-bromophenol may also be used, which reacts with 2-chloronitrobenzene under basic conditions to give 2,2′-disubstituted diphenyl ether. Reduction of the nitro group with stannous chloride or iron filings in acetic acid followed by ring closure by heating in DMF solution in the presence of copper and potassium carbonate offered phenoxazine.
5. Reaction of 1-halo-2-nitrobenzene with 2-chloro-3-hydroxybenzoic acid afforded diphenyl ether as intermediate. Reduction of a nitro intermediate followed by formylation and hydrolysis yielded the title compound.1379
6. Palladium-catalyzed tandem CN bond formation between aryl halide and primary amine via an intermolecular/intramolecular process allowing one-pot synthesis of phenoxazine derivative has been reported.1380
332
2. Six-Membered Heterocycles
7. 2-Chlorophenoxazine has been reported to partially reverse VLB resistance in MDR carcinoma cell line GC3/ c1 and completely reversed the 86-fold VLB resistance in MDR-1 overexpressing breast carcinoma1381 cell line BC 19/3. A new and efficient synthesis of 2-chlorophenoxazine has been reported1381, 1382 by the reaction of 2-bromophenol with 2,5-dichloronitrobenzene using KOH as a base forming an intermediate, which after reduction followed by cyclization in formic acid afforded the title compound.
Physical Properties Phenoxazine is a green-gray powder with mp of 154–159°C. It is soluble in most organic solvents. Its solution in concentrated sulfuric acid shows violet or violet-red fluorescence. Chemical Reactivity 1. Electrophilic substitution (a) Bromination: Phenoxazine on reaction with bromine in benzene afforded 3-bromo- and 3,7-dibromophenoxazine.1383
(b) Chlorination: Phenoxazine on chlorination with thionyl chloride gave tetrachlorophenoxazine.1384
(c) Nitration: Phenoxazine reacts violently with dilute nitric acid to yield tetranitrophenoxazine.1385
(d) Friedel-Crafts acylation: Condensation of phenoxazine with acetyl chloride in the presence of aluminum chloride yielded 3-acetylphenoxazine as a minor component and 10-acetylphenoxazine as a major component.1386
2. Nucleophilic substitution: Phenoxazine is slowly metalated by n-butyllithium in ether. Metalation followed by carbonylation of phenoxazine yields phenoxazine-4-carboxylic acid.1387
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
333
3. Oxidation: In acidic solution, phenoxazine is oxidized by a variety of reagents like potassium permanganate, hydrogen peroxide, bromine, etc. to form a radical cation (A), which on neutralization or basification deprotenates to radical (B). The radical either polymerizes to polyphenoxazine or oxidizes to phenoxazine3(3H)-one (C).1383, 1388
4. Vilsmeier-Haack reaction: 10-Ethylphenoxazine reacts with N-methylformanilide in the presence of phosphorous oxychloride in 1,2-dichlorobenzene to afford 3-formyl 10-ethylphenoxazine.1389
Phenoxazine reacts with tetracyanoquinodimethane (TCQD) to afford α,α′-di( 3-phenoxazinyl)-p- phenylenedimalononitrile and p-phenylenedimalonitrile. The reaction is proposed to take place in two steps. In the first step an intermediate 1,6-addition product (A) is formed, which undergoes oxidation to give radical (B). In the next step the radical then reacts with phenoxazine to give the product.1390
334
2. Six-Membered Heterocycles
2.8.9 Phenothiazine
Phenothiazine also known as 10H-dibenzo-1,4-thiazine, is a tricyclic heterocycle in which 1,4-thiazine ring is fused with two benzene rings at 2,3 and 5,6 positions. Structural and Reactivity Aspects The complete structure of phenothiazine was established by using X-ray crystallography.1391 The X-ray analysis of this heterocycle shows that the molecule has a folded configuration with the dihedral angle between the two planes of the benzene ring being 158.5°. The bond distances (in Å) and bond angles in degrees are shown in the figure given below
The 1H and 13C NMR spectral data1392,1393 of phenothiazine are given below. 1 H NMR(CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1/9: 6.62; H-2/8: 6.93; H-3/7: 6.74; H-4/6 6.89
C-1/9: 114.48; C-2/8: 127.40; C-3/7: 122.62; C-4/6: 126.82; C-1a/9a: 141.79; C-4a/6a: 118.33
Importance in Natural Product, Medicine and Materials The chemistry of phenothiazines has received a considerable importance due to their extremely important therapeutic properties. Methylene blue, an azine dye was earlier used for the treatment of malaria. Phenothiazines exhibit a complex range of action on the central nervous system (CNS). They act on CNS by inducing sedative and antiemetic effect, affecting skeletal muscles, endocrine system and also potentiating the action of analgesics. Some of the well-known drugs of this category are chlorpromazine, promazine, acetophenazine, perphenazine, thioridazine etc.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
335
Synthesis (i) Phenothiazine is synthesized by reaction of diphenylamine with sulfur in the presence of aluminum chloride as a Lewis acid catalyst.
(ii) By Smiles rearrangement: Reaction of 2-chloronitrobenzene with 2-aminobenzenethiol in an alkaline medium yields the corresponding 2-amino-2′-nitrodiphenyl sulfide, which on treatment with carboxylic acids provides an N-acetylated product. The resulting 2-acetamido-2′-nitrodiphenyl sulfide undergoes Smiles rearrangement under alkaline conditions, followed by intramolecular cyclization to yield phenothiazine.1394,1395
NO2 Cl
H2N
NO2 NH2 RCOOH
+ HS
S
NO2 NHCOR S
OH Smiles rearrangement
H N S
–HNO2
COR N NO2 S
Furthermore, a thermal Smiles rearrangement of 1′-amino-4-methyl-2-nitrodiphenyl sulfide was also carried out at 90°C to generate 3-methylphenothiazine. This reaction was thought to be proceeded by following mechanism.1396
This synthetic strategy has been successfully extended to synthesize 2-chlorophenothiazine1397 as a precursor for the synthesis of a neuroleptic drug, chlorpromazine.
(iii) Ullmann type synthesis: This synthetic protocol involves a reaction of 2-halonitrobenzene with 2-halothiophenol to yield 2-halo-2′nitrodiphenyl sulfide which on standard reduction conditions forms 2-halo-2′aminodiphenyl sulfide. Finally, phenothiazine is obtained either by Ullmann reaction or via benzyne intermediate.1398,1399
336
2. Six-Membered Heterocycles
This procedure has also been found to be useful for the synthesis of 2-chlorophenothiazine as depicted in the following scheme. Cl
NO2 Cl
Br
Br NO2
+ HS
S
Cl
Br NH2 Red
Cl
S Ullmann reaction H N Cl S
(iv) In another approach, 10-phenyl phenoxazine is synthesized in excellent yield through a palladiumcatalyzed tandem C-N bond formation reaction between 2,2′-dibromophenyl sulfide and aniline in a one-pot operation.1400 This reaction possibly proceeds via a nucleophilic aromatic substitution in the first step followed by intramolecular cyclization to afford the desired product.
Physical properties Phenothiazine is a light yellow crystalline solid with an mp 180–181°C. It is insoluble in water, sparing soluble in ethanol but easily soluble in other organic solvents. It has a faint but bitter taste. Chemical reactions (i) N-Substitution: Due to the diverse pharmacological profiles associated with 10-substituted phenothiazines, much work has been done on the functionalization of secondary amine functionality of this molecule. The replacement of amine hydrogen has been carried out by using a variety of alkylating agents1401–1403 such as alkenes, alkynes and alkyl/aryl halides and acylating agents1404 such as carboxylic acid, chlorides and anhydrides as depicted in the scheme.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
337
Similarly, ethyl 2-(10H-phenothiazine-10-yl)acetate was prepared by heating a mixture of phenothiazine and ethyl bromoacetate in presence of potassium carbonate and copper powder.1405
Further, this N-substitution protocol has widely been adopted for the synthesis of numerous drug molecules and some representative syntheses are given in the following schemes. S +
CH2 CH2 CH2 N
Cl
N H
CH3
S
NaNH2
CH3
N CH2 CH2 CH2 N Promazine
S H3CS
S
(CH3CO)2O
N H
H3CS
H3CS O
N CH2CH2Cl CH3
N CH2CH2 H3 C Mesoridazine
N COCH3
K2CO3/CH3OH
S H3CS O
CH3
S
H2O2
N COCH3
CH3
H3CS O
NaNH2
N
S N H
(ii) Electrophilic substitution reaction: From π-electron charge densities calculation, it was established that position 3 is more reactive as compared to position 1, but due to ease of oxidation, the electrophilic substitution reaction on thiaphenozine scaffold is often complicated by the side reactions. (a) Halogenation: Phenothiazine on chlorination in dimethyl sulphoxide at 40°C affords 3,7-dichlorophenothiazine.1406 H N S
H N
Cl2, DMSO 40oC
Cl
S
Cl
However, when chlorination is carried out in presence of cupric chloride, 1,7-dichlorophenothiazine is obtained as a product.
338
2. Six-Membered Heterocycles
Additionally, bromination of 10-phenylphenothiazine in acetic acid, yields a mixture of 3-bromo-10- phenylphenothiazine and 3,7-dibromo-10-phenylphenothiazine.1407
Iodination: Bromine-lithium exchange of mono- and dibromophenothiazines on electrophilic trapping with iodine furnishes 3-iodo- and 3,7-diiodophenothiazines, respectively in excellent yields.1408
(b) Nitration: Phenothiazine on nitration with fuming nitric acid at 0°C gave 3,7-dinitrophenothiazine sulfoxides.1409
(c) Friedel Craft acylation: Reaction of phenothiazine with acetyl chloride in the presence of aluminium chloride as catalyst in boiling carbon disulphide affords 2,10-diacetylphenothiazine. When acetyl chloride is used in excess then 2,8,10-triacetylphenothiazine was isolated.1410
(iii) Reaction with nucleophiles: Phenothiazine on metallation with butyl lithium followed by treatment with carbon dioxide yields phenothiazine-1-carboxylic acid.1411
(iv) Oxidation: Phenothiazine can be oxidized by a number of oxidizing agents, which often result in a variety of products. Phenothiazine on oxidation first forms radical cation (A), which deprotonated in the presence of base to phenothiazinyl radical (B). Alternatively, phenothiazine also forms phenothiazonium cation (C) under oxidation and deprotonation conditions. In strong acidic medium, cation (C) can be converted to dication (D).1412,1413 However, the oxidation of phenothiazine is believed to proceed via comparatively more stable phenothiazinyl radical (B), which in fact dimerizes involving two resonating phenothiazine radical species to afford a stable product. Furthermore, the formation of these cationic and radical cationic species can also be observed visually via a color change in the solution. Phenothiazine gives a golden colored solution immediately when dissolves in concentrated sulfuric acid due to the formation of radical cation (A). On standing for several days the colour of solution changes to green because of the conversion of radical cation
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
339
(A) to dication (D) after the loss of one electron. Further, on dilution the color changes to red-brown which indicates the formation of phenothiazonium cation (C) in the solution.1414
Phenothiazine on oxidation with hydrogen peroxide in acetone followed by base treatment yields phenothiazine 5-oxide.1415
Phenothiazine on oxidation with aqueous acid affords phenothiazine -3(3H)-one. It was proposed that initially mesomeric phenothiazonium cation (E) was formed which on nucleophilic attack by water at C-3 gives an intermediate, which on further oxidation and deprotonation yields the desired product.1416,1417
(v) Duff formylation: Microwave assisted Duff formylation of phenothiazine with urotropine in acetic acid afforded 10(H)-3-formylphenothiazine in excellent yield.1418 This process requires shorter reaction time in comparison to conventional reaction protocol.
340
2. Six-Membered Heterocycles
2.9 SIX-MEMBERED HETEROCYCLES WITH TWO OXYGEN OR SULFUR ATOMS 2.9.1 Dioxane Dioxanes are six-membered, nonplanar, nonaromatic saturated heterocycles with two oxygen atoms replacing two methylene groups (CH2) of the cyclohexane ring. Depending on the position of both oxygen atoms in the ring there are three possible isomeric forms, designated as 1,2-, 1,3-, and 1,4-dioxane.
2.9.2 1,3-Dioxane
1,3-Dioxanes or -m-dioxanes are cyclic acetals or ketals and are considered to be methylene ethers of 1,3-diols. Structural and Reactivity Aspects1419 It has been well established that 1,3-dioxane prefers to exist in chair conformation.1420 When a heteroatom is placed in a cyclohexane ring the bond lengths and bond angles changed. Thus in 1,3-dioxane the CO bond lengths shorten and the axial 1,3-hydrogens come closer in space, therefore there is greater van der Waals strain. Thus the cyclohexane ring is more stable in comparison to 1,3-dioxane, which has two heteroatoms.
The chair conformation of 1,3-dioxane was confirmed by X-ray crystallography of one of its derivatives 2-(p- chlorophenyl)-1,3-dioxane. The bonds lengths are comparatively shorter in comparison to cyclohexane. Hence 1,3-dioxane is more compact in comparison to cyclohexane. Bond lengths (in pm) and angles (in degrees) are shown in the following figure.
Bond lengths and bond angles in 1,3-dioxane derivative.
The 1H and 13C NMR spectra of 1,3-dioxane are given in the following table. H and 13C NMR spectral data of 1,3-dioxane
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 4.70; H-4/H-6, 3.80; H-5, 1.68
C-2, 95.4; C-4/C-6, 67.6; C-5, 26.8
Importance in Natural Products, Medicines, and Materials The importance of 1,3-dioxane originates from its structural features, its application in industrial and fine organic synthesis, and also its promising physiological properties. Special mention is made regarding the industrial application of this cyclic acetal in the production of isoprene, 1,3-diol, and a number of drugs.1421 1,3-Dioxane derivatives like cis-5-hydroxy-2-methyl-1,3-dioxane and trans-5-hydroxy-2-methyl-1,3-dioxane have been reported to be present in Spanish Fino sherry.1422
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
341
Synthesis 1. Prins reaction: Basically, Prins reaction is the acid-catalyzed addition of aldehydes to alkenes yielding different products depending on the conditions of the reaction. This reaction has also been used in the synthesis of 1,3-dioxanes. Reaction of 2-methylprop-1-ene with formaldehyde in the presence of aqueous sulfuric acid yields 4,4-dimethyl-1,3-dioxane as the major product.1423
The reaction has been proposed to take place by the following mechanism.
Polyaniline (PANI)-supported PTSA/FeCl3-catalyzed Prins reaction of paraformaldehyde with different alkenes in dichloromethane at different temperatures yields 1,3-dioxanes.1424
Prins reaction for 1,3-dioxane synthesis is also illustrated by condensation of isoeugenol with paraformaldehyde in the presence of a small amount of ion-exchange cationic resin as catalyst.1425
2. β-Haloacetals and ketals have been used as alkylating agents and in the preparation of Grignard reagents. 1,3-Dioxane is considered to be acetal, and the synthesis of their bromo derivatives has been reported.1426 The process involves reaction of acrolein with 1,3-propanediol in the presence of hydrogen bromide under nitrogen conditions yielding 2-(2-bromoethyl)-1,3-dioxane.
Similarly, 2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane is synthesized by reaction of methyl vinyl ketone with neopentanediol in the presence of gaseous hydrogen bromide.
3. Synthesis of chloro and bromo derivatives of 1,3-dioxane has also been reported.1427 The process involves heating 1-bromo-3-chloro-2,2-dimethoxypropane with 1,3-propanediol in the presence of concentrated sulfuric acid as catalyst yielding 2-(bromomethyl)-2-(chloromethyl)-1,3-dioxane.
342
2. Six-Membered Heterocycles
4. Alkenes undergo condensation with paraformaldehyde in the presence of indium tribromide in ionic liquids such as 1-butyl-3-methyl hexafluorophosphate or 1-butyl-3-methylimidozolum tetrafluoroborate to afford 1,3-dioxane derivatives in high yield.1428
5. Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione), which is a dioxane derivative, has attracted considerable attention as a reagent and intermediate in organic synthesis and is prepared by a reaction between acetone, malonic acid, and acetic anhydride.
6. Baylis-Hillman reaction: An important method for the synthesis of 1,3-dioxanes is via Baylis-Hillman reaction. The process involves reaction of phenyl acrylate with acetaldehyde in the presence of DABCO as catalyst forming an intermediate, which cyclizes with acetaldehyde to afford a 5-methylene-1,3-dioxane-4-one derivative.1429, 1430
7. Synthesis and stereochemistry of a novel 1,3-dioxane derivative is prepared by reaction of diacetylbenzene with 1,3-diol in the presence of a catalytic amount of p-toluenesulfonic acid. The anancomeric structure of these compounds, orientation of the groups bonded to the dioxane ring, and cis- and trans-isomerism of these compounds has been discussed on the basis of NMR and X-ray crystallography.1431
Physical Properties 1,3-Dioxane is a colorless liquid with a bp of 105°C. It is readily soluble in nearly all organic solvents.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
343
Chemical Reactivity 1. Hydrolysis: 1,3-Dixoane is hydrolyzed to 1,3-diols. The rate of the reaction is determined by the rate at which the cation A is formed.1432 3-Methyl-1,3-butanediol is obtained by stirring 2,2-dimethyl-1,3-dioxane with 2% sulfuric acid solution under reflux.1423
2. Protection: A simple, selective protection of both symmetrical and unsymmetrical substituted 1,3-diols obtained after cleavage of 1,3-dioxanes has been reported. The process involves regioselective cleavage of 1,3-dioxanes with acetyl chloride followed by conversion of the resulting chloromethyl ether acetate to an alkoxy methyl ether acetate.1433, 1434
Monoprotection is achieved by carrying out hydrolysis with potassium carbonate in the presence of methanol.
3. Synthesis of cyclopropenone 1,3-propanediol ketal: Cyclopropenone 1,3-propanediol ketal is stable and has proved to be a useful equivalent of the 1,3-dipole in a regiospecific three carbon + two carbon cycloaddition reaction with electron-deficient olefins.1435 The targeted compound1427 is synthesized by stirring an ether solution of 2-(bromomethyl)-2-(chloromethyl)-1,3-dioxane with freshly prepared potassium amide at −50 to −60°C.
4. Ring contraction: During nucleophilic displacement reaction of 5-hydroxy-2-methyl-1,3-dioxane, ring contraction is observed.1436
344
2. Six-Membered Heterocycles
5. Chiral synthesis: Several systems derived from 1,3-dioxane serve as chiral building blocks for stereoselective transformations. The cationic coupling of a 4-acetoxy-1.3-dioxane derivative with allyltrimethylsilane in the presence of boron trifluoride etherate yielded a product with anticonfiguration.1437
Similarly, 4-cyano-1.3-dioxane derivative was converted into a syn-derivative.1438
2.9.3 1,4-Dioxane
1,4-Dioxane, also known as p-dioxane, diethylene oxide, or 1,4-dioxacyclohexane, is a six-membered, saturated heterocyclic compound containing two oxygen atoms present at 1,4 positions of the cyclohexane ring. Structural and Reactivity Aspects1439 The 1,4-dioxane molecule, which is centrosymmetric, exists in chair conformation and this was also confirmed by the ab initio studies.1440 The CC and CO bond lengths are 152 and 142 pm, respectively, whereas the CCC and COC bond angles are 105 and 112 degrees, respectively.
The 1H and 13C NMR spectral data of 1,4-dioxane are given in the following table. H and 13C NMR spectral data of 1,4-dioxane
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2/H-3/H-5/H-6, 3.70
C-2/C-3/C-5/C-6, 67.8
Importance in Natural Products, Medicines, and Materials The 1,4-dioxane scaffold occurs in a wide range of natural products and pharmaceutical drugs. For example, compounds 1, II, III, IV, and V exhibit antiviral, anticancer, and cardiotonic activity.1441, 1442
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
345
Biologically active compounds containing 1,4-dioxane skeleton.
Synthesis 1. It is prepared by acid-catalyzed cyclic dehydration of ethylene glycol.1443
2. Dimerization of oxirane in the presence of acid as catalyst yields 1,4-dioxane.
3. Williamson synthesis: Upon action of a base on 5-halo-3-oxopent-1-ol, cyclization takes place yielding 1,4-dioxane.
4. Cyclocondensation of ethylene glycol with oxirane in the presence of an acid catalyst yields 1,4-dioxane.
5. Asymmetric synthesis: Asymmetric synthesis of chiral 1,4-dioxanes has been developed by means of organic catalytic enantioselective desymmetrization of oxetanes. With the oxetane bearing an ethylene glycol ether at the 3-position and by using BINOL-derived chiral phosphoric acid as a catalyst, the intramolecular reaction proceeded smoothly at room temperature resulting in stereo-controlled reopening of the oxetane ring to form chiral 1,4-dioxanes.1442
Synthesis of an enantiomerically pure (R)-7 compound (1,4-dioxane derivative) has been reported to take place in three steps from commercially available epichlorohydrin (S)-4. The chiral compound (R)-7 is transformed to dithioacetal derivative (A) from which the two antiviral compounds (I) and (II) have been synthesized.1441
346
2. Six-Membered Heterocycles
Physical Properties 1,4-Dioxane is a colorless, volatile, hygroscopic liquid with a bp of 101°C and a mild ethereal odor. It is miscible with water and nearly all organic solvents. The structure of dioxane is quite stable. It is resistant to reaction with acids, oxides, and oxidizing agents. This stability, under a wide variety of conditions, makes dioxane quite suitable for use as an organic solvent. Chemical Reactivity 1. Halogenation: Thermal chlorination of 1,4-dioxane in carbon tetrachloride leads to the formation of heptochloro1,4-dioxane in good yield.
When chlorination is carried with sulfuryl chloride with UV radiation and ice cooling such that the internal temperature is 30–35°C, 2,3-dichloro-1,4-dioxane is obtained.
When chlorination is carried out at 10°C with a trace of benzoyl peroxide, trans-2,5-dichloro-1,4-dioxane was obtained.1444
2. Acetylation: Refluxing 1,4-dioxane with lead tetraacetate in a flask covered with aluminum foil and heated with a “power light” of a 500 W lamp yielded 2-acetoxy-1,4-dioxane.1445
When acetylation is carried out with acetic anhydride in the presence of ferric chloride, a ring-opening process takes place leading to the formation of bis(2-acetoxyethyl) ether and 1,2-diacetoxyethane.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
347
However, when acetylation is carried out with acetyl chloride in the presence of aluminum chloride as catalyst, 2-chloroethyl acetate is isolated.
3. Photolysis: Although dioxane is used as a solvent in many photochemical reactions, the photochemistry of dioxane has also been discussed.1446 When dioxane was irradiated using a 40 W medium pressure lamp through quartz in a nitrogen atmosphere, four products were isolated after preparative GLC.
4. Adduct formation: Dioxane acts as an n-electron donor and forms a stable adduct with Lewis acid or other acceptor molecules. These adducts find use as reagents in organic synthesis. (a) Dioxane-monochloroborane: The reagent was prepared by reaction of dioxane and dioxane-BCl3 with diborane. The adduct obtained is liquid and stable up to 25°C and is used to hydroborate simple unhindered olefins to corresponding dialkylchloroboranes.1447
(b) Dioxane-sulfur trioxide: Use of sulfur trioxide as sulfonating agent is limited because it often leads to charring. Sulfonation is therefore carried out with its adduct with dioxane. The donor/acceptor complex of dioxane with sulfur trioxide is quite stable and its crystal structure has also been studied.1448 This adduct is chiefly used for the sulfonation of alcohols, alkenes, carbonyl, and aromatic compounds.
(c) Dioxane-bromine adduct: This is chiefly used for bromination reactions. For example, bromination of furan with a dioxane-bromine complex at −5°C yields 2-bromofuran.
2.9.4 1,4-Dioxin
1,4-Dioxin, also referred to as p-dioxin or simply dioxin, is a six-membered unsaturated, nonconjugated, nonaromatic oxygen heterocycle consisting of four carbon atoms and two oxygen atoms at the 2- and 4-positions of the ring. Structural and Reactivity Aspects1449 This heterocyclic ring of 1,4-dioxin is made up of 8π electrons, is nonplanar, and is classified as nonaromatic. The 1 H NMR spectrum shows one singlet at δ 5.50 suggesting it to be a symmetrical cyclic vinyl ether.
348
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials The 1,4-dioxin nucleus has been found to be present in a number of natural products. Some lignan derivatives like eusiderin and silybin have been found to possess this skeleton.1450, 1451
Natural products containing 1,4-dioxin skeleton.
The Chinese traditional medicine “Shi Hu” prepared from the stems of several Dendrobium species is widely used as an antipyretic, and is beneficial to eyes and as a tonic. Dendrocandin B, a novel dioxin derivative, was isolated from Dendrobium candidum, one of the most popular Dendrobium species.1452 The structure of the 1,4-dioxin derivative caleteucrin isolated from Cafea prunifolia was established by single crystal X-ray diffraction.1453
Dendrocandin B one of the constituent of “Shi Hu” possess 1,4-dioxin skeleton.
Dihydro-1,4-dioxin carboxyanilide derivatives A and B have been reported to possess fungicidal activity.1454
Biological active compounds with 1,4-dioxin skeleton.
Synthesis 1. 1,4-Dioxin is synthesized by dechlorination of 2,3,5,6-tetrachloro-1,4-dioxane with magnesium and iodine in boiling dibutyl ether.
2. Reductive elimination of bromine from 2,3-dibromo-2,3-dihydro-1,4-dioxin on reaction with phenylmagnesium bromide in diethyl ether yields 1,4-dioxin.
3. Heating 2,5-dimethoxy-2,3,5,6-tetraphenyl-1,4-dioxane or 2-methoxy-2,3,5,6-tetraphenyl-2,3-dihydro-1,4-dioxin with acetic anhydride in the presence of a catalytic amount of concentrated sulfuric acid, zinc(II) chloride, or iron(II) chloride gives tetraphenyl-1,4-dioxin.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
349
4. trans-2,5-Bis(iodomethyl)-1,4-dioxane when heated with aqueous sodium hydroxide causes elimination of a molecule of hydrogen iodide and yields 2,5-bis(methylene)-1,4-dioxane, which undergoes isomerization in the presence of a palladium-on-charcoal catalyst to afford 2,5-dimethyl-1,4-dioxin.
5. Heating benzoin with methanol in the presence of hydrogen chloride gave a mixture of trans-6-methoxy-2,3,5,6tetraphenyl-1,4-diox-2-ene and trans,trans-2,5-dimethoxy-1,4-dioxane. This mixture when treated directly with zinc chloride in boiling acetic anhydride gave tetraphenyl-p-dioxin.1455
6. Reaction of methyl phenylchloropyruvate with potassium phthalimide in chlorobenzene under the conditions of Gabriel reaction yielded 2,5-dimethoxycarbonyl-3,6-diphenyl-1,4-dioxin and 2,6-dimethoxycarbonyl-3, 5-diphenyl-1,4-dioxin.1456
7. Diels-Alder reaction: Furan and maleic anhydride undergo cycloaddition reaction forming an adduct, which is converted to an epoxide. The epoxide undergoes retro-Diels-Alder reaction forming 1,4-dioxin and regenerating maleic anhydride.1457
350
2. Six-Membered Heterocycles
Physical Properties 1,4-Dioxin is a colorless, highly flammable liquid with a bp of 75°C. Chemical Reactivity 1. Halogenation: 1,4-Dioxin behaves as a typical unsaturated ether, and bromine added to one of the double bonds giving 2,3-dibromo-2,3-dihydro-1,4-dioxin. Similarly, two molecules of chlorine added across both the double bonds affords 2,3,5,6-tetrachloro-1,4-dioxane.1458
2. Oxidation: 1,4-Dioxin undergoes one electron oxidation electrochemically or chemically to give a radical cation, which further loses the second electron to give rise to Hückel 6π electron structure.1459
Electrochemical oxidation of 2-chloro-2,3-dihydro-1,4-dioxin in the presence of alcohol yields chloroacetal with addition of the alkoxy group at C-3.
3. Photolysis: Photolysis of tetraphenyl-p-dioxin in tert-butanol gave benzil as the major product and tolan as the minor product. When photolysis was carried out in benzene for 2.5 h in a nitrogen atmosphere, besides benzil and tolan, trans-dibenzoylstilbene was also formed. Photolysis in the presence of air produced benzil as the exclusive product; however, photolysis in benzene in an oxygen atmosphere again produced benzil as the exclusive product. The reaction pathways are depicted in the following diagram.1455
4. Thermolysis: On thermolysis, tetraphenyl-p-dioxin is first converted to cis-dibenzoyl stilbene, which on heating at higher temperatures is converted to 3,3,4,5-tetraphenylfuran-2(3H)-one. The reaction has been proposed to take place by the following pathway.1455
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
351
2.9.5 Dibenzo-1,4-Dioxin Dibenzo-1,4-dioxin, also referred to as dibenzodioxin, dibenzo-p-dioxin, dibenzo[b,e][1,4]dioxin, or oxanthrene, is a tricyclic heterocyclic compound in which two benzene rings are connected to the 1,4-dioxin ring.
Structural and Reactivity Aspects X-ray crystal analysis of 2,7-dichlorodibenzo-1,4-dioxin suggests that the molecule is planar. The bond distances (in Å) and bond angles (in degrees) are shown in the following figure.1460
Bond length and bond angles of dibenzo-1,4-dioxin.
The 1H NMR of 1-chlorodibenzo-1,4-dioxin1461 and the 13C NMR of tetrabromodibenzo-1,4-dioxin1462 are given in the following table. 1
H and 13C NMR spectral data of dibenzo-1,4-dioxin derivatives
1 H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
Ar-H, 6.97–6.83 (5H); H-3, 6.81 (t), H-2, 6.74 (dd)
C-1, 145.7; C-2, 116.3; C-3, 117.9; C-4, 101.3; C-4a, 140.2; C-10, 129.7; C-5a, 138.4; C-6, 110.3; C-7, 129.7; C-8, 115.9; C-9,118.7; C-9a, 142.4
The mass fragmentation of dibenzo-1,4-dioxin is also discussed below.1463
Mass fragmentation pattern of dibenzo-1,4-dioxin.
352
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials Dibenzo-1,4-dioxins are unusual natural products that are produced by the coupling of phenoxy radicals. The biosynthesis of the halogenated derivatives of this class of compound have been reported to follow the same route as suggested for diphenyl ethers, followed by nucleophilic displacement of halogen and formation of the second bond of dioxin.
Biosynthesis of halogenated derivatives of dibenzo-1,4-dioxin.
A number of natural products bearing this skeleton have been isolated from the sponges Tedania ignis and Dysidea dendyi.
Natural products containing dibenzo-1,4-dioxin skeleton.
A number of phlorotannins such as phlorofucofuroeckol A with a dibenzo-1,4-dioxin skeleton isolated from the edible brown alga Ecklonia kurome Okamura have been reported to inhibit the action of α2-macroglobulin and α2-plasmin inhibitor.1464, 1465
A number of synthetic dibenzodioxin derivatives have been reported to possess anticancer activity.1466 Certain polychlorodibenzo-1,4-dioxins formed during the manufacture of polychlorophenols are highly toxic to humans. Synthesis 1. Dichlorobenzene is activated toward nucleophilic substitution reaction by carrying out complexation with ferrocene, whereby a cationic (cyclopentadienyl) iron complex of 1,2-dichlorobenzene is obtained. This complex reacts with benzene 1,2-diol in the presence of base to afford a cationic (cyclopentadienyl) complex of dibenzo1,4-dioxin, which on irradiation with light yields dibenzo-1,4-dioxin.1467, 1468
2. Sodium or potassium salt of 2-halophenol when heated at high temperatures in the presence of copper catalyst undergoes self-condensation to give dibenzo-1,4-dioxin.1469
353
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
3. 2-(2-Chlorophenoxy)phenolates when heated at 120–130°C in the presence of potassium carbonate in DMF undergo cyclization to give dibenzo-1,4-dioxin.
4. Benzene 1,2-diols are activated under basic conditions to give 1,2-diolate anions, which undergo condensation with 1,2,4,5-tetrachlorobenzene to give 2,3-dichlorodibenzo-1,4-dioxin.
Similarly, nitro-substituted 2-chloro-1,2,3- trinitrobenzene.
dioxins
can
be
synthesized
by
treating
benzene-1,2-diol
with
5. An improved synthesis of substituted dibenzo-1,4-dioxin by reaction of catechol with 1,2-dichloro- or 2-chloronitrobenzenes in the presence of metallic potassium in hexamethylphosphoramide has been reported.1461
Chemical Reactivity 1. Electrophilic substitution reaction (a) Nitration: Nitration of dibenzo-1,4-dioxin with nitric acid at −20°C yields a 2,7-dinitro derivative.1470
(b) Friedel-Crafts acylation: Acylation of dibenzo-1,4-dioxin with acetyl chloride or propanoyl chloride in the presence of anhydrous aluminum chloride afforded a 2,7-diacyl derivative.1471
(c) Halogenation: Dibenzo-1,4-dioxin is chlorinated by bubbling chlorine gas into a well-stirred solution of dibenzo-1,4-dioxin in glacial acetic acid. 2-Chlorodibenzo-1,4-dioxin was the major product. When chlorination was carried out under similar conditions, except photoirradiation with UV light, 2,7-dichlorodibenzo-1,4dioxin was obtained. Similarly, synthesis of 2-bromodibenzo-1,4-dioxin was achieved by treating dibenzo-1,4dioxin in glacial acetic with potassium bromide-bromate while reaction with bromine in acetic acid afforded 2,7-dibromodibezo-1,4-dioxin.1469
354
2. Six-Membered Heterocycles
2. Sandmeyer’s reaction: Sandmeyer’s reaction of chlorodibenzo-1,4-dioxinamines can be used to introduce different functional groups into the aromatic ring. Nitro-substituted chlorodibenzo-1,4-dioxins are easily converted to diazonium salt on treatment with tert-butylnitrite. Treatment of diazonium salt with copper(I) [37Cl] chloride gave 37Cl-labeled dichlorodibenzo-1,4-dioxin.
3. Nucleophilic substitution reaction: Reaction of dibenzo-1,4-dioxin with 2 equivalents of butyllithium forms 1,9-dianion, which on first reaction with carbon dioxide followed by esterification with methanol in the presence of acid yields 1,9-diester.1472
4. Photochemistry: Photochemistry of dibenzo-1,4-dioxin initially involves opening of the ring by aryl-oxygen bond homolysis to give a biradical, which on reduction by hydrogen abstraction from the medium gave 2-phenoxyphenol. Further photolysis of 2-phenoxyphenol afforded 2,2′-biphenol as the major component and 4-hydroxydibenzofuran as the minor product.1473
However, a detailed study by Rayne et al. suggested that dibenzo-1,4-dioxin initially underwent singlet-state photochemically initiated aryl-ether bond homolysis yielding 2-spiro-6-cyclohexa-2,4-dien-1-one and subsequently 2,2′-biphenylquinone, which undergo excited-state hydrogen abstraction from organic solvent to give 2,2-dihydroybiphenyls.1474
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
355
2-Nitrodibenzo-1,4-dioxin in the presence of a primary amine like propylamine in polar solvent undergoes a photosubstitution reaction to give isomeric (N-propylamino)hydroxynitrodiphenyl ethers.1475
2.9.6 1,4-Dithiin
1,4-Dithiin, also known as 1,4-dithia-2,5-cyclohexene, is 2,2-diethoxyethane-1-thiol a six-membered heterocycle that contains two carbon-carbon double bonds, four carbon atoms, and two sulfur atoms. This heterocyclic ring, which is made up of 8π electrons, is nonplanar and is classified as nonaromatic rather than antiaromatic. Structural and Reactivity Aspects1476a X-ray diffraction studies of the parent compound 1,4-dithiin revealed that the ring is nonplanar and exists in a boat conformation in solid state with a butterfly-flapping angle of 137 degrees or 141 degrees between the two SCCS planes.
Boat conformations of 1,4-dithin.
1,4-Dithiin is nonaromatic due to the absence of a diamagnetic ring current. In addition, the 1H NMR spectrum exhibits a singlet at 6.21 ppm, which is almost equal to the observed value for dihydro-1,2-dithiin. The 13C NMR of the parent compound in CDCl3 also showed a single peak at δ 121.3 ppm suggesting it to be a symmetrical molecule.1476b Importance in Natural Products, Medicines, and Materials The 1,4-dithiin skeleton is found in a number of biologically active compounds such as dimethipin, a commercial plant growth regulator. Depending on the type and number of substitutions on the ring and unsaturation in the ring, this ring structure has been found to exhibit either herbicidal or microcidal activity. 1476c
Synthesis 1. The parent compound is obtained from 2,2-diethoxyethane-1-thiol by vapor-phase dealkoxylation of 2,5-dialkoxy-1,4-dithiane1477 over alumina at 270°C.
356
2. Six-Membered Heterocycles
Distilling a mixture of 1,4-dithiane-2,5-diol in N,N-dimethylformamide in the presence of thionyl chloride and pyridine yields 1,4-dithiin in high yield.1476b
2. Bunte salt formed by the reaction of phenacyl bromide with sodium thiosulfate underwent cyclization under acidic conditions to yield 2,5-diaryl-1,4-dithiin.1478
3. Reaction of cis-1,2-dichloroethylene with disodium cis-ethylenedithiolate in DMSO yielded 1,4-dithiin.1479
4. Tetraphenyl-1,4-dithiin is obtained by condensation of benzoin with hydrochloric acid and hydrogen sulfide.1480
5. Photolysis of 1,2,3-thiadiazole leads to elimination of a molecule of nitrogen forming a diradical, which underwent dimerization to form 1,4-dithiin.
6. Upon irradiation of 4,5-diphenyl-1,3-dithiole-2-one, photodecarbonylation takes place forming tetraphenyl-1,4-dithiin.
7. [5 + 1] cyclization: 1-Alkynyl ethynyl sulfide on reaction with sodium sulfide in methanol underwent [5+1] cyclization to afford monosubstituted 1,4-dithiin.1481
Cis-1,2-ethylenedithiolate reacts with 1,3-butadiyne to afford 2-vinyl-1,4-dithiin.1482
Physical Properties 1,4-Dithiin has an mp of 99–100°C. Chemical Reactivity 1. Electrophilic substitution reaction: 1,4-Dithiin being nonaromatic does not undergo electrophilic substitution reaction. However, its diaryl derivative undergoes substitution in two steps.1483
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
357
2. Electrophilic addition reaction: 1,4-Dithiin on reaction with chlorine underwent electrophilic addition reaction to yield a dichloro derivative.
3. Reaction with nucleophiles: The presence of electron-withdrawing groups on the ring facilitates nucleophilic attack. For example, tetracyano-1,4-dithiin underwent reaction with a variety of nucleophiles to give fivemembered products.1484
Unsubstituted 1,4-dithiin on reaction with alkyllithium underwent ring opening of dithiin. Lithiation of 1,4-dithiin with butyllithium in diethyl ether at −110°C gave a 2-lithio derivative. The lithio derivative on a rise in temperature from −110 to −60°C opened the ring to give dilithium salt, which on subsequent methylation gave the sulfane derivative.
1,4-Dithiin on reaction with butyllithium in diethyl ether at −78°C yields a 2-lithio derivative, which can easily be transformed into an alkyl derivative.
4. Oxidation: Oxidation of 1,4-dithiin with 30% hydrogen peroxide in the presence of glacial acetic acid at room temperature yields 1,4-dithiin-1,1-dioxide.1485
358
2. Six-Membered Heterocycles
2-p-Methoxyphenyl-5-phenyl-1,4-dithiin on oxidation with peracid yields the monosulfone derivative, which on heating thermally yields 2-p-methoxy-4-phenylthiophene.
In the case of unsymmetrically substituted 1,4-dithiins the sulfur atom, which has the higher electron density (in terms of mesomeric effect), is oxidized.1471
5. Thermolysis: The parent unsubstituted molecule is thermally stable and can be distilled at 190°C without decomposition. However, when subjected to the action of heat, substituted 1,4-dithiins undergo ring contraction with extrusion of sulfur to yield thiophene derivatives.
Similarly, thermolysis of tetraphenyl-p-dithiin takes place with extrusion of sulfur to yield tetraphenyl thiophene.1480
6. Photolysis: Unsubstituted 1,4-dithiin on photolysis in the absence of oxygen undergoes [2+2] cyclodimerization.1486
7. Cycloaddition reaction: 1,4-Dithiin reacts as a dienophile in a thermal [4+2] cycloaddition reaction with reactive dienes like 2,5-dimethyl-3,4-diphenylcyclopentadienone to give the cycloaddition product in high yield.1487
2.9.7 1,3-Dithiane
1,3-Dithiane, also known as m-dithane or 1,3-dithiacyclohexane, is a six-membered cyclohexane derivative in which two methylenes of the cyclohexane have been replaced by two sulfur atoms. Structural and Reactivity Aspects The 1H and 13C NMR spectral data of 1,3-dithiane, which helped in the interpretation of its structure, are given in the following table.1488
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
359
H and 13C NMR spectral data of 1,3-dithiane
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.67 (s); H-4, H-6, 2.7 (m); H-5, 2.0 (m)
C-2, 31.9; C-4, H-6, 29.8; C-5, 26.8
The mass spectral fragmentation of 1,3-dithiane has been studied by 2H labeling and metastable defocusing.1489
Mass fragmentation pattern of 1,3-dithiane.
The basic structure of 1,3-dithiane was confirmed on the basis of the X-ray crystal structure of 2-phenyl-1,3-dithane, which suggests that the molecule exists in the chair conformation.1490 The following figure shows bond angles in degrees and bond lengths in Å.
Bond length and bond angles of 1,3-dithiane.
Importance in Natural Products, Medicines, and Materials 1,3-Dithiane is one of the constituents isolated from garlic and other allium species. Dithiane-incorporated compounds have been reported to possess pesticidal,1491 insecticidal,1492 and human 5α-reductase inhibitory activity. Recently, a number of dithiane-incorporated pregnane derivatives were synthesized and evaluated for their in vitro antifungal and antibacterial activity.1493
Dithiane incorporated steroids (pregnane) derivatives.
Synthesis 1. The parent compound is synthesized by refluxing a solution of 1,3-propanedithiol and methylal (dimethoxymethane) in boron trifluoride diethyl etherate, glacial acetic acid, and chloroform.1494
This method requires special precautions to avoid side reaction. However, an improved method involving condensation of 1,3-propanedithiol with ethylal in the presence of montmorillonite KSF clay has been reported.1495
2. 2-Substituted dithiane is synthesized by the reaction of 1,3-propanedithiol with benzaldehyde in the presence of hydrogen chloride gas1496 at 0°C.
360
2. Six-Membered Heterocycles
3. A mild method for the preparation of 1,3-dithane from the reaction of aldehydes and ketones with propane-1,3thiol in the presence of lithium perchlorate as Lewis acid has been reported.1497
An environmentally friendly method for the synthesis of 1,3-dithanes by the reaction of aliphatic and aromatic carbonyl compounds with propane 1,3-thiol in the presence of a catalytic amount of tungstate-sulfuric acid under solvent-free conditions has also been reported.1498 4. A facile synthesis of 1,3-(2-13C)- and 1,3-(213C, 2-2H2)dithiane in two steps from [13C]- or [13C, 2H3]methyl phenyl sulfoxide has been reported. The process involves reaction of [13C] methyl phenyl sulfoxide with trifluoroacetic anhydride to afford (phenylthio)[13C]methyl 2,2,2-trifluoroacetate, which on reaction with 1,3-propanedithiol yielded 1,3-(2-13C)dithiane. Similarly, [13C, 2H2]methyl phenyl sulfoxide reacts with trifluoroacetic anhydride to afford (phenylthio)[13C, 2H2]methyl 2,2,2-trifluoroacetate, which on reaction with 1,3-propanedithiol yielded 1,3(2-13C, 2H2)dithiane.1499
5. Dieckmann reaction: 3,5-Dithia-1,7-heptadioic ester in the presence of sodium ethoxide afforded 5-keto-1,3-dithiane.
6. Terminal alkyne on reaction with aldehyde in the presence of H2S using boron trifluoride as a catalyst delivered 2-aryl-1,3-dithiane.
Physical Properties 1,3-Dithiane is a colorless to yellow crystalline solid with an mp of 53–54°C. It is hygroscopic, very slightly soluble in water, but easily soluble in ether, chloroform, benzene, and THF. Chemical Reactivity 1. 1,3-Dithiane derivatives are versatile intermediates in the synthesis and interconversion of monocarbonyl and dicarbonyl compounds.1500 1,3-Dithianes react with a strong base such as n-butyllithium forming lithiated 1,3-dithiane, which acts as a nucleophilic agent. This on reaction with an electrophile, usually alkyl halides, and subsequent hydrolysis with mercuric oxide or mercuric chloride yielded an aldehyde or ketone.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
361
(a) Synthesis of ketones: Aldehydes and open chain ketones have been synthesized from dithiane. Cyclobutanone, which was earlier synthesized by reaction of diazomethane with ketene Synthesis of cyclobutanone has been reported in two steps. In the first step, 5,9-dithiaspiro[3,5]nonane is synthesized by reaction of 1,3-dithiane with butyllithium followed by reaction with 1-bromo-3-chloropropane. In the second step, 5,9-dithiaspiro[3,5] nonane is refluxed at 90–110°C with triethylene glycol, mercury(II) chloride, and cadmium carbonate in a nitrogen atmosphere.1501
(b) Reaction of 1,3-dithiane with butyllithium followed by reaction with 2-cyclohexen-1-one yields 1-(1,3-dithian2-yl)-2-cyclohexen-1-ol, which on reaction with mercuric oxide and boron trifluoride etherate in THF yielded 3-hydroxy-1-cyclohexene-1-carboxaldehyde.1502
Unsaturated aldehydes have also been synthesized by the reaction of 1,1-diethoxymethyl-2.3-epoxypropane with 2-lithiodithane yielding 2-(2-acetoxy-3,3-diethoxypropyl)-1,3-dithane, which on hydrolysis with HgO-BF3 afforded 3-acetoxy-4,4-diethoxybutanal followed by reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produced 4,4-diethoxy-2-butenal.1503
(c) 2-Phenyl-1,3-dithiane on reaction with n-butyllithium followed by thiomethylation with (methylsulfinothioyl) methane delivered 2-methylthio-2-phenyl-1,3-dithiane, which on reaction with lindole in chloroform using BF3 etherate as a catalyst produced 3-(2-phenyl-1,3-dithian-2-yl)-1H-indole.1504 This on heating in acetone in the presence of CuCl2 and CuO gave 3-benzoylindole. However, reduction with lithium aluminum hydride (LAH) in the presence of ZnCl2 and CuCl2 delivered 3-phenylmethyl-1H-indole.
(d) A total and stereoselective synthesis of racemic echinolone (A), a juvenile hormone mimic, has been reported1505 using 2-methyl-1,3-dithiane as precursor.
362
2. Six-Membered Heterocycles
(e) Dioxaspiro compound (B), which is the aggregating pheromone of Pityogenes chalcographus, is prepared by sequential alkylation of 1,3-dithane with a chloro derivative and bromoperoxide. The oxirane ring was cleaved with LiBHEt to give an intermediate, which on hydrolysis yielded the diastereomeric mixture of the dioxaspiro compound (B).1506
(f) Vermiculin, a macrocytic aglycoside dilactone, which has been reported to possess antibacterial, antiprotozoal, and immunosuppressant activity and is isolated from Penicillium vermiculatum, has also been synthesized by Umpolung reaction/process.1507
2. Oxidation: Enantiomerically pure 1S(−)-1,3-dithiane-1-oxide has been synthesized in three steps. In the first step, 1,3-dithiane is made to react with 1M solution of sodium hexamethyldisilazide in THF. The resulting yellow solution is then made to react with butyllithium followed by reaction with ethyl 2,2-dimethylpropanoate. 2-(2,2-Dimethylpropanoyl)-1,3-dithiane obtained as colorless needles (mp 97–99°C) is made to react with (+)-[(8,8-dimethoxycamphoryl)sulfonyl]oxaziridine whereby a mixture of anti- and syn-1S-(2,2dimethylpropanoyl)-1,3-dithiane-1-oxide is obtained as a colorless crystalline solid (mp 103–105°C). Refluxing this enantiomeric mixture with 5% ethanolic sodium hydroxide yields the desired product.1508
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
363
3. Vinylogous acyl triflates undergo tandem nucleophilic addition reaction1509 to 2-methyl-1,3-dithiane to yield alkyne building blocks. 2-Methyl-2-(1-oxo-5-heptynyl)-1,3-dithiane is synthesized by reaction of 2-methyl-1,3dithiane with n-butyllithium and 2-methyl-3-trifluoromethanesulfonyloxy-cyclohex-2-en-1-one at −78°C.
2.9.8 Dibenzo[b,e]-1,4-Dithiin (Thianthrene)
Thianthrene, also known as 9,10-dithiaanthracene or di-σ-phenylene disulfide, is a tricyclic heterocyclic compound with two sulfur atoms connecting the two benzene rings. Earlier, on the basis of molecular weight determination (C12H8S2), the compound was named diphenylenedisulfide. However, later it was named thianthrene due to its similarity to anthracene. Structural and Reactivity Aspects On the basis of X-ray crystallography, thianthrene has a folded C2v configuration with the bond angle between the two planes defined by two aromatic rings and sulfur, being 128 degrees. The bond lengths in Å as derived from X-ray analysis are shown in the following figure.1510
Bond length (in Å) values of thianthrene.
The 1H and 13C NMR spectral data of thianthrene are given in the following table.1511, 1512 H and 13C NMR spectral data of thianthrene
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1,4,6,9, 7.48; H-2,3,7,8, 7.23
C-3, 127.6; C-4, 128.7; C-4a, 135.5
Importance in Natural Products, Medicines, and Materials Thianthrene has been detected from the oil produced following steam distillation of the roots of the American herb Porophyllum ruderale (Bolivian coriander). An extract prepared from the powdered roots of the Indian globe thistle (Echinops echinatus Roxb.) also confirmed the presence of thianthrene. Thianthrene finds use as an ingredient of the coolant moderator fluids circulating in a nuclear reactor,1513 and also as a component of extreme pressure lubricants.1514 Mesulfen, a 2,7-dimethyl derivative of thianthrene, finds use in the treatment of scabies-producing mites and in antiacne therapy.
364
2. Six-Membered Heterocycles
Synthesis 1. A convenient method for the synthesis of thianthrene involves heating benzene with sulfur monochloride in the presence of anhydrous aluminum chloride as catalyst.
It was proposed that during the reaction diphenylsulfide was formed as an intermediate, which then slowly reacts with sulfur to form thianthrene.
2. Heating benzene with sulfur dichloride in the presence of aluminum chloride as catalyst also yields thianthrene.
3. Thianthrene in higher yield is obtained by carrying out pyrolysis of diphenyldisulfide.
A free radical mechanism was proposed for the said reaction.1515
4. Reaction of diphenyl disulfide with triethyloxonium fluoroborate or diethoxycarbonium fluoroborate yields thianthrene together with aryl sulfides.1516
5. Pyrolysis of 2-mercaptodiphenyl sulfide yields thianthrene.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
365
6. 2,7-Difluorothianthrene is synthesized by reaction of 4-fluorobenzenethiol with fuming sulfuric acid, followed by treatment with zinc in acetic acid.1517
Physical Properties Thianthrene is a white crystalline nonhygroscopic solid with mp of 156–158°C. It is odorless with a very low pressure. It is insoluble in water but soluble in nearly all organic solvents. Chemical Reactivity 1. Electrophilic substitution reaction: Thianthrene behaves as a normal aromatic compound, and electrophilic substitution reaction takes place preferably at the para position to the sulfur atom. For example, halogenation takes place in a stepwise manner.1518, 1519
2. Alkylation: Liquid-phase tert-butylation of thianthrene with tert-butylalcohol in isooctane was carried out at moderate temperatures (below 100°C) in the presence of large pore zeolites and mesoporous aluminosilicates yielding 2-, 2,6-, and 2,7-di-tert-butyl derivatives.1520
3. Chloromethylation of thianthrene with chloromethyl methyl ether in the presence of anhydrous SnCl4 in chloroform at −20°C yields 2,7-bis(chloromethyl)thianthrene together with a polymeric product.1521
4. Oxidation: Thianthrene on treatment with benzenediazonium salt in glacial acetic acid, is oxidized to thianthrene 5-oxide. The best results are, however, obtained on reaction with 2-and 4-nitrobenzenediazonium sulfate.1522
366
2. Six-Membered Heterocycles
Oxidation of thianthrene with bromine in the presence of alkoxide yields a mono(dialkoxysulfurane) derivative.
Thianthrene on reaction with dilute nitric acid in glacial acetic acid at reflux temperature results in the formation of thianthrene 5-oxide.1523
Reaction of thianthrene with excess sulfuryl chloride yields thianthrene trans-5,10-dioxide.1524
5. Metalation: Thianthrene on reaction with butyllithium in diethyl ether at room temperature afforded a 1-lithio derivative, which was easily transformed to carboxylic acid or a hydroxyl derivative by reaction with dry ice1525 and butylmagnesium iodide,1523 respectively.
Similarly, a number of other 1-substituted thianthrene derivatives were synthesized, as listed in the following diagram.1526
6. Formation of radical cation: Solution of thianthrene in 96%–97% sulfuric acid is paramagnetic and it has been proposed that this is due to the presence of radical cation.1527
Thianthrene perchlorate is of particular interest because it has been used for the synthesis of a number of derivatives.
REFERENCES 367
7. Hydrodesulfuration: Desulfuration of thianthrene in the presence of nickel complexes has been proposed. Two paths were proposed: (Path A) When reaction was carried out with THF and a soluble complex of (2,2′-bipyridyl)(1,s-cyclooctadiene) nickel, dibenzothiophene was the major product (55%) and biphenyl (15%) was the minor product. (Path B) When reaction was carried out in the presence of a novel nickel complex like LiAlH2(THF)n(bpy)Ni, then biphenyl was the major product (15%) and dibenzothiophene (5%) was the minor product.1528, 1529 Benzene was also obtained during the reaction.
8. Ring fission: In a nickel-promoted catalytic reaction, thianthrene is cleaved unsymmetrically by Grignard reagent to afford 1,2-bis(methylthio)benzene and o-xylene.
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2. Six-Membered Heterocycles
Chapman, D. M.; Hester, R. E. J. Phys. Chem. 1997, 101, 3382. Kim, H. Y.; et al. Bioorg. Med. Chem. Lett. 2005, 15, 3207. Yang, W.; Sun, J. Angew. Chem. 2016, 128, 1900. Soc, A. F. J. Phys. Chem. Russe. 1906, 38, 471. Altona, C.; Knobler, C.; Romers, C. Acta 1963, 16, 1217. Kreilein, M. M.; Eppich, J. C.; Paquette, L. A. Org. Synth. 2005, 82, 99. Mazzocchi, P. H.; Bowen, M. W. J. Org. Chem. 1975, 40, 2689. Kanth, J. V. B.; Brown, H. C. Org. Lett. 1999, 1, 315. Richtera, L.; Taraba, J.; Touzin, J. Collect. Czech. Chem. Commun. 2006, 71, 155. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, Structure, Reaction, Syntheses and Applications. Wiley-VCH Verlag, 2003; 369. Hobbs, J. J.; King, F. E. J. Chem. Soc. 1960, 4732. Hansel; et al. Chem. Ber. 1975, 108, 1482. Li, Y.; Wang, C.-L.; Guo, S.-X.; Yang, J.-S.; Xiao, P.-G. Chem. Pharm. Bull. 2008, 56, 1477. Ober, A. G.; Fronczek, F. R.; Fixher, N. H. J. Nat. Prod. 1985, 48, 242. Hahn, H.-G.; Chang, K. H.; Nam, K. D. Bull. Korean. Chem. Soc. 2001, 22, 149. Lahri, S.; Sabraj, V.; Bhat, V.; Jemmis, E. D.; George, M. V. Proc. Indian Acad. Soc. Sec. A 1977, 86, 1. Memedov, V. A.; et al. Chem. Heterocycl. Compd. 2000, 36, 911. Alan, A. R.; Cadogan, J. I. G.; Gosneya, I. J. Chem. Soc. Perkin. Trans. I 1994, 8, 927. Summerbell, R. K.; Umhoefer, R. R. J. Am. Chem. Soc. 1939, 61, 3020. Schroth, W.; Borsdorf, R.; Herzschuh, R.; Seidler, J. Z. Chem. 1970, 10, 147. Boer, F. P.; et al. Adv.in Chem 120; 14. 1973. Lee, H. H.; Denny, W. A. J. Chem. Soc. Perkin Trans. I 1990, 1071. Utkina, N. K.; et al. J. Nat. Prod. 2001, 64, 151. Calder, I. C.; Johns, R. B.; Desmarchelie, J. M. Org. Mass. Spectrosc. 1970, 4, 121. Fukuyama, Y.; et al. Chem. Pharm. Bull. 1989, 37, 349. Fukuyama, Y.; et al. Chem. Pharm. Bull. 1990, 38, 133. Spicer, A.; Denny, A. Anti-Cancer Drug Des. 2000, 15, 453. Cambie, R. C.; Janssen, S. J.; Rutledge, P. S.; Woodgate, P. D. J. Organomet. Chem. 1991, 420, 387. Cambie, R. C.; Clark, G. R.; Rutledge, P. S.; Woodgate, P. D. J. Organomet. Chem. 1996, 507, 1. Gilman, H.; Dietrich, J. J. J. Am. Chem. Soc. 1957, 79, 1439. Ueda, S. J. Pharm. Soc. Jpn. 1963, 83, 657. Szmant, H. H.; Alfonso, L. M. J. Am. Chem. Soc. 1957, 79, 205. Palmar, B. D.; Boyd, M.; Denny, W. A. J. Org. Chem. 1990, 55, 4383. Guan, B.; Wan, P. J. Photochem. Photobiol. A: Chem. 1994, 80, 199. Rayne, S.; Ryan, S.; Wan, P. Photochem. Photobiol. Sci. 2005, 4, 876. Leoni, M. A.; Bettinetti, G. F.; Minoli, G.; Albini, A. J. Org. Chem. 1980, 45, 2331. (a) Kobayashi, K.; Gajurel, C. L. Sulfur Rep. 1986, 7, 123. (b) Grant, A. S.; Faraji-Dana, S.; Graham, E. J. Sulfur Chem. 2009, 30, 135. (c) Chee, G.-L.; Bhattarai, B.; Nash, J. D.; Madec, K.; Hasinoff, B. B.; Brewer, A. D. Can. J. Chem. 2013, 91, 649. Parham, W. E. In: Organic Sulfur Compounds; Kharasch, N., Ed.; Vol. 1; Pergamon Press: New York, 1961; pp 246. Buess, C. M.; Brandt, V. O.; Srivastava, R. C.; Carper, W. R. J. Heterocycl. Chem. 1972, 9, 887. Russell, J. Org. Magn. Reson. 1972, 4, 433. Lahri, S.; Sabraj, V.; Bhat, V.; Jemmis, E. D.; George, M. V. Proc. Indian Acad. Soc. Sec. A 1977, 86, 1. Zilverschoon, A.; Meijer, J.; Vermecr, P.; Brandsma, L. Recl. Trav. Cliint. Pays-Bas 1974, 94, 163. Schroth, W.; Billig, F.; Zschunke, Z. Z. Clreni 1969, 9, 184. Parham, W. E.; Nicholson, I.; Traynelis, V. J. J. Am. Chem. Soc. 1956, 78, 850. Simmons, H. E.; Vests, R. D.; Vladuchick, A.; Webster, O. W. J. Org. Chem. 1980, 45, 5113. Parham, W. E.; Wynberg, H.; Ramp, F. L. J. Am. Chem. Soc. 1953, 75, 2065. Li, Y.; et al. Sci. Sin. Ser. B Eng. Ed. 1988, 31, 1062. Gollnick, K.; Hartmann, H. Tetrahedron Lett. 1982, 2657. Cane, D. J.; Graham, W. A. G.; Vanca, L. Can. J. Chem. 1978, 56, 1538. Brwoie, J. H.; White, P. Y. Org. Mass Spectrosc. 1972, 6, 317. Kalff, H. T.; Romers, C. Acta Crystallogr. 1966, 20, 490. Mitsudera, H.; Kamikado, T.; Uneme, H.; Manabe, Y. Agric. Biol. Chem. 1990, 50, 1723. Mitsudera, H.; Konishi, K. J. Pesticide Sci. 1991, 16, 387. Shingate, B. B.; et al. Chem. Biointerface 2015, 5, 306. Corey, E. J.; Seebach, D. Org. Synth. Coll. 1988, 6, 556. Patney, H. K. Org. Prep. Proc. Int. 1994, 26, 377. Stutz, P.; Stadler, P. A. Org. Synth. Coll. 1988, 6, 169. Tietze, L. F.; Weigand, B.; Wulff, C. Synthesis 2000, 69. Karami, B.; Taei, M.; Khodabakhshi, S.; Jamshidi, M. J. Sulfur Chem. 2012, 33, 65. Martinez, R. A.; et al. J. Label. Compd. Radiopharm. 2014, 57, 338. Corey, E. J.; Seebach, D. Angew. Chem. Int. Ed. 1965, 1075, 1077. Seebach, D.; Beck, A. K. Org. Synth. Coll. 1988, 6, 316. Rigby, H. L.; Neveu, M.; Pauley, D.; Ranu, B. C.; Hudlicky, T. Org. Synth. Coll. 1993, 8, 309. Vedejs, E.; Fuch, P. L. J. Org. Chem. 1971, 36, 366. Stutz, P.; Stadler, P. A. Org. Synth. Coll. 1988, 6, 109.
1505. 1506. 1507. 1508. 1509. 1510. 1511. 1512. 1513. 1514. 1515. 1516. 1517. 1518. 1519. 1520. 1521. 1522. 1523. 1524. 1525. 1526. 1527. 1528. 1529.
FURTHER READING
Orsini, F.; Pelizzoni, F. J. Org. Chem. 1980, 45, 4726. E. Hungerbuehler; R. Naef; D. Wasuth; D. Seebach; H. R. Loosli; A. Wehrli, Helv. Chim. Acta, 63: 1960, 1980. Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147. Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.; Andrews, D. M. Org. Synth. Coll. 2004, 10, 378. Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Org. Synth. 2011, 88, 353. Rowe, I.; Post, B. Acta Crystallogr. 1958, 11, 372. Sharpless, N. E.; Bradley, R. B.; Ferretti, J. A. Org. Magn. Reson. 1974, 6, 115. Meier, H.; Konnerth, U.; Graw, S.; Echter, T. Chem. Ber. 1984, 117, 107. R. O. Bolt; B. J. Fontana; J. R. Wright. U.S. Patent 2,883,331, 1959. Hugel, G. Riv. Combust. 1955, 9, 417. Schonenberg, A.; Mustafa, A. J. Chem. Soc. 1949, 889. Miller, B.; Hans, C. H. J. Org. Chem. 1971, 36, 1513. Edson, J. B.; Knauss, D. M. J. Polymer. Sci. 2004, 42, 6353. Fries, K.; Vogt, W. Liebigs Ann. Chem. 1911, 381, 312. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1955, 77, 5944. Armengol, E.; Orma, A.; Garcla, H.; Primo, J. Appl. Catal. A Gen. 1997, 149, 411. Dronov, V. I.; Nigmatullina, R. F. Russ. Chem. Bull. 1976, 25, 2609. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1956, 78, 2163. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1957, 79, 991. Savin, E. D.; Nedelkin, V. I.; Zverev, Z. V. Chem. Hetrocycl. Compd. 1997, 33, 333. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1957, 79, 208. Sheikh, M. C.; et al. Synthesis 2014, 46, 42. Murata, Y.; Shine, H. J. J. Org. Chem. 1969, 34, 3368. Eisch, J. J.; Hellenbeck, L. E.; Han, K. I. J. Am. Chem. Soc. 1986, 108, 7763. Bird, C. W.; Hollins, E. M. J. Organomet. Chem. 1965, 4, 245.
Further Reading 1530. 1531. 1532. 1533. 1534.
Paudler, W. W.; Barton, J. M. J. Org. Chem. 1966, 31, 1720. Hammond, G. S.; et al. J. Am. Chem. Soc. 1964, 86, 3103. Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R. Org. Lett. 2009, 11, 991. Lee, L. F.; Howe, R. K. J. Org. Chem. 1984, 49, 4780. Tomita, M. J. Pharm. Soc. Jpn. 1934, 54, 891.
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2 Six-Membered Heterocycles 2.1 STRUCTURE AND REACTIVITY ASPECTS Replacement of the methine (CH) group of benzene and methylene group (CH2) in cyclohexane by a heteroatom such as nitrogen, sulfur, and oxygen gives an important class of six-membered heterocyclic compounds. The introduction of nitrogen in benzene gives an important compound called pyridine. The introduction of nitrogen, however, does not alter the aromatic behavior of the resulting ring. Similarly, the replacement of methylene by NH in cyclohexane results in a saturated heterocyclic compound called piperidine.
Six membered nitrogen heterocycles.
Introduction of oxygen in benzene results in heterocycles where oxygen is divalent, the lone pair is involved in bonding, and the oxygen atom carries a positive charge. The resulting compound is called pyrylium salt and is not very stable, though it possesses some aromatic character. The other oxygen-containing six-membered heterocycles are 2H-pyran, 4H-pyran, 3,4-dihyro-2H-pyran, and tetrahydropyran.
Six membered oxygen heterocycles.
Similarly, sulfur analogs are designated thiopyrylium salts, thiopyran, 1,4-dithiin, and 1,3-dithirane.
Six membered sulfur heterocycles.
2.1.1 Six-Membered Nitrogen Heterocycles Insertion of the electronegative nitrogen into the benzene ring causes significant polarization of the molecule, which not only leads to the generation of more resonating structures but additionally stabilizes those structures in which the negative charge is on the nitrogen atom. The resonance energy of pyridine was found to be 31.9 kcal/mol.
The Chemistry of Heterocycles. https://doi.org/10.1016/B978-0-12-819210-8.00002-3
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© 2019 Elsevier Ltd. All rights reserved.
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2. Six-Membered Heterocycles
N
N
N
N
N
Resonating structures of pyridine.
The importance of charged structures in the resonance hybrid is well reflected by the high value of the dipole moment (2.26 D). The resonance hybrid structures of pyridine are well supported by the bond length values; the CC bond length values are intermediate between those known for a single bond (154 pm) and a double bond (134 pm). The CN bond length is shorter than the CC bond length but again is intermediate between the CN single bond (147 pm) and the CN double bond (125 pm). The smaller CN bond length value leads to slight deviation of bond angle values of a perfect hexagon (120 degrees).
Bond length and bond angles of pyridine.
Though pyridine is isoelectronic with benzene the presence of the nitrogen atom in the ring influences its chemical reactivity. Due to the presence of electronegative nitrogen in the ring, electron density at the 2,4- and 6-positions is decreased, whereas electron density is greater at nitrogen and at position 3. Pyridine is basic in nature but a weaker base compared to its saturated analog. The basic properties of pyridine are largely due to the presence of a lone pair of electrons on nitrogen. As a result, it readily forms pyridinium salts on reaction with acids. Lewis acids, which are good electron acceptors, react with pyridine to form tetrahedral salts. The electronegative nitrogen of pyridine causes significant polarization of the molecule, and as a result there is electron withdrawal from the ring toward the nitrogen (see resonance structures). The ring carbons are electron deficient and thus highly deactivated toward electrophilic substitution reactions. In addition, electrophilic substitution reactions take place under acidic conditions, which first protonate the nitrogen atom resulting in the formation of pyridinium salts. The resultant positive charge on nitrogen causes the electrons from the ring to drift toward it, thereby deactivating the C-2, C-4, and C-6 carbon atoms. Hence, electrophilic substitution reaction takes place, if at all, only under extreme conditions and that too at C-3 and C-5 carbon atoms.
2.1.2 Six-Membered Oxygen Heterocycles In the pyrylium cation the positively charged oxygen still has a lone pair of electrons in an sp2 hybrid orbital, which is in the plane of the ring. Hence the pyrylium cation is aromatic and a number of resonating structures are possible with a positive charge on C-2, C-4, and C-6.
Resonating structures of pyrylium cation.
As the pyrylium cation is aromatic, it should be stable, but it is highly reactive and does not undergo electrophilic substitution reaction. Instead, the pyrylium cation reacts rapidly with nucleophiles to produce adducts, which are not aromatic. 2H- and 4H-pyrans contain a methylene group in the ring; as a consequence they lack the conjugated double bond characteristic. Hence they are unsaturated, closed chain compounds devoid of aromatic character.
2.1 Structure and Reactivity Aspects
5
2.1.3 Benzene-Fused Nitrogen Heterocycles A pyridine ring fused with a benzene ring gives rise to new heterocyclic compounds like quinoline, isoquinoline, and quinolizinium salt.
Benzene fused nitrogen heterocycles.
These compounds possess 10π electrons, are aromatic in nature, and undergo electrophilic substitution reactions quite readily. Quinoline and isoquinoline are weakly basic because the lone pair of electrons on nitrogen is not involved in formation of delocalized π molecular orbital. As a result, both these compounds also undergo nucleophilic substitution reactions on the heterocyclic ring. Quinolizinium salts, however, do not undergo electrophilic substitution reaction. Nevertheless, they undergo nucleophilic substitution at C-4.
2.1.4 Benzene-Fused Oxygen Heterocycles A six-membered oxygen heterocyclic ring fused with a benzene ring gives rise to new heterocyclic compounds like 2H-chromene, 4H-chromene, chroman, 1-benzopyrylium salt, and 2-benzopyrylium salt.
Benzene fused oxygen heterocycles.
2H- and 4H-chromenes, because of the presence of a double bond in the heterocyclic ring, undergo addition as well as cycloaddition reactions. The benzopyrylium salt in which the oxygen carries a positive charge makes the ring aromatic. The positive charge of the benzopyrylium salt is distributed unevenly over the heterocyclic ring. As a result, the following resonance structures are possible. The benzopyrylium salts are extremely susceptible to attack by nucleophilic reagents but are inert to attack by electrophilic reagents.
Resonating structures of benzopyrylium cation.
2.1.5 Six-Membered Heterocycles With Two Heteroatoms When two carbon atoms of the benzene ring are replaced by nitrogen, oxygen, and sulfur, six-membered heterocycles with two heteroatoms result. Diazines are six-membered aromatic heterocyclic compounds with two nitrogen atoms in the ring. There are three isomers of diazines: pyridazine (1,2-diazine), pyrimidine (1,3-diazine), and pyrazine (1,4-diazine).
Diazine isomers.
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2. Six-Membered Heterocycles
There are four bicyclic variants of these diazenes in which a benzene ring is fused to the diazine moiety. These bicyclic diazines, commonly called the benzodiazines, are still known by their trivial names and are designated as cinnoline (benzo[c]pyridazine), phthalazine (benzo[d]pyridazine), quinazoline (benzo[d]pyrimidine), and quinoxaline (benzo[e]pyrazine).
Benzodiazine isomers.
Dioxanes are six-membered, saturated, heterocyclic compounds containing two oxygen atoms in the ring. There are three isomers of dioxane and their names indicate the position in which hydrogen atoms of the cyclohexane ring have been replaced by oxygen, namely 1,2-dioxane, 1,3-dioxane, and 1,4-dioxane. 1,4-Dioxin is a six-membered heterocyclic, which contains two carbon-carbon double bonds and four carbon-oxygen bonds. This heterocyclic ring, which is made up of 8π electrons, is nonplanar and is classified as nonaromatic.
Six membered heterocycles with two oxygen atoms.
Structures equivalent to dioxanes in which oxygen atoms have been replaced by sulfur are referred to as dithianes, whereas structures analogous to dioxins are referred to as dithiins.
Six membered heterocycles with two sulfur atoms.
1,3-Dioxane and dithiane are cyclic acetals and thioacetals and they are commonly used as protecting groups for aldehydes and ketones.
2.1.6 Tautomerism in Six-Membered Heterocycles The hydroxyl derivatives of pyridine are both weak acids and bases and thus can exist as zwitterions. However, the 2- and 4-hydroxyl derivatives of pyridine are stabilized by mesomerism with uncharged canonical structures, which are thus more stable than the zwitterions. Thus 2- and 4-hydroxyl derivatives of pyridine exist chiefly in their carbonyl tautomeric form commonly known as 2- and 4-pyridones, respectively. The pyridone forms are favored in the solid phase or in polar medium, whereas their hydroxyl derivatives are the predominant tautomer in very dilute solutions, in nonpolar solvent or in the gas phase.
Tautomeric structures of 2-hydroxy and 4-hydroxypyridine.
2.2 Importance in Natural Products, Medicines, and Materials
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The preference for the two pyridones to exist in the amide form is the presence of a strong carbonyl group and still the aromaticity of the compound is preserved. There are two electrons each on the two carbon-carbon double bonds and one lone pair on the trigonal nitrogen, and delocalization of the lone pair of electrons on nitrogen proves the point.
2.2 IMPORTANCE IN NATURAL PRODUCTS, MEDICINES, AND MATERIALS Six-membered heterocycles are derivatives of benzene or cyclohexane in which one of the carbon atoms has been replaced by a heteroatom like nitrogen, oxygen, and sulfur. These heterocycles are not only widely distributed in nature but are also the major components of biological molecules like RNA and DNA. Nucleic acid in the form of DNA and RNA, which control cellular function and heredity, have bases like adenine, guanine, uracil, thymine, and cytosine, which are important purine and pyrimidine derivatives. A number of compounds containing six-membered heterocyclic nuclei play an important part in metabolism. For example, vitamin B3 (nicotinamide) and vitamin B6 (pyridoxine) are required for the biosynthesis of nicotinamide adenine dinucleotide phosphate (NADP+) and pyridoxal phosphate (PLP). A six-membered heterocyclic nucleus is not only present in drugs, vitamins, natural products, biomolecules, and biologically active compounds exhibiting antitumor, antiinflammatory, antifungal, antibacterial, antidepressant, anti-HIV, antimicrobial, antimalarial, and antidiabetic activity but they are also the key structural unit of pharmaceutical drugs and agrochemicals available in the market. A number of six-membered heterocycles also find application in material science such as dye stuffs, fluorescent sensors, brightening agents, and analytical reagents.
2.2.1 Nitrogen Heterocycles Nitrogen heterocycles like pyridine and its derivatives, piperidine, quinoline, isoquinoline, diazines, and triazines, are the most developable heterocyclic rings and have been widely used in drug design. They are structurally very important because these nuclei are present in a large number of drugs, which offer a broad range of biological as well as pharmaceutical activities. A simple glance at the Food and Drug Administration database shows that nearly 60% of the drugs are nitrogen-based heterocycles. A list of a few important, biologically active compounds, drugs, pharmaceutical agents, insecticides, pesticides, etc. are shown in the following diagram (for details consult the individual chapter).
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2. Six-Membered Heterocycles
2.2 Importance in Natural Products, Medicines, and Materials
9
Drugs, insecticide, pesticide and herbicides containing nitrogen heterocycles.
2.2.2 Oxygen Heterocycles Oxygen-containing heterocycles, in which one or more oxygen atoms are present in the ring, constitute an important class of heterocyclic compound due to their natural abundance and diverse biological activity. They are usually classified as monocyclic oxygen heterocycles and fused oxygen heterocycles. Some of the common six-membered monocyclic oxygen heterocyclic compounds are dioxanes, pyrans, dioxins, tetrahydropyran, etc. For fused heterocycles, examples include chromenes, chromans, coumarins, etc. A number of oxygen heterocycles have the potential to be used as solvents in organic reactions. For example, tetrahydropyran has been found to be an excellent solvent for organic as well as organometallic reactions. Oxygen heterocycles also form the basis of sugar chemistry and many of their derivatives have shown potential to be used in pharmaceuticals as drugs to treat certain types of diseases. Many natural and synthetic six membered and their fused counterparts are known and find wide application in the treatment of some deadly diseases. A list of a few of these biologically active compounds is shown in the following diagram (for details consult the individual chapter).
Drugs containing oxygen heterocycles.
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2. Six-Membered Heterocycles
2.2.3 Sulfur Heterocycles Sulfur heterocycles that exist as isolated and fused systems are regarded as thioethers, alkylaryl, and diarylthioethers. Some of the common examples are thiane, dithiane, and thianthrene. These sulfur heterocycles are determinants in many biological systems and are often known to form metal complexes with metal ions. A few biologically active sulfur heterocycles are shown in the following diagram (for details consult the individual chapter).
2.3 SIX-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH ONE NITROGEN ATOM 2.3.1 Pyridine Pyridine, also called azabenzene, is a six-membered basic heterocycle consisting of five carbon atoms and one nitrogen atom. It is structurally related to benzene with one of the methine groups (CH) of benzene is replaced by nitrogen. The name pyridine is derived from the Greek word for fire pyr and the suffix idine used to signify the aromatic base. Pyridine was first discovered by Scottish chemist Thomas Anderson in 1849 as one of the constituents of bone oil.
Compounds containing the pyridine nucleus play an important part in metabolism. For example, vitamin B3 (nicotinamide) and vitamin B6 (pyridoxine) are required for the biosynthesis of NADP+ and PLP. A number of pyridine-based compounds are of commercial interest because they are easily available in the market as drugs and agroproducts such as herbicides, insecticides, fungicides, and plant growth regulators.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
Natural products, drugs, herbicide and vitamins containing pyridine nucleus.
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2. Six-Membered Heterocycles
Structural and Reactivity Aspects1a 1. Structure of pyridine The structure of pyridine is quite similar to benzene, except that one of the methine groups (CH) of the ring has been replaced by nitrogen. The cyclic structure of pyridine is thus made of five carbon atoms and one nitrogen atom, each of which is sp2 hybridized. Because the lone pair of electrons on nitrogen is not involved in the ring system, it is readily available for protonation. Thus pyridine behaves as a tertiary base. Like benzene, pyridine is also planar but the ring system is slightly distorted. Insertion of the electronegative nitrogen into the benzene ring causes significant polarization of the molecule, which not only leads to the generation of more resonating structures but additionally stabilizes those structures in which the negative charge is on the nitrogen atom. The resonance energy of pyridine was found to be 31.9 kcal/mol.
Resonating structures of pyridine.
The importance of charged structures in the resonance hybrid is well reflected by the high value of the dipole moment (2.26 D). The resonance hybrid structures of pyridine are well supported by the bond length values. The CC bond length values are intermediate between those known for the single bond (154 pm) and double bond (134 pm). The CN bond length is shorter than the CC bond length but again intermediate between the CN single bond (147 pm) and CN double bond (125 pm). The smaller CN bond length value leads to slight deviation of bond angle values of a perfect hexagon (120 degrees) (Fig. 2.1).
FIG. 2.1 Bond length and bond angles.
2. Molecular orbital structure of pyridine The nitrogen atom of pyridine is sp2 hybridized. It has three sp2 hybrid orbitals and one unhybridized p orbital perpendicular on the hybrid orbitals. Two of the sp2 hybrid orbitals contain one electron each, whereas the third hybrid orbital contains a lone pair of electrons. The five carbon atoms of the pyridine are also sp2 hybridized and each contains three sp2 hybrid orbitals with one electron each and one unhybridized p orbital. Two hybrid orbitals of nitrogen are involved in bond formation with two adjacent carbon atoms, C-2 and C-6, forming two sp2–sp2 CN sigma bonds. Each of the three carbon atoms, C-3, C-4, and C-5, is bonded to two adjacent carbon atoms, thus forming five sp2–sp2 CC sigma bonds. Each of the five carbon atoms still has one hybrid orbital, which overlaps with the 1s orbital of hydrogen forming five CH sigma bonds. An unhybridized 2p orbital, which is perpendicular to the plane of the sp2 orbital, still remains on each sp2-hybridized carbon and nitrogen atom. These unhybridized 2p orbitals can overlap with the other two neighboring atoms in two possible ways (Fig. 2.2), resulting in the formation of three π molecular orbitals.
FIG. 2.2 Two possible sideways overlap of unhybridized 2p orbitals.
The overlapping of these unhybridized p orbitals results in the formation of a continuous π ring system, which encompasses all the six atoms (five carbon and one nitrogen) containing all the six π electrons. As a result, the six π electrons are delocalized over all six atoms (Fig. 2.3). As each p orbital consists of two lobes, this delocalization acquires two doughnut-shaped electron clouds, one of which lies above and the other below the plane of the ring.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
13
FIG. 2.3 pi electron cloud above and below the plane of the ring.
3. Spectroscopic data1a Due to the presence of electronegative nitrogen atom in the aromatic ring, the α-hydrogen and α-carbon atoms experience a strong deshielding effect. The typical 1H and 13C NMR chemical shift values of pyridine are given in the following table. H and 13C NMR spectral data of pyridine
1
1
H NMR δ (ppm)
13 C NMR δ (ppm)
H-2/H-6: 8.5 9 H-3/H-5: 7.38 H-4: 7.75
C-2/C-6: 149.8 C-3/C-5: 123.6 C-4: 135.7
The UV spectrum of pyridine in ethanol shows two absorption bands at 251 and 270 nm. The first band is due to π→π* transition, whereas the second one is due to n→π* transition. Synthesis 1. Industrially, pyridine is manufactured by aerobic gas phase condensation of crotonaldehyde, formaldehyde, and ammonia.
2. Chichibabin pyridine synthesis1b–d: This reaction is named after Aleksei Chichibabin, a Russian organic chemist, and is still being used in the industry. The reaction involves condensation of an aldehyde, ketone, α,βunsaturated carbonyl compound, or any combination of the foregoing with ammonia or an ammonia derivative under pressure.
Acetaldehyde and formaldehyde undergo Knoevenagel-type condensation forming acrolein, which is then condensed with acetaldehyde and ammonia into dihydropyridine and finally to pyridine with the aid of a solid-state catalyst.
3. [2 + 2 + 2] cycloaddition reaction-Bonnemann cyclization: The first paper concerning acetylene heterocyclization with nitriles in the presence of cobalt complex as a catalyst was reported to obtain substituted pyridine2 in 23% yield by Japanese researchers. This cycloaddition reaction later came to be known as
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2. Six-Membered Heterocycles
Bonnemann cyclization after the German chemist Professor H. Bonnemann. This reaction was catalyzed by a low-valence Co complex formed in situ by the reduction of compounds of di- or trivalent cobalt with the use of NaBH4, BuLi, EtMgX, Hg, Li, LiH, and LiAlH4, leading to the construction of monosubstituted pyridine3 with high atom efficiency.3 Another important feature of this reaction is that acetylene and nitriles are efficiently co-cyclized under mild photochemical conditions in the most environmentally friendly solvent, water.
According to the proposed mechanism, oxidative coupling of alkyne with the catalyst would generate the unsaturated cobalt-cyclopentadiene complex A, which then coordinates with nitrile to give nitrile complex B, which subsequently transforms to metallocycloheptatriene C or intermediate D, finally yielding substituted pyridine derivative.4
Cobalt-catalyzed synthesis of pyridines from chiral nitriles and symmetrical alkynes has also been reported5 in good yields. The [2+2+2] cycloaddition of alkynes and nitriles has also been carried out efficiently for the construction of substituted pyridines6 in the presence of rhodium-(I) complexes as catalyst.
The cyclotrimerization of acetylene and hydrogen cyanide over a red-hot iron tube to yield pyridine7 was first observed by Sir William Ramsay.
Since then, arene-iron complexes, which are isoelectronic with CpCo species, have been used for the synthesis of substituted pyridine derivatives.8
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
15
Transition metals like Ti and Zr have also been used for the synthesis of pyridine derivatives via [2+2+2] cycloaddition of alkynes and nitriles.9 The reaction involves formation of dialkoxytitanacyclopentadiene from the acetylenes and the divalent titanium alkoxide (η2-propene)Ti(O-i-Pr)2 (generated in situ from Ti(O-i-Pr)4 and i-PrMgCl). Addition of a third alkyne gives a single aryl titanium compound and the addition of a nitrile gives a single metalated pyridine derivative, which is easily demetalated by hydrolytic workup.
A titanium-mediated [2+2+2] pyridine synthesis involving the reaction of an alkyne, a nitrile, and isopropyl magnesium chloride with titanium isopropoxide has also been reported.10 It has been observed that metallocyclopentadienes are formed by the coupling of 2 mol of alkynes with nitriles, leading to the generation of a single pyridine derivative. However, if two different alkynes and a nitrile are used, a mixture of regioisomers is obtained. A method has been reported in which aza zirconacyclopentadiene prepared in situ from an alkyne and nitrile reacts with a different alkyne to afford a single isomer of pyridine.11
4. [5 + 1] Condensation reaction: Condensation of a δ-dicarbonyl compound with ammonia or any other suitable nitrogen source led to the construction of pyridine derivatives.
Several variations of this method have been developed.12 These 1,5-dicarbonyl compounds have been prepared13 by a variety of methods, such as ozonolysis of 1,6-diene.
16
2. Six-Membered Heterocycles
A novel method for the synthesis of substituted pyridine has been reported.14 The reaction involves zinc triflatepromoted [1+5] cycloaddition of isonitrile with N-formylmethyl-substituted enamide, facile aerobic oxidative aromatization, and intermolecular acyl transfer from pyridinium nitrogen to 5-hydroxy oxygen followed by acylation of the 4-amino group by acyl chloride yielding 2-substituted-4-acylamino-5-acyloxypyridines.
5. From enamines: Suitably substituted enamines under acidic and basic conditions undergo cyclization to yield pyridine derivatives.
Tetrasubstituted pyridines are obtained by treating dienones with N-bromosuccinimide. 6. Hantzsch synthesis: This synthesis is also known as Hantzsch pyridine synthesis or Hantzsch dihydropyridine synthesis, and is a reaction reported by the German chemist Arthur Rudolf Hantzsch in 1881. This is a multicomponent synthesis, involving a reaction between an aldehyde, 2 equivalents of β-dicarbonyl compound, and ammonia or any appropriate amine.15 The initial product of the reaction is a dihydropyridine derivative, which on subsequent oxidation yields pyridine. The driving force for the second step is aromatization and it can easily be carried out with nitric acid, ferric chloride, manganese dioxide, and potassium permanganate.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
17
The initial product of the reaction is 1,4-dihydropyridine, also called Hantzsch product, and is important because of its structural resemblance to the reduced nicotinamide adenine dinucleotide, which has interesting biological activity as an antihypertensive agent. Since then a number of antihypertensive agents of this class of compounds have been synthesized.16
Antihypertensive agents containing 1,4-dihydropyridine nucleus.
A clean and effective one-pot procedure for the synthesis of 1,4-dihydropyridine via Hantzsch reaction in water without the use of catalyst and/or organic solvent has been reported.17 Hantzsch dihydropyridine synthesis has also been carried out in a microwave flow reactor.18 Mechanism: The first step is visualized as proceeding through a Knoevenagel-type condensation reaction leading to the generation of an intermediate I. In the next step the second intermediate, an ester enamine II, is produced by the condensation of a second equivalent of β-ketoester with ammonia.
Condensation between the two intermediates leads to the generation of a dihydropyridine derivative.
18
2. Six-Membered Heterocycles
7. Guareschi synthesis: This reaction, which is a modification of Hantzsch synthesis, is named after the Italian chemist Icilio Guareschi and is also known as a Guareschi-Thorpe reaction. The reaction deals with the synthesis of pyridine derivatives by condensation of an amide of cyanoacetic ester (a primary amide) with acetoacetic ester in the presence of ammonia.19
This method has been used in the synthesis of ethionamide, an antibiotic prodrug used for the treatment of tuberculosis.
8. Boger reaction: This is a hetero [4+2] cycloaddition reaction named after its inventor Dale L. Boger,20 an American medicinal and organic chemist. The process involves the reaction of an enamine (generated in situ from a ketone and an amine) with 1,2,4-triazine to form substituted pyridine derivatives.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
19
The mechanism involves reaction of ketone with an amine (like pyrrolidine) leading to the generation of enamine, which undergoes a hetero Diels-Alder reaction with 1,2,4-tirazine. The initial adduct formed expels nitrogen followed by rearomatization and extrusion of amine leading to the formation of substituted pyridines.
9. Bohlmann-Rahtz pyridine synthesis: This is a cycloaddition reaction reported21 by H. Bohlmann and D. Rahtz in 1957 for the synthesis of trisubstituted pyridine derivatives. The reaction involves Michael addition of ethynyl ketone with enamine leading to the generation of aminoketone, which after cyclodehydration afforded the trisubstituted pyridine derivatives.
However, no mechanistic studies have been carried out, but the intermediate isolated and characterized by 1H NMR points toward the following mechanism. In the first step of the reaction, Michael addition of ethynyl ketone to enamine and subsequent proton transfer led to the generation of aminoketone as intermediate, which on heating at higher temperatures facilitated E/Z isomerization and cyclodehydration to produce substituted pyridines.
The Bohlmann-Rahtz reaction has been used for the synthesis of thiopeptide antibiotic.22 Some of the drawbacks of the Bohlmann-Rahtz reaction, like purification of the intermediate and high temperature for cyclodehydration, have been overcome by Bagley and coworkers.23
Synthesis of trisubstituted pyridine in a continuous flow microreactor involving the use of Brønsted acid catalyst, without the isolation of intermediate by the Bohlmann-Rahtz procedure, has been reported.24 10. Krohnke pyridine synthesis: This is a reaction named after Fritz Krohnke between α-pyridinium methyl ketone salts and α,β-unsaturated carbonyl compounds, which led to the construction of pyridine derivatives.25
20
2. Six-Membered Heterocycles
A simple and efficient synthesis of 2,4,6-triarylpyridines by Kroknke procedures involving reaction between chalcones and ammonium acetate under solvent-free conditions has been reported.26 Mechanism:
11. Ciamician-Dennstedt rearrangement: This is a [2+1] cycloaddition reaction in which pyrrole reacts with dichlorocarbene under basic conditions (by heating sodium chloroacetate) yielding a bicyclic product, which after elimination of hydrogen chloride produced 3-chloropyridine.27
12. Diels-Alder reaction: Oxazoles and acyclic acid undergo Diels-Alder reaction, leading to the generation of an adduct, which under acidic conditions eliminated a molecule of water yielding pyridine 4-carboxylic acid derivative.
Oxazole also reacts with acrylonitrile in the presence of triethylamine to yield 4-cyanopyridine, which on hydrolysis yields pyridine.
13. By ring transformation reactions: A new approach for the synthesis of di- and trisubstituted pyridines has been developed28a by heating a mixture of 6-aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles with ammonium acetate or ammonium carbonate in pyridine at 120°C for 4 h. Disubstituted pyridines, 2-amino-6-arylpyridines were obtained by knocking out the 4-methylthio group through hydrogenation in the presence of Raney Ni as catalyst in ethanol for 6 h.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
21
Tetrasubstituted pyridines have also been obtained28b by the base-catalyzed ring transformation of 6-aryl-4- methylthio-2H-pyran-2-one-3-carbonitriles by using cyanamide as a nitrogen nucleophile. Base-catalyzed ring transformation of methyl 6-aryl-4-methylthio-2H-pyran-2-one-3-carboxylates by formamidine acetate in dimethylformamide using powdered KOH as a base at room temperature gave methyl 6-aryl-4- methylthiopyridine-3-carboxylate in more than 65% yields after usual workup and purification.28c
The precursor 6-(4-pyridyl)-4-methylthio-2H-pyran-3-carbonitrile is highly versatile for the construction of dipyridinyl, terpyridinyl, and polypyridinyl with a phenyl spacer by selecting mono- and diacetyl ketones as a source of carbanion for successive base-catalyzed ring transformation28d, e reactions.
22
2. Six-Membered Heterocycles
Pyrillium salts on reaction with ammonia yield pyridine derivatives.
14. [3 + 3] Condensation reaction: A [3+3]-type condensation reaction of o-acetyl ketoximes and α,β-unsaturated aldehydes that are synergistically catalyzed by salts of copper(I) and an amine leading to the synthesis of substituted pyridines is reported. This reaction allows modular synthesis of a variety of substituted pyridines under mild conditions.28f
15. K.T. Potts and his coworkers prepared symmetrical and asymmetrical 2,6-disubstituted 4-methylthiopyridines by enolate addition of ketone to α-oxoketene dithioacetals in the presence of potassium tert-butoxide to afford 1,5-diketones, which on further reaction with ammonium acetate in acetic acid delivered 2,6-diaryl 4-methylthio pyridines.29
Physical Properties Pyridine is a colorless hygroscopic liquid with a boiling point (bp) of 115.2°C and a characteristic unpleasant odor. It is miscible with water and virtually all organic solvents. It is used as a polar, basic, low reactive solvent for a number of condensation, dehalogenation, elimination, and esterification reactions. Chemical Reactivity Though pyridine is isoelectronic with benzene the presence of a nitrogen atom in the ring influences its chemical reactivity. Due to the presence of electronegative nitrogen in the ring, the electron density at the 2,4- and 6-positions is decreased, whereas electron density is greater at nitrogen and at position 3. 1. Electrophilic reaction at nitrogen: Pyridine is basic in nature but is a weaker base compared to its saturated analog. The basic properties of pyridine are largely due to the presence of a lone pair of electrons on nitrogen. As a result, it readily forms pyridinium salts on reaction with acids. Lewis acids, which are good electron acceptors, react with pyridine to form tetrahedral salts. For example, pyridine reacts with aluminum chloride to form a complex in which the unshared pair of electrons on nitrogen fills the sp2 orbital of aluminum.
Some of these pyridinium salts are crystalline, quite stable, and are of synthetic importance, for example, pyridinium polyhydrogen fluoride is a convenient source of hydrogen fluoride for the addition across carbon-carbon double bonds and for conversion of alcohols to alkyl halides.30 Pyridinium chlorochromate (Corey reagent) and pyridinium dichromate are good oxidizing agents, chiefly used for the oxidation of alcohols.
Some important pyridinium salts.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
23
Pyridinium tribromide, which finds use as a brominating agent, is obtained by first treating pyridine with hydrogen bromide followed by treating the pyridine hydrogen bromide with bromine. This complex is used as a brominating agent.
Similarly, pyridine sulfur trioxide complex, which finds use as a sulfonating agent is obtained by treating pyridine with sulfur trioxide.31
Amination of nitrogen is achieved by treating pyridine with hydroxylamine O-sulfonic acid followed by acid treatment with hydriodic acid, producing 1-aminopyridinium iodide.32
Pyridinium salts with alkyl and acyl groups bonded to nitrogen are formed by reaction of pyridine with alkyl, acyl, or sulfonyl halides.33 These N-acyl salts have been found to serve as acyl transfer agents for the synthesis of esters and amides.
Pyridine also reacts with peracids, or a mixture of hydrogen peroxide and acids, yielding pyridine-N-oxide, which is of immense synthetic importance. 2. Electrophilic substitution reactions at carbon: The electronegative nitrogen of pyridine causes significant polarization of the molecule, and as a result there is electron withdrawal from the ring toward the nitrogen (see resonance structures). The ring carbons are electron deficient and thus highly deactivated toward electrophilic substitution reactions. In addition, electrophilic substitution reactions take place under acidic conditions, which first protonate the nitrogen atom resulting in the formation of pyridinium salts. The resultant positive charge on nitrogen causes the electrons from the ring to drift toward it, thereby deactivating C-2, C-4, and C-6 carbon atoms. Hence electrophilic substitution reaction takes place, if at all, only under extreme conditions also at C-3 and C-5 carbon atoms. This can be seen from the following resonating structures in which the electronegative nitrogen does not acquire a positive charge (structures I and II are least stable), hence the transition state leading to substitution at C-3 is energetically more favorable.
24
2. Six-Membered Heterocycles
From the foregoing resonating structures it can be seen that when the attack takes place at C-2 and C-4 there are two resonating structures marked I and II, respectively, in which there is a positive charge on the electronegative nitrogen atom. These structures are particularly very unstable. However, there is no such structure in which the attack takes place at C-3. Thus the carbocations generated from attack at C-3 are relatively more stable in comparison to carbocations generated from attack at the C-2- and C-4-positions. Thus electrophilic substitution takes place at C-3. (a) Halogenation: Direct halogenation of pyridine does not take place. However, bromination takes place in the presence of oleum at 130°C with the intermediate formation of pyridinium 1-sulfonate.34
Chlorination can also be carried out in the presence of aluminum chloride at 200°C.35
Iodination of pyridine via α-metalation using lithium di-tert-butyltetramethylpiperidino-zincate (TMP-zincate) takes place at room temperature using iodine as an electrophile.
(b) Sulfonation: Pyridine does not undergo sulfonation in the presence of concentrated sulfuric acid or oleum. However, heating pyridine with fuming sulfuric acid with a catalytic amount of mercuric sulfate at 230°C gives a 70% yield of pyridine 3-sulfonic acid.36
(c) Nitration: 3-Nitropyridine in low yield is obtained37 by heating pyridine with a mixture of nitric acid and sulfuric acid at 300°C. 3-Nitropyridine in high yield is obtained by carrying out nitration with
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
25
dinitrogen pentoxide in organic solvent, followed by treating the reaction mixture with aqueous SO2/ H2SO3− solution38
(d) Mercuration: Pyridine on heating at 180°C with mercuric acetate gave a salt, which rearranged to 3-pyridylmercuric acetate. The mercury derivative is then converted to pyridine mercuric chloride39 and finally to 3-bromopyridine40on reaction with bromine.
(e) Alkylation: 4-Ethylpyridine has been synthesized41 by heating pyridine with zinc dust and acetic anhydride. 4-Ethylpyridine was synthesized42 earlier by heating N-ethylpyridinium iodide in a sealed tube at 300°C. Heating pyridine with ethyl iodide43 or by distilling 4-ethylpyridine carboxylic acid with lime44 yielded pyridine.
(f) Acylation: Pyridine and related heterocycles cannot be directly acylated because of the presence of nitrogen, which deactivates the ring for attack by cations. Hence Friedel-Crafts and related reactions fail. However, heterogenous bimolecular reduction of pyridine with metal has led to the generation of C-acylated derivatives. The process involves treating pyridine with aluminum or magnesium metal and ethyl benzoate in the presence of mercury. The acylation is proposed to take place by the following mechanism.45
26
2. Six-Membered Heterocycles
3. Nucleophilic substitution reaction: Because pyridine contains an electronegative nitrogen in the ring, it undergoes nucleophilic substitution reaction with strong nucleophiles like amide ions, hydroxides, or organolithium compounds. The substitution takes place preferably at C-2 or C-4 and less readily at C-3. In addition, it is important to note that the last step of the nucleophilic substitution reaction is different from the electrophilic substitution reaction. In the electrophilic substitution reaction there is loss of proton, whereas in the nucleophilic substitution reaction the hydrogen is lost as hydride.
(a) Chichibabin reaction: This is a nucleophilic reaction used for the amination of pyridines, quinolines, and other nitrogen-containing heterocycles with alkali metal amides. Amination takes place at the α-position because of the close proximity of this position to the nitrogen, and the sigma complex formed is easily stabilized. The reaction involves heating pyridine with sodium amide in toluene at 100°C.
Mechanism: The nucleophile attacks the 2-position of the heterocyclic ring followed by loss of the hydride ion and subsequent elimination of the hydrogen molecule with the formation of sodium salt of 2-aminopyridine, which on treatment with water yielded 2-aminopyridine.
(b) Pyridine reacts with hydroxide ion at high temperatures to yield 2-pyridone, the stable isomer of 2-hydroxypyridine.
Reaction of pyridine with phenyllithium in dry ether at 110°C for 8 h under stirring produced 2-phenylpyridine.46
Nucleophilic substitution reaction takes place more readily47when the pyridine ring is already substituted with electron-withdrawing groups like nitro, cyano, or halogens.
The C-2 selective alkenylation of pyridine is achieved by activating the pyridine ring in situ through the addition of a catalytic quantity of mild Lewis acid like dimethylzinc or trimethylaluminum. When dimethylzinc is used as a
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
27
catalyst, C-2 monoalkenylated product is obtained, whereas in the presence of trimethylaluminum as catalyst, C-2 alkenylated product is obtained.48
4. Reduction reactions: Pyridine or its derivatives are more easily reduced as compared to benzene. Reduction to piperidine has been carried out by numerous methods like electrolysis49, 50 and hydrogenation over palladium (H2-Pd), but reduction with lithium triethylborohydride is most efficient.
Selective reduction of pyridine to 1,4-dihydropyridine has also been carried out under Birch reduction conditions.
Formation of 1,2-dihydropyridine was accomplished by reduction of pyridine with sodium borohydride in the presence of methyl chloroformate to methyl pyridine-1(2H)-carboxylate (60%) and methyl pyridine-1(4H)-carboxylate (40%).51
Sodium borohydride as reducing agent has also been used for the synthesis of N-sulfonyl-1,2- and 1,4-dihydropyridine but the yield of this reaction depends on the type of solvent used. When reaction is carried out with methanesulfonyl chloride in methanol at −65°C, a 1,2-dihydro derivative is formed in 35% yields. However, when benzenesulfonyl chloride is used,52 the ratio of 1,2 to 1,4 was 8:1.
Activation of acetic anhydride using a catalytic amount of Lewis acid like copper(II) triflate led to the regioselective introduction of the methoxycarbonylmethyl group at the C-2-position, allowing the practical synthesis of N-acetyl-1,2-dihydropyridyl acetic acid as the major product.53
Reduction of pyridine to 1-acyl-1,2-dihydropyridines with the arylacetylene group at the C-2-position was achieved by use of zinc salts in stoichiometric quantity. During the reaction, 1-ethoxycarbonylpyridinium chloride was generated in situ by mixing pyridine and ethyl chloroformate in acetonitrile. Phenylacetylene was then added in the presence of zinc bromide and N,N-diisopropylethylamine affording a 1,2-dihydro derivative54
28
2. Six-Membered Heterocycles
Reduction of pyridine to its dihydro derivative is also achieved55 by indium-promoted allylation of Nacylpyridinium salts.
Tris(pentafluorophenyl)borane-catalyzed silylative reduction of pyridines has been reported.56 Depending on the nature and position of the substituent, structurally diverse azacycles were synthesized. Reduction with formic acid, however, leads to the formation of N,N-dimethylpiperidinium formate.57
5. Dimerization: 2,2′-Bipyridine which is an important chelating reagent was earlier synthesized58a by heating pyridine with ferric chloride, or with iodine58b or nickel-alumina catalyst58c at temperatures ranging from 300 to 400°C. It is now prepared59 by heating pyridine with a Raney nickel catalyst (W7-J) at moderate temperature.
The reaction is considered to involve an anion radical resulting from the transfer of electrons from metal to heterocycle.
6. Photochemical reactions: Photolysis of pyridine at 254 nm in butane solution at −15°C for 15 min led to the formation of Dewar pyridine, which reverted back to pyridine at elevated temperature. When irradiated in aqueous sodium borohydride solution, Dewar pyridine is trapped by reaction with water followed by reduction of a double bond to yield the stable bicyclic compound 2-azabicyclo[2.2.0]hex-5-ene. Similarly, when irradiated in water, hydration takes place with addition of water across the imine double bond. The unstable hydrated Dewar pyridine then undergoes a ring-opening process to yield 5-amino-2,4-pentadienal. The intermediacy and structure of Dewar pyridine has been proved by NMR spectroscopy.60
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
29
Flash photolysis of pyridine yielded acetylene and hydrogen cyanide as the product,61 whereas irradiation of the pyridine matrix isolated in argon at 8 K gave hydrogen cyanide and cyclobutadiene as secondary products.62 Existence of azaprefulvene intermediate has been suggested as a result of the deactivation of the S2 (π, π*) state of pyridine.63 The deactivation pathway for excited pyridine was also studied and it was observed that the primary product from the vibrationally excited S2 (π, π*)vib pyridine molecule was a vibrationally excited ring-opened biradical, formed by the cleavage of the CN bond.64
7. Diels-Alder reaction: Normally, pyridine, like any other aromatic compound, does not undergo Diels-Alder reaction but under certain conditions it reacts with a powerful dienophile like dimethyl acetylenedicarboxylate (DMAD) to yield a 1:2 adduct. Initially, a zwitterion is formed, which after cyclization and rearrangement yields the adduct 65
8. Minisci reaction of pyridine: A new method66 for the generation of alkyl radicals by silver-catalyzed oxidative decarboxylation of carboxylic acids with peroxydisulfate has been reported. By this method, nucleophilic addition to protonated pyridinium ion takes place, which on oxidation gave an alkylated product.
Pyridine is also attacked by admantyl radical to give a mixture of C-2 and C-4 isomers.67
30
2. Six-Membered Heterocycles
9. Ring-opening reactions: Pyridine is a stable compound and is not cleaved by acid. However, the pyridine ring is cleaved in the form of its pyridinium salts (addition compound) with sulfur trioxide, chlorosulfonic acid, etc. The most important cleavage reaction is the treatment of pyridinium salt of sulfur trioxide with strong aqueous sodium hydroxide, which gave a sodium salt of glutaconic aldehyde.
The pyridine ring is also opened by nucleophilic reagent. 2,4-Dinitropyridinium chloride is formed by the reaction of pyridine with 2,4-dinitrochlorobenzene at 110°C, which on reaction with KOH formed a deep red-colored compound. Treatment of this intermediate compound with dilute aniline and acid gave 2,4-dinitroaniline and glutaconic aldehyde dianil.
3-Acetylaminopyridine on reaction with cyanogen bromide in the presence of primary aromatic amine yields pentamethinium salt.
10. Reactions via pyridyne intermediate: Polyfunctionalized pyridine derivatives, which are of immense importance, can easily be accessed through a reactive pyridine intermediate. Pyridyne, which is analogous with benzyne, exists in two isomeric forms: 2,3-pyridyne (2,3-didehydropyridine) and 3,4-pyridyne (3,4-didehydropyridine). They are formed by reaction of 3-chloro-, 3-bromo-, and 3-iodopyridine with a strong base like potassium amide in liquid ammonia. The pyridynes formed react with a variety of reagents to yield a product that could not be formed by reaction with pyridine. Studies have shown that the stability of 3,4-pyridyne is 9.0 kcal/mol more compared to 2,3-pyridine. Besides, 3,4-pyridyne has more triple bond character than 2,3-pyridyne. Though 2,3-pyridyne could not be isolated, there are a number of reactions in which this intermediate has been trapped. The first reported trapping of 2,3-pyridyne with furan was reported in 1962. In this reaction 2-chloro-3- bromopyridine was treated with lithium amalgam and furan in a sealed tube for 7 days. The product of the reaction was quinolone. It was proposed that quinolone was produced by 2,3-pyridyne being trapped with furan to give epoxyquinoline, which could then be transformed to quinolone via oxygen abstraction by lithium.
Further proof for the intermediacy of 2,3-pyridyne was obtained by reaction of 4-ethoxypyridine with lithium amalgam and furan.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
31
A number of reactions have been reported showing the existence of 2,3-pyridyne. However, in 1992, Walter, Carter, and Banerjee confirmed the existence of 2,3-pyridyne by NMR spectroscopic method.68 In this reaction, the 2,3-pyridyne generated was trapped with three different furans. When 2-methylfuran trapped the pyridyne intermediate, two regioisomeric products were formed and their ratio was determined on the basis of NMR.
2.3.2 Pyridine N-Oxide
Pyridine N-oxide is an oxidation product of pyridine characterized by the presence of a so-called “donative” (or coordinate covalent) bond between nitrogen and oxygen. This bond is formed by the overlap of the nonbonding pair of electrons on nitrogen with the empty orbital on the oxygen atom. This bond is usually represented by an arrow or by formal charges (formula I or II; in this book, formula II has been used).
Pyridine N-oxide is a planar, colorless, hygroscopic, crystalline compound obtained by the oxidation of pyridine. It is chiefly used as an oxidizing agent in organic synthesis and as a ligand in coordination chemistry. Structural and Reactivity Aspects The molecular structure of pyridine N-oxide was determined by gas phase electron diffraction.69 The bond lengths and bond angles were determined by applying least square analysis on the experimental molecular analysis. N1C1= 1.384 ± 0.11 Å, C2C3 = 1.381 ± 0.009 Å, C3C4 = 1.393 ± 0.008 Å, N1O = 1.290 ± 0.015 Å. ∠C2N1C6 = 120.9 ± 1.8 degrees, ∠C3C4C6 = 114.1 ± 2.5 degrees. The 1H and 13C NMR spectral data70, 71 of pyridine N-oxide are given in the following table. H and 13C NMR spectral data of pyridine N-oxide
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 8.23; H-3, 7.70; H-4, 7.30
C-2, 139.4; C-3, 127.2; C-4, 125.7
The chemistry and application of pyridine N-oxide have attracted great attention because this nucleus has been found to be present in a number of pharmaceuticals, biologically active agents, and natural products.
32
2. Six-Membered Heterocycles
A number of pyridine N-oxide derivatives not only possess antiviral activity but they also qualify as potential anti-HIV agents.72
Pyridine N-oxide derivatives possessing antiviral activity.
Three naturally occurring compounds with a pyridine N-oxide nucleus and a disulfide functional group have been reported to possess significant antibacterial activity.73
Pyridine N-oxide derivatives possessing antibacterial activity.
Besides a number of pharmaceutical drugs, the analgesic and antiinflammatory drugs niflumic acid, pranoprofen, and the antiulcer drug omeprazole are manufactured involving the use of heterocyclic N-oxides. Additionally, these N-oxides have been used as protecting groups, auxiliary agents, oxidants, ligands in metal complexes, and catalysts. Synthesis 1. By oxidation of pyridines: Pyridine N-oxide is prepared by the oxidation of pyridine with peracetic acid.74 Oxidation has also been carried out with perbenzoic acid,75 monoperphthalic acid,76 peracetic acid, and hydrogen peroxide.77–79 A higher yield of pyridine N-oxide is obtained by carrying out reactions with methyl isonicotinate in the presence of MTO catalyst.80.
2. Transformation of isoxazole rings: 5-Cyanomethyl-2-isoxazoline on reaction with a catalytic amount of 1,5-diazobicyclo[5.4.0]undec-5-ene (DBU) in boiling xylene yields 6-substituted-2-aminopyridine N-oxide. The reaction is thought to proceed through the reactive Z-vinylene hydroxylamine.81
Physical Properties Pyridine N-oxide is a stable dipolar molecule and is more reactive in comparison to the parent pyridine molecule. Enhanced reactivity is due to the electron release of the oxygen into the ring. This fact is proved by the value of the dipole moment, which in the case of pyridine N-oxide is 4.25 D, almost twice that of pyridine (2.23 D). The difference in dipole moment between pyridine N-oxide and pyridine is much lower than expected. The smaller difference in dipole moment between them points to a significant contribution from the resonance structures derived due to movement of electrons from oxygen to the ring. In these structures the oxygen is neutral, whereas ring carbons at C-2 and C-4 are negatively charged, implying that these positions are susceptible to electrophilic substitution reaction.
Resonating structures of pyridine N-oxide showing movement of electrons from oxygen to ring.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
33
However, if the direction of polarization is reversed, then in that case the C-2 and C-4 carbon atoms of the ring become positively charged, thus making the ring susceptible to nucleophilic substitution reaction.
Resonating structures of pyridine-N-oxide showing movement of electrons from the ring.
Chemical Reactivity 1. Electrophilic substitution reaction (a) Chlorination: Reaction of pyridine N-oxide with phosphorous oxychloride yields 2-chloropyridine as the major product, while 4-chloropyridine is the minor product.
(b) Nitration: Pyridine N-oxide reacts when heated with fuming nitric acid and concentrated sulfuric acid at 130°C for 3.5 h, yielding 4-nitropyridine N-oxide.82, 83 The pyridine derivative is regenerated by carrying out deoxygenation with triphenylphosphine.
(c) Sulfonation: Sulfonation of pyridine N-oxide takes place under drastic conditions by heating it with oleum and mercuric sulfate at 220–240°C affording 3-sulfonylpyridine N-oxide.
(d) Acylation: Reaction of pyridine N-oxide with acetic anhydride yielded 2-acetoxypyridine as the major product and 3-acetoxypyridine as the minor product. However, when reaction with acetic anhydride is carried out in boiling anisole or benzonitrile a number of other minor products like 2-(p-methoxyphenyl)pyridine, 2-(mmethoxyphenyl)pyridine, 2-(p-cyanophenyl)pyridine, and 2-(m-cyanophenyl)pyridine, respectively, were also obtained.84
(e) Reaction of pyridine N-oxide with mercaptans like methylmercaptan in the presence of acetic anhydride yielded a 2-substituted product. However, when bulky groups like tert-butylmercaptan are used, substitution may also take place at the 3-position.85
34
2. Six-Membered Heterocycles
The reaction has been found to take place by the following mechanism.
2. Reactions via metalation (a) Direct alkylation of pyridine N-oxide is achieved by treating it with n-butyllithium in inert nonprotonic solvent, which abstracts a proton from the α-position of the pyridine N-oxide yielding a carbanion, which is then trapped with aldehydes or ketones to yield 2-(1-hydroxycyclohexyl)- and 2,6-bis-(1-hydroxyalkyl) pyridine-1-oxide.86
(b) Direct arylation of pyridine N-oxide to prepare its 2-aryl derivatives in the presence of Pd(OAc)4 and PtBu3 has been reported. The reaction takes place with the formation of a PtBu3-ligated arylpalladium acetate complex. Mechanistic studies of the reaction have also been reported.87
(c) Heteroarylation of pyridine N-oxide is reported. The reaction is catalyzed by Pd(II) with copper(I) oxidative cross-coupling between pyridine N-oxide and electron-rich heteroarenes such as thiophene and furan. Cu(OAc)2-H2O was used as oxidant during the reaction.88
Palladium(II)-catalyzed coupling between pyridine N-oxide and N-substituted indoles has also been reported.89, 90 (d) A novel method for the selective 2-substitution of pyridine N-oxide via directed ortho metalation has been reported. The reaction involves the addition of iso-PrMgCl to pyridine N-oxide in tetrahydrofuran (THF) at −78°C that generated an ortho-metalated species, which could be trapped with aldehydes, ketones, and halogens to generate 2-substituted pyridine N-oxides.91
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
35
(e) Reaction with Grignard reagent: Reaction of pyridine N-oxide with phenyl magnesium bromide in THF yielded 2-phenylpyridine. In this reaction an intermediate product was also obtained, which on treatment with acetic anhydride was also converted to 2-phenylpyridine.92
Another method for the synthesis of 2-substituted alkyl-, alkynyl-, and arylpyridines has also been reported. The reaction involves addition of Grignard reagent to pyridine N-oxide in THF, followed by treatment of the resulting 2,4-dienal oxime with acetic anhydride at 120°C, resulting in the formation of 2-substituted pyridines.93
3. Deoxygenation of pyridine N-oxide: Deoxygenation of pyridine N-oxide is carried out with potential reducing agents. Sulfur and some of its compounds, on reaction with pyridine N-oxide at 115–150°C, form pyridine with oxygen atoms being bonded to sulfur or released as water.94
Deoxygenation by selective transfer of oxygen from pyridine N-oxide to triphenylphosphine in the presence of rhenium catalyst yielded pyridine.95
Similarly, pyridine N-oxide is transformed to pyridine by treating it with 2-chloroalkyl-trichlorophosphonium hexachlorophosphorates.96
Deoxygenation has also been reported to be carried out with phosphorous oxychloride97 and trifluoroacetic anhydride.98 4. O-Alkylation: Alkylation of pyridine N-oxide with alkyl halide in acetonitrile afforded N-alkoxypyridinium halide.99
5. Cycloaddition reaction: Pyridine N-oxide undergoes a cycloaddition reaction with nitrilium salt in methylene chloride at 0–23°C for 20–45 min. 1,5-Sigmatropic rearrangement take place yielding salt.100
36
2. Six-Membered Heterocycles
Pyridine N-oxide reacts with strained 3,3,6,6-tetramethyl-1-thia-4-cycloheptyne at room temperature and gave an unstable intermediate (A), which rearranged to spiro-3H-azepine derivative (C) via azanorcaradiene (B).101
6. Synthesis of substituted pyridines from pyridine N-oxide (a) Oxidative addition of Heck acceptors to pyridine N-oxide in the presence of palladium acetate, silver carbonate, and a pyridine additive in 1,4-dioxane provided 2-alkenylated pyridine N-oxide in moderate to excellent yield, which on deoxygenation yielded 2-alkenylpyridines. Arylation was also carried out under similar reaction conditions affording 2-phenylpyridine N-oxide102
(b) In the presence of a nickel catalyst, pyridine N-oxide underwent regio- and stereoselective insertion of alkynes to afford (E)-2-alkenylpyridine N-oxide in good yield, which on deoxygenation yielded substituted pyridines.103
(c) 2-Aryl pyridines are best synthesized by reacting pyridine N-oxide with 4-bromotoluene in the presence of lead acetate and phosphonium salt yielding 2-(4′-methylphenyl)-pyridine N-oxide, which is then treated with zinc dust.104, 105
A method for the transition metal-free regiospecific synthesis of 2-substituted alkyl-, alkynyl-, and arylpyridines has been reported. The reaction involves addition of Grignard reagent to pyridine N-oxide in THF, followed by treatment of resulting 2,4-dienal oxime with acetic anhydride at 120°C, resulting in the formation of 2-substituted pyridines.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
37
(d) A general and efficient method for converting pyridine N-oxides to 2-aminopyridines in one step has been reported. The reaction takes place with the use of commercially available reagents like t-BuNH2, Ts2O, and trifluoroacetic acid (TFA).106
2-Aminopyridine amides in excellent yield are formed by warming a mixture of imidoly chloride (formed in situ by reaction of a secondary amide with a stoichiometric amount of oxalyl chloride and 2,6-lutidine in CH2Cl2 at 0°C) with pyridine N-oxide at room temperature.107
Synthesis of 2-aminopyridines has also been reported by the reaction of pyridine N-oxide with activated isocyanides.108
(e) A transition metal-free method for the direct introduction of acetylenes into the heterocyclic system using SNH methodology has been reported. This method, which is complementary to a Sonogashira cross-coupling reaction, provides a versatile tool for the synthesis of a series of ethynyl azines.109
(f) Deoxydative substitution of pyridine N-oxide by thiophenol in the presence of sulfonyl halide leads to the generation of 2-phenylthiopyridine and 3-phenylthiopyridine.110
7. Reissert-Henze reaction: Pyridine N-oxide can be converted to 2-cyanopyridine or 4-cyanopyridine in a ReissertHenze reaction by activation of an N-oxide function by O-acylation111 or O-alkylation.112 However, activation of N-oxide and subsequent cyanation can be carried out in one step by heating the N-oxide in acetonitrile with 3–4 equivalents of trimethylsilyl cyanide in the presence of triethylamine.113
38
2. Six-Membered Heterocycles
8. Photochemical reactions (a) Photolysis of pyridine N-oxide in basic aqueous solution gave anion A114 as the quantitative product.
(b) In the presence of secondary amines, added either before or after photolysis of the pyridine N-oxide solution, conjugated nitrile B was obtained.115
(c) UV irradiation of pyridine N-oxide leads to 2-formylpyrrole. According to initial mechanistic hypothesis, UV irradiation of pyridine N-oxide to 2-formylpyrrole takes place through the successive formation of the following four intermediates: 1-aza-7-oxa-norcaradiens (A), 1,2-oxazepine (B), vinylic nitrene (C), and pyrrolenine (D).116
2.3.3 Picolines Methylpyridines, formerly called picolines, are referred to as α,β- and γ- or 2,3- and 4-methyl derivatives of pyridine with the chemical formula C6H7N. The three compounds are structural isomers and their name is designated with the position of methyl group presence.
Structural and Reactivity Aspects117 All three methylpyridines are colorless liquids at room temperature. They are comparatively stronger bases compared to the parent compound, pyridine, primarily due to the +I effect of the methyl group, which increases the availability of the lone pair of electrons on nitrogen. Among all three methylpyridines, 2-methylpyridine (pKa 5.96) and 4-methylpyridine (pKa 6.05) are stronger bases compared to 3-methylpyridine (pKa 5.68). The dipole moments of 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine are 1.96, 2.30, and 2.57 D, respectively.117
39
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
Physical data of methylpyridines Compound
Boiling Point (°C)
Density (d20)
Solubility in Water
2-Methylpyridine
129.5
0.9462
Miscible
3-Methylpyridine
143.9
0.957
Miscible
4-Methylpyridine
144.9
0.9558
Miscible
H NMR data of methylpyridines (chemical shifts in δ, ppm)
1
1
H NMR spectral data of methylpyridines H-2
H-3
H-4
H-5
H-6
2-Methylpyridine (CDCl3)
2.54 (methyl)
7.12
7.53
7.08
3-Methylpyridine
8.44
2.32 (methyl)
7.465
7.159
8.499
4-Methylpyridine
8.44
7.08
2.32 (methyl)
7.08
8.44
8.47
C NMR data of methylpyridines (chemical shifts in δ, ppm)
13
C NMR spectral data of methylpyridines
13
C-2
C-3
C-4
C-5
C-6
2-Methylpyridine
158.7
123.5
136.1
120.8
149.5
3-Methylpyridine
150.9
133.1
136.4
123.4
147.3
4-Methylpyridine
150.1
125.0
147.0
125.0
150.1
Methylpyridines form stable salts with both organic and inorganic acids. They do not form stable salts with weaker acids like sodium acid succinate and sodium bisulfite but form stable salts with a stronger base such as 2,3,5,6-tetramethylpyridine. Importance in Natural Product, Medicine, and Materials Methylpyridines are of immense importance because they have been used for the synthesis of a variety of agrochemicals and pharmaceuticals. For example, 2-methylpyridine has been used for the synthesis of picloram-a herbicide and amprolium-a coccidiostat. 3-Methylpyidine has been used for making insecticides such as chloropyrifos and herbicides such as fluazifop-butyl. 4-Methylpyidine has been used for the synthesis of the antitubercular drug isoniazid.
2.3.4 2-Picoline (2-Methylpyridine)
2-Methylpyridine is a liquid and finds use as a solvent or as an intermediate in the dye and resin industry. 2-Methylpyridine was the first pyridine derivative, isolated from coal tar in 1846 by T. Anderson. Synthesis 1. It was chiefly synthesized by the condensation of acetaldehyde with ammonia in the gaseous phase.118
40
2. Six-Membered Heterocycles
2. Industrially, 2-methylpyridine is manufactured from acetone. The process involves reaction of acetone with acrylonitrile in the presence of isopropylamine as catalyst yielding 5-oxohexanenitrile as intermediate followed by cyclization in the gas phase over supported metal catalysts like Ni/SiO2 or Pd/Al2O3 in the presence of hydrogen.119
3. 2-Methylpyridine is also synthesized by the reaction of acetaldehyde imine with 2 equivalents of acrylamine. The intermediate product formed underwent cyclization to dihydropyridine derivative, which on deamination and oxidation afforded the desired product.
4. Bonnemann cyclization: Reaction of 2 mol of acetylene with 1 mol of acetonitrile in the presence of Co(I) catalyst leads to the generation of 2-methylpyridine.120
5. β,γ-Unsaturated ketoxime of hex-4-en-2-one in the presence of sodium phenoxide and palladium-based catalyst, delivered 2-methylpyridine.
6. Thermal decarboxylation of 2-pyridylacetic acid in water affords the corresponding methylpyridine derivative.121
7. 2-Methylpyridine has also been synthesized by the reaction of ethanol and ammonia in the presence of oxygen over ZSM-5 zeolite promoted by Cd, Co, or Fe and H-Y zeolites.122 The reaction is thought to take place by the following mechanism.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
41
2-Methylpyridine has also been synthesized by heating acetone, formaldehyde, methanol, and ammonia over ZMS-5 at higher temperatures.123 8. Cyclization of pent-4-en-2-one oxime in the presence of a catalytic amount of palladium halogenide yields 2-methylpyridine.124
Chemical Reactivity 1. 2-Methylpyridine reacts with chloroform or bromoform in strongly alkaline medium to give a carbylamine test.117 2. 2-Methypyridine is widely used in the synthesis of 2-vinylpyridine, which on copolymerization with butadiene and styrene leads to the formation of an adhesive used for bonding textiles to elastomers. The synthesis of 2-vinylpyridine is achieved by the addition of aqueous formaldehyde to 2-picoline followed by dehydration of the resultant product.
3. Oxidation of 2-picoline with potassium permanganate afforded picolinic acid.125
4. Photochemical irradiation of 2-methylpyridine vapors at 238–266 nm resulted in the formation of 3-methyl- and 4-methylpyridine in a 10:1 ratio.126 The reaction takes place with the intermediate formation of azaprismane.
42
2. Six-Membered Heterocycles
However, Caplain and coworkers reported127 that irradiation of 2-methylpyridine resulted in the formation of 4-methylpyridine as an exclusive product. They reported evidence to show that the reaction takes place by the involvement of radical intermediates by irradiating 2-methylpyridine in cyclohexane,128 which led to the formation of 6- and 4-cyclohexyl-2-methylpyridine, biscyclohexane, and methylcyclohexane.
5. Coniine, an alkaloid, was synthesized by treating 2-methylpyridine with phenyllithium. The alkyllithium generated on nucleophilic substitution with bromoethane followed by reduction yields coniine.
Alternatively, reaction of 2-picoline with acetaldehyde in the presence of anhydrous zinc chloride gives a product, which on reduction with sodium and ethanol yields 2-propylpiperidine. Both the reactions had been used for establishing the structure of coniine.
6. 2-Methylpyridine is oxidized to its corresponding aldehyde by treating it with 1 equivalent of iodine at room temperature. The crystalline complex so formed was dissolved in dimethyl sulfoxide (DMSO) and the reaction mixture heated at 140–160°C yielded picolin-2-aldehyde.129
7. Sulfonation of 2-methylpyridine with oleum at 250°C results in the formation of 2-methylpyridine-5-sulfonic acid.
8. The presence of nitrogen atoms in pyridine has an important influence on the activation of the methyl group. The main feature of the reactivity is the deprotonation of the hydrogen of the methyl group by a strong base. The anion produced is mesomerically stabilized involving the ring nitrogen. Since such anions are stabilized in the same way as enolates, the term “enaminate” has been used to describe nitrogen containing enolates like anion.
The enaminate anion produced can undergo a wide variety of reactions. Alternatively, side chain reactions can also be performed by first carrying out electrophilic addition on nitrogen, thereby making the side chain hydrogens more acidic. Deprotonation generates an enamine or enamide.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
43
(a) 2-Methylpyridine can readily undergo aldol condensation and this reaction is best carried out in the presence of acetic anhydride or Lewis acid such as zinc chloride. 2-Methylpyridine reacts with aldehyde at 200°C in the presence of zinc chloride or acetic anhydride to yield 2-styrylpyridine (stilbazole).130
Chloral also condenses with 2-methylpyridine. (b) 2-Methylpyridine can easily be benzoylated in the presence of phenyllithium.
(c) Nitration of 2-methylpyridine can be carried out with sodamide in liquid ammonia in the presence of propyl nitrate131 at −35°C.
(d) 2-Pyridylacetone was prepared132 first by metalation of 2-methylpyridine with butyllithium followed by the action of dimethylacetamide (DMA).
Similarly, 2-methylpyridine reacts with butyllithium. The methyl anion generated reacts with methyl 3,3-dimethylpentanoate and 1-cyano-3-butene to give two different ketones in moderate yields.133 (e) 2-Methylpyridine can be easily alkylated by treating with an alkyl halide like butyl chloride in the presence of sodium amide.134
(f) 2-Picoline on reaction with phenyllithium or sodamide yields a carbanion-like intermediate, which reacts with a variety of electrophiles to yield different products.
44
2. Six-Membered Heterocycles
9. 2-Picoline on reaction with α-bromopyruvate leads to the generation of an intermediate, which was cyclized to indolizine in the presence of sodium carbonate.
10. Cationic surfactants, which find use in gene therapy, were synthesized. The procedure involves reaction of 2-methylpyridine with butyllithium and α,ω-dibromoalkane, leading to the generation of a base, which on quaternization with dodecyl methanesulfonate yields the surfactant molecule.135
11. Ethyl 2-pyridylacetate is prepared by treating 2-picoline with phenyllithium.136 The resulting picolyllithium solution on reaction with dry carbon dioxide gave lithium salt of acid, which was esterified by treating with ethanolic HCl.
12. Free radical chlorination of 2-picoline by N-chlorosuccinimide yields a mixture of mono- and dichlorinated products.137
Similarly, free bromination of 2-picoline by N-bromosuccinimide yields 2-bromomethylpyridine as the exclusive product.138
13. Benzylic sulfonation of 2-methylpyridine is achieved by quenching 2-lithiomethylpyridine with 1-(phenylsulfonyl)benzotriazole at −78°C in THF.139
14. 2-Methylpyridine on treatment with n-butyllithium followed by treatment with 1,6-dibromohexane yields 1,8-bis(2-pyridyl)octane.140
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
45
15. Reaction of 2-methylpyridine with 2-bromoacetylthiophene in refluxing dry THF afforded 2 picolinium salt, which has been used for the synthesis of a variety of aniline and thiophene derivatives possessing antimicrobial activities.141
16. 2-Methylpyridine condenses with chloral to yield an alcohol, which undergoes dehydration to yield the unsaturated product.
2.3.5 3-Picoline (3-Methylpyridine)
Synthesis 1. Reaction of a mixture of acetaldehyde and formaldehyde with ammonia in the gas phase over HZSM-5 catalyst yields 3-methylpyridine as a major product in addition to pyridine as a minor product.142
2. 1,5-Diamino-2-methylpentane (a derivative of 2-methylglutaronitrile) in the presence of zeolites is cyclized to 3-methylpiperidine, and then aromatized to 3-methylpyridine by catalytic dehydrogenation.143
3. Reaction of a mixture of acrolein and propionaldehyde with ammonia in the gas phase yielded 3-methylpyridine.
46
2. Six-Membered Heterocycles
4. Reaction of lithium aluminum hydride with excess pyridine yields lithium tetrakis (N-dihydropyridyl) aluminate, which on reaction with methyl iodide produced 3-methylpyridine.144
Chemical Reactivity 1. 3-Methylpyridine has been easily oxidized in the gas phase using a fixed-bed reactor charged with vanadium pentoxide on high surface titanium dioxide to nicotinic acid.145 Oxidation of 3-methylpyridine with potassium permanganate also yields nicotinic acid.146
2. Ammoxidation of 3-methylpyridine, followed by partial hydrolysis of the intermediate 3-cyanopyridine, yielded pyridine 3-carboxamide.
Ammoxidation of 3-picoline to nicotinonitrile was also carried out with a V-Mo-P oxide catalyst prepared from 11-molybdo-1-vanado phosphoric acid by thermal decomposition.147 3. 3-Methylpyridine can be aminated at position 2 with sodium amide yielding 2-amino-3-methylpyridine and 2-amino-5-methylpyridine. The introduction of the amino group by Chichibabin reaction has been widely used for the replacement of the amino group by other groups.148
4. Free radical chlorination of 3-picoline by N-chlorosuccinimide yields 3-chloromethylpyridine exclusively by a free radical mechanism.149
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
47
2.3.6 4-Picoline (4-Methylpyridine)
Synthesis 1. 4-Methylpyridine is chiefly synthesized by the condensation of acetaldehyde with ammonia.
2. Thermal decarboxylation of 4-pyridylacetic acid in water affords the corresponding 4-methylpyridine.150
3. 4-Methylpyridine N-oxide, when reduced with oxorhenium catalyst in the presence of triphenylphosphine in benzene, afforded 4-methylpyridine.151
Chemical Reactivity 1. 4-Methylpyridine is comparatively more basic than pyridine. 2. 4-Methylpyridine reacts with chloroform or bromoform in strongly alkaline medium to give a carbylamine test. 3. N-Alkylation of 4-methylpyridine can be carried out by treating it with methyl iodide to yield quaternary salt.
4. 4-Methylpyridine can be successfully aminated at 150°C at position 2 giving a reasonable yield of 4-methylpyridin-2-amine.
48
2. Six-Membered Heterocycles
5. As in the case of 2-methylpyridine, 4-methylpyridine is also reactive and on formation of enaminate anion by the base it reacts with styrene to form 4-(3-phenylpropyl)pyridine.
6. Nitration of 4-methylpyridine can also be carried152 out with sodamide in liquid ammonia in the presence of propyl nitrate at −33°C.
7. 4-Methylpyridine can be oxidized with potassium permanganate affording isonicotinic acid.
8. 4-Methylpyridine readily undergoes aldol condensation with carbonyl compounds and this reaction is best carried out in the presence of acetic anhydride or Lewis acid such as zinc chloride.153
Condensation of 4-methylpyridine with different aryl aldehydes afforded heterostilbenes.
9. Reduction of 4-methylpyridine to its 1,2-dihydro derivative was achieved by carrying out the addition of silylboronic acid ester in the presence of palladium catalyst, 1,2-silaboration took place leading to the generation of N-boryl-2-silyl-1,2-dihydropyridine regioselectively.154
10. A reaction of 4-methylpyridine with fluorine gas at −78°C followed by reaction with isonitrile at −50 to 0°C led to the formation of picolinamide. The reaction is thought to proceed with the initial formation of carbene, which undergoes an addition reaction with isonitrile, followed by aromatization and hydrolysis to finally yield picolinamide.155
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
49
11. 4-Methylpyridine on reaction with phenyllithium undergoes phenylation at the 2-position and the product is carboxylated by treating with carbon dioxide yielding 4-methyl-6-phenylpyridine-3-carboxylic acid.156
12. Photochemistry: Vapor phase photolysis of 4-methylpyridine with a mercury arc lamp for 72 h produced 2-methylpyridine and pyridine.157
However, Caplain and coworkers reported158 that irradiation of 4-methylpyridine in cyclohexane resulted in its photoisomerization to 2-methylpyridine and photosubstitution with cyclohexane to 6- and 4-cyclohexyl-2-methylpyridine.
13. Reaction with sulfur: 4-Picoline on boiling with elemental sulfur at 145°C under argon yielded products like 1,2-di[4-pyridyl]-ethane (1), 1,2-di[4-pyridyl]-ethene (2), 2,3-tri[4-pyridyl]-propane (3), tetra[4-pyridyl]thiophene (8), E and Z isomers of 1,2,3-tri[4-pyridyl]-propene (4 and 5), 6-[4-pyridyl]-thieno[3,2-c]pyridine (6), and 10-[4-pyridyl]-pyrido[3″4″:5′.4′]cyclopenta[2′,3′:4,5]thieno[2,3-]pyridine (7).159
50
2. Six-Membered Heterocycles
2.3.7 Piperidine
Piperidine, also referred to as azacyclohexane, is one of the most recognizable structural entities among heterocyclic molecules. Piperidine has a structure similar to cyclohexane with one of the methylene groups being replaced by the secondary amino (NH) group. In 1853 piperidine was first isolated from the alkaloid piperine, which is abundantly found in the black pepper Piper nigrum. Structural and Reactivity Aspects160 1. Conformation Like cyclohexane, piperidine prefers the chair conformation. In the stable chair conformation the lone pair of electron or hydrogen on nitrogen can occupy either the axial or equatorial position. Thus piperidine is thought to exist in four different chair conformations in which structures I and IV are equivalent and structures II and III are equivalent. Conformer I, in which the NH bond is equatorial, is more stable in the gas phase and in solution as compared to II and III, in which the NH bond is axial.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
51
Conformations of piperidine.
2. Structural data: Spectral methods have been quite helpful in studying the conformational analysis of piperidines160 The 1H and 13C NMR spectra of piperidine are given in the following table. H and 13C NMR spectral data of piperidine
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2/H-6, 2.77; H-3/H-4/H-5, 1.52
C-2/C-6, 47.5; C-3/C-5, 27.2; C-4, 25.5
Importance in Natural Products, Medicines, and Materials The piperidine nucleus is present in numerous natural alkaloids like quinine, pergoline, etc. Besides being the structural feature of a number of alkaloids, the piperidine nucleus has also been found to be present in a number of pharmaceuticals.
Drugs containing piperidine nucleus.
52
2. Six-Membered Heterocycles
Piperidine has been used as a solvent in a number of reactions. In addition, it is a reactant in the synthesis of dipyridamole, a vasodilator, and etiozoline, a diuretic. Synthesis 1. Piperidine is mostly prepared by catalytic reduction of pyridine. Reduction has been carried out by a number of methods such as catalytic hydrogenation over platinum oxide,161 Na/C2H5OH,162 Raney nickel,163 copperchromium oxide,164 H2-Pd,165 and H2-Pt,166 but reduction with lithium triethylborohydride is highly efficient.
Reduction of pyridine in the presence of sodium and protic solvent is quite similar to Birch reduction of arenes that takes place in two steps. The first step is transfer of a single electron forming a radical anion followed by 1,2- or 1,4-addition of hydrogen.
2. Cyclization of 1,5-dichloropentane in the presence of ammonia results in the formation of piperidine.
3. Reductive cyclization of 1,5-dicyanopentane or 1,5-diaminopentane with hydrogen in the presence of copper chromite as catalyst yields piperidine.
4. Reaction of tetrahydrofurfuryl alcohol with ammonia under reductive conditions yields piperidine.
5. Hofmann-Löffler-Freytag reaction: A new method for the selective iodine-catalyzed CH amination of 2-arylsubstituted piperidines has been reported. The reaction involves visible light-induced initiation of a radical CH and an iodine-catalyzed CN bond formation. Under these conditions the preference for formation of pyrrolidine within the Hofmann-Löffler domain is altered in favor of free radical-promoted piperidiene.167
6. Synthesis of C2 symmetric piperidines: The process involves reaction of enantiomerically pure (S)-1,2epoxypropane with a solution of methyl phenyl sulfone dianion (from methyl phenyl sulfone and 2 equivalents
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
53
of n-butyllithium) yielding 4-(benzenesulfonyl)-(2S,6S)-heptanediol, which on reaction with p-toluenesulfonyl chloride afforded a bis(tosylate) derivative. Heating the neat solution of bis(tosylate) in an excess of benzylamine produced only the antipiperidine168
7. Photo-irradiation of a deareated suspension of cadmium sulfide particles in an aqueous solution of a mixture of stereoisomers of 2,6-diaminopimelic acid (DAP) [(S,S):R,S):(R,R)] afforded piperidine-2,6-dicarboxylic acid (PDC) via a redox-combined mechanism. The ratio of PDC produced depends on the kind of CdS photocatalysis, its pretreatment, and loading of platinum (or its oxides) particles. However, synthesis of optically pure (R,R) or (S,S)-PDC could be achieved by photocatalytic reaction of activated CdS particles with (R,R) or (S,S)-DAP, respectively.169
Physical Properties Piperidine is a colorless liquid with a bp of 106°C and an unpleasant odor. It is miscible with water. It behaves as a secondary amine (pKa = 11.2) and is a stronger base than pyridine (pKa = 5.2). Piperidine is as polar as diethyl ether or benzene, but is less polar compared to chloroform or ethyl acetate. The dielectric constant of piperidine is 5.8, which is quite similar to that of diethyl ether or benzene but much weaker compared to pyridine (12.4).
54
2. Six-Membered Heterocycles
Chemical Reactivity 1. Hofmann exhaustive methylation: This reaction is quite useful in studying the nature of nitrogen. A primary amine consumes 3 mol of methyl iodide, secondary amine 2 mol, and tertiary amine 1 mol. The quaternary ammonium iodide formed on reaction with moist silver oxide is converted to hydroxide, which on heating undergoes Hofmann elimination. Piperidine undergoes methylation in two stages. After the second stage a nitrogen-free molecule, penta-1,4-diene, is formed, which rearranges to 1,3-diene under conditions of the reaction.
2. Piperidine undergoes nucleophilic addition to methoxycarbonylacetylene in a variety of solvents. This has often been used as a standard reaction to establish a solvent effect on reaction rates in case of nucleophilic addition to the carbon-carbon triple bond.170
3. Piperidine on reaction with benzoyl chloride yields 1-benzoyl piperidine.171 The benzoyl derivative on reaction with phosphorous tribromide yields 1,5-dibromopentane.172
4. Piperidine on reaction with methyl iodide yields 1-methylpiperidine. The N-methyl derivative on reaction with cyanogen bromide undergoes ring fission.
5. N-Ethylpiperidine can also be obtained by treating it with ethylene.173
6. Naphthyl derivatives of piperidine are prepared by heating it with sodium naphthalene 2-sulfonate in the presence of sodamide.174
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
55
7. Reaction of piperidine with quinolizinium iodide yields trans, trans-1-piperidinyl-4-(2-pyridyl)butadiene in good yields.
8. Asymmetric α-alkynylation of piperidine was carried out in four steps involving transformation to chiral nonracemic N-sulfinylpiperidine, which on anodic oxidation is transformed to N-sulfinyliminium ion equivalent. Alkynylation followed by acidic deprotection yielded the asymmetric product.175
9. Diarylmethylamine derivatives of piperidine are of interest because they have been used in the synthesis of drugs like cetirizine, flunarizine, and manidipine. The synthesis was achieved in one step by heating piperidine with 4-bromoanisole and 4-fluorobenzaldehyde in the presence of cobalt bromide.176
10. Spirodienones are useful intermediates in the synthesis of paracyclophanes used as building blocks for nanotubes. Spirocyclohexenone and spirocyclohexadienone have been synthesized by the reaction of piperidine with cyclooctanecarboxyaldehyde, yielding a product, which on reaction with methyl vinyl ketone, followed by reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), yields the desired product.177
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2. Six-Membered Heterocycles
11. Piperidine on reaction with calcium hypochlorite in the presence of glacial acetic acid yields Nchloropiperidine, which on heating with ethanolic potassium hydroxide yields tripiperidine.178
12. Piperidine when refluxed with a solution of benzaldehyde in toluene containing a few drops of acetic acid yields 3,5-dibenzylpyridine.179
13. Oxidation of piperidine with hydrogen peroxide in the presence of selenium dioxide as a catalyst at room temperature yields nitrones, which are easily transformed to isoxazolidines by 1.3-dipolar cycloaddition.180 Isoxazolidines have been found to be useful intermediates for the synthesis of β-amino ketones, β-amino acid esters, and β-lactams.
14. α-Metalation of piperidine via tert-butylformamide has been accomplished. Alkylation of these α-amino carbanions via their lithio or cuprate derivatives yields α-alkylated piperidines in good yields.181
15. Aromatization and alkylation/arylation: A benzene solution of aldehyde and piperidine when passed over alumina at 420°C yields 3-alkylpyridine.182
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57
The reaction is proposed to take place by the following mechanism.183
16. Piperidines on reaction with doubly activated ketene dithioacetals in alcohol at reflux temperature undergo addition followed by elimination to yield N,S- and N,N-acetals depending on the stoichiometry of the added piperidine.184, 185 However, in the case of less reactive ketene dithioacetals, more vigorous reaction conditions are required and the products isolated are characterized as a mixture of N,S- and N,N-acetals.186, 187
17. Piperidines react with suitably functionalized 2H-pyran-2-ones such as 6-aryl-4-methylthio-2H-pyran-2one-3-carbonitriles or carboxylates in alcohol at reflux temperature to produce the cyclic aminal 6-aryl-4piperidino-2H-pyran-3-carbonitriles/carboxylates through Michael addition followed by elimination of methyl mercaptan.188
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2. Six-Membered Heterocycles
2.3.8 Pyridones The pyridine ring carries many substituents. The hydroxy derivatives of pyridine are both weak acids and bases and thus can exist as zwitterions. However, the 2- and 4-hydroxy derivatives of pyridine are stabilized by mesomerism with uncharged canonical structures, which are thus more stable than zwitterions. Thus 2- and 4-hydroxy derivatives of pyridine exist chiefly in their carbonyl tautomeric form, commonly known as 2- and 4-pyridones, respectively. The pyridone form is favored in the solid phase or in polar medium, while their hydroxy derivatives are the predominant tautomer in very dilute solution, nonpolar solvent, or the gas phase.
Tautomeric form of 2- and 4-hydroxypyridine.
The preference for the two pyridones to exist in amide form is the presence of a strong carbonyl group and still the aromaticity of the compound is preserved. There are two electrons each on the two carbon-carbon double bonds and one lone pair on the trigonal nitrogen, and the delocalization of lone pair of electrons on nitrogen proves the point.
The 3-hydroxy derivative in polar solvents, however, exists in equilibrium with the zwitterionic tautomeric form. The exact ratio of either of the forms, however, depends on the type of solvent that has been used.
2.3.9 2-Pyridone
2-Pyridone, which is also known as 2-hydroxypyridine, 2(1H)-pyridinone, 2-pyridinol, 1,2-dihydro-2-oxopyridine, finds use in peptide synthesis. It is known to form hydrogen-bonded structures related to the base-pairing mechanism found in RNA and DNA. Structural and Reactivity Aspects The structure of 2-pyridone has been examined by Penfold189 and on the basis of X-ray crystalline data the bond lengths in Å and bond angles in degrees were determined and are shown in the following diagram.
Bond lengths and bond angles of 2-pyridone.
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59
2-Pyridone is stable and there is strong intermolecular hydrogen bonding between the nitrogen of one molecule and the oxygen of another, and this arrangement is repeated throughout the structure linking molecules in endless helices. This conclusion is drawn from the fact that the NH bond distance is 1.02 Å, which is nearly similar to the covalent bond length of 1.0 Å. The observed bond lengths and bond angles are best explained in terms of contributions from the five resonance structures.
Percentage contribution of different resonating structures.
On the basis of electronegative trends, canonical structures with a negative charge on oxygen have greater significance than those with a negative charge on carbon. The former structures therefore cause a high polarity in the NHO hydrogen bond. 2-Pyridone can also form a dimer with two hydrogen bonds. This dimeric form is present in solution. However, the ratio of dimerization depends on the polarity of the solvent.
Hydrogen bonding between two pyridones forming a dimer.
The 1H and 13C NMR data190a of 2-pyridone confirm that they may be regarded as a 6π-delocalized electron system with aromatic character. H and 13NMR spectral data of 2-pyridone
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-3, 6.60; H-5, 6.60; H-4, 7.30; H-6, 7.23
C-2,162.3; C-3, 119.8; C-5, 104.8; C-4, 140.8; C-6, 135.2
In the infrared (IR) spectrum of 2-pyridone, a medium intensity band at 3198 cm−1 and a strong band at 3165 cm−1 are for the NH stretching vibration. A strong band at 1650 cm−1 for the carbonyl group suggests the existence of a 2-hydroxy derivative of pyridine in carbonyl tautomeric form. Importance in Natural Products, Medicines, and Materials Functionalization of the 2-pyridone core has attracted much attention because this nucleus has been found to be present in a number of pharmaceutical agents, biologically active agents, and unnatural products.191 A number of drugs containing a 2-pyridone skeleton such as amrinone,192 milrinone,193 perampanel,194 and pirfenidone195 are in clinical use.
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2. Six-Membered Heterocycles
Drugs containing 2-pyridone skeleton.
In addition, 2-pyridone has been used in the synthesis of rosiglitazone—an antidiabetic drug. Synthesis 1. Pyridine on oxidation with hydrogen peroxide forms pyridine N-oxide, which undergoes a rearrangement reaction with acetic anhydride to form 2-pyridone.196
2. 2-Pyrone obtained by the cyclization of 5-oxopent-2-enoic acid is converted to 2-pyridone via an exchange reaction with ammonia or an equivalent nitrogen source.
3. Pyridine N-oxide forms a stable complex with antimony pentachloride, which on thermolysis followed by hydrolysis yields 2-pyridone by regioselective transfer of oxygen to the 2-position.
4. Photolysis of pyridine N-oxide leads to the generation of 2-pyridone. The reaction is thought to proceed via a singlet excited state with oxaziridine as the postulated intermediate.
5. When an N-methylpyridinium ion reacts with sodium hydroxide, the hydroxide ion is added reversibly and exclusively at position 2, forming 2-hydroxy-1,2-dihydro-N-methylpyridine, which on oxidation yields N-methyl-2-pyridone.197
6. Pyridine reacts with the hydroxide ion at higher temperatures to yield 2-pyridone.
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7. Heating 2-fluoropyridine with lithium hydroxide and hydrogen peroxide at 50oC for 21 h yields 2-pyridone.198
8. 2-Pyridone in high yield is obtained by the reaction of 2-bromopyridine with CuI and N,Ndimethylethylenediamine (DMEDA) in the presence of potassium phosphate under microwave irradiation.199
9. 2-Pyridone in excellent yield is obtained by reduction of 2-benzoyloxypyridine in the presence of 10% palladium and activated carbon.200
10. Reaction of 6-chloro-3-nitropyridine-2-amine with NaOH in methanol and water under milder conditions yields 2-pyridone.201
11. Guareschi synthesis: Stirring a mixture of sodium methoxide, acetone, and ethyl formate yields sodium formyl acetone, which on refluxing with cyanoacetamide and piperidine acetate for 2 h delivered 3-cyano-6-methyl-2(1)-pyridone.202
12. 1,4-Addition of 2-(phenylsulfinyl)acetamide to α,β-unsaturated ketone followed by cyclization and sulfoxide elimination yields 2-pyridones.203
13. Microwave-assisted synthesis of 2-pyridone: Carbonyl compounds were made to react with N,N-dimethylformamide dimethylacetal yielding enaminones, which without purification reacted with methylene nitriles at 100oC for 5 min in 2-propanol in the presence of a catalytic amount of piperidine and afforded 2-pyridones.204
14. Buchwald-Hartwig amination: An efficient synthesis of amino-substituted 2-pyridone under microwave irradiation was carried out by amination of bromo-2-benzyloxypyridines in the presence of palladium catalyst followed by hydrogenolysis of benzyl ether.205
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2. Six-Membered Heterocycles
15. Michael addition: A number of 2-pyridone derivatives have been synthesized involving Michael addition of an acetonitrile derivative to an appropriate α,β-unsaturated carbonyl substrate. 3-Cyanopyridone was synthesized in good yield by the reaction of enones and enals with cyanoacetamide.206a
3-Cyanopyridones were also synthesized by Knoevenagel condensation of acetophenone with ethyl cyanoacetate in the presence of sodium acetate. The α,β-unsaturated carbonyl compound is then converted to enaminonitrile, which on reaction with primary amine under solvent-free conditions yielded the pyridone derivative. Recently, Ram et al. reported206b a synthesis of highly functionalized 2-pyridones through ring transformation of methyl 6-aryl-4-methylsulfanyl-2H-pyran-2-one-3-carboxylate with formamidine acetate in moderate yields.
Physical Properties 2-Pyridone is a colorless crystalline solid with a melting point (mp) of 105–107°C. It is soluble in water, methanol, and acetone. Chemical Reactivity 1. Electrophilic aromatic substitution reaction: 2-Pyridone containing an activating group readily undergoes substitution reaction at either the C-3- or C-5-position.
2. Replacement of oxygen function (a) The carbonyl group of pyridines can be replaced by a good leaving group. The reaction involves treatment of pyridone with phosphoryl chloride or phosphorous pentachloride leading to the generation of chloropyridine. The chloro group is a good leaving group and thus chloropyridine can undergo a cross-coupling reaction with organometallic reagent to form a new carbon-carbon bond.
(b) The carbonyl group of pyridone can also be replaced with a suitable leaving group by heating it at high temperature with a secondary amine like pyrolidine in the presence of phosphorous pentoxide.207
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63
(c) The oxygen of pyridone can also be replaced by sulfur by treating it with Lawesson’s reagent yielding thiopyridones.
3. Alkylation, arylation, and acylation: 2-Pyridone is a weak acid (pKa ≈ 11), hence deprotonation in basic medium produces ambident anions, and as a result electrophilic attack may take place at O, N, and C. (a) When 2-pyridone reacts with diazomethane, methylation of nitrogen as well as oxygen takes place, in which the N-substituted pyridone predominates.208
Alkylation of 2-pyridone can also be carried out by first preparing its metal salts and then treating them with different alkyl halides. A mixture of N-alkyl and O-alkyl products are obtained.209a
N- as well as O-alkylation of 2-pyridone takes place under Mitsunobu reaction conditions. The reaction does not require the presence of a strong base because primary and secondary alcohols were used. In comparison to Nalkylated product, O-alkylated was the major product.209b
(b) O-Alkylation can also be achieved by heating 2-pyridone with methyl iodide or ethyl iodide in the presence of silver carbonate.
Reaction of sodium salt of 2-pyridone with triethyloxonium fluoroborate yields N-ethyl-2-pyridone, 2-ethoxypyridine, and N-ethyl-2-ethoxypyridinium fluoroborate.210
Irradiation of 2-pyridone with benzyl bromide in a microwave for 5 min at 196°C under solvent-free conditions afforded a mixture of 3-benzyl-2-pyridone, 5-benzyl-2-pyridone, and 3,5-dibenzyl-2-pyridone. However, on conventional heating of 2-pyridone with benzyl bromide in DMSO in an oil bath at 196°C for 5 min only 1-benzyl-2- pyridone was obtained.211
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2. Six-Membered Heterocycles
Manganese-mediated C-3 alkylation and arylation of 2-pyridones with diethylmalonate and arylboronic acid, respectively, has been reported.212
C-3 arylation of N-alkyl-2-pyridone with arylboronic acid in the presence of an environmentally friendly and abundant iron catalyst under mild reaction protocols has been reported.213
N-Methyl-2-pyridones are easily arylated in one step at the C-3-position by alkylboronic acid in the presence of iron catalyst.214
4. Acyl derivatives of 2-pyridone are best prepared by acylation of the sodium derivative of pyridone.
5. Cycloaddition reaction: Cycloaddition of 2-pyridone and its N-methyl derivative with dimethylacetylene dicarboxylate produced a [4+2] cycloadduct product.
6. Reaction in which the hydroxyl group predominates: 2-Hydroxypyridine on reaction with aqueous sodium hypochlorite and alcoholic sodium iodide yields 2-hydroxy-5-iodopyridine in 48% yield.214
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65
7. Kolbe-Schmitt reaction: Sodium salt of 2-pyridone undergoes a Kolbe-Schmitt reaction, and instead of the expected introduction of the carboxylic group at the ortho-position, the carboxylic group enters the 5-position.
2.3.10 4-Pyridone
4-Pyridone is also known as 4-hydroxypyridine, 4(1H)-pyridinone, and 4-pyridinol. 1H-Pyridine-4-one is an important scaffold among the N-alkylated heterocycles because this structural motif is an essential core in natural products and medicinal targets. Structural and Reactivity Aspects The 1H and 13C NMR data215of 4-pyridone confirm that it may be regarded as a 6π-delocalized electron system with aromatic character. 1
H and 13C NMR spectral data of 4-pyridone
1
H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-2/H6, 7.98; H-3/H5, 6.63
C-2/C-6, 139.8; C-4, 175.7; C-3/C-5, 115.9
The IR spectrum of 4-pyridone shows a medium intensity band at 3200 cm−1. A strong band at 3104 cm−1 is for the NH stretching vibration and a strong band at 1638 cm−1 is for the carbonyl group. Importance in Natural Products, Medicines, and Materials The 4-pyridone nucleus has attracted much attention in the development of antimalarial drugs resistant to P. falcifarum malaria. Drugs included in this category are GW844520, GW308678, and GSK932121 the diaryl ether substituted derivatives of anticoccidial drug clopidol.
Drugs containing 4-pyridone nucleus.
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2. Six-Membered Heterocycles
The 4-pyridone nucleus is also present in ciprofloxacin, an important antibacterial drug. 4-Pyridone has been used as a precursor for the synthesis of propyliodone, a diagnostic agent used in X-rays as a contrast agent and as an intermediate in the synthesis of pericyazine, a psychotropic agent. Synthesis 1. γ-Pyrone on reaction with ammonia yields 4-pyridone.
2. Cyclocondensation of heptane-2,4,6-trione with primary amine or ammonia yields 4-pyridone.
3. A simple method for the synthesis of 4-pyridones involves dimerization of N-acetoacetamides in the presence of sodium persulfate (Na2S2O8).216
Physical Properties 4-Pyridone is a crystalline compound with mp of 150°C and is soluble in water. Chemical Reactivity 1. Alkylation, arylation, acylation, and benzoylation: 4-Pyridone reacts with aliphatic acid anhydrides, acid chlorides, or free acids in the presence of dicyclohexylcarbodiimide and yields only the N-acyl derivative, i.e., 1-acetyl-4-pyridone, as the isolable product.217 This N-acyl derivative, however, equilibrates in solution affording a mixture with 4-acetoxypyridine.218
Similarly, 4-pyridone undergoes benzoylation with benzoyl chloride to yield the pyridine derivative.
N-Alkylation of 4-pyridone is achieved by first converting it into its O-trimethylsilyl ether derivative, selective reaction at nitrogen and subsequent removal of silicon yields N-alkylpyridone.219
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
67
Metalation followed by alkylation is achieved by first deprotonation of the α-proton of 1-methyl-4-pyridone with n-butyllithium, yields a 2-lithio derivative, which is used for the generation of 2-substituted 4-pyridone derivatives. The 2-lithio-4-pyridone was subsequently treated with THF at −78°C to 0°C with a range of acylating and alkylating agents, which generated a series of 2-substituted 4-pyridones.220
Reaction of 4-pyridone anions (obtained by the reaction of 4-pyridone with potassium tert-butoxide) with benzhydrylium ions (diarylcarbenium ions) and structurally related Michael acceptors in DMSO or CH3CN yielded N- and O-substituted derivatives.221
2. Electrophilic substitution reaction (a) Nitration of 4-pyridone takes place by heating it with a mixture of nitric and sulfuric acid yielding 3-nitropyridone.222
(b) Bromination of 4-pyridone with bromine in aqueous potassium bromide, buffered in the pH range of 3–5, yielded 3-bromopyridone as the major product. However, when bromination was carried out with concentrated hydrobromic acid, 3,5-dibromo-4-pyridone was the major product.223
68
2. Six-Membered Heterocycles
The reaction has been proposed to proceed by the following mechanism.
3. Replacement of oxygen: Chlorination of 4-pyridone with phosphorous oxychloride yields 4-chloropyridine.
4. Kolbe-Schmitt reaction: Sodium salt of 4-pyridone undergoes a Kolbe-Schmitt reaction, yielding a mixture of 4-oxo-1,4-dihydropyridine-3-carboxylic acid and 4-oxo-1,4-dihydropyridine-3,5-dicarboxylic acid.
5. Addition reaction: N-Protected pyridones like N-tert-butoxylcarbonyl-4-pyridone undergo 1,4-addition reaction with Grignard reagent in the presence of chlorotrimethylsilane (TMSCl) or boron trifluoride etherate (BF3·Et2O) yielding 2-substituted 2,3-dihydropyridones in excellent yield. The substituted pyridone derivative may react further with Grignard reagent to yield trans-2,6-disubstituted piperidones.224
2.3.11 Quinoline (Benzo[b]Pyridine)
Quinoline, also known as 1-aza-naphthalene, benzo[b]pyridine, or benzazine, is a bicyclic derivative of pyridine obtained by ortho-condensation of the benzene ring to the pyridine ring. Quinoline was first isolated from coal tar in 1834 by Friedlieb Ferdinand Runge, a German analytical chemist. Coal tar still remains the principal source of commercial quinoline. The name quinoline is derived from the alkaloid quinine, which has been used for centuries for the treatment of malaria.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
69
Structural and Reactivity Aspects225 Due to the presence of a nitrogen atom in the molecule there is unequal distribution of electron density in the pyridine as well as benzene rings. As a result, there is alteration in the physicochemical reactivity of the quinoline moiety. The electronegative nitrogen not only causes inductive polarization in the σ bond framework but also in the π electron system. The electronegative nitrogen also helps to stabilize those canonical structures in which nitrogen is negatively charged. The molecular dimensions of quinoline have not been accurately determined. The bond length and bond angles determined from X-rays of the Ni complex of quinoline were found to be different from those reported for quinolinium ion. The electron density calculations for quinoline and its protonated form as obtained by HMO treatment are listed in the following diagram.225
Hückel calculation shows there is π electron deficiency at positions 2 and 4, while the highest electron densities are at positions 1(N), 8, 3, and 6. On protonation there is an increase in the π electron density at position 3. The chemical reactivity of quinoline toward nucleophilic substitution (I) by −OH, BF4−, and CN− and toward electrophilic substitution (II) by sulfonation, nitration, and mercuration is shown in the following diagram.225
The 1H and 13C NMR data of quinoline confirm it to be a 10π-delocalized electron system with aromatic character.225 H and 13C spectral data of quinoline
1
1 H NMR (CCl4) δ (ppm)
13
C NMR (CCl4) δ (ppm)
H-2, 8.80; H-3, 7.26; H-4, 8.00; H-5, 7.68; H-6, 7.43; H-7, 7.61; H-8, 8.05
C-2, 150.89; C-3, 121.67; C-4, 136.12; C-5, 128.46; C-6, 129.95; C-7, 129.86; C-8, 130.5; C-9, 149.28; C-10, 128.89
Importance in Natural Products, Medicines, and Materials The quinoline nucleus is present in a number of natural products like tecleabine, tecleoxime, and quinine, which are significant with respect to medicinal chemistry and biomedical use. In addition, the quinoline nucleus has also been identified in a number of naturally occurring alkaloids having diverse biological and pharmaceutical properties. These compounds have been found to display antimalarial, antibacterial, antifungal, anticancer, and anti-HIV activities.226
70
2. Six-Membered Heterocycles
Natural products and drugs containing quinoline nucleus.
Quinoline is also used as a reactant for the synthesis of 8-hydroxyquinoline, which is a versatile chelating agent. Furthermore, quinoline on oxidation yields pyridine-2,3-dicarboxylic acid, which is a precursor to an herbicide sold under the brand name Assert. Synthesis 1. During structure elucidation of quinoline, its structure was confirmed by synthesis in which allylaniline was passed over glowing lead oxide to form 1-nitrocinnamaldehyde.227
2. Quinoline is synthesized by the reaction of aniline with acrolein. During the process, two new bonds were formed leading to the generation of a new ring.
3. Skraup synthesis: This reaction is named after the Czech chemist Zdenko Hans Skraup.228 The process involves heating aniline or its derivative having a vacant ortho-position with glycerol, concentrated sulfuric acid, and an oxidizing agent.
Mechanism: The reaction most likely proceeds with the acid-catalyzed dehydration of glycerol to α,β-unsaturated aldehyde-acrolein (generated in situ).
Aniline adds to the carbon-carbon double bond of acrolein to yield a product, which then undergoes a ring closure process. Dehydration yields 1,2-dihydroquinoline, which on oxidation yields quinoline.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
71
Several modifications for the synthesis of quinoline derivatives by Skraup reaction have also been reported.229 4. Doebner-Miller synthesis: The reaction named after German chemists Oscar Doebner and Wilhelm von Miller is in fact a modification of Skraup synthesis and involves reaction of primary arylamine with the unsubstituted ortho-position with a carbonyl compound in the presence of proton acid and oxidant to yield quinoline.230
The reaction initially allows the formation of Schiff’s base. Two molecules of this base undergo self-condensation to form quinoline.
Several modifications for the synthesis of quinoline derivatives by Doebner-Miller reaction have also been reported.229, 231 5. Doebner synthesis: The reaction named after Oscar Doebner involves a reaction of aniline with an aldehyde and pyruvic acid to yield 2-substituted quinoline 4-carboxylic acid, which decarboxylates to give 2-substituted quinoline.232
72
2. Six-Membered Heterocycles
Mechanism: The best pathway involves condensation of aniline with aldehyde to form a Schiff’s base, which is then attacked by the enol form of pyruvic acid to yield an intermediate, which undergoes intramolecular cyclization yielding a product that is oxidized to a quinoline derivative.
6. Combes quinoline synthesis: This reaction is named after Alphonse-Edmond Combes, a French chemist, who first reported the reaction in 1888.233 The reaction involves condensation of arylamines with 1,3-diketones. Enamine formed during the reaction undergoes ring closure in the presence of concentrated sulfuric acid to yield a quinoline derivative.
Mechanism: The reaction involves nucleophilic addition of aniline to the protonated carbonyl carbon of the 1,3-diketone. Proton transfer followed by loss of a molecule of water leads to an enamine, which under the influence of sulfuric acid undergoes ring closure, followed by aromatic annulation, yielding a quinoline derivative.
7. Friedlander quinoline synthesis: This reaction is named after German chemist Paul Friedlander is another useful method for the synthesis of quinoline. The reaction involves condensation of 2-aminobenzaldehyde or 2-aminoacetophenone with an aldehyde or ketone containing an active methylene group in the presence of an acid or base.234 The acids and bases more commonly used are trifluoroacetic acid, toluenesulfonic acid, Lewis acids, and sodium hydroxide.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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Mechanism: The first step of the reaction is the formation of a Schiff’s base, which then undergoes ring closure leading to the generation of quinoline.
Several modifications of the Friedlander reaction have been reported. For example Niementowski reaction and Pfitzinger synthesis. (a) Niementowski reaction235: By this reaction, 4-hydroxyl quinoline derivatives are synthesized by reaction of anthranilic acid with ketones.
Mechanism: As in the case of the Friedlander reaction, this reaction also takes place with the formation of an imine intermediate.
(b) Pfitzinger synthesis236: This is also known as the Pfitzinger-Borsche reaction. It involves the condensationcyclization of 2-aminophenylglyoxalic acid derived by alkaline hydrolysis of isatin with acetone to yield quinoline 4-carboxylic acids.
74
2. Six-Membered Heterocycles
Quinoline derivative in excellent yield is also obtained by reaction of isatin with chloropyruvic acid.237
Faced with several difficulties, a number of improvements have been made238 and this condensation reaction can now also be performed under acidic conditions.239 A microwave-assisted Pfitzinger-type condensation reaction was carried out between isatin and sodium pyruvate yielding quinoline-2,4-dicarboxylic acid.240
8. Meth-Cohn synthesis241: This reaction, also known as the “Vilsmeier approach,” is the conversion of acetanilides into 2-chloro-3-substituted quinolones by a reaction with Vilsmeier’s reagent in warm phosphorous oxychloride.242
2-Substituted quinoline derivatives in good yield were produced by the cyclization of deactivated acetanilide in the presence of trimethylammonium bromide under Vilsmeier-Haach conditions244 or when Meth-Cohn synthesis was ultrasonically irradiated.245 9. Conrad-Limpach synthesis: Discovered by Max Conrad and Leonhard Limpach this is the reaction of anilines with β-ketoesters to yield 4-hydroxyquinoline.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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10. Gould-Jacobs reaction: Condensation of aniline with acetyl malonic ester or ethoxymethylenemalonate generates anilinomethylenemalonic ester, which on heating at high temperature underwent cyclization to yield an ester. Saponification of the ester followed by decarboxylation produced 4-hydroxyquinoline.246
A microwave-assisted condensation reaction between aromatic amine and ethoxymethylenemalonate under s olvent-free conditions not only increases the yield but also shortens the reaction time.247, 248 11. Knorr quinoline synthesis: The reaction named after Ludwig Knorr is one of the oldest but is still a useful method for the synthesis of quinoline. The reaction requires condensation between arylamine and βketoester forming an anilide derivative, which in the presence of sulfuric acid undergoes cyclization forming 2-hydroxyquinoline.249
12. Camps quinoline synthesis: o-Acylaminoacetophenone in the presence of aqueous alkali is transformed to a mixture of 2-hydroxyquinoline and 4-hydroxyquinoline.250
13. Baylis-Hillman synthesis: This reaction is also known as the Morita-Baylis-Hillman reaction. It is a useful method for the formation of a carbon-carbon single bond yielding a product with a new stereocenter called Baylis-Hillman adduct.251 This reaction procedure has been used for the synthesis of a quinoline Baylis-Hillman adduct of o-halobenzaldehes.252
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2. Six-Membered Heterocycles
14. Heck quinoline synthesis: One-pot synthesis of substituted quinolines via Heck reaction of 2-bromoanilines with allylic alcohol followed by dehydrogenation with diisopropyl azodicarboxylate (DIAD) has been reported.253
15. By reduction: o-Nitrocinnamic aldehyde or ketone on reduction cyclizes in situ to yield a quinoline derivative.
When reduction is carried out with triethylphosphite, alkoxyquinoline is the product.
16. From oxazole: Acid-catalyzed condensation of an o-chlorobenzaldehyde derivative with 4,5-dihydrooxazole leads to the generation of a 3-substituted-2-quinolone derivative.
Palladium-catalyzed hydrogenation/heterocyclization of acetylenic derivatives yields quinolines.254
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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Palladium-catalyzed reaction of 2-aminobenzyl alcohol with ketones in toluene or polyethylene glycol255 afforded quinoline in good yields. 17. A new, convenient, efficient and eco-friendly montmorillonite K10 clay-catalyzed synthesis of a quinoline derivative has been reported. The reaction involves treating aniline derivative with cinnamaldehyde under solvent-free conditions with the assistance of microwave irradiation.256
18. A new photochemical method for the synthesis of 2,4-diiodoquinoline derivative by cyclization of o-alkynylaryl isocyanide with iodine has been developed.257
Physical Properties Quinoline is a colorless, hygroscopic liquid with a smell similar to pyridine. Quinoline is only sparingly soluble in water but miscible with nearly all organic solvents. Quinoline when exposed to light for a longer duration turns yellow and subsequently brown. The bp of quinoline at 760 mm was found to be 237.1°C. Its freezing point was reported to be −14.94°C, whereas the calculated value was −14.85°C. The density of quinoline at 25°C has been reported to be 1.08981. The dipole moment of quinoline has been determined both in the vapor phase and in the liquid phase. In the vapor phase the dipole moment was 2.29 D, whereas in carbon tetrachloride it was found to be 2.27 D. Quinoline is a base because the lone pair of electrons on the nitrogen atom of pyridine is not involved in the formation of a delocalized π-molecular orbital. Quinoline is aromatic with a resonance energy of 47.3 and is considered to be a resonance hybrid of the following contributing structures.
Resonance structures of quinoline.
Structures I, II, and III are of lower energy; however, additional charged structures IV–VIII are also possible because of the presence of the electronegative nitrogen atom. The dipole moment of quinoline is 2.10 D, which confirms the presence of charge separation within the ring. Chemical Reactivity 1. Electrophilic substitution reaction: The nitrogen atom of quinoline has a deactivating effect on the ring toward the substitution reaction. Consequently, the electrophilic substitution reaction does not take place in the pyridine ring but in the benzene ring substitution can take place at the C-5- and C-8-positions. Attack at C-5 and C-8 is favored because the intermediate produced as a result of electrophilic attack at these positions can be represented by resonance structures in which the aromaticity of the heterocyclic ring is still preserved.
Electrophilic substitution at C-5 and C-8.
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(a) Sulfonation: Sulfonation of quinoline with oleum at 90°C yields chiefly quinoline-8-sulfonic acid. However, because this product is sterically hindered, at higher temperatures it rearranges to 6-sulfonic acid.258
(b) Nitration: In comparison to pyridine, nitration of quinoline can be carried out under mild conditions. Nitration with the nitrating mixture (HNO3 + H2SO4) gives a mixture of 5- and 8-nitroquinoline in equal amount.
On nitration with transition metal salts like zirconium nitrate, quinoline yields a 7-nitro derivative.
Reaction with acetyl nitrate yields mainly 3-nitroquinoline. The reaction is thought to proceed by the 1,4-addition of acetyl nitrate to quinoline, followed by electrophilic attack on the 1,4-dihydro derivative.
(c) Halogenation: The product obtained after reaction of halogens with quinoline depends on the type of reagent used and the reaction conditions employed. For example, bromination of quinoline in the presence of silver sulfate and 98% sulfuric acid gave a mixture of 5- and 8-monosubstituted quinoline (when quinoline is used in excess). When bromine is used in excess, in addition to the two monosubstituted derivatives, 5,8-disubstituted quinoline is also formed.259
When bromination is carried out with bromine in the presence of pyridine, 3-bromoquinoline is the only product.260
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Formation of 3-bromoquinoline most likely takes place by the addition-elimination mechanism.
Regioselective iodination of quinoline at the C-3-position under metal-free conditions has also been reported, by carrying out a reaction in the presence of tert-butyl hydroperoxide and 1,2-dichloroethene.261
Iodination of quinoline is also achieved by reacting quinoline, K2S2O8, and sodium iodide in the presence of metal salts like bismuth nitrate or cerium nitrate.262
Iodination of quinoline at the 8-position (major product) is achieved via α-metalation using lithium di-tert- butyltetramethyl-piperidinozincate (TMP) at room temperature and using iodine as electrophile. However, 2-iodoisoquinoline is obtained as the minor product.263
(d) Mercuration: At room temperature quinoline reacts with mercuric acetate forming quaternary N-mercuric acetate. However, at higher temperatures further substitution takes place and in the presence of sodium chloride a mixture of 3- and 8-quinolinemercurichlorides is obtained.
2. Nucleophilic substitution reaction: Nucleophilic addition reactions give tetrahydroquinolines, which are important synthetic intermediates and structural units of alkaloids and biologically active compounds.264 However, nucleophilic substitution reaction takes place in the quinoline in the heterocyclic ring and also at the 2- or 4-positions. (a) Chichibabin reaction: Quinoline reacts with potassium amide in liquid ammonia at −70°C to yield 2-amino-1, 2-dihydroquinoline (the 2-quinoline adduct rearranges to 4-quinoline adduct at higher temperatures), which on oxidation with potassium permanganate yields 2-aminoquinoline.
(b) Hydroxylation: Quinoline is hydroxylated directly by reacting it with potassium hydroxide at high temperature. The formation of 2-quinolone is thought to proceed by the SNAr process with hydride ion as the leaving group.265
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(c) Alkylation of quinoline with ethylene over a silicon-alumina catalyst gave 2-ethylquinoline as intermediate.266 Similarly, reaction of quinoline with formaldehyde in boiling alcohol gave 2-(2-hydroxyethyl)quinoline as intermediate.267 Both the intermediates on dehydrogenation and dehydration yielded 2-vinylquinoline.
Alkylation of quinoline was also achieved by treating it with olefins in the presence of an Rh(I)-phosphine catalyst. The reaction proceeds with the intermediacy of a substrate-based N-heterocyclic carbene complex.268
An enantioselective Petasis-type reaction of quinoline with phenylboronic acid in the presence of a thiourea catalyst resulted in the formation of 1,2-adduct.269
Reaction of quinoline with allyltrimethylsilane in the presence of chloroformate only took place when silver triflate was present in a catalytic amount. It was found that silver triflate increased the electrophilicity of N-acylquinolinium salt.270, 271
The attack of different Grignard and organolithium reagents on the quinoline nucleus yields the dihydro intermediate, which after hydrolysis and oxidation principally yields a 2-substituted quinoline derivative.272, 273
3. Substitution reaction by a free radical mechanism: Irradiation of quinoline in neutral ether sensitized by benzophenone gave 2- and 4-substituted quinolones. The reaction proceeds via an excited quinoline (due
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to π→π* transition). The C-2 radical and C-4 radical could combine with the α-oxyalkyl radical to give dehydrogenated C-2- and C-4-substituted quinolones.274, 275
Nitration of quinoline with dinitrogen tetroxide gave 7-nitro as the major product276 and nitration with pernitrous acid gave an equal amount of 6- and 7-nitroquinoline.277 The mechanism involved an attack by a hydroxyl radical to give intermediates, which on combination with a nitro radical followed by elimination of a molecule of water yielded 7-nitroquinoline.
4. Addition reactions: The most important addition reactions of quinoline are reduction reactions. Direct hydrogenation of quinoline is the most convenient route to tetrahydroquinolines, which are important synthetic intermediates. Due to the stability of 1,2-dihydroquinoline, there are a variety of addition reactions. Reduction of quinoline can be carried out with a variety of reagents. However, the pyridine ring is more easily reduced in comparison to the benzene ring. (a) Catalytic hydrogenation of quinoline with nickel occurs rapidly, generating 1,2,3,4-tetrahydroquinoline (A).278, 279 Catalytic hydrogenation can also be carried out with PtO2, ammonium acetate, and Pd/C. Extended hydrogenation times or under more drastic conditions generated cis-decahydroquinoline (C) and trans-decahydroquinoline (D).280 Catalytic hydrogenation of quinoline also led to the generation of 5,6,7,8-tetrahydroquinoline (D)281 along with 1,2,3,4-tetrahydroquinoline in a ratio of 47:2. 5,6,7,8-tetrahydroquinoline282 is also obtained by carrying out hydrogenation with platinum oxide and concentrated hydrochloric acid at room temperature with a hydrogen pressure of 50 psi.
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Sodium in liquid ammonia reduces quinoline to 1,2-dihydroquinoline. However, 1,2-dihydroquinoline was found to be unstable and later on it was reported that it was not 1,2- but 1,4-dihydroquinoline.283 Nevertheless, reduction with lithium in liquid ammonia with no proton source gave 1,2,3,4-tetrahydroquinoline. If methanol is present during the reduction process, 5,8-dihydroquinoline is the product.284
Reductive alkylation of quinoline with lithium metal in liquid ammonia gave 1,4-dihydro-1-alkyl derivative in high yield.285
One-pot reductive alkylation of quinoline was also carried out by treating it with sodium borohydride in carboxylic acid media yielding N-alkyl-1,2,3,4-tetrahydroquinoline.286
Enantioselective hydrogenation of quinoline derivatives using an iridium/phosphine/iodine system led to the synthesis of a tetrahydroquinoline derivative in excellent yield. This procedure has been applied for the synthesis of three naturally occurring alkaloids: angustureine, galipimine, and cuspareine.287
Enantioselective addition of organolithium reagent to quinoline in the presence of diamines, which are used as a chiral reagent, have led to the synthesis of enantiomerically enriched 2-substituted 1,2-dihydroquinoline.288 (b) Reissert reaction: Addition of KCN to quinoline in the presence of benzoyl chloride yields 1-benzoyl-2-cyano1,2-dihydroquinoline, also known as Reissert compound. The Reissert compound on hydrolysis in acidic medium yields an aldehyde and quinoline 2-carboxylic acid (quinaldic acid). Similarly, ethyl chloroformate and potassium cyanide react with quinoline to give a Reissert addition compound.
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The first enantioselective Reissert-type reaction was reported in 2001. The reaction involved reacting quinoline with electron-rich aromatic acid, a low polarity solvent, in the presence of a Lewis acid/Lewis base bifunctional catalyst.289
(c) Alkylation or arylation of quinoline with alkyl- or aryllithium (Reissert reaction) yields exclusively 2-alkylor 2-arylquinoline. The reaction takes place with the addition of organolithium reagent in a 1,2-fashion yielding an adduct, which on hydrolysis yields a 1,2-dihydroquinoline derivative. The dihydro derivative on oxidation with nitrobenzene yields 2-alkylquinoline and on reduction with sodium in ethanol, 2-substituted 1,2,3,4-tetrahydroquinoline is the product.
Quinoline reacts with phosphoryl chloride and phosphorochloridate to give a quaternary compound, which on reaction with indole yields a 1,2-dihydroquinoline derivative.290
5. Oxidation reactions (a) Depending on the type of reagent, oxidation affects both rings of quinoline. When oxidation is carried out with alkaline potassium permanganate solution, the pyridine ring remains intact, while the benzene ring is oxidized leading to the generation of quinolinic acid291 (pyridine 2,3-dicarboxylic acid). However, acidic permanganate solution oxidizes the pyridine ring, while the benzene ring remains intact leading to the formation of Nacylanthranilic acid.
(b) Ozonolysis of quinoline at −25 to −35°C yields glyoxal and 2,3-diformylpyridine.292 However, ozonolysis in dilute acetic acid gave a high yield of nicotinic acid, probably through a quinolinic acid intermediate. Nicotinic acid is also obtained by oxidation with potassium permanganate.
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(c) Oxidation of quinoline with peracid afforded quinoline N-oxide.
6. Ring-opening reaction: When quinoline reacts with thiophosgene in the presence of a base, fission of the Nheterocyclic ring takes place leading to the generation of 2-isothiocyanato-cinnamaldehyde.293
The reaction is thought to proceed with the formation of a dihydro intermediate, which underwent ring fission to yield Z-isothiocyanate, which subsequently isomerizes in situ to an E-isomer.
7. Formation of biquinolines: Heating quinoline with rhodium on carbon gave a high yield of 2,2′-biquinoline and an appreciable quantity of 2,3′-biquinoline.294
8. Nucleophilic substitution: The nitrogen atom of quinoline, by means of inductive and conjugative effects, activates the halogen atom at the 2- and 4-positions toward a nucleophilic substitution reaction.
For 4-haloquinoline, an elimination-addition mechanism with the formation of aryne intermediate has been proposed. As a result, a mixture of products is obtained.
2.3.12 Isoquinoline (Benzo[c]quinoline)
Isoquinoline, also known as 2-azanaphthalene, benzo[c]pyridine, or 2-benzanine, is a structural isomer of quinoline. It was first isolated in 1885 by Hoogewerf and van Dorp295 from the quinoline fraction of coal tar by fractional crystallization.
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Structural and Reactivity Aspects296 Isoquinoline has structural and spectroscopic properties similar to quinoline. Like quinoline it has been classified as a π-deficient system. The X-ray analysis of 3-methylisoquiline establishes it to be a planar molecule. The two CN bond lengths of 1.300 Å for the C1N bond and 1.366 Å for the NC3 bond are quite similar to the 1.34 Å bond distance for the CN bond in pyridine. Various bond lengths of 3-methylisoquinoline are listed in the following diagram.
Bond lengths of 3-methylisoquinoline.
The UV spectra of isoquinoline showed three wavelength bands [λmax nm/εmax] at 217 (37,000), 266 (4030), and 318 (3100) that correspond to π→π* transition. The n→π* transition band was not observed because it may have been masked by the π→π* transition band. The 1H and 13C NMR data of isoquinoline confirms it to be a 10π-delocalized electron system with aromatic character. 1
H and 13C NMR spectral data of isoquinoline
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1, 9.15; H-3, 8.45; H-4, 7.50; H-5, 7.51; H-6, 7.57; H-7, 7.50; H-8, 7.87
C-1, 150.89; C-3, 143.1; C-4, 120.4; C-5, 126.5; C-6, 130.6; C-7, 127.2; C-8, 127.5; C-4a, 135.7; C-8a, 128.8
Due to the presence of a lone pair of electrons on nitrogen, isoquinoline is basic, reacts with proton or electrophilic species at nitrogen, and yields isoquinolium salts. Basicity is increased by electron-donating substituents and decreased by electron-withdrawing groups. Since the lone pair of electrons on the nitrogen of isoquinoline is not delocalized into the π aromatic system of the molecule, isoquinoline is π electron deficient and as a consequence electrophilic substitution reaction takes place at a slower rate compared to naphthalene. When isoquinoline reacts with an electrophile, an intermediate is formed in which the electrophile is bonded to nitrogen, making the pyridine ring more π deficient; as a result, further electrophilic substitution reaction takes place on the benzene ring through a high-energy doubly charged Wheland-type intermediate yielding 5-substituted as the major product.
Electrophilic substitution in isoquinoline.
Nucleophilic substitution by hydride transfer by strong nucleophilic reagents such as Grignard reagents, organolithiums, sodium amide, etc. yield an intermediate stable product, which can be oxidized to yield a substitution product.
Nucleophilic substitution reaction in isoquinoline.
Importance in Natural Products, Medicines, and Materials Isoquinoline is important because this nucleus is present in a large number of alkaloids297 like berberine and papavarine, and is also a useful template for medicinal chemistry.298 Papaverine, an opium alkaloid, finds use as a muscle relaxant and a vasodilator. Antihypertensive drugs like debrisoquine, quinalapril, and quinalaprilat all contain an isoquinoline nucleus. Quinisocaine or dimethisoquin is a topical anesthetic, which finds use as an antipruritic. Hexadecamethylenediisoquinolium dichloride, which is used as a topical antiseptic, is prepared by N-alkylation of isoquinoline with an appropriate alkyl halide.
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2. Six-Membered Heterocycles
Natural products and drugs containing isoquinoline nucleus.
Synthesis 1. Bischler-Napieralski synthesis: This reaction is named after August Bischler and Bernard Napieralski. The reaction involves intramolecular cyclization of phenylethyl amides in the presence of POCl3 or P2O5 to give 3,4-dihydroisoquinoline, which can subsequently be oxidized to isoquinoline.299
Mechanism (by POCl3): Amide reacts with POCl3 to give imidoyl chloride (A), which on heating is converted to nitrilium salt (B). Intramolecular electrophilic aromatic substitution gives 3,4-dihydroisoquinoline.300
Mechanism (by PCl5): The amide derivative reacted with PCl5 to give the crystalline hydrochloride of benzimidoyl chloride. This salt loses hydrogen chloride at room temperature to give the cyclized product.301
Bischler-Napieralski reaction has most widely been used for the construction of dihydro- and tetrahydroisoquinoline units in the synthesis of natural products.302–304 2. Pictet-Gams reaction: This reaction named after A. Pictet and A. Gams305 is a variation of Bischler-Napieralski and involves cyclization of acylated aminomethyl phenyl carbinols or their ethers with phosphorous pentoxide in toluene or xylene. A postulated mechanism has been proposed by Fritton306 that involves the formation of oxazoline as an intermediate.
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Since the Pictet-Gams reaction requires strong acidic conditions and high temperatures to form the isoquinoline framework, a number of modifications are used such as milder reaction conditions and a mixture of trifluoroacetic anhydride and 2-chloropyridine or DMAP for electrophilic amide activation.
3. Gabriel-Colman rearrangement: This is the rearrangement of phthalimido ester in the presence of a strong base to yield substituted isoquinoline derivatives.307
The ester on hydrolysis followed by decarboxylation and hydrogenation yielded 1-hydroxyisoquinoline (isocarbostyril).
Mechanism: The base removes the acidic proton leading to the generation of ester enolate. Cycloproponation onto one of the phthalimide carbonyls yields an intermediate, which rearranges with ring expansion and subsequently aromatizes to isoquinoline.
N-Phthalimidoglycine ethyl ester have now been used to synthesize 4-hydroxyisoquinoline derivatives by adopting the Gabriel-Colman pathway.308
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2. Six-Membered Heterocycles
4. Pictet-Spengler synthesis: This reaction named after Ame Pictet and Theodor Spengler309 is a chemical reaction in which β-arylethyl amine undergoes ring closure after condensation with an aldehyde, ketone, or 1,2-dicarbonyl compound to give corresponding tetrahydroisoquinoline.
5. Pomeranz-Fritsch reaction: A general method for the synthesis of isoquinoline named after Casar Pomeranz and Paul Fritsch is also sometimes called Pomeranz-Fritsch cyclization because it involves acid-mediated cyclization of an appropriate aminoacetal intermediate obtained by reaction of aldehyde with amine.310, 311
Mechanism: Condensation between aldehyde and amine gives the imine, which on cyclization followed by elimination yields the isoquinoline derivative.
In 1965 Bobbit et al.312 carried out modification in Pomeranz-Fritsch reaction and as a result they synthesized 1,2,3,4-tetrahydroisoquinoline in high yield. In this modification the Schiff base obtained from aromatic aldehyde and amino acetal is first hydrogenated over platinum oxide to a secondary amine, which is cyclized with 6N HCl. The resulting 1,2,3, 4-tetrahydro-4-hydroxyisoquinoline is then hydrogenolyzed over 5% platinum-carbon to 1,2,3,4-tetrahydroisoquinoline.
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A new modification was proposed by Jackson et al.313 Schiff’s bases obtained from alkoxybenzaldehydes and aminoacetaldehyde dimethyl acetal were hydrogenated to benzyamines, which were converted to N-tosylates. The latter in the presence of dilute acid was readily cyclized to isoquinoline.
According to Schlittler-Müller modification,314 diethoxyethanal reacts with benzyl amine forming the desired imine, which is then cyclized to substituted isoquinoline.
6. Aza-Wittig reaction: 1,2-Monoazabisylide prepared in situ by the reaction of 1-[[(triphenylphosphoridiene) amino]methyl]benzotriazole with diethylphosphite anion on reaction with phthalaldehyde in the presence of butyllithium produced isoquinoline.315
7. From indene: Isoquinoline in high yield is prepared by treating indene with ozone at −70°C followed by reduction of dialdehyde with dimethylsulfide in the presence of ammonium hydroxide.316
8. Beckmann rearrangement: An environmentally friendly method for the synthesis of isoquinoline involves treating E,E-cinnamaldoxime under ambient reaction conditions on zeolites and alumina. E-Z isomerization takes place followed by Beckmann rearrangement leading to the formation of isoquinoline as a major product and cinnamonitrile as a minor constituent.317
9. Metal-catalyzed synthesis: Reaction of N-tert-butylbenzaldimines with internal alkynes in the presence of copper acetate catalyst in refluxing dichloroethane yielded isoquinolines in good yield.318
Zirconocene-copper-mediated coupling of benzocyclobutanes in the presence of nitriles yields 3-substituted isoquinoline.319
Reaction of o-tolualdehyde tert-butylimine with butyllithium in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine in THF at 0°C led to the formation of benzyl anion, which reacted with benzonitrile in THF and yielded an isoquinoline derivative.320
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2. Six-Membered Heterocycles
Palladium-catalyzed α-arylation of ketones with aryl halides containing a protected aldehyde or ketone at the o-position led to the generation of a pseudo-1,5-dicarbonyl intermediate, which on treatment with an acidic ammonium source led to concomitant acetal deprotection and aromatization and finally yielded an isoquinoline derivative.321
The Co(I)-catalyzed cycloaddition of nitrile with octa-1,7-dyne affords 5,6,7,8-tetrahydroisoquinoline.
Silver(I)-catalyzed aminofluorination of aryliminoalkynes with N-fluorobenzenesulfonimide (NFSI) led to the synthesis of 4- fluoroisoquinoline.322
A palladium-catalyzed, microwave-assisted, one-pot reaction of o-bromoarylaldehydes with terminal alkynes and ammonium acetate led to the synthesis of disubstituted isoquinolines.323
Cyclization of iminoalkynes in the presence of silver(I)-exchanged K-10 montmorillonite clay has also been used for the synthesis of isoquinoline in good yield.324
Physical Properties Isoquinoline is either a colorless crystalline, low-melting, hygroscopic solid with an mp of 26.48°C or a high- boiling liquid with a bp of 243.25°C (760 mm Hg), volatile in steam. Its density at 30°C is 1.0901 g/mL, whereas its viscosity at the same temperature is 3.2528 cP. Heat of aromatization (−∆Hn) of 85.32 eV and a resonance energy (ER)
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of 34.1 kcal/mol were calculated for isoquinoline. The dipole moment of isoquinoline at 30°C in benzene is 2.49 D. It has relatively low solubility in water but dissolves in nearly all organic solvents. Chemical Reactivity Isoquinoline is aromatic with a resonance energy of 143 kJ/mol and is considered to be a resonance hybrid of the following contributing structures. Structures I, II, and III, which are of lower energy, are the major contributors to the resonance hybrid. Additional charged structures IV–VIII are also possible, but there is disruption of the π system of both rings in these structures.
Resonance structures of isoquinoline.
1. Reaction with bases: Strong bases like Grignard reagent and organolithium tend to react like nucleophiles with isoquinoline. There are examples where isoquinoline has been converted into Grignard reagent by treatment with (iPr)2NMgCl, which has been shown to add to the variety of iodobenzenes.325 2. Reaction with acids: Isoquinoline being basic reacts with acids to form salts. Protonation usually takes place under strong acidic conditions at position 5. When isoquinoline is exposed to strong acidic conditions, reduction of the benzene ring takes place.326
3. Electrophilic substitution reaction: Electrophilic substitution reaction takes place preferably on ring carbon atoms and preferably at positions 5 and 8. (a) Nitration: Nitration of isoquinoline is better in comparison to quinoline because 5-nitroisoquinoline is obtained as the major product and 8-nitroisoquinoline as the minor constituent.
(b) Halogenation: Direct bromination takes place in the presence of strong protic acid or Lewis acid leading to the formation of 5-bromoisoquinoline as the major product.
5-Bromoisoquinoline327 is also obtained by treating isoquinoline with NBS in concentrated sulfuric acid with temperatures between −22 and −26°C.
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2. Six-Membered Heterocycles
Reaction of isoquinoline with hydrochloric acid yields isoquinoline hydrochloride. Bromination of hydrochloride in the presence of nitrobenzene yields 4-bromoisoquinoline by the following mechanism.328
The iodination of isoquinoline takes place via α-metalation using lithium di-(tert-butyl)tetramethyl-piperidino-zincate (TMP) at room temperature using iodine. The chemoselective deprotonative zincation yielded 1-iodoisoquinoline in high yield.329
Isoquinoline is selectively brominated at the 5-position using NBS in sulfuric acid and then subsequently nitrated without isolating the 5-bromo derivative by treating it with potassium nitrate yielding 5-bromo-8-nitroisoquinoline.330
(c) Sulfonation: Sulfonation of isoquinoline takes place in the presence of oleum at temperatures up to 180°C to afford 5-sulfonic acid.
4. Nucleophilic substitution reaction: Nucleophilic substitution reaction takes place preferably in the heterocyclic ring and chiefly at the 1-position. (a) Chichibabin reaction: Amination of isoquinoline with sodium amide in liquid ammonia yields 1-aminoisoquinoline.
(b) 1-Nitroisoquinoline can be synthesized when isoquinoline is treated with a mixture of potassium nitrite, dimethylsulfoxide, and acetic anhydride. The key step of the reaction is the nucleophilic addition of nitrite to isoquinoline, which is already quaternized by reaction through nitrogen with a complex of dimethylsulfoxide and acetic anhydride.331
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(c) Ziegler reaction: Reaction of isoquinoline with butyllithium yields the 1-substitution product 1,2dihydroisoquinoline, which is dehydrogenated in the presence of nitrobenzene to yield 1-butylisoquinoline.
(d) Reissert reaction: Isoquinoline on reaction with KCN in the presence of acylating agent PhCOCl yielded 2-acyl-1-cyano-1,2-dihydroisoquinoline. Useful transformations can be carried out with this 1,2-dihydro compound, commonly called Reisseit compound. When made to react with a strong base, deprotonation takes place yielding an anion, which rearranges to 1-benzoylisoquinoline after loss of cyanide followed by 1,2-acyl shift. When made to react with an electrophilic reagent like benzyl chloride in the presence of a strong base, 1-substituted isoquinoline derivative is formed, first with the formation of anion followed by cyanide elimination.332 Similarly, methylation can also be carried out by treating the Reisseit product with methyl iodide in the presence of phenyllithium, followed by base treatment.333
A new method has been developed for adding the benzyl group at the 4-position. The reaction involves treating isoquinoline with a metallic reagent, which results in addition taking place at the 1-position generating an intermediate, which then reacts with various benzyl chlorides followed by loss of N,N-diethyl o-toluamide.334
There are several methods to add the hydroxyl group to isoquinoline. For instance, on treating isoquinoline with potassium hydroxide at high temperature, addition takes place at the 1-position, which quickly tautomerizes to amide (isocarbostyril).335
5. Oxidation: Oxidation of isoquinoline with alkaline potassium permanganate solution yields a mixture of phthalic acid and pyridine 3,4-dicarboxylic acid. However, when oxidation is carried out with neutral potassium permanganate solution, phthalimide is the exclusive product.
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2. Six-Membered Heterocycles
6. Reduction: Isoquinoline is hydrogenated less readily in comparison to quinoline. Isoquinoline can be reduced to 1,2,3,4-tetrahydroisoquinoline by catalytic hydrogenation over platinum, by tin and hydrochloric acid, or by sodium in ethanol. Catalytic hydrogenation of isoquinoline over Raney nickel has been reported to proceed consecutively via 1,2,3,4-tetrahydroisoquinoline (A), 5,6,7,8-tetrahydroisoquinoline (B), and cisdecahydroquinoline (C) to trans-decahydroquinoline (D).
1,2,3,4-tetrahydroisoquinoline is also obtained by carrying out reduction with lithium triethylborohydride (super-hydride).336 One-pot reductive alkylation of isoquinoline was carried out by treating it with sodium borohydride in carboxylic acid media yielding N-alkyl-1,2,3,4-tetrahydroisoquinoline.337
7. Zincke’s reaction: A reaction named after Theodor Zincke is a reaction in which pyridine or its benzo derivative is transformed into pyridinium salt by reaction with 2,4-dinitrochlorobenzene.338
8. Electrocyclic reaction: Isoquinoline undergoes ring closure reactions to yield a compound in which there is an additional ring fused at nitrogen and the C-1-position. When isoquinoline is treated with DMAD, quinolizine tetracarboxylate is the product. But when in addition to DMAD phenyl isocyanate is also present, then pyrimido isoquinoline is produced in excellent yield.
Isoquinoline reacts with the oxirane ring in the presence of acetic acid yielding oxazolidine.339, 340
Isoquinoline reacts with DMAD in the presence of ethyl bromopyruvate to yield pyrrole [2,1-a]isoquinoline in high yields. The reaction is thought to proceed with the formation of a zwitterionic intermediate.341
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Isoquinoline reacts with benzyltrimethylstannanes in the presence of chloroformate to yield a 1-benzyl-1,2- dihydro derivative.342, 343
9. Nucleophilic substitution by displacement of a good leaving group: The nitrogen atom of isoquinoline by means of inductive and conjugative effects activates the halogen atom at the 1- and 3-positions toward a nucleophilic substitution reaction. 1,3-Dichloroisoquinoline under the action of red phosphorus and hydroiodic acid removes one of the halogens, which is then treated with sodium methoxide, yielding 3-methoxyisoquinoline. However, if 1,3-dichloroisoquinoline is directly treated with sodium methoxide, 1-methoxy-3-chloroisoquinoline is the product.
The bromine atom in 5-bromoquinoline undergoes replacement by cyanide by treating it with cuprous cyanide.
4-Bromoisoquinoline in the presence of palladium phosphine catalyst was carbonylated in ethanol to produce 4-carbethoxyisoquinoline.
Benzoquinolines Benzoquinolines are quinoline derivatives in which a benzene ring is fused to a quinoline molecule. All together there are five benzoquinoline derivatives, namely acridine (2,3-benzoquinoline), benzo[c]quinoline, (phenanthridine, 3,4-benzoquinoline), benzo[f]quinoline (5,6-benzoquinoline), benzo[g]quinoline (6,7-benzoquinoline), and benzo[h] quinoline (7,8-benzoquinoline).
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2. Six-Membered Heterocycles
Benzoquinolines.
Benzoquinolines form quaternary salts with alkyl halides. These quaternary salts have been used to distinguish between the linear and angular benzoquinolines. The linear benzoquinolines form bright yellow-colored hydrochlorides, whereas angular benzoquinolines form colorless hydrochlorides. For example, 1,3-diphenylbenzo[f]quinoline is colorless and forms colorless salt, whereas 2,4-diphenylbenzo[g]quinoline is yellow in color and forms orange-red salt. Fluorescence also helps to distinguish between two types of benzoquinolines. Angular benzoquinolines have a moderately strong blue-violet fluorescence, whereas linear benzoquinolines exhibit very light blue fluorescence.
2.3.13 Benzo[c]quinoline (Phenanthridine)
Phenanthridine, also referred to as benzo[c]quinoline or 5-azaphenanthrene, is an important nitrogen-containing compound formed by replacing the carbon atom of the central ring of phenanthrene by nitrogen. It is one of the products of the destructive distillation of coal from the high-boiling anthracene oil fraction. The discovery of phenanthridine was first reported by Pictet and Ankersmit in 1889 and they synthesized it by pyrolysis of benzylideneaniline.344, 345
Structural and Reactivity Aspects346 X-ray analysis of phenanthridine shows the molecule to be planar in the solid state with a mean deviation of 0.002 Å from the mean plane of carbon and nitrogen atoms. The bond angles (in degrees) and bond length (in Å) are given in the following table.347, 348
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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Bond lengths and bond angles of phenanthridine Bond length (Å)
Bond angles (o)
C(1)–C(2) 1.392
C(9)–C(10) 1.417
C(2)–C(1)–C(6) 121.58
N(14)–C(13)–C(12) 125.59
C(2)–C(3) 1.409
C(10)–C(11) 1.437
C(2)–C(1)–N(14) 118.87
C(1)–N(14)–C(13) 120.61
C(3)–C(4) 1.420
C(11)–C(12) 1.410
C(6)–C(1)–N(14) 119.48
H(15)–C(2)–C(1) 121.52
C(4)–C(5) 1.387
C(2)–H(15) 1.109
C(1)–C(2)–C(3) 119.67
H(15)–C(2)–C(3) 118.55
C(5)–C(6) 1.424
C(3)–H(16) 1.101
C(2)–C(3)–C(4) 120.03
H(16)–C(3)–C(2) 119.07
C(6)–C(1) 1.419
C(4)–H(17) 1.196
C(5)–C(4)–C(3) 119.48
H(16)–C(3)–C(4) 121.10
C(1)–N(14) 1.392
C(5)–H(18) 1.130
C(4)–C(5)–C(6) 121.63
H(17)–C(4)–C(3) 112.75
N(14)–C(13) 1.291
C(8)–H(19) 1.106
C(5)–C(6)–C(1) 117.58
H(17)–C(4)–C(5) 113.93
C(13)–C(12) 1.486
C(9)–H(20) 1.179
C(5)–C(6)–C(7) 121.49
H(18)–C(5)–C(4) 118.90
C(12)–C(7) 1.426
C(10)–H(21) 1.105
C(12)–C(7)–C(8) 116.27
H(18)–C(5)–C(6) 119.30
C(7)–C(6) 1.475
C(11)–H(22) 1.089
C(12)–C(7)–C(6) 117.59
H(19)–C(8)–C(9) 121.38
C(7)–C(8) 1.417
C(13)–H(23) 1.069
C(8)–C(7)–C(6) 125.87
H(19)–C(8)–C(7) 117.62
C(9)–C(8)–C(7) 120.72
H(20)–C(9)–C(8) 117.60
C(8)–C(9)–C(10) 124.77
H(20)–C(9)–C(10) 110.23
C(9)–C(10)–C(11) 115.78
H(21)–C(10)–C(9) 125.08
C(12)–C(11)–C(10) 119.25
H(21)–C(10)–C(11) 119.50
C(7)–C(12)–C(13) 115.57
H(22)–C(11)–C(12) 123.83
C(11)–C(12)–C(7) 122.85
H(22)–C(11)–C(10) 117.10
C(11)–C(12)–C(13) 121.58
H(23)–C(13)–N(14) 120.95
C(8)–C(9) 1.352
H(23)–C(13)–C(12) 113.50
The 1H NMR and 13C NMR chemical shifts of phenanthridine are given in the following table. In 1H NMR spectrum determination, phenanthridine was labeled with tritium. Regiospecificity and extent of labeling were also determined.349 H and 13C NMR spectral data of phenanthridine.
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1, H-10, 8.43; H-2, 7.67; H-3, H-8, 7.56; H-4, 8.17; H-6, 9.17; H-7, 7.90; H-9, 7.70
C-1, 121.0; C-2, 127.0; C-3, 128.3; C-4, 130.4; C-6, 153.1; C-7, 129.8; C-8, 128.2; C-9, 126.6; C-10, 121.3; C-1a, 126.6; C-4a, 144.1; C-7a, 142.0; C-10a, 127.7
The UV spectrum of phenanthridine (in ethanol) showed four bands at 245 nm (log ε 4.65), 289 nm (log ε 4.01), 330 nm (log ε 3.01), and 346 nm (log ε 3.01). The first two bands may be due to π→π* transition, whereas the third and fourth bands appear to be due to n→π* transition. The mass spectrum of phenanthridine shows a base peak at m/z 179. Other fragments along with appropriate metastable peaks are shown in the following diagram.
Mass fragmentation pattern of phenanthridine.
Importance in Natural Products, Medicines, and Materials Phenanthridines have been reported to possess enormous synthetic and biological activity.350 They have been reported to possess antifungal, antibacterial, antiprotozoal, and anticancer activities.351–353 Phenanthridine derivative 3,8-diamino-5-ethyl-6-phenylphenanthridinium, also known as ethidium bromide, is a trypanocidal and possible antiviral agent that has been used for decades as a standard DNA- and RNA-fluorescent marker. The phenanthridine
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2. Six-Membered Heterocycles
nucleus is present in a number of natural products, which have been reported to possess a wide variety of biological activity. For example, trispheridine and bicolorine have been reported for trypsominiasis,354 chelerythrine for antifungal,355 sanguinarine for antibacterial,356 and nitidine and fagaronine for antitumor treatment.357 In addition, the phenanthridine nucleus is also present in phenanthriplatin, which is an improved anticancer compound.358
Natural products and drugs containing phenanthridine nucleus.
Synthesis 1. Hubert-Pictet reaction: This is one of the direct methods for the synthesis of phenanthridine. The reaction involves cyclodehydration of acyl-o-aminodiphenyl in the presence of phosphorous oxychloride. Nitrobenzene was used as a solvent in the present reaction, due to its high boiling point and good ionizing properties.359
2. Phenanthridine is also obtained by the reaction of o-aminobiphenyl with formic acid. The intermediate, formamidobiphenyl, undergoes cyclization in the presence of polyphosphoric acid to give phenanthridine.
Phenanthridine and derivatives are also synthesized by the treatment of o-phenylaniline and its homologs with cyclic ketones under hydrothermal conditions.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
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3. Reaction of methyl 2-(2-nitrophenyl)phenylacetate with methanolic sodium hydroxide yields an acid, which on reductive decarboxylation yields phenanthridine.360
4. Phenanthridine is also prepared by the photolysis of benzylidenaniline.
5. Reaction of o-chlorobenzaldehyde with aniline led to the formation of Schiff’s base, which undergoes cyclization in the presence of potassium amide followed by deamination to yield phenanthridine. The reaction probably takes place via a benzyne intermediate.361
6. 3-Bromo-4-chloroquinoline reacts with lithium amalgam and furan to give phenanthridine. The reaction also takes place via a benzyne intermediate.362
7. Substituted phenanthridines are synthesized by one-pot annulations of 2-isocyanobiaryls with organoboronic acids under heating conditions. In the reaction, the isocyano group acts as a radical acceptor, which under radical cyclization yields phenanthridine.363
8. Substituted phenanthridines have been synthesized by the metal-free ion visible light-induced aerobic oxidative cyclization of 2-isocyanobiaryl.364
9. Substituted phenanthridines have also been synthesized by microwave-assisted [2+2+2] cyclotrimerization of alkynes.365
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2. Six-Membered Heterocycles
Physical Properties Phenanthridine is a colorless crystalline compound with mp of 108°C, which gives a weak blue fluorescein in dilute alcoholic solution. It is a weak base (pKa = 3.30 in 50% alcohol) forming colorless crystalline salts with mineral acids. It is a weaker base in comparison to quinoline and acridine. It has a dipole moment of 2.39 D.366 Chemical Reactivity 1. Electrophilic substitution reaction: Phenanthridine, because of its 9 nonequivalent positions where attack of electrophiles can take place, hence it is not possible to predict the most likely position at which the electrophilic substitution reaction will. (a) Nitration: Reaction of phenanthridine with a nitrating mixture results in the formation of 1-nitrophenanthridine and 10-nitrophenanthridine.
(b) Halogenation: Fluorination of phenanthridine with a mixture of gases, fluorine, and iodine afforded 6-fluorophenanthridine.
Bromination of phenanthridine gave 2-bromophenanthridine as the only product when the reaction was carried out with NBS. However, when bromination was carried out with molecular bromine in the presence of silver sulfate in 92% sulfuric acid, a mixture of 1-bromo-, 4-bromo-, and 2-bromophenanthridines was obtained. 2. Nucleophilic substitution reaction Chichibabin reaction: Reaction of phenanthridine with sodium amide in liquid ammonia yields 6-aminophenanthridine.
3. Oxidation reaction: Ozonolysis of phenanthridine followed by treatment with alkaline hydrogen peroxide readily yields 6-phenanthridone and quinoline-3,4-dicarboxylic acid.
4. Reduction reaction: Phenanthridine is readily reduced to 5,6-dihydrophenanthridine by the action of Sn/HCl. The same compound is obtained by hydrogenation of phenanthridine over Raney nickel.367
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5. Reissert reaction: Phenanthridine readily forms Reissert compound (a compound formed by the reaction of an acyl group and a cyano group to nitrogen and carbon atoms, respectively) by reacting it with KCN/C6H5COCl.
2.3.14 Benzo[f]quinoline
Benzo[f]quinoline is one of the structural isomers of the benzoquinoline family and is also known as 5,6-benzoquinoline, naphthopyridine, and 1-azaphenanthrene. It has been isolated from the high-boiling basic fraction of coal tar.368 Structural and Reactivity Aspects369 The 1H and 13C NMR data of benzo[f]quinoline confirm it to be a 14π heteroaromatic system. 1
H and 13C spectral data of benzo[f]quinolline
H NMR (CDCl3), δ (ppm)
C NMR (CDCl3), δ (ppm)
1
13
H-2, 8.94; H-3, 7.50; H-4, 8.87; H-5, 8.55; H-6, 7.67; H-7, 7.67; H-8, 7.99; H-9, 7.99; H-10, 7.99
C-2, 130.64; C-3, 128.62; C-4, 149.55; C-5, 125.02; C-6, 127.25; C-7, 128.03; C-8, 122.49; C-9: 121.21; C-10, 130.82; C-4a, 131.58; C-4b, 125.34; C-8a, 129.52; C-10a, 148.05
Mass spectrum: The molecular ion of benzo[f]quinoline appeared at m/z 179, which was also the base peak. The molecular ion undergoes loss of HCN leading to a fragment at m/z 151. Subsequent further fragmentation yields fragments at m/z 90 and m/z 76, respectively.
Mass fragmentation pattern of benzo[f]quinoline.
Importance in Natural Products, Medicines, and Materials Benzo[f]quinoline and benzo[h]quinoline are environmental contaminants and they have been detected in automobile exhausts, urban air particulates, and cigarette smoke. Both of them have been shown to be metabolically activated to products mutagenic to Salmonella typhimurium. Benzo[f]quinoline and its derivatives find use in various fields of chemistry, including pharmaceutical chemistry. These compounds have been found to exhibit antibacterial, antimicrobial, antimalarial, antipsychotic, uridine diphosphate glucuronosyl transferase, and peripheral dopaminergic activity.370 Synthesis 1. Skraup synthesis: Synthesis of benzo[f]quinoline by Skraup’s procedure was reported earlier.371, 372 However, an improved procedure involving heating 2-naphthylamine, glycerol, and sulfuric acid in the presence of arsenic acid has been reported.369
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2. Six-Membered Heterocycles
Similarly, 5-carboxybenzo[f]quinoline has been synthesized from 2-amino-3-naphthoic acid.373 2. Reaction of 4,7-phenanthroline 7-oxide with methylsulfinyl carbanion yields benzo[f]quinolines. C-8 is probably the position of nucleophilic attack and subsequent ring opening and ring closure on to the methyl sulfinyl carbon leads to expulsion of the N-oxide group.374
3. Photolysis of trans-2-stilbazole in cyclohexane solution in the presence of oxygen was carried out, and benzo[f] quinoline along with a minor pyridine photoproduct was also obtained.375
4. Stirring a mixture of arenecarbaldehyde, naphthalene-2-amine, and acetone at 50°C in THF in the presence of 5 mol% of iodine afforded benzo[f]quinolines in good yield.376
Similarly, refluxing a mixture of arenecarbaldehyde, naphthalene-2-amine, and cyclopentanone in THF in the presence of 5 mol% iodine afforded benzo[f]cyclopenta[c]quinoline in high yield.
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103
5. Reaction of 2-aminonaphthalene-1-sulfonic acid with aromatic aldehyde in absolute ethanol leads to the generation of Schiff’s base. Condensation of the Schiff’s base with acetone in the presence of acid yields substituted benzo[f]quinoline derivative.377
6. Reaction of 2-naphthylamine with ethylpropiolate in toluene as solvent and trifluoroacetic acid as acid and microwave irradiation at 150°C yielded ethylbenzo[f]quinoline-2-carboxylate.378
Physical Properties 5,6-Benzoquinoline is a crystalline compound with mp of 93°C, bp 350°C/721 mm Hg, soluble in dilute acids, alcohol, ether, and benzene. It is used as a reagent for the determination of cadmium. Chemical Reactivity 1. Acetylation: The interaction of benzo[f]quinoline with ethyl alcohol and carbon tetrachloride in the presence of copper catalysts Cu(OAc)2, CuI, CuBr2, Cu(acac)2, Cu(C6H5CO2)2, or CuCl2·2H2O under optimized reaction conditions led to the formation of 2-acetylbenzo[f]quinoline. However, the highest yield was obtained when copper acetate was used as catalyst. The structure of the compound was confirmed by X-ray analysis.379
2. Alkylation: Reaction of benzo[f]quinoline with methyl sulfinyl carbanion in DMSO at 70°C using sodium hydride as a base yielded 5- and 6-methylbenzo[f]quinoline.380
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2. Six-Membered Heterocycles
3. Bromination: Reaction of benzo[f]quinoline with cyanogen bromide in methanol followed by application of bromine and sodium carbonate gave 2-bromo-4-cyano-1,3-dimethyl-1,2,3,4-tetrahydrobenzo[f]quinoline, which on hydrolysis resulted in the quantitative formation of 2-bromobenzo[f]quinoline.381
4. Nitration: Benzo[f]quinoline on reaction with fuming nitric acid and concentrated sulfuric acid at −15°C yields 7-nitrobenzo[f]quinoline. However, when the temperature was raised to 0°C, then 7,9-dinitrobenzo[f]quinoline was obtained.382
5. Fluorination: Electrochemical fluorination of benzo[f]quinoline using Et4NF.4.45HF as the electrolyte at a constant electric potential of 2.5 V was carried out. The electrolytic product was subsequently treated with aqueous alkali at room temperature whereby 7,10-difluoro- and 7,7,10,10-tetrafluorobenzo[f]quinoline were isolated383
6. Nucleophilic substitution: Positions close to the nitrogen are electrophilic and can thus undergo nucleophilic addition with alkyllithiums. Deprotonation was achieved by treating benzo[f]quinoline with a super-basic system like BuLi-LiDMAE and then quenching the reaction mixture with different electrophiles like C2Cl6, CBr4, and PhSSPh yielding 3-chloro-, 3-bromo-, and 3-phenylthiobenzo[f]quinoline.384
7. Reduction: Hydrogenation of 5,6-benzoquinoline methoiodide over Raney nickel in the presence of diethylamine yielded 1,2,3,4-tetrahydro-1-methyl-5,6-benzoquinoline.385
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105
Catalytic hydrogenation of benzo[f]quinoline with platinum oxide in trifluoracetic acid and subsequent treatment with acetic anhydride (Eliel’s method386) yielded 4-acetyl-1,2,3,4,7,8,9,10-octahydrobenzo[f]quinoline, 7,8,9,10-tetrahydrobenzo[f]quinoline, and 5,6,6a,7.8.9.10,10a-octahydrobenzo[f]quinoline.387
Selective reduction of the heterocyclic ring of benzo[f]quinoline takes place in the presence of chlorotris(triphenylphosphine)rhodium(I) as hydrogenation catalyst.388 8. Epoxidation: The 5,6-bond of benzo[f]quinoline is the reactive site and under phase transfer conditions it reacts with sodium hypochlorite solution to yield benzo[f]quinoline-5,6-epoxide.389
9. Replacement reaction: A chlorine atom bonded to carbon adjacent to the nitrogen of the ring is a better leaving group in comparison to those in which they are away from nitrogen. Thus 1-methyl-3-chloro-benzo[f] quinoline reacted faster with hydrazine hydrate to yield a hydrazine derivative in comparison to 1-chloro-3methylbenzo[f]quinoline.390 Reaction of hydrazine derivative with nitrous acid and formic acid leads to the generation of cyclic compounds.
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2. Six-Membered Heterocycles
2.3.15 Benzo[h]quinoline
Benzo[h]quinoline is one of the structural isomers of the benzoquinoline family and is also known as 7,8-benzoquinoline and 1-naphthaquinoline. Structural and Reactivity Aspects The NMR spectrum of benzo[h]quinoline was reported by Donckt et al.,391 which was not very clear. However, a simplified 1H and 13C NMR of its acetyl derivative is reported here.392 1 H NMR (400 MHz, δ ppm from tetramethylsilane [TMS] in CDCl3) 3.00 s (3H, COCH3), 7.67 d (1H, J = 9 Hz, H-5), 7.80 t (1H, J = 8 Hz, H-9), 7.77 t (1H, J = 8 Hz, H-8), 7.88 d (1H, J = 9 Hz, H-6), 7.93 (1H, H-7), 8.23 s (2H, H-3, and 4), 9.35 d (1H, J = 8 Hz, H-10) 13 C NMR (100 MHz, δ ppm from TMS in CDCl3) 200.68 (CO), 25.77 (CO-CH3), 118.87 (C-3), 124.48 (C-10), 124.92 (C-5), 127.50 (C-9), 127.97 (C-7), 128.35 (C-4a), 128.63 (C-8), 133.71 (C-10a), 130.00 (C-6), 131.63 (C-6a), 136.49 (C-4), 151.60 (C-2) Importance in Natural Products, Medicines, and Materials A number of natural products, chiefly alkaloids, have been isolated, which possess a benzo[h]quinoline nucleus. For example, two alkaloid derivatives (A and B) have been isolated from the fruits of Macleaya cordata and they possess a benzo[h]quinoline nucleus.
Alkaloids containing benzo[h]quinoline nucleus.
A benzo[h]quinoline moiety has been recognized as a potential precursor to analogs of a number of agents with anticancer activity393 and significant antioxidant activity against various in vitro antioxidant systems. These derivatives bind DNA via intercalative modes thereby protecting DNA from harmful free radical reactions.394 Synthesis 1. Skraup synthesis: Synthesis of 7-nitrobenzo[h]quinoline has been achieved by heating 4-nitro-1-naphthylamine with glycerol and sulfuric acid in the presence of an oxidizing agent like arsenic acid.395
Synthesis of benzo[h]quinoline by the Skraup procedure is also carried out by heating 1-naphthylamine with glycerol in the presence of Sulfo-mix,396 ferrous sulfate, and boric acid.397
2. Reaction of 1-naphthylamine with ethylpropiolate in toluene as solvent and trifluoroacetic acid as acid and microwave irradiation at 150°C yielded ethylbenzo[h]quinoline-3-carboxylate.398
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
107
Chemical Reactivity 1. Acetylation: The interaction of benzo[h]quinoline with ethyl alcohol and carbon tetrachloride in the presence of copper catalysts Cu(OAc)2, CuI, CuBr2, Cu(acac)2, Cu(C6H5CO2)2, or CuCl2·2H2O under optimized reaction conditions led to the formation of 2-acetylbenzo[h]quinoline. However, the highest yield was obtained when CuI was used as catalyst.399
2. Alkylation: Reaction of benzo[h]quinoline with methyl sulfinyl carbanion in dimethylsulfoxide at 70°C using sodium hydride as a base yielded 4-, 5-, and 6-methylbenzo[h]quinoline.400
3. Chlorination: Palladium(IV) complexes have been reported to be intermediates in the functionalization of arene/alkane CH bonds. The method employs palladium(II) acetate as catalyst in conjugation with a terminal oxidant such as PhICl2 or N-halosuccinimide. Reaction kinetic reveals that palladium complex formed during the reaction is the complex from which CCl bond formation takes place during the catalysis process.401
4. Fluorination: Electrochemical fluorination of benzo[h]quinoline using Et4NF.4.45HF as the electrolyte at a constant electric potential of 2.5 V was carried out. The electrolytic product was subsequently treated with aqueous alkali at room temperature whereby 5-fluoro-, 5,6-difluoro-, and 7,10-difluorobenzo[h]quinoline were isolated.402
5. Nucleophilic substitution: Carbon adjacent to the nitrogen is electrophilic and thus undergoes nucleophilic addition of alkyllithiums. Deprotonation was achieved by treating benzo[h]quinoline with a super-basic system like BuLi-LiDMAE and then quenching the reaction mixture with different electrophiles like C2Cl6 and CBr4 yielding 2-chloro and 2-bromobenzo[h]quinoline.403
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2. Six-Membered Heterocycles
6. Amination: Direct amination of benzo[h]quinoline was achieved by treating it with p-dodecylbenzylsulfonyl azide in dichloroethane in the presence of dichloro(η5-pentamethylcyclopentadienyl)-rhodium(III) dimer and silver hexafluoroantimonate(V).404
7. Epoxidation: Reaction of benzo[h]quinoline with Fremy’s salt afforded 7,8-dione derivative, which on reduction with potassium borohydride afforded dihydro diol. Epoxidation of the dihydro diol with an excess of m-chloroperbenzoic acid afforded the antidiol epoxide.405, 406
8. Reduction: Hydrogenation of benzo[h]quinoline with platinum oxide in trifluoracetic acid yielded 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinoline, 1,2,3,4,7,8,9,10-octahydrobenzo[h]quinoline, and 7,8,9,10-tetrahydrobenzo[h]quinoline.407
Selective reduction of the heterocyclic ring of benzo[h]quinoline takes place in the presence of chlorotris(triphenylphosphine)rhodium(I) as hydrogenation catalyst.408 9. Replacement reaction: A chlorine atom in a position adjacent to the nitrogen of the ring is a better leaving group in comparison to those in which they are away from nitrogen. Thus 2-chloro-4-methylbenzo[h]quinoline reacted faster with hydrazine hydrate to yield hydrazine derivative in comparison to 4-chloro-2-methylbenzo[h] quinoline.409 Reaction of these hydrazino derivatives with nitrous acid and formic acid leads to the generation of cyclic compounds.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
109
2.3.16 Acridine (Dibenzo[b,e]pyridine)
Acridine, also known as bibenzo[b,e]pyridine and benzo[b]quinoline, is a linear, planar, tricyclic aromatic nitrogen heterocycle structurally related to anthracene with one of the central CH groups being replaced by nitrogen. Acridine was first isolated from the high-boiling anthracene fraction of coal tar in 1870 by Carl Grabe and Heinrich Caro. On account of its acrid smell and its irritating action on the skin and mucous membrane, this new compound was given the name “acridin” (acris meaning sharp or pungent). Acridines were first developed as dyes and then in the early 20th century they were evaluated for their pharmacological properties. Structural and Reactivity Aspects Under the influence of different solvents, acridine is known to crystallize in six different polymorphs. They differ greatly in their stability and crystal habit. Some of them have been studied in detail.410 Acridine has been classed as a π electron deficient heterocycle; as a result, it shows poor fluorescence properties. Its blue fluorescence in dilute aqueous or dilute alcoholic solution is one of its most characteristic properties. Potentiometric titration values indicate that acridine pKa 5.60 is a stronger base than quinoline pKa 4.94 or pyridine pKa 5.23. Studies have shown that the pKa value of acridine is more sensitive to the solvent effect compared to quinoline or pyridine.411 The HOMA and NICS (1) values calculated 1 Å above the ring critical point for rings A, B, and C of acridine are 0.6275, 0.7287, and 0.6271 and −16.0218, −22.4097, and −16.0185, respectively. The standard molar heat capacity Cp, m0 in the crystalline state at 0.1 MPa and 298.15 K was calculated to be 203.5 J K‑1 mol‑1 and measured at 201.5 J K‑1 mol‑1. Gas phase basicity (GB298), proton affinity, and protonation entropy (Sprot) of aciridine were determined to be 224.4, 232.5, and 0.7 kcal mol‑1.412
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2. Six-Membered Heterocycles
From the study of the different spectroscopic techniques, their spectra show the relationship of spectra to their structure. The UV and 13C NMR spectral data413 of acridine are given in the following table. UV and 13C NMR spectral data of acridine UV (ethanol) λ (nm) ε
13
C NMR (CDCl3) δ (ppm)
249 (5.22), 339 (3.81), 351 (4.0), 379 (3.44)
C-1, 129.5; C-2, 128.3; C-3, 125.5; C-4, 130.3; C-9, 135.9; C-1a, 126.6; C-4a, 149.1
Importance in Natural Products, Medicines, and Materials A number of pharmaceutical agents and dye stuffs have been found to possess an acridine nucleus like mepacrine, also called quinacrine (antimalarial, antiprotozoal, and antirheumatic agent), acriflavinium chloride (topical antiseptic), proflavine (disinfectant bacteriostatic against Gram-positive bacteria), ethacridine (antiseptic), bucricaine (anesthetic), amsacrine (antileukemic), asulacrine (anticancer), nitracrine (antitumor), tacrine (cholinesterase inhibitor for Alzheimer’s disease) acridine orange (fluorescent cationic dye), and quinacrine mustard (a fluorescent probe).
Dyes and drugs containing acridine nucleus.
Synthesis 1. Bernthsen synthesis: This reaction is named after August Bernthsen, a German chemist,414 who first reported acridine synthesis in which diphenylamine was condensed with benzoic acid in the presence of zinc chloride at higher temperatures. Thus this method is used for the synthesis of 9-substituted acridines.
2.3 Six-Membered Isolated and Benzo-Fused Heterocycles With One Nitrogen Atom
111
The yield of acridine by the Bernthsen method was low; hence in 1962 F.D. Popp reported an improved method in which polyphosphoric acid was used in lieu of zinc chloride.415
Microwave-assisted Bernthsen synthesis of a variety of 9-substituted acridines has been reported.416
Acridines are also obtained by heating o-arylaminophenylketones in the presence of strong acids like sulfuric acid or polyphosphoric acid.
All these reactions are cyclodehydration reactions with the cyclization being intramolecular SEAr in nature. 2. Ullmann reaction: This reaction is named after Fritz Ullmann, a German chemist. The reaction involves condensing o-chlorobenzoic acid with aniline or anthranilic acid in the presence of a copper catalyst, yielding N-phenylanthranilic acid, which on treatment with sulfuric acid or polyphosphoric acid undergoes cyclization to yield 9-acridone. Reduction followed by oxidation yields acridine. Alternatively, in Goldberg’s method, Nphenylanthranilic acid on reaction with phosphorous oxychloride yields 9-chloroacridine, which on reduction followed by oxidation yields acridine417
Halogen-substituted aryl ketones have also been used for the synthesis of 9-substituted acridines.
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2. Six-Membered Heterocycles
3. Friendlander synthesis: This reaction involves heating salt of anthranilic acid with cyclohex-2-enone at 120°C, whereby 9-methylacridine is obtained
4. From acridones: A number of methods have been reported for the synthesis of acridine by reduction of acridones. Acridone on reaction with phenyllithium yields an adduct, which on acidification yields 9-phenylacridine in good yield.
Distillation of 9-acridone with zinc dust yields acridine.
Distillation of benzylaniline through a red-hot tube (700°C) yields acridine. Similarly, distillation of benzal-2- aminophenol over zinc yields acridine.
5. From 9-chloroacridine: Reaction of 9-chloroacridine with p-toluenesulfonyl hydrazine yields the corresponding acridyl derivative, which on treatment with sodium hydroxide yields acridine.
6. From acylated diphenylamines: Acylated diphenylamine when heated in the presence of I2/HI yields 9-phenylacridine.417
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7. From large rings: 9-Methylacridine is formed by the ring contraction of azepines.
Physical Properties Acridine, a lachrymator, causes skin irritation, is a yellow crystalline solid with mp of 114°C, and has an irritating odor. It is sparingly soluble in water, alcohol, and ether. It is aromatic in nature with a resonance energy of the order of 105 kcal/mol. It is weakly basic in nature and has a pKa value of 5.6, a slightly stronger base in comparison to pyridine. Chemical Reactivity 1. Electrophilic substitution reaction: Reaction of acridine with electrophiles often results in disubstitution at the 2- and 7-positions. (a) Nitration: Reaction of acridine with a nitrating mixture at 0°C results in the formation of 2,7-dinitroacridine.
(b) Bromination: Reaction of acridine with bromine results in the formation of di- as well monobromoacridine.
(c) Chlorosulfonation: Reaction of acridine with chlorosulfonic acid results in a mixture of 1-sulfonyl chloride and 1,8-disulfonyl chloride.418
2. Nucleophilic substitution reaction: Acridine undergoes nucleophilic substitution reaction chiefly at the 9-position and this is due to decrease in electron density at this position in comparison to the 1-, 2-, 3-, or 4-positions. Acridine reacts with nucleophiles leading to the generation of an acridane derivative, which undergoes rearomatization, depending on the stability of the acridane and reaction conditions.
Nucleophilic substitution in acridine.
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2. Six-Membered Heterocycles
Chichibabin reaction of acridine with sodium amide in liquid ammonia yields 9-aminoacridine.419
3. Reactivity of position 9: Reaction of acridine with N,N-dimethyl aniline yields 9,9′-biacridanyl (biacridane) as the major product. Biacridane along with 9-aminoacridine is also obtained when melted acridine reacts with sodamide420 under solvent-free conditions.
Reaction of acridine with reactive methylene compounds adds at the 9-position to form 9,10-dihydroacridine (acridane), which under suitable reaction conditions is rearomatized. For example, malonitrile on reaction with acridine yields an adduct, which on oxidation with MnO2 yields a 9-substituted nitrile derivative.
Similarly, nitromethane in basic medium reacts with acridine to yield 9-(nitromethyl)-9,10-dihydroacridine, whereas reaction with phenylmethylsulfone yields an adduct, which on elimination of phenylsulfinic acids yields 9-methylacridine.
Another useful reaction is the carboxylation at C-9. The process involves reaction of acridine with potassium cyanide, yielding 9-cyanoacridine, which is then hydrolyzed with H2SO4/NaNO2 to a carboxylic acid derivative.421
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Enolizable ketones like methyl ketones also react with acridine under Emmert reaction conditions and lead to the generation of 9-acridinyl ketones.422 The reactivity of such methyl ketones was found to be enhanced when they were used in the methyl iminium form.
Isopropyl at position 9 was introduced by the reaction of acridine with isopropyl carboxylic acid in the presence of silver nitrate.
Indole and its derivatives also react with acridine under solvent-free conditions. The heteroaromatic ring acts as a nucleophile with the conjugation taking place at position 3 of the indole ring, but if position 3 is occupied then conjugation takes place at the 2-position.
4. Oxidation: Acridine on oxidation with acidic sodium dichromate solution yields acridone, whereas oxidation with alkaline potassium permanganate solution yields quinoline-2,3-dicarboxylic acid.
5. Reduction: Acridine can be reduced by a number of methods. When reduction is carried out with an excess of lithium and ethanol in ammonia (Birch reduction), 1,4,5,8-tetrahydroacridine is the product.423
When reaction is carried out with sodium or sodium amalgam, lithium or lithium aluminum hydride, or Zn/ HCl, then reduction takes place in the pyridine ring leading to the generation of 9,10-dihydroacridine (acridane).424 However, a better yield of acridane was obtained when reduction was carried out with NiCl2-2H2O in THF and when reaction was carried out with [RuH2(η2-H2)(PCy3)2]; as a result, reduction selectively takes place in the benzene ring producing 1,2,3,4,5,6,7,8-octahydroacridine.425 When reduction was carried out with Rh/C or Rh/Al2O3, then tetradecahydroacridine was obtained.426 When reduction was carried out in μ3-oxo-trirhodium(III) acetate, then 1,2,3,4-tetrahydroacridine was the exclusive product.
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2. Six-Membered Heterocycles
Reductive alkylation takes place when acridine reacts with n-pentanoic acid in the presence of UV light yielding 9-n-butylacridine.427
6. Electrophilic reaction at nitrogen: The pyridine-type nitrogen of the central ring of acridine is the main nucleophilic site of the molecule and thus it can easily undergo N-alkylation with methyl iodide, methyl triflate, dimethylsulfate, etc. resulting in the formation of N-methylacridinium salt.428 N-Oxidation of acridine can easily be carried out with hydrogen peroxide and m-chloroperbenzoic acid (m-CPBA).429
Ethoxycarbonylcarbene generated by thermal, photochemical, or catalytic decomposition of diazoacetate attacks the nitrogen atom of acridine yielding a stable ylide.430
7. Cycloaddition reaction: 1,3-Dipolar cycloaddition reaction of acridine with different nitrile oxides in toluene led to the synthesis of 1-substituted-3a,11b-dihydroisoxazolo[4,5-a]acridines.431
8. Photochemical reaction: Photochemical pericyclic (4π + 2σ + 2σ) addition of acridine to quadricyclane and norbornadiene in benzene solution yielded an isomeric mixture of a 1:1 Diels-Alder adduct.432
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2.3.17 Quinolizinium Ion
The bicyclic 6-6 system with one of the bridgehead carbon atoms has been replaced by a positively charged nitrogen atom and is designated as the quinolizinium cation. It is aromatic and isoelectronic with naphthalene, quinolone, and isoquinoline. It is commonly included in the category of compounds classified as azonia aromatic heterocycles. Besides quinolizinium there are three other 6-6 systems, which carry one bridgehead nitrogen. These are classified on the basis of an additional hydrogen atom and are called 2H-quinolizine, 4H-quinolizine, and 9aH-quinolizine, but none of them have been isolated as a stable species.
Quinolizines.
Structural and Reactivity Aspects The structure of quinolizinium hexafluorophosphate has been determined by X-ray analysis.433 The quinolizinium ring is planar and the maximum deviation from the best plane for the C-1 atom is only 0.010(1) Å. In comparison to naphthalene the N5-C9a and N5/C9a-C1 have been contracted by 0.04 and 0.03 Å, respectively. The quinolizinium cation is aromatic because its delocalization energy or resonance energy (3.89) is nearly the same as that of naphthalene (3.68).434 Electron density of the quinolizinium cation has been calculated by the Hückel molecular orbital (HMO) and Pariser-Parr-Popple (PPP) methods and the results are summarized in the following table. Electron density of quinolizinium cation Method
C1
C2
C3
C4
N5
C9a
HMO
1.005
0.916
1.011
0.856
1.550
0.874
PPP
1.010
0.976
1.013
0.940
1.185
0.940
The 1H and 13C NMR data of the quinolizinium cation are given in the following table. From the spectral data, the quinolizinium ion has been proved to be aromatic. In the 1H NMR spectrum the H-4 and H-6 protons are highly deshielded due to the positive charge on the nitrogen atom. H and 13C NMR spectral data of quinolizinium ion
1
1
H NMR (DMSO-d6), δ (ppm)
H1, 8.65; H2, 8.42; H3, 8.15; H4, 9.49; H6, 9.49; H7, 8.15; H8, 8.42; H9, 8.65
13
C NMR (DMSO-d6), δ (ppm)
C1, 127.9; C2, 138; C3, 125; C4, 137; C6, 137; C7, 125; C8, 138; C9, 127.9; C9a, 143.0
The absorption spectrum of the quinolizinium cation shows a well-defined absorption bands in the near-UV and visible region at 226 (log ε 4.25), 272 (log ε 3.42), 283 (log ε 3.47), 310 (log ε 4.03), 316.5 (log ε 3.98), and 323.5 (log ε 4.23). Comparison of these values with those of naphthalene shows bathochromic shift due to the presence of cationic nitrogen. Importance in Natural Products, Medicines, and Materials Quinolizinium salts and their benzo analogs, which have been classified as azonia aromatic compounds, have in recent years gained importance and are widely studied because of their biological activities. Many alkaloids such as berberine, palmatine (used in treatment of jaundice, dysentery, hypertension, etc.), columbamine, simperverine, and flavopereurine are known to possess a quinolizinium structure. Recently, natural alkaloid semperverine has been reported to be a promising anticancer drug.435 Besides berberine a number of its derivatives were also found to affect the proliferation of human HCT116 and SW613-B3 colon carcinoma cell lines.436 Their benzo derivatives are used for the treatment of diseases linked to smooth muscle cell contraction such as hypertension and asthma.437
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2. Six-Membered Heterocycles
Alkaloids containing quinolizinium ion nucleus.
Besides these compounds also find use as fluorescent dyes,438 antitumor agents,439 DNA intercalators,440 and nonlinear optical and ionic liquids.441 Synthesis 1. The first synthesis of the parent quinolizinium ion was reported by Woodward and Beaman.442 The reaction involved condensation of 3-isopropoxyacrolein with 2-picolyllithium. The intermediate product obtained was cyclized.
2. [3 + 3] condensation: The yield of the quinolizinium cation by the Woodward method was low. Hence improvement was introduced by involving a reaction of 2-picolyllithium with β-ethoxypropioanaldehyde yielding an alcohol, which on consecutive reaction with hydroiodic acid and potassium carbonate was converted into tetrahydroquinolizinum alcohol. The alcohol on dehydration, followed by dehydrogenation, yields the quinolizinium cation.443
Another useful method involving the [3+3] approach involves reaction of 2-cyanopyridine with 3-ethoxypropylmagnesium bromide, which after initial formation of imine and its hydrolysis yields the ketone. Cleavage of the ether by HBr leads to the formation of a bromo derivative, which cyclizes by refluxing in chloroform. Refluxing the bicyclic intermediate with acetic anhydride yields the quinolinizium cation.444
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119
Substituted quinolizinium salts are synthesized by treating 2-cyanopyridine with suitably substituted 3-ethoxypropylmagnesium bromide.
3. Cyclization of 1-(α-pyridyl)-4-ethoxy butanone in the presence of HBr and chloroform yielded 1-oxo1,2,3,4-tetrahydroquinolizinium bromide, which on dehydration with acetic anhydride containing a drop of concentrated sulfuric acid yielded quinolizinium bromide.445
4. Westphal synthesis: This reaction has proved to be a useful method for preparing polycyclic systems containing a bridgehead quaternary nitrogen.446 In this reaction, pyridinium salts, which possess an alkyl group at the 2-position and an acceptor activated with the methyl group at nitrogen, undergo a base-catalyzed cyclocondensation reaction with 1,2-dicarbonyl compounds yielding the quinolizinium ion.
A modified Westphal synthesis was introduced, which involved acylation and subsequent N-quaternization of β-(2-pyridyl)-substituted β-hydroxyketone (obtained by aldol condensation of pyridine 2-aldehyde with methylene ketones) with bromoacetate or bromoacetonitrile yielding pyridinium salt, which on treatment with Bu2NH are cyclized to quinolizinium salt by intramolecular aldol condensation followed by elimination of acetic acid.
5. [4 + 2] condensation: Reaction of 2-ethoxycarbonyl-1-methylpyridinium salt with acrylonitrile yields a heterobetaine. Removal of the cyano substituent by acid hydrolysis and decarboxylation affords the ketone, which on refluxing with acetic anhydride produces the quinolizinium cation.
6. Ring-closing metathesis: The first example of olefin ring-closing metathesis of appropriate N-(3-butenyl)-2vinylpyridinium in the presence of Grubbs catalyst led to generation of the dihydroquinolizinium cation, which can be dehydrogenated to the quinolizinium cation.447
120
2. Six-Membered Heterocycles
Ring-closing metathesis reaction of 1-butenyl-2-vinylpyridinium salts and 2-butenyl-1-vinylpyridinium salts using Grubbs second-generation and Hoveyda-Grubbs catalyst leading to the generation of 3,4-dihydro- and 1,2-dihydroquinolizinium salts has also been reported.448 Ring-closing enyne metathesis on appropriately substituted pyridinium substrates in the presence of HoveydaGrubbs catalyst to 1- and 2-vinyl-substituted 3,4-dihydroquinolizinium cations have also been reported.449
7. Quinolizinium ionic liquids or low-melting solids with an unbranched cation core have been synthesized. These ionic liquids have been found to show extremely high fluorescence quantum yields. The synthetic process involves a quaternization reaction between methylpyridine and ethyl 2-bromoacetate leading to the generation of pyridinium bromide salt. The Westphal synthetic procedure was applied by treating the pyridinium salt with 3,4-hexanedione in the presence of triethylamine. Cyclocondensation takes place leading to the generation of quinolizinium bromide salt. Anionic metathesis reaction from the bromide ion to NTf2 or BF4 or dichloroacetic acid (DCA) afforded the desired ionic liquid.450
8. A method for the synthesis of quinolizinium salts from 2-ethylpyridines and diphenylacetylene in the presence of Rh(III) catalyst along with an excess amount of copper(II) salt has been reported. Mechanistic studies suggest that 2-vinylpyridine is formed from 2-ethylpyridine in situ by copper-promoted C(sp3)-H hydroxylation, followed by dehydration. Thereafter, Rh(III)-catalyzed pyridine-directed vinylic C(sp2)-H activation and annulation with diphenylacetylene provided the substituted quinolizinium salt.451
1.1.1 Chemical Reactivity 1. Electrophilic substitution reactions: Electron localization energies calculated by Acheson and Goodall452 suggest that quinolizinium salts are unreactive toward electrophilic attack. However, bromination is an exception;
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121
bromine first reacts with quinolizinium bromide in a reversible process to form perbromide, which under drastic SEAr conditions leads to the generation of 1-bromoquinolizinium bromide.453
However, 1- and 2-hydroxyquinolizinium salts readily undergo bromination as well as nitration. This is because they behave as typical phenols. It is for this reason that 2-hydroxyquinolizinium salts behave as strong acids and readily lose their proton to give 2-quinolizone.
It has been observed that the hydroxyl group present at the 1-position directs the incoming group to the 2 -position, whereas the hydroxyl group present at the 2-position directs the incoming group to the 1-position. A bromo derivative in better yield is obtained when bromination is carried out with bromine in hydrobromic acid.454
Nitration with nitric acid yielded 2-nitrated betaine.
The 4-hydroxyquinolizinium ion, which exists in equilibrium with quinolizin-4-one, in its most stable tautomeric form on nitration with nitric acid in acetic acid yields a 1,3-dinitro derivative. However, when nitration is carried out with cupric nitrate in acetic anhydride, a mixture of 1-nitro and 3-nitro isomers is obtained.454b
1-Aminoquinolizinium salt on bromination gives a 2-bromo derivative as the major component and a 2,4-dibromo derivative as the minor component.
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2. Six-Membered Heterocycles
2. Nucleophilic substitution reaction: Theoretical calculations suggest that nucleophilic substitution takes place at the 4-position with formation of an intermediate (pseudo base), which under applied reaction conditions undergoes ring opening to form the most stable product.
Reaction of the quinolizinium cation with nucleophiles like secondary amines and aminodienes has been reported. On reaction with piperidine, ring opening takes place yielding trans-1-piperidinyl-4-(2-pyridyl)butadiene.455
Reaction of methyl magnesium bromide with quinolizinium salt leads to the generation of 1-methyl-4-(2-pyridyl)1,3-butadiene in good yield. The ring-opening reaction is thought to proceed via a 4-substituted-4H-quinolizine derivative. Reaction of phenyl magnesium bromide, however, leads to the generation of cis- and trans-isomers.456
Some halogen-substituted quinolizinium ions readily undergo nucleophilic substitution reaction. 4-Chloroquinolizinium salt on reaction with sodium sulfide yields the thione derivative and with sodium malonic ester delivers an ester derivative.
3. Reaction with reducing agents: Quinolizinium iodide is completely hydrogenated in the presence of Adam’s catalyst yielding quinozilidine iodide.
Reduction of quinolizinium bromide with lithium aluminum hydride and sodium borohydride in THF causes ring-opening reactions leading to the generation of different pyridine derivatives. The hydride reduction is thought to proceed by ring-opening reaction of 4H-quinolizine.457
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
123
However, reduction of quinolizinium bromide with sodium borohydride in ethanol resulted in formation of a mixture of reduced quinolizine derivatives.
4. Sonogashira reaction: Sonogashira is a cross-coupling reaction between aryl or vinyl halide with terminal alkyne in the presence of a palladium catalyst leading to the formation of a carbon-carbon bond.458 The first example of the Sonogashira reaction on heteroaromatic cations involves reaction between 2-bromoquinolizinium bromide and triisopropylsilylacetylene in the presence of palladium catalyst leading to the generation of a 2-ethynyl quinolizinium derivative.459
5. Stille coupling reaction: This is also known as the Migita-Kosugi-Stille reaction, and involves coupling between organotin compounds (known as organostannanes) and a variety of organic electrophiles in the presence of a palladium catalyst.460 The first application of the Stille reaction on heteroaromatic cations involves a reaction of bromoquinolizinium salts with various tributylstannyl compounds in the presence of palladium catalyst yielding different substituted quinolizinium salts.461
2.4 SIX-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH TWO AND MORE NITROGEN ATOMS 2.4.1 Diazines Diazines are six-membered, aromatic, heterocyclic compounds that contain two sp2-hybridized nitrogen atoms in the ring. There are three isomers of diazines: pyridazine (1,2-diazine), pyrimidine (1,3-diazine), and pyrazine (1,4diazine). All three isomers are colorless compounds readily soluble in water.
124
2. Six-Membered Heterocycles
There are four types of bicyclic variants of these diazenes in which a benzene ring is fused to the diazine moiety. These bicyclic diazines, commonly called the benzodiazines, are still known by their trivial names and are designated as cinnoline (benzo[c]pyridazine), phthalazine (benzo[d]pyridazine), quinazoline (benzo[d]pyrimidine), and quinoxaline (benzo[e]pyrazine).
2.4.2 Pyridazine
Pyridazine, one of the three isomeric diazines, has two nitrogen atoms present at adjacent positions to each other; hence it is also known as orthodiazine. This ring system is rarely found in any natural product and the first natural product containing this nucleus was reported only after 1970. Historically, pyridazine was first named by Knorr, while Fisher was the first to synthesize the substituted pyridazine; however, it was Tauber who first synthesized the unsubstituted pyridazine.462 Structural and Reactivity Aspects463 Pyridazine has been considered to be a resonance hybrid of two Kekulé structures (I and II). Both the structures are nonequivalent. However, structure II makes a greater contribution to the resonance hybrid.
Resonance structures of pyridazine.
Pyridazine being a 6π heteroaromatic diazine is electron deficient due to the inductive effect of nitrogen atoms that induces a partial positive charge on carbon atoms. The π electron density in pyridazine in comparison to pyridine is consistent with the observed lower reactivity toward electrophiles compared to nucleophiles.
Calculated π electron density of pyridazine as compared to pyridine.
Based on X-ray diffraction, gas-phase electron diffraction, and microwave spectroscopic studies, pyridazine has a planar slightly distorted hexagonal geometry.464 The bond length and bond angles are shown in the following figure.
Bond lengths and bond angles of pyridazine.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
125
The 1H and 13C NMR data of pyridazine confirm it to be a 6π heteroaromatic system. H and 13C NMR spectral data of pyridazine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-3, 9.17; H-4, 7.52; H-5, 7.52; H-6, 9.17
C-3, 153.00; C-4, 130.00; C-5, 130.3; C-6, 153.00
In comparison to pyridine, the presence of additional nitrogen in pyridazine is responsible for the downfield shift of ring protons and carbons at the 3- and 6-positions in the 1H and 13C NMR, respectively. The UV spectrum of pyridazine shows two bands at 241 nm (log ε 3.02) and 340 nm (log ε 2.26). The first band is due to π→π* transition, whereas the second band at a longer wavelength is due to n→π* transition. The n→π* transitions are usually very weak, but in pyridazine, since the two nitrogen atoms are present at two adjacent positions, this transition of pyridazine is comparatively stronger in comparison to its other two isomers. The mass spectrum of pyridazine has been reviewed. It displays the fragmentation mode of M—N2-H2.
Mass fragmentation pattern of pyridazine.
Importance in Natural Products, Medicines, and Materials465 Pyridazine has been considered by GlaxoSmithKline as one of the most developable heteroaromatic rings in drug design.466 Though examples of natural products containing the pyridazine nucleus are very few, this nucleus has proved to be a useful ligand for different targets and has a privileged structure for drug discovery. Some of the natural products containing this nucleus are quaternary salt, pyridazinomycin, an antifungal and antibiotic isolated from Streptomyces violaceoniger sp. griseofucus,467 azamerone isolated from marine sediment-derived bacterium Streptomyces sp. CNQ-766,468 antrimycin isolated from Streptomyces xanthocidicus MG-125-CF1, which shows activity in vitro against Mycobacterium smegmatis and Mycobacterium tuberculosis,469 and cirratiomycin isolated from Streptomyces cirratus 248-Sq2, which is active in vitro against a narrow range of lactobacilli and some strains of Streptococcus.470
Biologically active natural products containing pyridazine skeleton.
Pyridazine is structurally important because this nucleus is present in a large number of drugs, which offer a broad range of agrochemicals and pharmacological agents. For example, a number of herbicides like credazine, pyridafol, and pyridate contain this nucleus.
126
2. Six-Membered Heterocycles
Herbicide containing pyridazine nucleus.
In addition, this nucleus is found within the structures of a number of pharmaceuticals and clinically used drugs like cadralazine, minaprine, pipofezine, hydralazine, moxiraparine, and lodaxaprine.
Drugs containing pyridazine skeleton.
An interesting aspect of pyridazines is that they increase the water solubility of a lipophilic drug. For example, if the phenyl ring of diazepam is replaced by an isosteric pyridazine ring, about a two-unit decrease in the log P is observed.
Increase in water solubility of lipophilic drug due to presence of pyridazine.
A number of drug molecules contain basic functions and as free bases are not fit for industrial production because the free bases are often oily, low melting, not very stable, become colored on oxidation, and are also not very water soluble. However, when a pyridazine nucleus is present in the molecule, salt formation becomes possible, yielding colorless water-soluble crystalline salt.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
127
Synthesis 1. From maleic anhydride: Maleic anhydride or its derivative on reaction with hydrazine gives maleic hydrazide, which on reaction with phosphorous oxychloride is converted to 3,6-dichloropyridazine. The halogenated derivative on dehalogenation with hydrogen over Pd/C yields pyridazine.471
Dialkyl pyridazines were also synthesized by reaction of appropriately substituted maleic anhydride with hydrazine in benzene solution.472
2. From γ-ketoacid: γ-Ketoacid on reaction with hydrazine yields a cyclic carboxylic acid derivative, which on decarboxylation followed by reaction with phosphorous oxychloride yields 3-chloropyridazine. Dehalogenation with hydrogen over Pd/C yields pyridazine.
3. Cyclocondensation reaction of saturated 1,4-dicarbonyl compound with hydrazine, semicarbazide, or similar hydrazine derivative in the presence of mineral acid yields pyridazines.
6-Substituted pyridazine-3-(2H)-one was synthesized by cyclocondensation of γ-ketocarboxylic acid with hydrazine followed by dehydrogenation of the dihydrocompound.473
Unsaturated 1,4-dicarbonyls also undergo cyclization with hydrazine to yield alkylated/arylated pyridazine.474 The (Z) alkenyl diketone reacts readily with ethanolic hydrazine hydrate at room temperature to yield a pyridazine derivative; however, reaction with (E) isomer produces pyridazine at elevated temperatures.475
4. Schmidt-Druey synthesis: A one-pot synthetic procedure that allows condensation of 1,2-diketones, α-methylene ester, and hydrazine led to the formation of pyridazin-3(2H)-one.476
128
2. Six-Membered Heterocycles
5. [4 + 2] cycloaddition reaction of tetrazines with alkynes: Tetrazines due to the presence of four electronwithdrawing nitrogen atoms in the ring are commonly used as azadiene in [4+2] cycloaddition reactions. 1,2,4,5-Tetrazine reacts with electron-rich dienophile to produce the pyridazine derivative. This inverse electrondemanding Diels-Alder reaction proceeds via a bridged intermediate, which after loss of nitrogen yields the desired pyridazine.477
Similarly, cycloaddition reaction of 1,2,4,5-tetrazine with alkynylboronate ester yielded boronic ester, which undergoes a Suzuki coupling reaction to generate a pyridazine derivative.478, 479
Thiophene S,S-dioxides substituted with bulky groups at the 3- and 4-positions undergo Diels-Alder addition with N-phenyltriazolinedione to give an adduct, which on hydrolysis is converted to a 4,5-substituted pyridazine derivative.480
6. Ring enlargement reaction: Furan derivatives are transformed into pyridazines in two steps. In the first step, furan is converted to 2,5-dialkoxy-2,5-dihydrofuran by oxidative addition of 2 mol of alcohol, followed by acidpromoted ring expansion in the presence of hydrazine.481
7. From ketazine dianion: The dianions of alkyl aryl ketazines generated by treating alkyl aryl ketazines with 2 equivalents of lithium diisopropylamide rearrange to pyrrole/tetrahydropyridazine/pyrazole depending on the type of ketazine. Ketazine dianions without substituents on the carbon termini (acetophenone azine) or with electron-withdrawing substituents rearrange to tetrahydropyridazine.482
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
129
Dibromocyclopropene undergoes a 1,3-dipolar cycloaddition reaction with α-diazoester leading to the formation of unstable cyclopropane-fused pyrazolines, which after loss of hydrogen halide readily rearranges to pyridazines.483
8. From 1,2-diazepines: Pyridazines can be obtained by contraction of 1,2-diazepines. The C-5 carbon of diazepine on halogenation followed by dehydrohalogenation leads to the generation of a diazonorcaradiene intermediate, which rearranges to pyridazine.484
9. Diaza-Wittig reaction: A simple and safe method for the synthesis of substituted pyridazine from 1,3-diketones involving a diaza-Wittig reaction as the key step has been reported. The process involves reaction of methyl acetoacetate with p-acetamidobenzene- sulfonyl azide (p-ABSA) in acetonitrile to yield α-diazo-β-ketoester, which in the presence of titanium tetrachloride is converted to aldol on reaction with aldehyde. Mild oxidation of aldol with 1-hydroxy-1,2-benziodoxol-3(1H)-one-1-oxide (IBX) followed by diaza-Wittig reaction with hexamethyl phosphorous triamide (HMPT) affords pyridazine in good yield.485
Physical Properties At room temperature, pyridazine is a colorless liquid with a pyridine-like odor, bp of 208°C (mp ‑8°C), density d423.5= 1.1035, and surface tension 50.15 dynes/cm2 at 0°C. A high boiling point indicates the involvement of intermolecular association. Pyridazine possesses a high dipole moment (3.9 D). This abnormal high dipole moment is because the two nitrogen lone pairs are located on the same side of the ring. As a result, there is a greater pull of electrons on that side, resulting in high dipole moment. Chemical Reactivity 1. Quaternization: Pyridazine reacts with alkyl halide or dialkyl sulfates in the presence of a base to yield monoquaternary salt. The position of alkylation is determined by the presence of the alkyl group on the ring. For example, in 3-methylpyridazine the alkylation takes place mainly at N-1, although N-2 is more electron rich. Similarly, in 3-methoxy-6-methylpyridazine the N-1 is alkylated.486
130
2. Six-Membered Heterocycles
Pyridazine functionalized at the nitrogen position to form NO, NN, and NC bonds results in activation of the C-3-position, which reacts further to yield more complex heterocycles. Thus pyridazine on reaction with an aqueous solution of hydroxylamine sulfonic acid (HOSA), potassium iodide, and potassium hydrogen carbonate yields the aminated pyridazine. Subsequent [3+2] cycloaddition with butyne-2-one generates pyrazolol[1,5-b]pyridazine in two steps. This compound has been used as a cyclin-dependent kinase inhibitor for the treatment of solid tumors.487
2. Reaction with nucleophilic reagents: The introduction of the second nitrogen into the pyridine results in diazines reacting with alkyl- and aryllithium compounds to form a stable dihydro adduct. These dihydro adducts can readily be transformed into corresponding substitution products. Pyridazine readily reacts with butyllithium to give a C-3 substitution product.
3-Substituted pyridazine-1-oxide adds cyanide (as KCN or (CH3)3SiCN) in the 6-position in the presence of acylating agent (Reissert reaction).
Direct introduction of organic perfluoro moiety in pyridazine involves nucleophilic addition of perfluoroalkyllithium reagent (generated in situ from perfluoroalkyl iodides, methyllithium, and lithium bromide complex) leading to the formation of dihydropyridazine adduct (tetrahydropyridazine is also formed as a by-product), which is quantitatively oxidized in air to corresponding 3-perfluoroalkylpyridazine.488
Reaction of pyridazine with lithium 2,2,6,6-tetramethylpiperidinide (LTMP) metalates the C-3-position. Coupling of benzaldehyde with the lithiated pyridazine yields the pyridazine benzyl alcohol derivative.489
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Reaction of Weinreb amide with lithiated pyridazine led to the synthesis of long chain α-ketopyridazines, a class of potent inhibitors of fatty acid amide hydrolyase.489
Other metals like zinc, aluminum, copper, and manganese have been used for metalation but it was observed that deprotonative cadmium leads to improved regioselectivity and efficiency.489
C-4 of pyridazine can also be functionalized by using a nonmetallic phosphagene base in place of LTMP. This reaction is highly C-4 regioselective and efficient. The process involves reaction of pyridazine with benzophenone in the presence of a phosphagene base and zinc iodide.
C-4 regioselective arylation of pyridazine is achieved by using a copper catalytic system (copper iodide/phenanthroline in a 1:1 ratio) in combination with hindered lithium triethylcarboxide in dimethylformamide (DMF).
Chichibabin reaction of diazines is quite uncommon due to reduced aromaticity of the diazine π system. However, the initial step is quite easy leading to the generation of a dihydro product, which can be oxidized in situ with potassium permanganate yielding 4-aminopyridazine.490
3. Oxidation: Nitrogen of the pyridazine is oxidized by reaction with m-CPBA in dichloromethane. This oxidation product, which is activated at C-3, reacts with excess aryl bromide to undergo regioselective CH arylation in the presence of palladium acetate and tri-tert-butylphosphine.489
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Pyridazine on reaction with peracid forms 1-oxide, which can then be made to undergo different substitution reactions.
4. Reduction: Pyridazine on reduction under pressure in the presence of a catalytic amount of platinum(IV) oxide in ethanol followed by treatment with ethanolic-HCl led to yield 1,2-dihydropyridazine salt.489
3,6-Dimethylpyridazine is reduced to a hexahydro derivative on reaction with sodium and alcohol.
Pyridazine is also reduced by nickel-aluminum alloy in sodium hydroxide/potassium solution to diamines.491
Partial reduction of pyridazine was achieved by treating it with benzylchloroformate and sodium cyanoborohydride in methanol at room temperature, which gave a mixture of products.492
5. Free radical reaction: 4-Isopropylpyridazine is formed predominantly in 10:1 regioselective ratio when pyridazine is stirred in the presence of tert-butylperoxide and bis(((isopropyl)sulfinyl)oxy)zinc (IPS) that act as an i-Pr radical donor.
6. Carboxylation: C-4 Carboxylation of pyridazine is achieved by treating it with carbon dioxide in the presence of [(I-t-Bu)AuOH] (I-t-Bu = 1,3-(di-tert-butylimidazol-2-ylidene) and potassium hydroxide in THF.
7. Cycloaddition: Pyridazine underwent a cycloaddition reaction with resublimed maleic anhydride in dry chloroform to yield a 1:2 adduct, which was assigned the analogous structure 1,2,3,4-tetrahydro-[1,2-b]pyridopyridazine-1,2,3,4-tetracarboxylic bis anhydride.493
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Benzonitrile oxide generated in situ undergoes a cycloaddition reaction with pyridazine to yield monocyclo adduct (A), which on standing in solvent in the presence of air undergoes slow autoxidation to afford pyridazinone. The monocyclo adduct (A), which is still reactive toward benzonitrile oxide on exposure to excess benzonitrile oxide, affords the bis-cycloadduct (B).494
Pyridazine undergoes Diels-Alder reaction with 2-methylene-imadazolidine. The Diels-Alder product loses nitrogen followed by ring aromatization to yield N,N′dimethyl-N-phenyl-1,2-ethanediamine.
8. Thermal and photochemical reaction: Pyridazine is converted to pyrimidine on heating to 300°C probably via a diazabenzvalene intermediate. However, photolysis of pyridazine yields mainly pyrazine probably via a transient intermediate similar to Dewar benzene.
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2.4.3 Pyrimidine
Pyrimidine is one of the three diazines containing two nitrogen atoms at 1- and 3-positions of the six-memebered aromatic heterocycle, hence it is also known as 1,3-diazabenzene, but pyrimidine is still the accepted IUPAC name. Structural and Reactivity Aspects495a In comparison to pyridine (pKa 5.2), pyrimidine is weakly basic (pKa 1.3). The decreased basicity of pyrimidine is due to the electron-withdrawing effect of the second nitrogen atom present in the ring. Pyrimidine being an aromatic compound can be represented as a resonance hybrid of a number of canonical structures.
Resonating structures of pyrimidine.
Pyrimidine is less aromatic compared to pyridine and benzene and this is because the resonance energy of pyrimidine (26 kcal/mol, 110 kJ mol−1) is comparatively less than benzene (36 kcal/mol, 150 kJ mol−1) and pyridine (31 kcal/mol, 117 kJ mol−1). The structure of pyrimidine has been determined by X-ray crystallography. It has a planar, slightly distorted hexagonal geometry. The crystal is orthorhombic P n a 21, with each unit cell consisting of four pyrimidine molecules. Pyrimidine is aromatic in character, and based on X-ray diffraction, gas-phase electron diffraction, and microwave studies the bond length and bond angles are very close to those of benzene.
Bond lengths and bond angles of pyrimidine.
The 1H and 13C NMR spectrum of pyrimidine is similar to pyridine, except that the presence of additional nitrogen in pyrimidine is responsible for the downfield shift of ring protons and carbon atoms at the 2-, 4-, and 6-positions. H and 13C NMR spectral data of pyrimidine
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 9.26; H-4, 8.78; H-5, 7.35; H-6, 8.78
C-2, 158.4; C-4, 156.9; C-5, 121.9; C-6, 156.9
The UV spectrum of pyrimidine shows three bands at 228 nm (log ε 3.48), 243 nm (log ε 3.50), and 272 nm (log ε 2.62). The first two bands are due to π→π* transition, whereas the third band at a longer wavelength is due to n→π* transition. Importance in Natural Products, Medicines, and Materials Heterocycles containing pyrimidine are of great interest because they constitute an important class of natural as well as synthetic products because many of their derivatives not only exhibit useful biological activities but are clinically very important. The three nucleobases, thymine, cytosine, and uracil, which are essential building blocks of nucleic acids DNA and RNA, all contain pyrimidine derivatives. The pyrimidine ring is also present in vitamins like riboflavin, thiamine, and folic acid, which are important growth factors for the human body.
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Nucleobases and vitamins containing pyrimidine nucleus.
In medicinal chemistry, pyrimidine derivatives are well known for their therapeutic importance. Many pyrimidine derivatives have been developed as chemotherapeutic agents and are being widely used. The barbituric acid derivative veranal is used as a hypnotic. The most potent drug Viagra, which has been used for male impotence, is precisely a pyrimidine derivative. It is the drug used to treat erectile dysfunction and pulmonary arterial hypertension. Zidovudine, also known as azidothymidine, a nucleoside analog, is an antiretroviral drug used for the successful treatment of HIV/ AIDS infections. Imatinib is a chemotherapeutic drug that is used to slow down or stop the growth of cancer cells.
Drugs containing pyrimidine nucleus.
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2. Six-Membered Heterocycles
Synthesis 1. From malonic esters: Condensation between malonic esters and urea in the presence of a base led to the formation of barbituric acid.495b
Barbituric acid on treatment with phosphorous oxychloride yields 2,4,6-trichloropyrimidine, which on reduction with zinc dust and water yields pyrimidine.496
The yield of pyrimidine from the foregoing method was not very successful. However, pyrimidine in better yield was obtained by carrying out reduction of 2,5-dichloropyrimidine with hydrogen and palladium barium sulfate in the presence of magnesium oxide.
If the reaction is stopped after 2 mol of hydrogen have been absorbed, then pyrimidine can be isolated. However, if the reduction process is allowed to proceed, then 1,2,3,4-tetrahydropyrimidine is isolated.497 Instead of malonic ester, malic acid has also been used for the synthesis of pyrimidine. Decarboxylation of malic acid with concentrated sulfuric acid yields α-formyl acetic acid, which on reaction with urea gives uracil.498 This on reaction with phosphorous oxychloride in dimethylaniline results in the formation of dichloropyrimidine, which is reduced to pyrimidine.
A convenient synthesis of pyrimidine is by the reaction of 1,1,3,3-tetraethoxypropane with formamide.
2. Bredereck synthesis: Bredereck first synthesized 4,6-disubstituted pyrimidines by reacting β-diketones or βiminoketones with formamide.499
A few years later a more direct route to pyrimidine 4-carbaldehyde was put forth by Bredereck et al.500. In this method, vinylogous amide obtained by a reaction of pyruvaldehyde-dimethylacetal and dimethylformamide acetal
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137
was treated with formamidine to give pyrimidine acetal, which on treatment with dilute sulfuric acid afforded pyrimidine 4-aldehyde.
Bredereck improved upon his own procedure and synthesized pyrimidine in one step. The one-step procedure is simpler and easier than the three-step procedure used in the past. The process involves heating formamide at higher temperatures with 4,4-dimethoxyl-2-butanone.501
3. Pinner pyrimidine synthesis: This reaction involves the condensation of 1,3-dicarbonyl compounds with amidines in the presence of acid or base to yield pyrimidine derivatives.502
The mechanism of the reaction was studied by Katritzky et al. and they proposed the following mechanism for the condensation of methyl acetoacetate with acetamidine.503
4. Remfry-Hull synthesis: This is the condensation of α-butylmalondiamide with ethyl formate in ethanolic sodium hydroxide to yield 5-butyl-6-hydroxypyrimidin-4(3H)-one.504
The Remfry-Hull synthesis of 4,6-dihydroxypyrimidine from malondiamides and esters is modified to permit inclusion of an alkylamino group in position 5 or an alkyl group in position 2. Malondiamide reacts with formamide to give 4,6-dihydroxypyrimidine.505
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2. Six-Membered Heterocycles
5. Traube synthesis: The reaction named after Wilhelm Traube is in fact used for the synthesis of purines. The first step of the reaction involves the synthesis of pyrimidine, which is then converted to purine. Pyrimidine synthesis involves a reaction between guanidine hydrochloride with cyanoacetic ester in the presence of sodium ethoxide.506
A modification of Traube’s procedure was carried out and instead of 2,6-diamino-4-oxopyrimidine, 2,4-diamino- 6-hydroxypyrimidine was obtained.507
Hydroxy derivatives of pyrimidine were also synthesized by treating ethyl acetoacetate with thiourea yielding 2-thio-6-methyluracil, which was desulfurized with aqueous ammonia and Raney nickel catalyst to yield 4-methyl-6-hydroxypyrimidine.508
6. Biginelli synthesis: This is a multicomponent reaction between ethyl acetoacetate, aryl aldehyde, and urea leading to the formation of 3,4-dihydropyrimidin-2-(1H)-one.509 The reaction is catalyzed by Brönsted acid or Lewis acid.
A new one-pot synthesis of Biginelli 3,4-dihydropyrimidine derivatives under planetary ball milling, solvent-free and catalyst-free conditions has been reported.510 There are number of modifications that have been proposed for the traditional Biginelli reaction, but most of them lack the experimental and conceptual simplicity of the Biginelli reaction. However, there is one noticeable exception, called the Atwal modification of the Biginelli reaction.511
7. 4,5-Disubstituted pyrimidines are biologically active and they have been used as precious intermediates in drug discovery. Zinc chloride-catalyzed, three-component coupling reaction between variety of functionalized enamines, triethylorthoformate and ammonium acetate, led to the generation of mono- and disubstituted pyrimidines.512
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139
8. A simple high-yielding synthesis of pyrimidines from ketones in the presence of hexamethyldisilazane (HMDS) and formamide under microwave conditions has been described.513
9. Intermolecular cycloaddition reaction of alkynes (terminal or internal) with aryl nitriles in the presence of an NbCl5 complex yielded substituted pyrimidine with excellent chemo- and regioselectivity.514
Trimerization of acetonitrile in the presence of potassium methoxide yields 4-amino-2.6-dimethylpyrimidine.515
1,3,5-Triazines on reaction with electron-rich dienophiles yield pyrimidines.516
10. A novel three-component condensation reaction between functionalized enamine, triethylorthoformate and ammonium acetate in the presence of zinc chloride produces 4,5-disubstituted pyrimidine in moderate yield in a single step.517
A novel three-component condensation reaction between an aromatic aldehyde, ketone, and guanidine carbonate under solvent-free conditions led to the synthesis of 2-amino-4,6-diarylpyrimidine in good yield.518
11. Reaction of triflic anhydride with ketones in the presence of nitriles offers an improved method for the synthesis of pyrimidines. The reaction between ketone and tiflic anhydride generated (triflyloxy)carbonium ion, which is easily trapped by the nitrile by nucleophilic attack to give pyrimidines.519
140
2. Six-Membered Heterocycles
12. Reaction of α,β-unsaturated trifluoromethyl ketones with amidines in acetonitrile gave the corresponding 4-hydroxy-4-(trifluoromethyl)-3,5,6-trihydroxypyrimidines, followed by successive dehydration with phosphorous oxychloride-pyridine-silica gel, and oxidation with manganese(IV) oxide yielded 2,6-disubstituted 4-(trifluoromethyl)pyrimidines in excellent yield.520
Physical Properties Pyrimidine is a colorless, low-melting, hygroscopic solid with mp of 21°C (bp 123°C) and density d423.5= 1.529 g/cc. It is easily soluble in water. Chemical Reactivity 1. Quaternization: Pyrimidine reacts with alkyl halide to yield monoquaternary salt. Dialkylation is carried out with reactive electrophiles like Meerwein’s salt ([Et3O]BF4).521
2. Electrophilic substitution reaction: Due to the presence of two nitrogen atoms, electron density on all carbon atoms is reduced; as a result, electrophilic substitution reaction on pyrimidine takes place only under drastic conditions. However, the presence of an electron-donating group facilitates substitution reaction, probably by the addition-elimination pathway. Monoquaternary salt of pyrimidine undergoes bromination by heating it in nitrobenzene at 130°C.522, 523
Unsubstituted pyrimidine is unable to undergo nitration; however, the presence of two electron-releasing groups makes nitration of pyrimidine relatively easier. Thus 2,4-dihydroxy-6-methylpyrimidine undergoes nitration quite easily.
Similarly, halogenation is also carried out in the presence of electron-donating groups. However, sometimes a dihalo product is also formed.
3. Oxidation: Pyrimidine on reaction with peracid gives a poor yield of N-oxide.524 However, alkylpyrimidines give a satisfactory yield of an N-oxide derivative.
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4. Nucleophilic reaction: In pyrimidine, nucleophilic attack may take place at 2-, 4-, or 6-positions forming a dihydro product, which on oxidation yields the substituted pyrimidine derivative.
Nucleophilic attack in pyrimidines with organolithium compounds takes place at C-4 to give an adduct, which is readily aromatized on treatment with potassium permanganate or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.525, 526
Phenylmagnesium bromide readily adds to the C-4 carbon of pyrimidine to form an intermediate, which on hydrolysis yields dihydropyrimidine. Oxidation of dihydropyrimidine with KMnO4 in acetone yields 4-phenylpyrimidine.527
Nucleophilic substitution reaction at the C-2 position is rare, but when the C-4 position is occupied, then reaction takes place at C-2. For example, reaction of 4,6-dichloropyrimidine with allyllithium yields 2-allyl-substituted pyrimidine as the exclusive product.528
Similarly, 2-chloropyrimidine does not undergo nucleophilic substitution at the halogenated carbon, instead a halogen-retained product is obtained with the new substituent at position C-4.529
5-Bromopyrimidine reacts with lithium diisopropylamide to yield 5-bromo-4-lithiopyrimidine, which reacts with the second molecule of 5-bromopyrimidine to give a dimer, which undergoes aromatization to form bipyrimidine.530
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2. Six-Membered Heterocycles
An amination reaction of 2-chloro-4-phenylpyrimidine with potassium amide in liquid ammonia gives 4-amino- 4-phenylpyrimidine. Although it appears to be an addition-elimination process, isotopic labeling experiments revealed that nucleophilic ring-opening/ring-closure mechanism was involved.531
Pyrimidine on reaction with hydrazine is rearranged to pyrazole by the following mechanism.532
5. Gomberg-Hey reaction: Reaction of pyrimidine with diazotized p-nitroaniline yielded 2-p-nitrophenylpyrimidine and 4-p-nitrophenylpyrimidine. The reaction was thought to proceed by a free radical mechanism.533
6. Reduction: Pyrimidine is reduced by nickel-aluminum alloy in sodium hydroxide-potassium hydroxide solution to diamines.534
Partial reduction of pyrimidine was achieved by treating it with benzylchloroformate and sodium cyanoborohydride in methanol at room temperature.535
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7. Cycloaddition: [4+2] Cycloaddition reaction of pyrimidine with electron-rich alkynes takes place to yield regioselective-substituted pyridine products via loss of hydrogen cyanide.536
Benzonitrile oxide generated in situ undergoes a cycloaddition reaction with pyrimidine to yield biscyclo adduct (A) and triscyclo adduct (B).537
8. Dimroth rearrangement: A rearrangement reaction takes place in certain 1-alkyl-2-iminopyrimidines, where endocyclic and exocyclic nitrogen atoms switch places.
9. Hilbert-Johnson reaction: Reaction of 2,4-dialkoxypyrimidines with protected glycosyl halides yields pyrimidine nucleosides.
2.4.4 Pyrazine
Pyrazine, also known as 1,4-diazine, is a symmetrical six-membered aromatic heterocyclic compound that contains two nitrogen atoms at the 1- and 4-positions.
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2. Six-Membered Heterocycles
Structural and Reactivity Aspects The complete structure of pyrazine has been determined by X-ray analysis and electron diffraction studies.538 From X-ray analysis it has been proved that the ring is a planar hexagon with D2h symmetry. The CC bond length being similar to those of benzene (1.378 Å) is larger in comparison to the CN bond length. The ring angle at the heteroatom is smaller than that at the carbon atom. The other bond lengths and bond angles are shown in the following diagram.
Bond lengths and bond angles of pyrazine.
The symmetrical structure of 1,4-diazine is reflected in the 1H and 13C NMR spectra (in CDCl3) with one signal for the ring proton (δ 8.590) and one for the ring carbon atom (δ 145.9). The UV spectrum of pyrazine shows three bands at 261 nm (log ε 3.87), 267 nm (log ε 3.72), and 301 nm (log ε 2.88). The first two bands are due to π→π* transition, whereas the third band at a longer wavelength is due to n→π* transition. Importance in Natural Products, Medicines, and Materials Pyrazines are present in heat-processed food such as beef products, toasted barley, cocoa, coffee, peanuts, potato chips as well as in fresh foods like tomatoes, peas, green bell peppers, etc. Pyrazines are thought to arise by spontaneous heat-induced condensation between amino acids and sugars through Strecker’s degradation. A number of natural products containing this nucleus have been isolated. For instance, clavulazine isolated from Okinawa soft coral Clauvlaria viridis, botryllazine A from the red ascidian Botryllus leachi, and barrenazine from unidentified tunicate collected from Madagascar.539–541
Natural products containing pyrazine nucleus.
This nucleus is responsible for the flavor and pleasant aroma of a number of foodstuffs.542 Pyrazines have also shown interesting anti-HIV, antitubercular, and antibacterial activities. Pyrazines have also been used as pharmaceutical intermediates, for example, 2-methylpyrazine has been used for the synthesis of the antitubercular drug pyrazinamide. Pyrazinamide, itself a pyrazine derivative, along with rifampin and ethambutol, constitute first-line drugs for tuberculosis therapy. Besides pyrazinamide, a number of other pharmaceuticals with a pyrazine nucleus have shown numerous physiological effects, such as anti-HIV (oltipraz), proteasome inhibitor (bortezomib), narcotic addiction (varenceline), fungal antibiotic (aspergillic acid), pulmonary heart disease (ligustrazine), hypnotic (eszopiclone [Lunesta]), and eye drops for glaucoma or ocular hypertension (brimonidine).
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145
Food additive and drugs containing pyrazine nucleus.
Synthesis 1. Staedel-Rugheimer synthesis: The first synthesis of pyrazine from aminoketone was reported in 1876 by StaedelRugheimer. The process involves self-condensation of amino ketones followed by oxidation, which yields pyrazine.543 Amino ketone was, however, synthesized by the heating of 2-chloroacetophenonone and ammonia in an autoclave.
2. Gutknecht pyrazine synthesis: This reaction is a variation of Staedel-Rugheimer synthesis. The reaction involves treatment of ketone with nitrous acid from an oximino ketone followed by reduction to α-amino ketone, which dimerizes to dihydropyrazine via a pinacol-type process. The dihydropyrazine is then oxidized to pyrazine. The overall process of conversion of ketone to pyrazine is referred to as Gutknecht condensation.544
3. Catalytic dehydrogenation of ethanolamine in the presence copper, copper and zinc oxide, or zinc oxide and sodium carbonate at 250–300°C yields pyrazine.545
4. Deaminocyclization of ethylenediamine followed by dehydrogenation over copper chromite results in the formation of pyrazine.546
5. [4 + 2] condensation: Pyrazine is manufactured by the condensation of glyoxal and ethylenediamine at high temperatures on a copper-chromium oxide catalyst.
146
2. Six-Membered Heterocycles
Similarly, alkyl derivatives of pyrazine are synthesized by condensation of ethylenediamine with a 1,2-diketo derivative to yield the intermediate dihydropyrazine. Oxidation to pyrazine is carried out over copper chromite at 300°C.547
6. 2-Methylpyrazine is synthesized by the reaction of ethylenediamine and propylene glycol in the presence of a catalyst system such as copper-chromium, copper-zinc chromium, or zinc-phosphoric acid-manganese.548–550
The reaction is thought to proceed by the following mechanism.551
7. A condensation reaction between ethylene diamine and epoxide in the presence of a copper-chromium oxide catalyst yields pyrazine.552
Pyrazine has been conveniently synthesized by the reaction of ethylenediamine and ethylene oxide in the presence of aluminum oxide and nickel at 400°C.
8. Synthesis of unsubstituted pyrazine was also reported by Wolff and Marburg.553 The process involves heating chloroacetal and ammonia in a sealed tube, whereby diacetylamine was obtained, which on heating with hydrochloric acid yielded 2,6-dihydroxymorpholine. The oxygen of morpholine could be replaced by heating it with hydrazine or hydroxylamine under pressure.
9. Dehydrogenation of piperazine in the presence of a palladium-magnesium chloride-aluminum oxide catalyst yields pyrazine.
10. A simple, cost-effective, and environmentally friendly method for the synthesis of pyrazine derivatives has been reported. The process involves direct condensation between respective 1,2-diketo compounds and 1,2-diamines in aqueous methanol and catalyzed by potassium tert-butoxide at room temperature.554
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11. A novel regioselective method for the synthesis of alkylpyrazines involves condensation of α-oximido carbonyl compound with allylamine. The resulting imine is isomerized in the presence of potassium tert-butoxide to 1-hydroxy-1,4-diazahexatriene. Thermal electrocyclization-aromatization to pyrazine is achieved after O-acylation of the oxime with methyl chloroformate.555
12. Photolysis of vinyl azide in methanol gave a good yield of pyrazine probably via an azirine derivative.556
13. Synthesis of highly substituted pyrazine involving reaction of α-diazo oxime ethers with 2H-azirines in the presence of copper complexes has been reported.557
Physical Properties Pyrazine is a colorless, stable compound mp 54°C, bp 115°C and a zero dipole moment. It is readily soluble in water and sparingly soluble in alcohol and ether. It is a weaker base in comparison to pyridazine or pyrimidine. Chemical Reactivity Pyrazine being an aromatic compound can be represented as a resonance hybrid of a number of canonical structures. Due to the symmetrical nature of the molecule the dipole moment of pyrazine is zero.
Resonating structures of pyrazine.
148
2. Six-Membered Heterocycles
From the canonical structures it can be seen that in pyrazine there are electron deficiencies at 2, 3, 5, and 6. Thus these positions can be attacked by nucleophilic reagents. Studies have shown that nucleophilic reagents could attack the ring if there is at least one electron-releasing group like CH3, NH2, OH, etc. already bonded to the ring. 1. Electrophilic substitution reaction: Due to the presence of two nitrogen atoms, electron density on all carbon atoms is reduced; as a result, electrophilic substitution reaction on pyrazine takes place only under drastic conditions. However, the presence of an electron-donating group facilitates substitution reaction, probably by an addition-elimination pathway. Chlorination of 2-methylpyrazine could be carried out under milder conditions.558
Similarly, bromination of 2-aminopyrazine can also be carried out to yield 2-amino-3,5-dibromopyrazine.
Direct bromination of pyrazine is carried out by heating it with HBr and bromine.
2. Nucleophilic substitution reaction: Although pyrazine is more reactive than pyridine toward nucleophiles but Chichibabin reaction is unsatisfactory. However, 2-chloropyrazine on reaction with sodamide in liquid ammonia yields 2-aminopyrazine not by the addition-elimination mechanism but by the ANRORC mechanism.
Due to inductive and resonance effects of nitrogen atoms, the protons bonded to methyl carbon atoms are acidic and thus can easily be removed by a strong base. The resultant carbanion can undergo condensation and alkylation reactions.559, 560
2,3 and 2,6-dichloropyrazines on treatment with lithiodithiane react in the usual manner to yield 2-substituted pyrazine derivatives.561
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149
3. Reduction: Reduction of pyrazine with sodium and ethanol give piperazine.
Electrochemical reduction of pyrazine on silver electrodes from 1.0 M KBr solution yielded a 1,4-dihydropyrazine cation as the major product.562
Pyrazines are also reduced by nickel-aluminum alloy in sodium hydroxide solution.563 Partial reduction of pyrazine was achieved by treating it with benzylchloroformate and sodium cyanoborohydride in methanol at room temperature, whereby a mixture of products was obtained.564
4. Oxidation: Oxidation of pyrazine with hydrogen peroxide in acetic acid gives pyrazine N-oxide. The monoxide is formed first; however, on heating at higher temperature for a longer period of time with excess hydrogen peroxide, di-N-oxide is obtained.
Alkyl derivatives of pyrazine on reaction with hydrogen peroxide in acetic acid are converted to both mono-Noxide and di-N-oxide, with mono being the major product.565
Besides chemical oxidation, enzymatic oxidation of the alkyl group of pyrazine with bacteria such as Pseudomonas putida has been helpful in the oxidation of 2,5-dimethylpyrazine to its monocarboxylic acid derivative.566
5. Metalation: Ortho-halogen-substituted pyrazine derivatives have been synthesized by treating pyrazine with iodine in the presence of lithium-2,2,6,6-tetramethylpiperidide.
The 2-iodopyridazine formed reacts in the presence of palladium acetate to form a bipyridazine derivative.567
150
2. Six-Membered Heterocycles
6. Replacement of leaving group: Halogen and methoxy-substituted pyrazines react with soft nucleophiles such as amines, thiolate, and malonate anions to give substituted products.568
7. Hydroxycarbonylation: The reaction of pyrazine with oxalic acid monoesters under oxidative conditions led to hydroxycarbonylation.569
8. Cycloaddition: Benzonitrile oxide generated in situ undergoes a cycloaddition reaction with pyrazine to yield two isomeric biscyclo adduct products (A and B) with monocycloadduct as an intermediate.570
2.4.5 Piperazine
Piperazine, also known as 1,4-diazacyclohexane or hexahydro-1,4-diazine, is a six-membered heterocycle with two nitrogen atoms located at the 1- and 4-positions of the ring. Structural and Reactivity Aspects571 Like cyclohexane, piperazine prefers the chair conformation. In the stable chair conformation the NH bond favors the equatorial conformation.572
Conformations of piperazine.
The CC and CN bond lengths are 154.0 and 146.7 ppm, respectively. The CCN and CNC bond angles are 110 and 109 degrees, respectively.
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The 1H and 13C NMR spectral data of piperazine are given in the following table. H and 13C NMR spectral data of piperazine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3, 5, 6; 2.84
C-2, 3, 5, 6; 47.9
Importance in Natural Products, Medicine, and Materials Piperazine is an important scaffold that is found in a large number of biologically active compounds. Its amino and alcohol derivatives have considerable application in the preparation of hardeners of epoxy resins, insecticides, urethane catalysts, and antioxidants. Piperazine derivatives have also been developed as carbon dioxide capturing materials.573 A number of drugs available in the market have a piperazine skeleton. For example, cyclizine is used to treat nausea, vomiting, and dizziness, citrizine is a second-generation antihistamine, amoxapine is an antidepressant, and trimetazidine and ranolazine are used to treat angina pectoris.
Drugs containing piperazine nucleus.
Synthesis 1. Self-condensation of ethanolamine in the presence of ammonia at 150–200°C and 100–200 bar pressure yields piperazine.
2. Reaction of oxirane with ethylenediamine yields an intermediate, which cyclizes to piperazine.
3. Piperazine has been synthesized by heating diethylene triamine574 with Raney nickel at 150°C.
4. Selective reduction of pyrazine with isopropanol in the presence of the catalyst [Ir(COD)(NHC)PPh3]BF4 yields piperazine.575
152
2. Six-Membered Heterocycles
5. 2-Phenylpiperazine576 is synthesized by condensation of bromophenyl acetic acid ethyl ester with ethylenediamine followed by reduction of 3-phenylpiperazine-2-one obtained as intermediate with LiAlH4.
Synthesis of 2-phenylpiperazine has also been reported by reaction of oxirane derivative with ethylenediamine.577 6. 1,1-Dimethylpiperazinium salt: Reaction of dimethylamine with N-bis(2-chloroethyl)amine in methanol solution yields 1,1-dimethylpiperazinium chloride.578
7. Diastereoselective carboamination of N1-allyl-N2-aryl-N1-vinyl-propane-1,3-diamine with aryl bromide in the presence of palladium catalyst yields cis-piperazine.579
8. Reaction of N,N′-dimethylethylenediamine with tosylbis(2-(toxyloxy)ethyl)amine in the presence of potassium carbonate yields 1-methyl-4-tosylpiperazine.580
9. Reaction of diethanolamine and methylamine over zeolite yields N-methylpiperazine.581
Physical Properties Piperazine is a white crystalline solid with mp of 106oC, and behaves as a secondary amine. It is freely soluble in water and other protic polar solvents but sparingly soluble in diethyl ether and other nonpolar solvents. Chemical Reactivity 1. Acetylation: Synthesis of 1-acetylpiprazine: Piperazine reacts with acetyl chloride in glacial acetic acid under ultrasonic irradiation in a microreactor at 60°C for 4 min to give 1-acetylpiperazine in excellent yield.582
2. N-Formylation: Reaction of piperazine with chloroform and potassium fluoride on basic alumina in acetonitrile at room temperature for 24 h yields symmetrically 1,4-disubstituted as the major product and Nmonoformylated as the minor product.583
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
153
3. Reaction of piperazine with benzyl chloride in ethanol at 65°C yields piperazine dihydrochloride, which on treatment with absolute ethanol and dry hydrogen chloride followed by a reaction with aqueous sodium hydroxide yields 1-benzylpiperazine.584
4. Aroylation: One-step aroylation of piperazine is achieved by treating it with aroyl chloride in glacial acetic acid leading to the synthesis of 1-aroylpiperazine.585
5. Reaction of piperazine with ethyl chlorocarbonate under controlled conditions in aqueous solution gave 1-carbethoxypiperazine, which reacted with alcoholic methyl tosylate to yield 1-carbethoxy-4methylpiperazine.586 The title compound was found useful in the chemotherapy of filariasis.
6. Refluxing piperazine with phthalic anhydride in the presence of 4-dimethylaminopyridine as catalyst in dichloromethane as solvent yields 2-(piperazine-1-yl-carbonyl)benzoic acid.587
7. 1-(Phenylsulfonyl)piperazine was synthesized by the reaction of piperazine with arylsulfonyl chloride588 in dichloromethane at 0°C.
8. The reaction of piperazine with acrylonitrile in a molar ratio of 1:1.2 in the presence of recyclable inexpensive ionic liquid triethylammonium acetate at 25°C yields 3-(piperazine-1-yl)propanenitrile.589
Aza-Michael addition of piperazine onto methyl 2-propenoate in the presence of copper(II) acetylacetonate immobilized in recyclable ionic liquid [(bmim)BF4] afforded 1-(2-methoxycarbonylethyl)piperazine in high yields. However, disubstituted piperazine was also obtained as a minor component.590
154
2. Six-Membered Heterocycles
9. 6-Aryl-4-methylthio-2H-pyran-2-one-3-carbonitriles on reaction with piperazine or substituted piperazine in refluxing ethanol afforded 6-aryl-4-piperazinyl-2H-pyran-2-one-3-carbonitriles, which are used as versatile precursors for ring transformation reactions to construct a variety of heterocycles.591
2.4.6 Cinnoline
Cinnoline is also known as 1,2-diazanaphthalene. It is a benzo-fused derivative of pyridazine. As benzene ring is fused to the 5,6-position of the pyridazine ring, hence it is known as benzo[c]pyridazine. Cinnoline as the parent molecule does not occur in nature; however, this ring system was first discovered by von Richter. Structural and Reactivity Aspects The UV spectrum of cinnoline in ethanol displayed six absorption maxima at λmax 276 nm (log ε 3.45), 286 (log ε 3.42), 308.5 (log ε 3.29), 317 (log ε 3.25), 322.5 (log ε 3.32), and 390 (log ε 2.42). All the absorption maxima are attributed to π→π* transition except for the one at 390 nm, which is due to n→π* transition, due to nonbonding electrons of the ring nitrogen atoms.592 The 1H and 13C NMR data of cinnoline confirm it to be a benzo derivative of pyridazine.593 H and 13C NMR spectal data of cinnoline
1
1 H NMR (acetone d6) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-3, 9.32; H-4, 8.08; H-5, 8.01; H-6, 7.84; H-7, 7.93; H-8, 8.49
C-3, 146.1; C-4, 124.6; C-5, 127.9; C-6, 132.3; C-7, 132.1; C-8, 129.5; C-4a, 126.8, C-8a, 151.0
The 15N NMR chemical shifts of cinnoline (referenced against neat nitromethane) in dimethyl sulfoxide-d6 are 44.6 (N1) and 41.2 (N2), respectively.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
155
Importance in Natural Products, Medicines, and Materials Cinnoline represents a developing branch of organic compounds, which exhibit a wide range of biological activity. These compounds have been reported to possess anticancer,594 fungicidal and bactericidal,595, 596 antituberclular,597 and sedative598 activities. Previously, it was considered that no cinnoline derivative occurs in nature. However, very recently, natural products containing the cinnoline nucleus have been isolated. Schizocommunin has been isolated from cultures of Schizophyllum commune, a basidiomycetous fungus collected from the bronchus of patients suffering from allergenic bronchopulmonary mycosis. Schizocommunin was found to exhibit strong cytotoxicity against murine lymphoma cells. Symmetrical cinnoline 4849F was isolated from the cultures of Streptomyces sp. 4849. Cinnoline 4849F exhibited cytotoxicity against human breast cancer MCF-7 and human ovarian cancer A2780 cell lines. 3-Methylcinnoline and 4-methylcinnoline were analyzed to be present in the volatile fraction of Hibiscus esculentus.599
Natural products containing cinnoline nucleus.
This nucleus is found as a substructure in a number of drugs like cinoxacin and cintazone.
Drugs containing cinnoline nucleus.
Synthesis 1. From cinnoline derivatives: Thermal decarboxylation of cinnoline 4-carboxylic acid in benzophenone at 155– 165°C yields cinnoline as the major product along with 4,4′-dicinnolinyl as the minor constituent.600
Reduction of 4-chlorocinnoline with iron and 15% sulfuric acid yields 1,4-dihydrocinnoline, which on oxidation with mercuric oxide gave cinnoline.
Reduction of 4-hydroxycinnoline with lithium aluminum hydride in refluxing THF, followed by oxidation of partially reduced cinnoline with mercuric oxide, yields cinnoline.601
156
2. Six-Membered Heterocycles
2. From carbohydrates: When d-glucose is heated with an excess of phenylhydrazine in the presence of hydrochloric acid, d-glucose phenylosazone and 1-(3-cinnolinyl)-d-arabinotetritol are obtained. Treatment of a cinnonyl derivative with UV light in aqueous sodium hydroxide solution for 8 h gives cinnoline.602
3. From cyclooctatetraene: Cyclooctatetraene on reaction with bromine gave dibromide derivative, which on reaction with ethyl azodicarboxylate gives an adduct (A), which is debrominated with a Zn/Cu couple to give another adduct (B). Adduct B when heated to 350°C rearranges to 1,2-diethoxycarbonyl-1,2-4a,8atetrahydrocinnoline, which is dehydrogenated by o-chloranil to 1,2-diethoxycarbonyl-1,2-dihydrocinnoline. This dihydro product on alkaline hydrolysis in the presence of activated manganese dioxide yields cinnoline.603, 604
4. Diazotization of amines: Diazotization of o-aminobenzaldehyde followed by coupling with nitromethane in dilute solution gave nitroformaldehyde o-formylphenyl hydrazone, which on cyclization yielded 3-nitrocinnoline.605
5. Von Richter cinnoline synthesis: The reaction named after Von Richter involves thermal cyclization of 2-alkynylbenzenediazonium salts to a 4-hydroxycinnoline derivative.606
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
157
Von Richter transformed diazonium chloride derived from o-aminophenylpropiolic acid into a nitrogenous derivative. This nitrogenous derivative was named cinnoline because of its analogy with quinoline.
The 4-hydroxycinnoline-3-carboxylic acid obtained by the foregoing process can be easily converted to cinnoline. The process involves heating 4-hydroxycinnoline-3-carboxylic acid above its melting point, where carbon dioxide is liberated and 4-hydroxycinnoline is obtained. Distillation of 4-hydroxycinnoline with zinc dust yields cinnoline.
The foregoing synthesized 4-hydroxycinnoline synthesized can also be converted to cinnoline via 4-chlorocinnoline.607
Mechanism: Earlier papers suggested that von Richter reaction proceeds through A pathway.608, 609 However, recent studies suggest that during the reaction, simultaneous attack of the triple bond on the diazo group followed by attack of the halide ion affords halocinnoline, which is then hydrolyzed to yield a 4-hydroxycinnoline derivative (B pathway).610
6. Widman-Stoermer synthesis: Synthesis of 3- and/or 4-alkyl, aryl-substituted cinnolines by cyclization of diazotized o-aminoarylethylenes is accomplished by this method.611, 612
Esters of anthranilic acid on reaction with Grignard reagent followed by dehydration yields o-aminoarylethylenes, which on diazotization followed by cyclization yield 4-methylcinnoline.
158
2. Six-Membered Heterocycles
7. Borsche’s synthesis: Cinnoline has been prepared by standing a diazotized solution of 2-amino-5nitroacetophenone at room temperature overnight, which slowly cyclized to 4-hydroxy-6-nitrocinnoline.613
A modification of the Borsche-Herbert reaction was proposed, where phosphorous ylides of o-aminoacetophenones were used for cyclization.614 8. Stolle-Becker synthesis: The conversion of N-benzylideneaminoisatin in the presence of a base to 3-phenyl-4cinnolinecarboxylic acid is known as Stolle-Becker synthesis.615
However, no chemical/experimental evidence was provided regarding the reaction. Detailed experimental evidence supporting the validity of the Stolle-Becker reaction was provided by Baumgarten et al.616 The process involves reaction of benzaldehyde phenylhydrazone with 100% excess of oxalyl chloride yielding N-benzylideneamino-Nphenyloxamyl chloride, which on treatment with aluminum chloride in chloroform gave N-benzylideneaminoisatin. Treatment of the latter with hot 20% aqueous sodium hydroxide gave 3-phenyl-4-cinnolinecarboxylic acid.
9. Baumgarten synthesis: The yield of a cinnoline derivative by Stolle-Becker synthesis was not very successful. Hence Baumgarten developed a method in which 3-substituted cinnoline was synthesized in good yield. Reaction of a diazotized solution of 2-aminobenzaldehyde with nitromethane yielded nitroformaldehyde 2-formylphenylhydrazone as an intermediate, which cyclized in alkali to produce 3-nitrocinnoline.617
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
159
10. Barber’s synthesis: The synthetic approach to cinnoline was described in a British patent by Barber et al.618, 619 The process involves the reaction of benzenediazonium chloride with diethyl malonate and subsequent hydrolysis of the resulting condensation product followed by conversion to acid chloride. The acid chloride cyclized in the presence of titanium tetrachloride yielding 4-hydroxycinnoline-3-carboxylic acid, which was thermally decarboxylated at 205–215°C to hydroxyl cinnoline.
11. Neber-Bossel synthesis: This is a classical method for the formation of 3-hydroxycinnoline via N(2)C(3) bond formation. The process involves diazotization of (2-aminophenyl)hydroxyacetate followed by reduction of the diazonium salt obtained. The reduced product is then cyclized to 3-hydroxycinnoline on boiling with hydrochloric acid.620, 621
Physical Properties Cinnoline crystallizes out from ether as a solvate of colorless needles with mp of 24°C and from ligroin as a pale-yellow crystal with mp of 39°C. It has a quinoline-like odor and is soluble in water and most organic solvents. On exposure to air it liquefies and rapidly turns green. Cinnoline with a pKa value of 2.70 in water at 20°C is a weaker base in comparison to quinoline and isoquinoline. The dipole moment of cinnoline is 4.14 D, slightly lower in comparison to pyridazine (4.32 D). Chemical Reactivity 1. Salt formation: Cinnoline is a strong base and forms stable salts with hydrochloric acid and picric acid. It forms an addition compound with methyl iodide.622 2. Electrophilic substitution reaction: Diazines do not undergo an electrophilic substitution reaction unless electron-donating substituents are present. However, their benzo derivative undergo electrophilic substitution reaction chiefly at 5- and 8-positions. Cinnoline undergoes nitration in the presence of concentrated sulfuric acid yielding a mixture of 5- and 8-nitrocinnoline.623, 624
160
2. Six-Membered Heterocycles
3. Oxidation: When cinnoline is treated with hydrogen peroxide in acetic acid, a mixture of cinnoline 1-oxide and cinnoline 2-oxide are obtained, of which 2-oxide is the major component.625
The nitrogen-containing ring in cinnoline is stable to oxidation. Potassium permanganate oxidation of 4-phenylcinnoline yielded 5-phenylpyridazine-3,4-dicarboxylic acid, which was stepwise decarboxylated to 4-phenylpyridazine.622
4. Free radical reaction: Reaction of cinnoline with N-nitrosoacetanilide at 50–60°C for 3 h gave a mixture of products, of which 4,4′-dicinnolinyl was the major product. Formation of 4,4′-cinnolinyl is thought to take place by a free radical mechanism by two different paths.626
5. Reduction: On refluxing with lithium aluminum hydride in ether solution, cinnoline is reduced to 1,4-dihydrocinnoline.627 However, when cinnoline is refluxed with amalgamated zinc in 33% acetic acid for 2 h, indole is the product. It was observed that when the reduction process is stopped as soon as a yellow color of the reaction mixture is discharged, then the 1,4-dihydro derivative can be isolated at this stage, which on further reaction with amalgamated zinc in acetic acid yields indole.628
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
161
Cinnoline when heated with formic acid and formamide undergoes reductive formylation to yield 1-formamidoindole.629
4-Phenylcinnoline on reaction with zinc and acetic acid was converted to 3-phenylindole.622
6. Reaction with ketene: Cinnoline reacts with 2 equivalents of dimethylketene in ether to give an adduct (4-isopropilidene-1,1-dimethyl-4H[1,3,4]oxadiazino[4,3-a]cinnolin-2(1H)-one), which on alkaline hydrolysis yields amido acid.630
7. Replacement reaction: The chloro group of 4-chlorocinnoline has been replaced by different nucleophiles. 4-Chlorocinnoline on reaction with sodium ethoxide in ethanol, the chloro group is replaced by ethoxy group. Similarly the chloro group has been replaced by hydroxyl and aromatic amino group.622
2.4.7 Phthalazine
Phthalazine, like cinnoline, is also a 6,6-benzo-fused derivative of pyridazine, but unlike cinnoline, which has two nitrogen atoms at the 1- and 2-positions, phthalazine has nitrogen atoms at the 2- and 3-positions, hence it is known as benzo[d]pyridazine. Structural and Reactivity Aspects632 Phthalazine is isomeric with cinnoline because both contain nitrogen atoms at the ortho-position. However, cinnoline is 1,2-diazanaphthalene, whereas phthalazine is 2,3-diazanaphthalene. In contrast to cinnoline, which has a double bond between two nitrogen atoms, phthalazine has a single bond between them and is well confirmed by theoretical and experimental studies. Phthalazine is thus exclusively represented by the Kekulé structure.
162
2. Six-Membered Heterocycles
The exact structure of phthalazine has been determined by X-ray analysis. Bond lengths (in Å) are depicted in the following figure.
The UV spectrum of phthalazine in methyl cyclohexane shows five bands at 252 nm (log ε 3.629), 259 nm (log ε 3.668), 267 nm (log ε 3.587), 290 nm (log ε 1.108), and 296.5 nm (log ε 1.061). The first three bands are due to π→π* transition, whereas the fourth and fifth bands at longer wavelengths are due to n→π* transition.631 The structure of phthalazine was further confirmed by its 1H and 13C NMR data. The aromatic protons of the benzenoid ring appeared as a AA′BB′ system. 1 H NMR (acetone d6) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1/H-4, 9.60; H-5/H-8, 8.13; H-6/H-7, 8.00
C-1/C-4, 152.0; C-5/C-8, 126.7; C-6/C-7, 133.2; C-4a/C-8a, 126.7
The 15N NMR chemical shift632 of phthalazine (referenced against neat nitromethane) in dimethyl sulfoxide-d6 is δ 10.3. Importance in Natural Products, Medicines, and Materials Heterocycles containing phthalazine moiety are important targets in synthetic organic chemistry because this moiety is present in a number of biologically active compounds. Phthalazine derivatives have been reported to possess cytotoxic,633 antimicrobial,634 anticonvulsant,635 antifungal,636 anticancer,637 and antiinflammatory activities.638 Isolation of natural products containing phthalazine nucleus have recently been reported. Azamerone was isolated from marine-derived species of Streptomyces, while 6-asidotetrazolo[5.1-a]phthalazine was obtained from Gymnodinium breve, a toxic red tide dinoflagellate.639
Natural products containing phthalazine nucleus.
Besides, this nucleus is found within the structures of a number of drugs like hydralazine, budralazine, azelastine, and zopolrestat.
Drugs containing phthalazine nucleus.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
163
Chemical Synthesis640 1. Dehalogenation of phthalazines: Halogen atoms present at the 1- or 1- and 4-positions of phthalazine are easily removed by reduction. 1-Chlorophthalazine on catalytic reduction with 5% palladium on charcoal and 1,4-dichlorophathalazine on chemical reduction with phosphorous and hydroiodic acid yielded phthalazine.
1-Hydrazinophthalazine, when oxidized at room temperature by oxygen in ethanolic alkali or by heating with copper sulfate at pH 8, yielded phthalazine.
2. Reaction involving hydrazines: Phthalazine was first prepared by Gabriel and Pinkus641 in 1893 by treating tetrachloro-o-xylene with hydrazine.
Phthalazines are conveniently synthesized by condensation reaction between o-diaroylbenzenes or o-acylbenzoic acid and hydrazine.
Phthalazine has also been prepared by reaction of o-phthaldehyde with aqueous hydrazine sulfate.
This method has limited utility because it depends on the availability of o-phthaldehyde. However, a two-step convenient synthesis of phthalazine from phthalonitrile has been reported. The process involves reaction of dinitrile with hydrazine hydrate in dioxane and acetic acid yielding 1,4-dihydrazlnaphthalazine, which is oxidized with molecular oxygen to phthalazine.642
164
2. Six-Membered Heterocycles
The reaction of hydrazine with an appropriately substituted aromatic aldehyde, followed by cyclodehydration of acylhydrazone, yields phthalazine.
3. From tetrazines: Symmetrical tetrazines react with olefins to yield phthalazine derivatives.643
A new method has been reported for the synthesis of 4-imino-3,4-dihydrophthalazine from 2-(2-phenylhydrazono) acetaldehyde using 2-ethylidenemalononitrile and benzylidenemalonitrile via formation of a number of intermediates, which cyclizes in the presence of zinc chloride to yield phthalazine.644
A novel one-step synthesis of phthalazine from aromatic aldehydes has also been reported. The key step of the reaction is the transformation of aromatic aldehyde into a directed ortho-metalation group (DMG). This is achieved by reacting it with lithium amide derivatives to form R-aminoalkoxides. Commonly, N,N,N′-trimethylethylenediamine or bis(2-methoxyethyl)amine are used for the formation of R-aminoalkoxides. After the in situ formation of Raminoalkoxide or DMG, the dianion is formed by o-lithiation with n-BuLi. The dianion on reaction with dimethylformamide gives o-bis(aminoalkoxide), which after hydrolysis with aqueous ammonium chloride and hydrazine yields phthalazine.645
4. From phthalic anhydride: Reaction of phthalic anhydride with malonic acid in pyridine gave 2-acetylbenzoic acid, which was esterified with dimethyl sulfate. The acetyl group was brominated with phenyltrimethylammonium tribromide (PTT). The bromo derivative was treated with thiophenol or
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
165
3,4-difluorothiophenol using K2CO3 as a base yielding the thio derivative, which was cyclized by treating with hydrazine hydrate to yield a phthalazine derivative.646
5. From aldazines: Synthesis of 1-arylphthalazine is achieved by heating aromatic aldazines with aluminum chloride/triethylamine at 170–200°C. However, when reaction is carried out with aluminum chloride alone, phthalazine is obtained.647
Physical Properties At atmospheric pressure phthalazine forms white hard prism with mp of 90–91°C, which slowly turns yellow. It is readily soluble in water and all organic solvents except ligroin. The pKa value of phthalazine is 3.47 in water at 20°C. This higher base strength value in comparison to pyridazine (pKa 2.3) is explained on the basis of the single NN bond in phthalazine. Chemical Reactivity640 1. Salt formation: Phthalazine on reaction with various acids like hydrochloric, hydrobromic, hydroiodic, and picric acids forms salts. 2. Nitration: Phthalazine on nitration with potassium nitrate and concentrated sulfuric acid yielded 5-nitrophthalazine as the main product and 5-nitro-1(2H)-phthalazone as the by-product.648
3. Oxidation: Phthalazine on oxidation with alkaline potassium permanganate undergoes ring opening to generate pyridazine-4,5-dicarboxylic acid.
However, when there is an oxidizable group bonded to the carbon of the azine ring, oxidation of the attached group takes place first.
166
2. Six-Membered Heterocycles
4. Reduction: Phthalazine on reaction with sodium amalgam yields tetrahydrophthalazine, which on reaction with nitrous acid is transformed into dioxime of o-phthalaldehyde.
On reaction with zinc and hydrochloric acid, phthalazine yields α,α-diamino-o-xylene, which on warming with hydrochloric acid is transformed into dihydroisoindole.
Reductive acylation of phthalazine on reaction with benzyl chloroformate in the presence of sodium cyanoborohydride gave a separable mixture of 2-benzyloxycarbonyl-1,2,3,4-tetrahydrophthalazine and 2,3-dibenzyloxycarbonyl-1,2,3,4-tetrahydrophthalazine.649
5. N-Alkylation: Treatment of phthalazine with methyl iodide yields N-methylphthalazinium iodide, which on treatment with potassium hydroxide solution 2-methyl-1,2-dihydrophthalazine.
6. C-Alkylation/Arylation: Phthalazine on reaction with phenyl magnesium bromide gave 1-phenyl-1,2dihydrophthalazine, which on oxidation gave 1-phenyl phthalazine.
7. Photochemical reaction: Phthalazine dissolved in methanol containing HCl gas on irradiation yields 1-methylphthalazine.
Phthalazine on UV light irradiation in 2-propanol under nitrogen undergoes dual photoreduction to yield simultaneously two photo products, 1,2-dihydrophthalazine and 1,1′, 2,2′-tetrahydro-1,1′bisphthalazine.650
Irradiation of phthalazine in acidified methanol and ethanol yielded 2-methylphthalazine and 2-ethylphthalazine, respectively. The reaction is thought to proceed by a pathway involving electron transfer from the solvent to an excited state of protonated phthalazine.651
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
167
8. Reissert reaction: Phthalazine on reaction with benzoyl chloride and potassium cyanide in a methylene dichloride water solvent system yields a phthalazine Reissert compound.652
9. Replacement reaction: The halogen group of 4-halophthalazine has been replaced by different nucleophiles. For example, when 4-chlorophthalazine reacts with sodium alkoxide in alcohol, the chloro group is replaced by nucleophiles such as alkoxy group. Similarly chloro group has been replaced by hydroxyl and aromatic amino group.
10. 1,3-Dipolar cycloaddition reaction: Cycloaddition reaction of 2-[2-(3-nitrophenyl-2-oxoethyl)]phthalazinium with DMAD in the presence of an excess of triethylamine gave dimethyl cis-3-(3-nitrobenzoyl)-1-10bdihydropyrrola[2,1-a]phthalazine-1,2-dicarboxylate, which on reaction with tetrakis-pyridino Co(II)dichromate (TPCD) yielded dimethyl 3-(3-nitrobenzoyl)-pyrrolo[2,1-a]phthalazine-1,2-dicarboxylate.653
168
2. Six-Membered Heterocycles
2.4.8 Quinolizine
Quinazoline is also known as 1,3-diazanaphthalene. It is derived by fusion of the benzene ring to the 5,6-position of pyrimidine, hence it is also known as benzo[d]pyrimidine. Quinazoline has also been called phenmiazine, benzyleneamidine, benzo-1,3-diazine, and 5,6-benzopyrimidine. The name quinazoline was first proposed by Weddige because he observed that this compound was isomeric with cinnoline and quinoxaline, the two benzodiazines known at that time. Structural and Reactivity Aspects654 Quinazoline is a cyclic-conjugated 10π electron system with a resonance energy value of 127.2 kJ mol−1 and an aromaticity index of 143. The observed dipole moment of quinazoline in benzene is 2.2 D and this value is in good agreement with the calculated value (2.55 D). Quinazoline behaves chemically like its pyrimidine counterpart with the exception that quinazoline is more basic due to electrophilicity of the C-4-position. N
N N pKa 1.1
N pKa 3.3
pKa values of pyrimidine and quinazoline.
Fusion of the benzene ring with the pyrimidine rings results in altered reactivity of both the rings in quinazoline. The benzene ring is deactivated toward electrophilic attack due to the electron-withdrawing effect of the pyrimidine ring. There is significant electron depletion at C-2 and C-4 but only minor depletion at C-5, C-6, C-7, and C-8. Thus nucleophilic attack can take place at C-2 and C-4, whereas electrophilic attack can take place at C-5, C-6, C-7, and C-8. The structure of quinazoline was solved in 1976 by X-ray diffraction. The bond lengths and bond angles are given in the following table. Bond lengths and bond angles of quinazoline Bond
Bond length (nm)
Position
Interbond angle (o)
N(1)C(2)
0.1307
C(2)N(1)C(8a)
115.9
C(2)N(3)
0.1355
N(3)C(2)N(1)
128.3
N(3)C(4)
0.1307
C(4a)C(4)N(3)
123.5
C(4)C(4a)
0.1407
C(4)N(3)C(2)
115.2
C(4a)C(8a)
0.1400
C(8a)C(4a)C(4)
116.3
N(1)C(8a)
0.1372
N(1)C(8a)C(4a)
120.8
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
169
The UV spectrum of quinazoline in water showed three bands at 222 nm (log ε 4.57), 271 nm (log ε 3.40), and 305 nm (log ε 3.38). All three bands are due to π→π* transition. However, when the UV spectrum of quinazoline vapors was carried out an additional band was observed at 365 nm (log ε 0.200), and this was probably due to n→π* transition.655 In the 1H NMR spectrum of quinazoline the H-2 and H-4 protons are deshielded due to nitrogen atoms of the diazine ring and are observed at 9.23 and 9.29 ppm, with H-4 being most deshielded due to the resonance effect. Corresponding H-5 and H-8 are less shielded with H-8 being the least and observed at 7.01 ppm. In the 13C NMR spectrum of quinazoline the C-2 and C-4 carbon atoms were observed at 156.1 and 161.1 ppm, respectively. This downfield shifting is observed due to deshielding effect of the heteroatoms. 1
H and 13C spectral data of quinazoline
1
H NMR (CCl4) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 9.23; H-4, 9.29; H-5, 7.84; H-6, 7.58; H-7, 7.83; H-8, 7.01
C-2, 156.1; C-4, 161.1; C-5, 128.1; C-6, 128.8; C-7, 135.1; C-8, 129.3; C-4a, 126.0; C-8a, 151.3
The 15N NMR chemical shifts of quinazoline (referenced against neat nitromethane) in dimethyl sulfoxide-d6 showed two sharp signals at 97.8 (N1) and 86.5 ppm. Under electron impact, quinazoline fragments by consecutive loss of two molecules of hydrogen cyanide from molecular ion to give a benzyne radical.
Mass fragmentation pattern of quinazoline.
Importance in Natural Products, Medicines, and Materials Quinazolines are one of the most important nitrogen benzodiazenes and are found in a number of natural products: pharmaceuticals, pesticides, and functional organic materials. As main building blocks, the quinazoline nucleus is present in a number of natural alkaloids isolated from plants, animals, and microorganisms. The first quinazoline alkaloid to be isolated was vasicine in 1888. Later on, a number of quinazoline natural products were isolated and characterized.
Natural products containing quinazoline nucleus.
The structural diversity of quinazolines was broadened with isolation of asperlicins from Aspergillus alliaceus, which is a potent cholecystokinin antagonist, and benzomalvin from the fungus culture of Pencillium sp.
Natural products containing quinazoline nucleus.
170
2. Six-Membered Heterocycles
Quinazolines are found in a diverse array of synthetic and naturally occurring compounds and they have shown to possess diverse biological activities like sedative, analgesic, anticonvulsant, antitussive, antirheumatic, antidiabetic, anticancer, and antimicrobial. Besides, this nucleus is found within the structures of a number of drugs like prazosin, gefitinib, erlotinib, lapatinib, and vantetanib.
Drugs containing quinazoline nucleus.
Synthesis 1. From quinazoline derivatives: Unsubstituted quinazoline was first synthesized by Gabriel in 1903 by mild alkaline potassium ferricyanide oxidation of 3,4-dihydroquinazoline.
Oxidation of 4-hydrazinoquinazoline with a stream of oxygen through alkaline ethanolic solution for 2 h yielded quinazoline. Reaction of quinazoline-3-oxide with 2-butanone also yields quinazoline.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
171
2. From anilines: Protection of amino group with ethyl chloroformate followed by reaction with hexamethylenetetramine (HMTA) in TFA resulted in the formation of the cyclized product dihydrobenzoquinazoline, which on oxidation with K3Fe(CN)6 without separation of the intermediate yielded the quinazoline derivative.656
4-Arylaminoquinazolines have been synthesized by reaction of 2-aminobenzonitrile with anilines in the presence of aluminum chloride forming amidine as intermediate, which on heating with 85% formic acid at 90°C yielded 4-arylaminoquinazoline derivative.657
4-Arylquinazolines have also been synthesized by heating 5-nitroanthranilonitrile with dimethyl formamide acetal yielding an imine derivative, which on heating with 3-bromoaniline yielded the desired quinazoline derivative in excellent yield.658
Synthesis of 2,4-dihydroxyquinazolines has been reported. The process involves reaction of 2-aminobenzonitrile with carbon dioxide in the presence of a base to generate carbamate salt, which undergoes nucleophilic cyclization with attack of carbamate oxygen on nitrile functionality. Rearrangement takes place to yield an intermediate, which is protonated to yield 2,4-dihydroxyquinazolines.659
3. Microwave-promoted reaction: A microwave-promoted synthesis of 4-aminoquinazoline has been reported. The process involves heating anthranilonitrile, 2-thiophenenitrile, and potassium tert-butoxide in a domestic microwave oven for 3 min.660
172
2. Six-Membered Heterocycles
Reaction of an amino-protected derivative under microwave activation not only increased the yield of quinazoline but also reduced reaction time and the ratio of reagents used.661
4. Niementowski quinazoline synthesis: A chemical reaction between anthranilic acid and amide to form 4-oxo-3,4dihydroquinazolines is known as the Niementowski reaction, named after its discoverer Stefan Niementowski.662
5. Bischler synthesis: The process of heating 2-(acetamido)benzaldehyde with alcoholic ammonia or primary amine at 100°C to yield 2-methylquinazoline is known as Bischler synthesis. Initially, a 3,4-dihydro derivative is formed, which spontaneously undergoes dehydrogenation to quinazoline.
6. Riedel synthesis: This is a method for the direct synthesis of quinazoline by reaction between onitrobenzaldehyde and formamide. In the first step, o-nitrobenzylidene diformamide is formed, which on reduction with zinc and acetic acid gave quinazoline in good yield.663
7. Transition metal-mediated approach: Quinazoline is synthesized by the reaction of 2-nitrobenzaldehyde with formamide to give corresponding N-[1-formylamino-1-(2-nitrophenyl)-methyl]-formamide, which when treated with a palladium(II) and molybdenum(II) complex as catalyst in the presence of carbon monoxide under high pressure produced quinazoline.664
The Cu2O-catalyzed reaction between o-bromobenzylbromide and benzamidines using CsCO3 as a base and N,N′dimethylethylenediamine (DMEDA) as additive in solvent yields substituted quinazoline in one step.665
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173
A one-pot synthesis of quinazoline involving a three-component reaction between 2-aminoaryl ketone, an aldehyde, and ammonium acetate in the presence of a low-melting, inexpensive, nontoxic, easily biodegradable mixture of maltose-dimethylurea (DMU)-NH4Cl has been reported.666
8. [2 + 2 + 2] condensation: A one-pot synthesis of multiple substituted quinazoline by [2+2+2] cascade annulation of diaryliodonium salts and two nitriles has been reported. The reaction is also applicable for two different nitriles to give a regioselective product.667
9. Ring enlargement reaction: 2-Substituted quinazoline can be synthesized by the treatment of dihydrotriazolines with ammonia. The process involves the opening of five-membered rings to an amidine derivative, which undergoes cyclocondensation to yield a quinazoline derivative.668 Initially, triazoline is formed by a reaction of aldehyde with morpholine and subsequent reaction with aryl azide.
10. Ring contraction reaction: 3H-1,4-Benzodiazepines669 are used as a substrate for the construction of 4-substituted quinazolines by thermal ring contraction.
11. From o-fluorobenzaldehyde: Reaction of cyano- or nitro-substituted o-fluorobenzaldehyde with amidine resulted in the formation of an imine derivative, followed by intramolecular aromatic substitution at the fluorine-substituted carbon center yielding a quinazoline derivative.670
174
2. Six-Membered Heterocycles
Physical Properties Quinazoline is a solid, which crystallizes from petroleum ether and melts at 48–48.5°C. It is steam volatile and readily sublimes under vacuum. It has a characteristic pleasant odor and bitter taste. It is soluble in water and nearly all organic solvents. In a legal color test it gives a red color in acidic as well as basic medium. Chemical Reactivity 1. Quaternization: Methylation of quinazoline with methyl iodide and been demonstrated to produce 1-methylquanzolium iodide and 3-methylquanzolium iodide in a ratio of 1:5 in favor of the latter isomer.671
2. Electrophilic substitution reaction: Because quinazoline is π electron deficient, no electrophilic substitution takes place in the pyrimidine ring. However, under forcing conditions, an electrophilic substitution reaction can take place in the benzene ring. Nitration of quinazoline takes place, yielding 6-nitroquinazoline. Bromination of quinazoline with NBS in concentrated sulfuric acid at room temperature has been reported to yield 6-bromoquinazoline. In addition to a monosubstituted product, tri- and tetrabrominated products are also obtained.672
3. Nucleophilic substitution reaction: Quinazoline reacting with acetophenone at room temperature afforded 2-(3,4-dihydro-4-quinazolin)acetophenone. This reactivity is possibly due to -M and -E effects of the ring nitrogen atom and the effect of the fused benzene ring at the 4-position.673
Reaction of quinazoline with a reactive methylene compound like phenylacetonitrile in the presence of methoxide afforded 4,4'-biquinazoline and α-phenyl-4-quinazolineacetonitrile.674
The reaction is thought to proceed by the following mechanism.
Reaction of reactive methylene compound in the absence of a base catalyst yields quinoline derivatives. Quinazoline on reaction with malononitrile yields 2-aminoquinoline-3-carbonitrile and 2-hydroxyquinoline-3-carbonitrile.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
175
Reaction of quinazoline with alkylmagnesium bromide yields a 3,4-dihydro derivative, which without isolation is oxidized with potassium ferricyanide to 4-alkylquinazoline.
Reaction of quinazoline with excess 3,3-dimethylbutene in the presence of rhodium catalyst and tri(cyclohexyl) phosphine gave 2-alkylquinazoline in excellent yield.675
4. Amination (Chichibabin reaction): Reaction of quinazoline with sodium amide in DMA yielded 4-aminoquinazoline. However, when the amination reaction is carried out in the potassium amide/ liquid ammonia/potassium permanganate van der Plas system, in addition to 4-aminoquinazoline, 2% of 4,4′-diquinazolyamine is also obtained.
5. Oxidation: Quinazoline is oxidized in dilute acid with 2 equivalents of hydrogen peroxide at room temperature to quinazolin-4(3H)-one.
Quinazoline is stable to oxidation but on reaction with alkaline potassium permanganate under drastic conditions, the benzene ring is ruptured to yield 4,5-pyrimidinedicarboxylic acid.
Oxidation of quinazoline by a mutant strain of the bacterium Pseudomonas putida gives cis-5,6-dihydroquinazoline- 5,6-diol, cis-5,6,7,8-tetrahydroquinazoline-5,6-diol, and quinazolin-4(3H)-one.
6. Reduction: Quinazoline is reduced to 3,4-dihydroquinazolines effectively in the presence of Adam's platinum oxide676 catalyst.
However, reduction to 1,2,3,4-tetrahydroquinazoline takes place under forcing conditions. Reductive acylation of quinazoline on reaction with benzyl chloroformate in the presence of sodium cyanoborohydride gave 1,3-dibenzyloxycarbonyl-1,2,3,4-tetrahydroquinazoline.677
176
2. Six-Membered Heterocycles
7. Suzuki reaction: Microwave-promoted Suzuki reaction of quinazoline halide with boronic acid was carried out in the presence of stable catalyst tetrakis triphenylphosphine palladium and cesium carbonate afforded 4-substituted quinazoline in high yield.678
8. Ring-opening reaction: Quinazoline on reaction with hydroxylamine undergoes ring cleavage between C-2 and C-3 to yield N-(hydroxyiminomethyl)anthraniloaldehydeoxime.679
9. Replacement reaction: 4-Chloroquinazolines are important synthetic intermediates, which can undergo nucleophilic attack at C-4 to yield new quinazoline derivatives. The reaction is thought to proceed with activation of benzaldehyde by cyanide addition and activation of quinazoline as a 4-toluenesylfonyl derivative.680
Synthesis of an important intermediate is reported, which has been used in the synthesis of AX7593, a quinazoline- derived photoaffinity probe for epithelial growth factor receptor.681
2.4.9 Purine 6 1N 2
5
N7
4
N9 H
8
N 3
Purines are a group of cyclic diureides, aromatic in nature and consisting of a pyrimidine ring fused to an imidazole ring. The word purine (pure urine) was coined by Emil Fischer in 1884 for this naturally occurring derivative.
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177
Structural and Reactivity Aspects682a Purine exists in four tautomeric forms, 1H- (a), 3H- (b), 7H- (c), and 9H-tautomer (d), depending on the site of attachment of the proton to the ring nitrogen atoms. The 1H- and 3H-tautomers are much less stable in comparison to the 7H- and 9H-tautomers, which are present in equal concentration in the concentrated aqueous solution. However, in the solid state, 7H-purine is the dominant tautomer.
(A)
(B)
(C)
(D)
Different tautomers of purine.
The structure of purine was confirmed by X-ray, which shows that the imidazole ring is planar. However, the fused pyrimidine ring deviates from the coplanar arrangement. The bond lengths (in pm) and bond angles (in degrees) are shown in the following diagram.
Bond length and bond angles in purine.
The 1H and 13C NMR spectra of purine are comparable to the two fused rings of pyrimidine and imidazole, except that the protons in the imidazole ring are shifted downfield in comparison to the parent ring. H and 13C NMR spectral data of purine
1
1
H NMR (DMSO-d6) δ (ppm)
13
C NMR (DMSO-d6) δ (ppm)
H-2, 8.99; H-6, 9.19; H-88.68
C-2, 152.1; C-4, 154.8; C-5, 130.5; C-6, 145.5; C-8, 146.1
The mass spectrum of purine shows two consecutive losses of hydrogen cyanide, a pattern that is often observed in heterocyclic compounds containing two nitrogen atoms in one ring.
Mass fragmentation of purine.
Importance in Natural Products, Medicines, and Materials Purine is important because this skeleton is present in a number of natural products like saxitoxin, microxine, aplidiamine, and many others. A number of structures possessing the purine nucleus have been reported to show diverse biological activities. They have been reported to possess antitumor,682b anti-HIV,683 antiviral,684 anticonvulsant,685 and bronchodilator activity.686
178
2. Six-Membered Heterocycles
Saxitoxin
Microxine
Aplidiamine
Natural products containing purine skeleton.
A number of drugs have been shown to possess the purine skeleton. For example, 6-mercaptopurine, sold under the brand name Purinethol, is used for the treatment of leukemia and autoimmune diseases. Fludarabine, sold under the brand name Fludara, is used for the treatment of leukemia and lymphoma. Aciclovir, also known as acyclovir, is an antiviral agent used primarily for the treatment of herpes infection. Abacavir is used for the treatment of HIV/ AIDS. Dideoxyinosine (didanosine), sold under the brand name Videx, is used for the treatment of HIV/AIDS. Allopurinol, sold under the brand name Zyloprim, is used to decrease uric acid levels in blood.
Drugs containing purine nucleus.
Purines are important because some of their derivatives, particularly adenine and guanine, are monomeric building blocks of DNA and RNA nucleic acid poly chains. In addition to being building blocks of DNA and RNA, purines are also found in a number of other important biomolecules such as ATP, GTP, cyclic AMP, NADH, and coenzyme A. Besides adenine and guanidine, other notable purine derivatives are xanthine, hypoxanthine, theobromine, caffeine, and uric acid.
Important purine derivatives.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
179
Synthesis 1. Fischer synthesis: Fischer first synthesized687 purine from uric acid isolated from kidney stones. Uric acid reacted with PCl5 to give 2,6,8-trichloropurine, which on treatment with HI and PH4I gave 2,6-diiodopurine. The diiodo product on reduction with zinc dust yields purine.
Adenine is synthesized by treating 2,6,8-trichloropurine with aqueous ammonia followed by treatment with HI.
2. Traube synthesis: Purine has also been synthesized by heating 4,5-diaminopyrimidine688 with formic acid at 100°C under carbon dioxide and then slowly raising the temperature to 210°C. This method has been used for the synthesis of a number of purines unsubstituted at the 8-position.
Reaction between guanidine and cyanoacetic acid ester leads to the synthesis of pyrimidine derivative. An amino group is introduced at the 5-position by nitrosation followed by ammonium sulfide reduction yielding 4,5-diaminopyrimidine. The diamino derivative on treatment with formic acid yields purine.689 Formamide690 and formamidine691 have also been used in place of formic acid.
Reaction of 4-amino-5-nitrosopyrimidine with formic acid in the presence of Raney nickel yields purine.
A slight modification of this method includes heating 4,5-diaminopyrimidine with dithioformic acid in sodium hydroxide solution and heating the product obtained with sodium methoxide.
Adenine has also been synthesized by this method. The process involves reaction of 6-chloro-4,5-diaminopyrimidine with diethoxymethyl acetate furnishes 6-chloropurine, which on amination with ammonia yields adenine.
180
2. Six-Membered Heterocycles
3. 8-Substituted purine has been synthesized by treating 4,5-diaminopyrimidine with acetic anhydride.
8-Substituted purines are synthesized by treating 2,4,5,6-tetraaminopyrimidine with 4-methoxy benzoyl chloride followed by cyclization with phosphorous oxychloride.
4. Bergmann synthesis: 4,5-Diaminopyrimidine condenses with amidine salts to yield 8-substituted purine in high yield.692
5. Suzuki reaction: Disubstituted purines have been synthesized by Suzuki cross-coupling reaction. 2,4-Dichloropurine on reaction with MeZnBr yielded monosubstituted purine, which underwent a Suzuki crosscoupling reaction with phenylboronic acid yielding disubstituted purine.693
6. Domino Heck-Negishi reaction: A three-component domino Heck-Negishi coupling reaction for the synthesis of purine derivative with a carbon substituent at C-6 has been reported. The process involves organozinc reagent for the first time to trap an alkylpalladium intermediate of olefins in the domino Heck reaction.694
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
181
7. Purine in good yield is obtained by heating formamide in an oil bath at 160–200°C in an open vessel for 28 h.695
Synthesis of adenine has also been achieved in one step by heating formamide with phosphoryl chloride at 120°C in a sealed tube or by reaction of aminomalonimidamide with triethyl orthoformate.
8. Desulfurization: Desulfurization of sulfanyl-substituted purine leads to the generation of pure purine.
9. Reaction of alkylaminoacetonitriles with formimidamide acetate gives 7-substituted purine in good yield.
10. Diels-Alder reaction: Based on inverse electron demand, Diels-Alder cycloaddition reaction of 1,3,5-triazine and 2,4,6-tri(trifluoromethyl)-1,3,5-triazine with in situ-generated 1-substituted 5-amino-1H-imidazole separately produced functionalized purines.696
11. 7-Substituted purines have efficiently been synthesized from 4-amino-1H-imidazole-5-carbaldehyde oxime (prepared from 4-nitroimidazole697). Condensation of the amino group with orthoesters resulted in the formation of iminoethers. Cyclocondensation of the ortho groups with ammonia resulted in the formation of the purine ring system.698
Physical Properties Purine is slightly yellow to cream crystalline powder with mp of 214°C and is soluble in water.
182
2. Six-Membered Heterocycles
Chemical Reactivity 1. Protonation at nitrogen: Purine is a weak base and protonation of all the four nitrogen atoms is possible, but the most prominent cation is formed by protonation699 of N-1. 2. N-Alkylation: N-Alkylation of purine takes place at N-7 and/or N-9. Purine reacts with iodomethane to yield 7,9-dimethylpurinium salt.700 However, on reaction with dimethysulfate and vinyl acetate, alkylation takes place at N-7.
Base-induced coupling is the most popular method for carrying out N-alkylation reactions. The process involves generating a purinyl cation in the presence of a base such as metal carbonates like K2CO3 or Cs2CO3 or hydrides like NaH in a polar solvent.701
N-Alkylation of 6-chloropurine was carried out using Mitsunobu reaction. The process involved reacting purine with alcohol in the presence of diethylazodicarboxylate (DEAD). N-9-Alkylated product was the major product in comparison to the N-7-alkylated product.702
N-Alkylation of purines was also achieved under solid-liquid-phase transfer catalysis by use of 18-crown-6 or tetraglyme in the presence of potassium tert-butoxide as base.703
N-Alkylation of adenine with alkyl esters of phosphorous oxyacid takes place at the 3-position yielding 3-alkyladenine.704
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
183
3. Electrophilic substitution reaction: Nitration of 6-substituted purine with tetrabutylammonium nitrate/ trifluoroacetic anhydride (TBAN/TFAA) has been studied. The nitrating mixture selectively nitrates at the C-2 position.705
The reaction has been proved to take place in three steps. Electrophilic attack by trifluoroacetyl nitrate on the N-7 position results in nitroammonium species that are trapped by trifluoroacetate anions furnishing an N 7-nitramine intermediate, which undergoes a nitramine rearrangement, producing 2-nitro-4-chloropurine706 with elimination of TFA.
4. Nucleophilic substitution reaction (a) Chichibabin reaction: Reaction of purine with KNH2 in ammonia leads to the formation of 6-aminopurine (adenine).
(b) Halopurines, thiols, or sulfides react with organometallic compounds in the presence of a phosphine-nickel complex or palladium catalyst (Negishi reaction) to yield alkylated purines.
184
2. Six-Membered Heterocycles
(c) Nucleophilic addition of 2-thiobarbituric acid to 1,6-double bond of purine takes place to yield 1,6-dihydro-6(4,6-dioxo-2-thiohexahydropyrimidin-5-yl)purine.707
5. Deuteration: Purine is rapidly deuterated at C-8 in neutral water at 100°C. The reaction probably involves 8-deprotonation of purinium cation to give a transient ylide.
6. Oxidation: Direct oxidation of purines with peracid is the most favored method for the synthesis of purine-1 and -3-oxides. When an electron-donating substitute is present at C-6, then N-1 nitrogen is oxidized first. Adenine 1-oxide is synthesized in 84% yield by reacting adenine with hydrogen peroxide in the presence of acetic acid.
7. Reduction: Electrochemical reduction of purine takes place in two stages. In the first stage, 1,6-dihydropurine is formed, which on further reduction yields 1,2,3,6-tetrahydropurine. Hydrolysis of tetrahydropurine yields 4-aminoimidazole.708, 709
8. Photochemical reaction: Purine, which is relatively stable under the influence of UV light, undergoes photochemical alkylation on reaction with 1-propylamine yielding 6-propyl-9H-purine.710
Photoirradiation of adenine with isopropyl alcohol results in substitution of C(8) hydrogen with alcohol.711
9. Glycosylation: Synthesis of 2-deoxyribonucleoside was achieved by reaction of 1-α-chloro-2-deoxy-3,5di(ptoluyl)-erythro-pentofuranose with sodium salt of purine in acetonitrile.712 The two isomers formed, 9-β and 7-β, were in the ratio of 4:1.
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185
Efficient synthesis of purines and purine nucleosides, via an inverse electron-demand Diels-Alder reaction, has also been reported.713 10. Ring transformation: The imidazole ring of purines undergoes a ring-opening process leading to the generation of a pteridine derivative. Purine 2(1H)-one on reaction with glyoxal in aqueous sulfuric acid solution afforded pteridine 2(1H)-one monohydrate. Similarly, purine 2(1H)-one reacting with glyoxylic acid yielded pteridine 2,6(1H,5H)-dione.
3,9-Dimethyluric acid on chlorination-reductive dechlorination undergoes oxidative ring transformation to imidazo[1,5-c]imidazole.714
2.4.10 Pteridine
Pteridine is an aromatic heterocyclic compound formed by the fusion of pyrimidine and pyrazine. The word pteridine is derived from the Greek word pteron meaning wings, because most of the pteridine derivatives have been isolated from the wings of insects. Pteridines are normally colored compounds with the parent compound being yellow in color. Structural and Reactivity Aspects715 The structure of pteridine was confirmed by X-ray analysis, which not only confirmed the composition of the structure but also the point of fusion. Hence pteridine is also called pyrazino[2,3-d]pyrimidine. The bond length and bond angles as determined by X-ray are comparable with those of pyrimidine and pyrazine. Bond lengths (in pm) and bond angles (in degrees) are shown in the following diagram. 135
140 139 N
131
N 137
139
140
N
N 116120 129
130
Bond lengths and bond angles of pteridine.
N 136 136N 129
115
N
114 119 122 121 120
123 116
N
128
186
2. Six-Membered Heterocycles
The 1H and 13C NMR spectra of pteridine suggest it to be a π-deficient heteroaromatic system. The 1H and 13C NMR spectral data of pteridine are given in the following table. H and 13C NMR spectral data of pteridine
1
1
H NMR(CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 9.55; H-4, 9.80; H-6, 9.15; H-7, 9.33
C-2, 159.2; C-4, 164.1; C-6, 148.4; C-7, 153.0; C-9, 154.4; C-10, 135.3
The UV spectrum of pteridine in cyclohexane gave four absorption bands at 263 (log ε 3.10), 296 (log ε 3.85), 302 (log ε 3.87), and 396 nm (log ε 1.88). The first three bands are due to π→π* transition, whereas the fourth band is due to n→π* transition. Importance in Natural Products, Medicines, and Materials Pteridines have been isolated from natural sources where they are present as pteridinones or aminopteridones. They are present as pigments in the wings and eyes of insects and in the skin of fish and amphibians. For example, xanthopterin, a yellow pigment, was isolated from the English brimstone butterfly; leucopterin, a white pigment, was isolated from the cabbage white butterfly; and erythropterin was isolated from rub kip butterfly.
Pteridine isolated from natural source.
Folic acid and riboflavin, the essential metabolites of living organisms, possess a pteridine skeleton.
A number of pteridine-based compounds are of commercial interest because they are easily available in the market as drugs. For example, methotrexate is used clinically as an antineoplastic agent for several common acute leukemias. Folinic acid or leucovorin finds use as an adjuvant in cancer chemotherapy involving methotrexate and triamterene, a potassium-sparing diuretic that inhibits both the excretion of potassium ions and the reabsorption of sodium ions.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
187
Synthesis 1. Gabriel-Isay (Gabriel-Colman) synthesis: This reaction involves cyclocondensation of 5,6-diaminopyrimidine with symmetrical 1,2-dicarbonyl compounds like benzil or glyoxal to yield pteridines. The original reaction involved reaction of 6-methylpyrimidine-4,5-diamine with benzil to yield 4-methyl-6,7-diphenylpteridine.716
However, the parent pteridine is synthesized by reaction of pyrimidine 4,5-diamine with glyoxal or some other equivalent synthon.
The method works with symmetrical diketones; however, reaction of diaminopyrimidine with unsymmetrical diketones, α-keto aldehydes, α-keto acids, or their esters led to a mixture of pteridine derivatives. 2. Polonovski-Boon reaction: A general method for the synthesis of 7,8-dihydropteridine developed by Boon, Ramage, and their collaborators and independently by Polonovski is known as Polonovski-Boon reaction. The reaction involves condensation of 6-chloro-5-nitropyrimidine with an α-aminocarbonyl compound yielding an intermediate, which on reduction followed by cyclization yields a pteridine derivative.
3. Viscontini reaction: This efficient synthetic method involves condensation of sugar phenylhydrazones with 5,6-diaminopyrimidines under slightly acidic conditions to provide regioselectively 6-substituted pterins.
By this method, neopterin has been synthesized in much higher yield.717 4. Timmis synthesis: Base-catalyzed condensation of 4-amino-5-nitrosopyrimidines with compounds containing an activated methylene group like ketones, aldehydes, nitriles, and cyano acetic acid affords pteridines.718, 719
188
2. Six-Membered Heterocycles
Condensation of α-methylenenitrile with 2,4,6-triaminopyrimidine yielded triamterene, a potassium-sparing diuretic.
5. Pachter synthesis: This is a modification of Timmis reaction and involves reaction of 4,6-diamino-5-nitroso-2phenyl pyrimidine with a reactive methylene compound like benzyl methyl ketone in the presence of potassium acetate to yield 4-amino-7-methyl-2,6-diphenylpteridine.720
6. Blicke synthesis: Condensation of aminopyrimidines with aldehydes and HCN followed by cyclization using NaOMe as a base produced pteridine via cyanoamines.721
7. From pyrazines: Reaction of 3-(aminomethyl)pyrazin-2-amine with orthoformates followed by oxidative aromatization yields 6-substituted pteridine.
Taylor’s method for the synthesis of pteridines from pyrazines is a valuable alternative method to commonly apply a condensation reaction of diaminopyrimidines with dicarbonyl compounds. The process involves condensation of α-aminonitrile with α-ketoaldoximes to give 2-amino-3,5-disubstituted pyrazine-1-oxide, which is subsequently cyclized and deoxygenated to give 6-substituted pteridines.722
Degradation of tolualloxaine by oxidative methods yields 2,6-dihydroxypteridine.
2.4 Six-Membered Isolated and Benzo-Fused Heterocycles With Two and More Nitrogen Atoms
189
Reaction of 2,3-diamide of 2,3-pyrazinedicarboxylic acid with 2 mol of potassium hypobromite yields the potassium salt of 2,6-dihydroxypteridine, which on hydrolysis with acid yields 2,6-dihydroxypteridine.723
Physical Properties Pteridine is a yellow-colored solid with mp of 139.5°C. It is insoluble in water. Chemical Reactivity 1. Action of acid and base: Under appropriate conditions the pyrimidine ring of pteridine undergoes degradation with acid and alkali. 2,6-Dihydroxypteridine on heating with 100% sulfuric acid at 240°C gave 2-aminopyrazine. The same compound on heating with 2–3 equivalents of 12% alkali for 2 h at 170°C gave 2-amino-3-carboxylic acid. Both compounds were obtained in high yield.724
2. Nucleophilic addition: Pteridine readily undergoes nucleophilic addition with water, alcohol, and amines to form covalent adducts chiefly at the C-4- and C-7-positions. Nucleophilic addition of water to pteridine affords covalent hydrates. Under acidic conditions, 3,4-hydrated cation is initially formed, which slowly equilibrates with dehydrated 5,6,7,8-cation.
Pteridine undergoes nucleophilic addition reaction with methanol to yield an equilibrium mixture of 3,4-dihydro- 4-methoxypteridine (1:1 adduct) and 5,6,7,8-tetrahydro-6,7-dimethoxypteridine725 (2:1 adduct).
Amination of pteridine is achieved by a combination of nucleophilic addition and oxidation reaction. Thus pteridine on reaction with potassium permanganate in liquid ammonia yields 4-aminopteridine.
190
2. Six-Membered Heterocycles
3. Nucleophilic substitution reaction: Reaction of pteridine with Grignard reagent followed by oxidation led to the formation of a new carbon-carbon bond on the pyrazine ring, regioselectively at the C-7-position.
4. Oxidation: Pteridine derivatives like xanthopterin on treatment with molecular oxygen over platinum or on treatment with hydrogen peroxide are converted to leucopterin.724
5. Reduction: Tetrahydropteridine derivatives are highly reactive toward oxidation; as a result, it is difficult to isolate them. However, when electron-withdrawing groups are present on the ring they are stable and can easily be isolated. Thus 5,6,7,8-tetrahydropteridine-4-carboxylate can be isolated on reaction of suitably substituted pteridine with sodium borohydride.726
6. Heck reaction: Palladium-catalyzed coupling reaction of 6-chloropteridine with acetylenes yields alkynylsubstituted pteridines.727
7. Reaction with PCl5 and POCl3: Leucopterin on reaction with phosphorous pentachloride and phosphorous oxychloride yields a monochloro derivative, which is reduced by hydroiodic acid to 6-deoxyleucopterin.
8. Ring fission: Pteridines are thermally stable; however, in hot solutions they are unstable. They undergo fission of the pyrimidine ring in aqueous acid to yield 3-aminopyrazine-2-carbaldehyde.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
191
2.5 SIX-MEMBERED HETEROCYCLES WITH THREE AND MORE NITROGEN ATOMS Triazines are six-membered heterocycles analogous to benzene in which three carbon atoms have been replaced by three consecutive nitrogen atoms. There are three important isomers of triazines, which are distinguished from each other on the basis of the position of the nitrogen atoms, and are referred to as 1,2,3-triazine, 1,2,4-triazine, and 1,3,5-triazine.
2.5.1 1,2,3-Triazine
1,2,3-Triazine is the systematic name for one of the three isomers of triazines. However, in some literature the term v-triazine has been used. The letter v denotes that the nitrogen atoms are vicinal. A less satisfactory name, β-triazine, has also been used. Structural and Reactivity Aspects728 The structure of 1,2,3-triazine was elucidated by X-ray crystallographic analysis, which shows that the molecule is planar in nature. The bond lengths (in Å) are shown in the following figure.729 Bond angles (in degrees) were, however, derived from X-ray studies of 4,5,6-tris(4-methoxyphenyl)-1,2,3-triazine.
Bond lengths and bond angles of 1,2,3-triazine.
The UV spectrum of 1,2,3-triazine (in ethanol) shows a medium intensity band at 288 nm (log ε 2.93) and this may be due to n→π* transition. There is another band that appears as a shoulder in the short region at 232 nm and is due to π→π* transition. In the 1H NMR spectrum of triazine in CDCl3 the protons adjacent to the nitrogen, i.e., 4-H and 6-H, appear downfield as a doublet at δ 9.06 (2-H). The 5-H proton also appears as a doublet at δ 7.45. In the 13C NMR spectrum the 4-C and 6-C appear at δ 149.7, whereas 5-C appears at δ 117.9. The mass spectrum of triazine showed a strong peak at m/z 53, attributed to nitrogen elimination from the parent ion.
Mass fragmentation pattern of 1,2,3-triazine.
192
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials There has been no evidence of the occurrence of natural products containing the 1,2,3-triazine nucleus. A number of substituted 1,2,3-benzotriazines have been reported to have the ability of inhibiting VEGFR-2 kinase activity.730 However, there are reports that this nucleus is present in some pesticides, e.g., guthion.
Guthion, a pesticide containing 1,2,3-triazine skeleton.
Synthesis 1. Unsubstituted monocyclic 1,2,3-triazine is synthesized by oxidation of N-aminopyrazole with freshly prepared nickel peroxide with acetic acid.728 1-Aminopyrazole was, however, obtained by deprotonation with sodium hydride followed by amination with (O-mesitylenesulfonyl) hydroxylamine (MSH).
A number of alkyl- as well aryl-substituted monocyclic 1,2,3-triazines have also been synthesized from suitably substituted 1-aminopyrazoles.728 2. Deprotonation and lithium-halogen exchange of 4-bromopyrazole and subsequent trapping of C-lithiate by dimethylsulfide afforded thio-substituted pyrazole, which on N-amination with monochloroamine yielded N-aminopyrazole. Treatment of N-aminopyrazole with NaIO4 under biphasic ring expansion conditions yields 5-methylthio-1,2,3-triazine.731
Similarly, 5-methoxy-1,2,3-triazine and 5-(N-acetylamino)-1,2,3-triazine have been synthesized from 4-methoxypyrazole and 4-nitropyrazole, respectively.730
3. Thermal rearrangement of cyclopropenylazides yields substituted 1,2,3-triazines.
Physical Properties 1,2,3-Triazine is obtained as a colorless crystalline solid by crystallized with ether; it has mp of 70–71°C and sublimes readily.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
193
Chemical Reactivity 1. Cycloaddition reaction: The inverse electron demand Diels-Alder (IED-DA) reaction of parent 1,2,3-triazine that undergoes [4+2] cycloaddition reaction with different heterodineophiles has been reported. 1,2,3-Triazine underwent [4+2] cycloaddition with aliphatic amidine and imidate to give a pyrimidine derivative. Similarly, ynamines react with 1,2,3-triazine to yield pyridine derivatives.732
It was believed that electron-donating substituents would not only decrease the overall reactivity of 1,2,3- triazine but would also prevent cycloaddition reaction. It has been observed that though the rate of reaction was decreased on reaction with amidines but was quite effective for the synthesis of pyrimidine in excellent yield.732 To prove that the cycloaddition reaction takes place in a single step, 1,2,3-triazine substituted with electron donating group was treated with amidine 15N-20g doubly labelled with 15N, pyrimidine derivative incorporated with a single 15N label was obtained in high yield.
2. Oxidation: Oxidation of 4-methyl-1,2,3-triazine with m-CPBA in dichloromethane at room temperature yielded a mixture of 6-methyl-1,2,3-triazine-1-oxides and 4-methyl-1,2,3-triazine-2-oxides, whose structures were confirmed on the basis of NMR data.733
3. Reduction: Catalytic hydrogenation of 4,6-dimethyl-1,2,3-triazine on Pd/C yielded the 2,5-dihydro derivative.732
4. Hydrolysis: 1,2,3-Triazine is a stable molecule. However, when heated at higher temperatures in the presence of aqueous acid it undergoes ring fission to yield 1,3-dicarbonyl compounds.
194
2. Six-Membered Heterocycles
2.5.2 1,2,3-Benzotriazine 8 7
1
N
6 5
N2 N3
4
Structural and Reactivity Aspects The 1H NMR spectrum734 of parent 1,2,3-benzotriazine was recorded in [(CD3)2SO] showing one proton doublet at τ 0.15 and four proton multiplets from τ 1.45–1.86. Importance in Natural Products, Medicines, and Materials A number of substituted 1,2,3-benzotriazines have been reported to have the ability of inhibiting VEGFR-2 kinase activity, for example, CTZ12, a potent VEGFR-2 inhibitor used for the treatment of various cancers.735 There are reports that this nucleus is present in pesticide, guthion.
Synthesis 1. Stirring a solution of 1H-indaziol-1-amine in methylene chloride with a mixture of lead tetraacetate (LTA), calcium oxide, and dry methylene chloride yields the parent 1,2,3-benzotriazine.734
2. Oxidation of azidohydrazone with mercury(II) oxide gave diazo-azide, which on refluxing in benzene yields 4-methyl-1,2,3-benzotriazine.734
3. Oxidative cyclization of the hydrazones of o-aminophenyl ketones gave 4-substituted benzotriazine.734
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
195
4. Reaction of 4-cyano-2-methoxyphenol with different alkyl halides in the presence of potassium carbonate in DMF afforded 4-substituted-3-methoxybenzonitrile, which on selective nitration with nitric acid gave the nitro compound. The nitro compound was reduced to amine, diazotized with substituted aniline at 0°C to afford benzotriazine.735
5. Reaction of 1-o-chlorophenyl-3-cyanophenyltriazene with 70% aqueous ethanol gave 3-substituted 3,4-dihydro4-imino-1,2,3-benzotriazine, which rearranges to 4-anilino-1,2,3-benzotriazine.736
Physical Properties 1,2,3-Benzotriazine is a pale yellow crystalline solid with mp of 119–120°C. Chemical Reactivity 1. Vacuum pyrolysis of 1,2,3-benzotriazine and its methyl derivative with continuous wave CO2 laser yielded 1-azabenzocyclobutene and 2-methylbenzazete, respectively.737
Pyrolysis of 1,2,3-benzotriazine above 450°C resulted in fragmentation of the triazine ring to afford benzyne, which then dimerizes to biphenylene.738
2. Nucleophilic addition: Treatment of 4-phenyl-1,2,3-triazine with ethyl magnesium bromide in ether, followed by quenching of the resulting anion with methyl iodide, gave indazole.739
3. The C-4-position in 1,2,3-benzotriazine is very electrophilic and undergoes covalent hydration across the N3C4 bond to give 2-aminophenyl ketones.
196
2. Six-Membered Heterocycles
4. 4-Phenyl-1,2,3-benxotriazine on reaction with hydrazine forms hydrazone of 2-aminodiphenyl ketone.
5. Diels-Alder reaction: Heating a mixture of 1,2,3-benzotriazine (prepared by oxidation of indazol amine) and cyclohexanone enamine in dry chloroform in the presence of zinc bromide in a sealed tube at 90–100°C gave 1,2,3,4-tetrahydroacridine.740
Benzotriazine undergoes cyclization with enamines to produce a bicyclic intermediate, which eliminates nitrogen to produce quinolines. Benzotriazine in good yield is generated in situ from 1H-indazol-1-amine through LTA oxidation.
6. Heating a mixture of 1,2,3-benzotriazine and pyrrolidine-enamine of acetophenone in dry chloroform in the presence of zinc bromide in a sealed tube at 100°C gave 2-phenylquinoline.741
7. Oxidation: Reaction of 4-Methoxy-1,2,3-benzotriazine with m-CPBA at 20°C yields 4-methoxy-1,2,3-benzotriazine-2-oxide.742
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
197
8. Cycloaddition reaction: Reaction of 1,2,3-benzotriazine derivative with diphenylcyclopropenone gave pyrazolo[1,2-a] [1,2,3]benzotriazene-1-one, pyrazolo[1,2-a][1,2,3]benzotriazene-3-one, and pyrazolo[2,3-a]quinazoline-3-one adducts.
2.5.3 1,2,4-Triazine 4
3 2
N
N N
5 6
1
1,2,4-Triazine is the systematic name for one of the three isomers of triazines. However, in some literature the term as-triazine has been used because of asymmetry in the arrangement of nitrogen atoms in the ring. In older literature, less satisfactory names, α-triazine and isotriazine, have also been used. Structural and Reactivity Aspects743 1,2,4-Traizine is a π electron deficient heterocyclic system and is represented by two canonical structures I and II. Theoretical calculations have shown that structure I contributes more to the ground state of the molecule.
Resonating structures of 1,2,4-triazine.
The structure of 3-amino-1,2,4-triazine, determined by X-ray crystallographic analysis,744 revealed that the 1,2,4-triazine ring is planar but slightly distorted due to the presence of electronegative nitrogen atoms in the ring. The shorter bonds between C2N2 (1.319 Å) and between C3N3 (1.312 Å) suggest that the ring has an appreciable double bond character. The bond distances C1N1, C1N3, and C1N4 possess partial double bond character. The bond distances (Å) and bond angles (degrees) are depicted in the following table.
Bond lengths and bond angles of 1,2,4-triazine Bond lengths (Å)
Bond angles (o)
N(1)N(2) 1.334(2)
N(2)N(1)C(1) 118.06(12)
N(1)C(1) 1.351(2)
C(2)N(2)N(1) 119.48(12)
N(2)C(2) 1.319(2)
C(3)N(3)C(1) 114.73(12)
N(3)C(3) 1.312(2)
N(4)C(1)N(1) 117.04(12)
N(3)C(1) 1.358(2)
N(4)C(1)N(3) 117.87(12)
N(4)C(1) 1.330(2)
N(1)C(1)N(3) 125.08(12)
C(2)C(3) 1.394(2)
N(2)C(2)C(3) 120.59(14) N(3)C(3)C(2) 122.0(13)
198
2. Six-Membered Heterocycles
The UV spectrum of 1,2,4-triazine in methanol shows two absorption bands at 374 and 247.8 nm. The band at 374 is due to n→π* transition, whereas the band at 247.8 is due to π→π* transition. The 1H and 13C NMR spectral data of 1,2,4-triazine are given in the following table. H and 13C spectral data of 1, 2,4-triazine
1
1
H NMR (δ values in ppm)
13
C NMR (δ values in ppm)
H-3, 9.66; H-5, 8.84; H-6, 9.48
C-3, 158.1; C-5, 149.6; C-6, 150.8
The mass spectrum of 1,2,4-triazine shows the following fragmentation pattern, which has been confirmed by mass spectrum of 1,2,4-triazine 3d.745, 746
Mass fragmentation pattern of 1,2,4-triazine.
Importance in Natural Products, Medicines, and Materials 1,2,4-Triazine has occupied a unique position in medicinal chemistry because a number of these derivatives have been reported to possess promising biological activity. 1,2,4-Triazines have been reported to possess antifungal,747 anti-HIV,748 antiinflammatory,749 and antihypertensive activity.750 Besides these, they are used as herbicides and pesticides. 4-Amino-6-tert-butyl-3-(methylmercapto)-1,2,4-triazine (sencor, metribuzin, BAY 94337) is the best and most widely used herbicide. A number of clinically used drugs available in the market contain the 12,4-triazine nucleus. For example, azaribine is an antineoplastic and antipsoriatic drug, lamotrigine is an anticonvulsant drug used in the treatment of epilepsy,751, 752 tirapazamine is an anticancer agent, and furalazine is an antimicrobial agent.
Drugs possessing 1,2,4-triazine skeleton.
Synthesis 1. The first synthesis of unsubstituted 1,2,4-triazine was reported by Paudler and Barton in 1966. The process involves condensation of glyoxal with ethoxycarbonyl amidrazone and yields ethyl 1,2,4-triazine-3-carboxylate, which was converted to unsubstituted triazine by saponification followed by decarboxylation.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
199
Preparative synthesis of 1,2,4-triazine involves reaction of monomeric glyoxal with formamidazone hydrochloride in absolute methanol at −50°C.753
Unsubstituted triazine is also synthesized by oxidation of hydrazine-1,2,4-triazine with manganese(IV) oxide or silver(I) oxide.754
2. Desulfurization of 3-mercapto-1,2,4-triazine yielded 5,6-disubstituted 1,2,4-triazine.755
3. Condensation of amidrazone with diethyl dioxosuccinate resulted in the formation 5,6-disubstituted 1,2,4-triazine derivative. Cyclization as well as decarboxylation takes place simultaneously.756
4. Condensation of S-methylthiosemicarbazide with glyoxal or another α,β-dicarbonyl compound readily affords the 3-methylthio 1,2,4-triazine, which on reaction with hydrazine was easily converted to its 3-hydrazino derivative. Oxidation with activated manganese dioxide yielded 1,2,4-triazine. The yield of triazine was, however, low. This shortcoming was overcome by converting the 3-methythio-1,2,4-triazine to its 3-methoxy derivative, which is then converted to its 3-hydrazino derivative in high yield. Oxidation with activated manganese dioxide yielded the parent compound.757
5. [4 + 2] Domino annulation: Simple and efficient [4+2] domino annulations in one pot for the synthesis of 1,2,4-triazines have been reported. The process involves reaction of benzimidohydrazide with acetophenone,
200
2. Six-Membered Heterocycles
styrene, 1-phenylethanol, 1,2-diphenylethyne, and phenylacetaldehyde in the presence of oxidants like selenium dioxide, iodine, copper oxide, etc. yielding 1,2,4-triazine derivatives.758
6. Cyclization of acylhydrazones of 1,2-dicarbonyl compounds with ammonia yields 1,2,4-triazines.759, 760
7. Reaction of phenacyl bromide/chloride with acylhydrazide yields 1,2,4-triazine. The reaction is proposed to take place by the following mechanism.761
8. Substituted 1,2,4-triazines were conveniently synthesized in one step by condensation of amides with 1,2-diketones in the presence of a base, followed by cyclization with hydrazine hydrate.762
The reaction was also carried out under microwave irradiation without using solvent and better yields of triazines were obtained compared to the conventional process. 1,2,4-Triazines are also obtained by refluxing acylhydrazones with ammonium acetate in acetic acid. Acylhydrazone required as substrate was prepared by reaction of ethyl 3-oxobutanoate with p-toluenesulfonyl azide and triethylamine, which produced ethyl 2-diaza-3-oxobutanoate. This on treatment with triphenylphosphine followed by hydrolysis and acylation in the presence of pyridine763 afforded acylhydrazone. This on treatment with ammonium acetate in acetic acid delivered substituted 12,4-trazines.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
201
9. By ring enlargement: Heating 1-benzohydrazonyl-1,2,3-triazoles with a slight excess of sodium hydride in dry benzene gave 1,2,4-triazines. The reaction proceeds by the formation and decomposition of aryl(1,2,3-triazol1-yl)diazomethanes by Bamford-Stevens reaction, followed by ring enlargement of the resulting carbene.
Physical Properties 1,2,4-Triazine has a low mp of 16–17.5°C, and is a yellow-colored liquid with a bp of 158°C. It is soluble in nearly all organic solvents. It is stable to acid, less stable to base, and is hygroscopic. It is stable and can be stored at temperatures below 0°C. When stored in a refrigerator for a longer period of time, it becomes an amber-like solid, whose constitution has 1 mol of 1,2,4-triazine and 1 mol of water. Chemical Reactivity 1. Quaternization: 1,2,4-Triazines are weak bases because they are unable to form salts with dilute mineral acids. However, 3-methyl-5,6-dimethyl-1,2,4-triazine gave a good yield of colorless monomethiodide when quaternized in methanol.764 Reaction of 1,2,5-triazin-3-one with concentrated nitric acid, the ring is ruptured and 1,2-dicarbonyl compounds are isolated.
2. Cycloaddition reaction: 1,2,4-Triazine is a classical example of a synthetically accessible moiety capable of diene 4π participation in an IED-DA (Inverse Electron Demand-Diels Alder) reaction with electron-rich dienophiles. Cycloaddition reaction between 1,2,4-triazine and enamines is regioselective and takes place with [4+2] addition exclusively across C-3/C-6 of the triazine moiety with more nucleophilic carbon of the dienophile bonding to the C-3. The cycloaddition reaction is followed by in situ retro-Diels-Alder reaction with loss of nitrogen and in situ elimination of pyrroline yielding 3,4-disubstituted pyridines.765, 766
202
2. Six-Membered Heterocycles
3-Phenyl-1,2,4-triazine reacts with enamine first to form the 3,4-dihydropyridine derivative, which on oxidation followed by Cope elimination affords 2-phenydihydrocyclopenta[c]pyridine. Similarly, 6-phenyl-1,2,4-triazine initially forms the 3,4-dihydropyridine derivative, which after the elimination of amine yields 5-phenyldihydrocyclopenta[c] pyridine.
The IED-DA reaction of 1,2,4-triazines with electron-rich olefins has been used for the synthesis of natural products. For example, four members of the louisianin family (A, B, C, and D) are simple pyridine derivatives displaying both antibacterial and anticancer activity and have been synthesized from 1,2,4-triazine from a common tetrasubstituted pyridine intermediate.767
3. Covalent hydration: Addition of water to a solution of 1,2,4-triazine in TFA yields the hydrated compound, which is stabilized by protonation.
4. Nucleophilic substitution reaction: The most reactive position in 1,2,4-triazine where nucleophilic substitution reaction can take place is C-5 and the least reactive site is C-3.768 Reaction of 1,2,4-triazine with methylmagnesium iodide at room temperature yielded 5,6-dimethyl-3-phenyl- 2,5-dihydro-as-triazine, which on oxidation with potassium permanganate aromatized to 5,6-dimethyl-3-phenyl-1, 2,4-triazine. Similarly, in the presence of sodium hydride, reactive methylene compounds, phenylacetonitrile and acetophenone, add smoothly at position 5 to yield an adduct, which on oxidation yields the aromatic triazine derivative.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
203
Reaction of 1,2,4-triazine derivative with hydrazine and hydrogen peroxide separately yields 5-hydrazino-6- methyl-3-phenyl-1,2,4-triazine and 6-methyl-5-oxo-3-phenyl-2,5-dihydro-as-triazine.
Direct nucleophilic acylation of 1,2,4-triazine in which a nitronate anion serves as a nucleophilic acyl group has been reported. 1,2,4-Triazine reacts with nitromethane and other primary nitroalkanes in the presence of an excess of powdered KOH in DMSO to yield the oxime derivative, which is then cleaved by sodium dithionite to yield the carbonyl derivative.769
5. Reduction: 1,2,4-Triazines are reduced with zinc in glacial acetic acid/alcohol to the dihydro derivative along with the imidazole derivative.770
Reduction of 3-(methythio)-5-phenyl-1,2,4-triazine and 3-methoxy-5-phenyl-1,2,4-triazine with sodium borohydride separately gave 3-(methylthio)-5-phenyl-2,5-dihydro-1,2,4-triazine and 3-methoxy-5-phenyl-2,5-dihydro1,2,4-triazine respectively in good yield.771
Electrochemical reduction of 1,2,4-triazine leads to the unstable 1,4-dihydro derivative, which rearranges to 1,2- or 4.5-dihydro derivative. These derivatives are further reduced to imidazole or tetrahydro-1,2,4-triazine.772
204
2. Six-Membered Heterocycles
6. Suzuki reaction: Bromination of 3-amino-1,2,4-triazine followed by Suzuki coupling with a variety of boronic acids and subsequent deamination yielded substituted triazines. These triazines then react with trans-cyclooctene.773
7. Oxidation: Oxidation of 1,2,4-triazines with peracids yielded 1,2,4-triazin-5-ones.774
2.5.4 1,3,5-Triazine 5
4
N
6
N3 N
2
1
1,3,5-Triazine is the systematic name for one of the three isomers of triazines. However, in some literature the term s-triazine has been used, where s denotes symmetrical due to symmetry in the arrangements of all three nitrogen atoms in the ring. Structural and Reactivity Aspects775a X-ray studies suggest that the symmetrical 1,3,5-triazine molecule is planar but deviates quite markedly from regular hexagon. The CN bond distance is 131.9 pm and the CH bond distance is 100.0 pm. The NCN and CNC bond angles were found to be 126.8 and 113.2 degrees, respectively.775b The 1H and 13C NMR confirmed the symmetrical nature of the molecule with H- and C-atoms being highly deshielded (due to the presence of the alternating N-atom in the ring) and appearing as a singlet at δ 9.25 and δ 166.1, respectively. The UV spectrum of 1,3,5-triazine in cyclohexane shows two absorption bands at 218 (2.13) and 272 (2.89) nm. Importance in Natural Products, Medicines, and Materials In recent years, the 1,3,5-triazine skeleton has been one of the most interesting chemical cores and has been subjected to extensive studies. This scaffold has provided the basis for the design of compounds that have useful agricultural and medicinal applications. An important application of 1,3,5-triazine derivatives or compounds containing this skeleton is as herbicides, fungicides, and insecticides. Anilazine finds use as a fungicide, menazon as an insecticide, and simazine, atrazine, cyanazine, and prometon as herbicides.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
205
Fungicide, insecticide and herbicides containing 1,3,5-triazine skeleton.
Cyanuric acid is a disinfectant and herbicide used as a chlorine stabilizer in swimming pools. Cyanuryl chloride or cyanuric chloride is an important triazine derivative, which has been used as a starting material for the synthesis of herbicides, optical brighteners and reactive dyes. Melamine is used to produce melamine resin, a durable thermosetting plastic.
Important 1,3,5-triazine derivatives.
Molecules possessing a 1,3,5-triazine nucleus have been found to display a wide range of interesting biological activities and many are in use as drugs. For example, 5-azacytidine (trade name Vidaza) is used for the treatment of myelodysplastic syndrome and as an anticancer agent, tretamine, dioxadet, and altreamine are used as anticancer agents, hydramitrazine as an antispasmodic, and chlorazanil as a diuretic.
Drugs containing 1,3,5-triazine skeleton.
Chemical Synthesis 1. Unsubstituted 1,3,5-triazine is synthesized by thermal cyclocondensation of formamidine acetate and triethyl orthoformate.776
206
2. Six-Membered Heterocycles
2. Nef method: The method involves treating hydrogen cyanide with ethanol in ether saturated with hydrogen chloride. The resulting iminoethyl formate hydrochloride, on neutralization with sodium hydroxide, followed by distillation, yields s-triazine.777
3. A more satisfactory method for the synthesis of unsubstituted s-triazine is via so-called sesquihydrochloride of hydrocyanic acid (prepared from hydrogen cyanide and hydrogen chloride), which loses two-thirds of its hydrogen chloride and splits off one-third on reaction with a basic acceptor.
4. Trimerization of imidates in the presence of sodium acetate yielded trisubstituted s-triazine.778
5. Reaction of N′-acyl-N,N-dimethylamidine with amidine forms trisubstituted 1,3,5-triazines.779
6. Benzoguanamine, which is an intermediate for pharmaceuticals and is used to increase the thermoset properties of alkyd, acrylic, and formaldehyde resin, is synthesized by heating benzonitrile and dicyandiamide in the presence of potassium hydroxide and methyl cellosolve.780
7. Cyanuric acid,781 an important 1,3,5-triazine derivative, is synthesized by heating free cyanic acid at 150°C.
8. Cyanuric chloride (2,4,6-trichloro-s-triazine) is prepared by the action of chlorine on hydrocyanic acid in direct sunlight.782
9. Reaction between N-cyanoamidines and chloromethylene iminium salt yields the s-triazine derivative.783
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
207
10. Pinner triazine synthesis: This reaction, first reported by Adolf Pinner in 1890, involves reaction of arylamidines with phosgene yielding s-triazines.
11. Ostrogovich synthesis: The synthesis of s-triazine784 involves the reaction of thioacids with cyanoguanidine leading to the formation of an intermediate, which was cyclized to 2-thio-4-amino-6-methyl-s-triazine.
Physical Properties 1,3,5-Triazine is a white crystalline solid with mp of 85–86°C, a bp of 114°C, and is very volatile and hygroscopic. It is easily soluble in most organic solvents. Chemical Reactivity 1. Electrophilic substitution reaction: 1,3,5-Triazines under the influence of the inductive effect of the three nitrogen atoms do not undergo electrophilic substitution reaction. However, bromination reaction takes place probably via nucleophilic addition reaction.785
Similarly, chlorination of s-triazine takes place at higher temperature (200°C) yielding cyanuric chloride as the major product and dichlorotriazine as the minor product.
Reaction of s-triazine with dinitrogen pentoxide and quenched with methanol produces 1,3,5-trinitro-2, 4,6-trimethoxyhexahydrotriazine, which on chromatography yields cis- and trans-2,4,6-trimethoxy-1,3,5- trinitrohexahydrotriazine in equimolar ratio.786
2. Nucleophilic substitution reaction: 1,3,5-Triazines are susceptible to nucleophilic attack and the reaction probably takes place via a ring-opening process leading to the generation of important heterocycles like triazoles and benzimidazoles.787,788
208
2. Six-Membered Heterocycles
Due to symmetrical arrangement of nitrogen atoms in s-triazine, each carbon is susceptible to nucleophilic attack by alkyllithium to give a 1,4-adduct, which on hydrolysis yields 1,4-dihydrotriazine. However, on reaction with LiNR2, the triazine ring is opened leading to the formation of crystalline 3-lithio-1,3,5,7-tetraazaheptratriene.789, 790
The formation of lithium salt has been proposed to take place by the following mechanism.
Reaction of 1,3,5-triazine with amines takes place with the opening of the triazine ring forming corresponding amidines.791
s-Triazine reacts with sodium amide in xylene at 160°C (in an autoclave) forming disodium salt of cyanamide, which was confirmed by its transformation to dibutylcyanamide.791
s-Triazine reacts with hydroxylamine forming N,N′-dihydroxyformimidamide.
Nucleophilic attack of cyanamide on s-triazine in the presence of secondary amine leads to the formation of a dehydro-N-Mannich base. The reaction takes place with the formation of two intermediates with the following proposed792 mechanism.
Reaction of 1,3,5-triazine with dimethyl 1,3-acetonedicarboxylate produced dimethyl 4-hydroxypyridine-3,5- dicarboxylate.793
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
209
3. Formylating reagent: In Gatterman’s aldehyde synthesis, hydrogen cyanide can be substituted by 1,3,5-triazine. In the presence of hydrogen chloride, triazine undergoes electrophilic attack on aromatic compounds like furans, pyrroles, and polyhydroxybenzenes yielding an intermediate aldimine hydrochloride, which is hydrolyzed to aldehyde.794, 795
Formylation of 1-(2-hydroxyphenyl)-2-(4-hydroxyphenyl)ethan-1-one with 1,3,5-triazine, followed by cyclocondensation with boron trifluoride etherate, afforded isoflavones.796, 797
4. Methylating agent: 1,3,5-Triazine is very susceptible to nucleophilic attack. Two molecules of a primary amine can be added to each carbon atom leading to ring cleavage, release of ammonia gas, and 3 equivalents of disubstituted formamidine. Thus reaction of aliphatic or aromatic diamines with s-triazine yields heterocyclic derivatives.798
Electron-rich nitrogen of s-triazine can abstract a proton from the reactive methylene compounds like malonic acid derivatives yielding a carbanion, which can then be added to the triazine carbon. The intermediate aminomethyl recyclizes to produce 4,5-disubstituted pyrimidines.799
5. 1,3,5-Triazine functions as an azadiene in an IED-DA reaction, producing pyrimidine or a fused pyrimidine ring system. For example, 1,3,5-triazines on reaction with electron-rich alkyne dienophiles yield pyrimidines.800, 801
Under mild thermal conditions, 1,3,5-triazines also react with cyclic as well as acyclic enamines, which are electron- rich dienophiles, to give pyrimidines.
210
2. Six-Membered Heterocycles
5-Aminopyrazoles react with electron-deficient 1,3,5-triazines to give various pyrazolopyrimidines. This new type of IDA reaction is highly regioselective with the 5-amino group being the determining factor.802, 803
This new type of IDA reaction has been useful in the synthesis of the natural product nebularine in one step.
Tetrazine Tetrazines are thought to be benzene derivatives in which the four CH units of benzene have been replaced by four electronegative nitrogen atoms. There are three important possible isomers of tetrazines, namely 1,2,3,5-tetrazine, 1,2,3,4-tetrazine, and 1,2,4,5-tetrazine.
2.5.5 1,2,3,4-Tetrazine 1 6 5
N N
N2 N3
4
1,2,3,4-Tetrazine is one of the isomers of tetrazines, and is more commonly referred to as ν-tetrazine or osotetrazine. The parent 1,2,3,4-tetrazine is unstable and its stability is increased by fusion with five- and six-membered rings and also by making their oxides. Structural and Reactivity Aspects804 An X-ray of 5,7-di-tert-butyl-2-R-2H-cyclopenta[e]-1,2,3,4-tetrazine has been recorded. The X-ray reveals that the molecule is planar and CC bond lengths are in good accordance with the aromatic ring bonded to a five-membered ring. The NN bond lengths are of typical value due to resonance as depicted by the following resonance structures.
Resonating structures of 1,2,3,4-tetrazine derivative.
The selected bond lengths (Å) are given in the following table. Selected bond lengths of 1,2,3,4-triazine CN1
N1N2
N2N3
N3N4
CN4
1.312
1.328
1.358
1.300
1.344
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
211
The 1H and 13C NMR of benzotetrazine 1,3-dioxide in acetone-d6 have been recorded.
1
H and 13C NMR spectral data of benzotetrazine 1,3-dioxide
1
H NMR δ (ppm)
13 C NMR δ (ppm)
H-5, 7.92; H-6, 8.18; H-7, 7.91; H-8, 8.35
C-4a, 144.7; C-5, 125.2; C-6, 139.2; C-7, 132.3; C-8, 119.9; C-8a, 129.0
The 15N NMR spectrum of benzotetrazine 1,3-dioxide was quite helpful in ascertaining the tetrazine structure. The spectrum in acetone d6 showed four signals. N NMR spectral data of benzotetrazine 1,3-dioxide
15
N1
N2
N3
N4
−41.0
−23.9
−48.7
−81.9
The UV spectrum of benzotetrazine-1,3-dioxide shows two strong absorption bands at 310 and 420 nm. The first band is due to π→π* transition, whereas the second one is due to n→π* transition. Importance in Natural Products, Medicines, and Materials804 So far there have been no reports of the synthesis of the parent monocyclic 1,2,3,4-tetrazine. However, 1,2,3,4-benzotetrazine-1,3-dioxide is a stable compound, hence the biological activity of this compound is discussed here. 1,2,3,4-Benzotetrazine-1,3-dioxide is biologically active due to its ability to release nitrosating species during their reduction.805 Thus they are considered to be nitric oxide donors,806 which make them a promising drug molecule for treating cardiovascular, inflammatory, bacterial, and other viral diseases. 5-Nitro and 7-nitro derivatives of benzotetrazine 1,3-dioxide are effective thiol-dependent activators of cyclase. They exhibit hypotensive as well as reduced caspase activity. 1,2,3,4-Benzotetrazine-1,3-dioxide and its 6- and 7-bromo derivatives are inhibitors of ADP-induced aggregation of human platelets. Besides, they also showed antimetastatic properties.807 Synthesis808 There is no published work or evidence for the synthesis of the parent monocyclic 1,2,3,4-tetrazine. The first example of an aromatic 1,2,3,4-tetrazine-6-phenyl[1,2,3]triazolo[4,5-e]-1,2,3,4-tetrazine was reported in 1988. Otherwise, all others are either their substituted dihydro derivatives or their benzo oxide/dioxide derivatives. 1. The first synthesis of 1,2,3,4-tetrazine derivative was reported in 1972. The process involves nitrosation and reduction of sym-dimethylethylenediamine to yield N,N′-dimethyl-N,N′-diaminoethylenediamine, which on oxidation with sodium hypochlorite yields 1,4-dimethyl-1,4,5,6-hexahydro-1,2,3,4-tetrazine.809
Synthesis of the alkyl/aryl derivatives of dihydrotetrazine was also reported by oxidation of N,N′-dialkyl/diaryl-N,N′- diaminoethylenediamine with potassium ferricyanide in the presence of potassium permanganate.810 2. Azoxyanilines on diazotization yield the diazonium salt. The chloroform solution of diazonium salt at 40°C, when passed through a pad of silica gel, gave the 1,2,3,4-benzotetrazine-1-oxide derivative.
212
2. Six-Membered Heterocycles
1,2,3,4-Benzotetrazine-1,3-dioxide is obtained when the diazonium salt is treated with peroxybenzoic acid in aqueous acetonitrile at 0°C.
1,2,3,4-Benzotetrazine-1,3-dioxide was also obtained in high yield when appropriate N-nitroanilines were treated with phosphoric anhydride or PCl5 in acetonitrile at ambient temperature.811
3. The first example of synthesis of an aromatic 1,2,3,4-tetrazine, 6-phenyl[1,2,3]-triazolo[4,5-e]-1,2,3,4-tetrazine, was reported in 1988, and was obtained by oxidation of 4-amino-2,4-dihydro-2-phenyl[1,2,3]triazolo[4,5-d][1,2,3] triazole.812
4. (6R) and (6S) stereoisomers of 1,2,3,6-tetrahydro-1,2,3,4-tetrazine have been synthesized by stereoselective DielsAlder reaction of chiral 1,2-diazo-1,3-butadiene with diethylazodicarboxylate. Initially, the reaction was slow at room temperature but on microwave irradiation it was greatly accelerated.813
Chemical Reactivity814 1. Electrophilic substitution reactions: Nitration of 1,2,3,4-benzotetrazine 1,3-dioxide with a mixture of sulfuric acid and nitric acid gave a mixture of 5-nitro- and 7-nitro-1,2,3,4-benzotetrazine-1,3-dioxides815 in a ratio of 1:2.
However, heating 1,2,3,4-benzotetrazine 1,3-dioxide with an HNO3/oleum mixture afforded a 5,7-dinitro derivative without opening the tetrazine ring. Bromination of 1,2,3,4-benzotetrazine 1,3-dioxide with dibromoisocyanuric acid in trifluoroacetic acid containing a little amount of sulfuric acid gave a mixture of 5-bromo- and 7-bromo products in equal ratio.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
213
2. Nucleophilic displacement reactions: Reaction of nitro- and bromo-1,2,3,4-benzotetrazine 1,3-dioxide with KOH/MeOH, NaN3/DMF, Me2NH/DMF, and MeNH2/DMSO resulted in the displacement of the bromo and nitro groups by methoxy, azido, dimethylamino, and methylamino groups without opening the tetrazine ring.816
3. Reduction: Reduction of 1,2,3,4-benzotetrazine 1,3-dioxide with Na2S2O4 or SnCl2 afforded benzotriazole.817
The reduction was suggested to proceed with the formation of benzotetrazine 2-oxide, which underwent a ring- opening process. The open chain tautomer is then cyclized to thermodynamically more stable N-nitrosobenzotriazole, which on hydrolysis gave benzotriazole.
4. Photochemical reaction: Photochemical reaction of 1,4-dimethyl-1,4,5,6-tetrahydro-1,2,3,4-tetrazine at room temperature yields 1,3,5-trimethyl-1,3,5-triazinane. The triazinane product is formed probably due to trimerization of formaldehyde N-methylimine, obtained from the diradical formed after evolution of nitrogen from tetrazine.818
Degradation of 6-phenyl[1,2,3]triazolo[4,5-e]-1,2,3,4-tetrazine in solution gave a mixture of triazole and tetrazole. The reaction probably takes place with the stepwise elimination of nitrogen.819
214
2. Six-Membered Heterocycles
2.5.6 1,2,3,5-Tetrazine 1 6
N
5N
N2 N3
4
1,2,3,5-Tetrazine is one of the isomers of tetrazine, which is more commonly referred as as-tetrazine. In this isomeric tetrazine, three nitrogen atoms are adjacently present, while the fourth nitrogen is present at position 5 of the ring. So far, there is no published work on the synthesis of the parent monocyclic 1,2,3,5-tetrazine. However, few biologically active compounds are known in which the tetrazine moiety is fused to the pyrazole ring. The two most important compounds of this category are temozolomide and mitozolomide. Both the compounds have been reported to exhibit antitumor activity.
Biologically active compounds with 1,2,3,5-tetrazine skeleton.
Synthesis 1. as-Tetrazine derivatives, along with some known compounds, have been synthesized by electrochemical oxidation of cyanamide with a platinum anode in aqueous potassium hydroxide solution followed by treatment of the anolyte with hydrochloric acid or carbon dioxide. The tetrazine derivatives obtained were 4-amino-6-cyanoamino-1,2,3,5-tetrazine, 4-amino-6-cyanoguanidino-1,2,3,5-tetrazine, and 4-ureido-6-cyanoguanidino-1,2,3,5-tetrazine.820
2. 5-Amino-4-cyano-3-methylpyrazole obtained from benzyl alcohol in four steps via a solid phase synthesis is converted to pyrazolo[5,1-d]-[1.2.3.5]tetrazine-4(3H)-one under one-pot sequential reaction conditions.821
3. Reaction of nitrilimine with 2-aminopyrimidine in the presence of triethylamine yielded pyrimido[2,1-d]1,2,3,5-tetrazine.822
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
215
Chemical Reactivity820,823 1. 4-Amino-6-cyanoamino-1,2,3,5-tetrazine when warmed at 40°C with dilute sulfuric acid or dilute hydrochloric acid gave amidinobiuret and nitrogen.
2. When hydrogen chloride gas was introduced into the dry acetone solution of potassium salt of 4-amino-6cyanoamino-1,2,3,5-tetrazine, hydrochloride of the base was the initial product, which on treatment with water gave 2,4-diamino-6-chloro-1,3,5-triazine.
3. When 4-amino-6-cyanoguanidino-1,2,3,5-tetrazine is heated with dilute mineral acid, it decomposes to melamine, carbon dioxide, ammonia, and nitrogen.
4. When 4-ureido-6-cyanoguanidino-1,2,3,5-tetrazine is heated with dilute mineral acid, it decomposes to melamine, carbon dioxide, ammonia, and nitrogen.
2.5.7 1,2,4,5-Tetrazine 4
5
N 6
N N
3
N2
1
1,2,4,5-Tetrazine is a six-membered planar and symmetrical nitrogen heterocycle with four nitrogen atoms present at the 1,2,4,5-positions of the ring. Of the three possible tetrazine isomers, 1,2,4,5-tetrazine is most commonly known as sym-tetrazine or s-tetrazine. Structural and Reactivity Aspects823 s-Tetrazine, which was first synthesized by Pinner in 1893, can best be represented by two degenerate Kekulé’s structures.
Kekule structure of s-tetrazine.
216
2. Six-Membered Heterocycles
The structure of 1,2,4,5-tetrazine has been determined by X-ray crystallography and the molecule was found to be almost planar and symmetrical. The experimental bond lengths and bond angles are in good agreement with the values calculated by semiempirical methods. Bond lengths and bonds angles of s-tetarzine Bond lengths (Å)
Bond angles (o)
NN
CN
NNC
NCN
1.321
1.334
115.6
127.2
The UV spectrum of 1,2,4,5-tetrazine in ethanol shows two strong bands at 274 (log ε 3.56) and 538 nm (log ε 2.75). The first band is due to π→π* transition, whereas the second band is due to n→π* transition. The symmetrical structure of 1,2,4,5-tetrazine is reflected in the 1H and 13C NMR spectra (in acetone d6) with one signal for the ring proton (δ 11.05) and one for the ring carbon atom (δ 161.2). The mass spectrum of s-tetrazine is found to be very simple and it fragments as follows.
Mass fragmentation pattern of s-tetrazine derivative.
Importance in Natural Products, Medicines, and Materials The most important feature regarding tetrazine is its high electron affinity, resulting in electrochemical reversible reduction potential, and its low-lying characteristic, which results in n→π* transition in the visible region, thereby making tetrazines deeply colored molecules. Because of these features, tetrazines display unique photochemical and electrochemical properties,824 which find use in a number of applications. 3,6-Disubstituted tetrazines find use in the development of sensors, optical switches, and solar cells. s-Tetrazines substituted with heteroatoms display fluorescent properties. Some are even fluorescent in a crystalline state, which makes them the smallest organic fluorophore fit for sensing applications. Dipyridyl-s-tetrazine and related molecules have frequently been used as bridging ligands in metallo-organic compounds.825 They are particularly useful in organic chemistry as synthetic intermediates for the synthesis of a number of natural products.826 New nanocomposite materials have also been obtained by reaction of s-tetrazine827 with C60 or carbon nanotubes.828 Tetrazine-N-hydro(di, tetra, hexa) derivatives exhibit numerous biological activities and some of them have been tested positive for antitumor activity.829 Besides, they are also used for intracellular small molecule imaging, postsynthetic DNA labeling, and in vivo imaging. Synthesis 1. Oxidation: There is no direct method for the synthesis of s-tetrazine. It is always obtained by oxidation of its 1,2-dihydro or 1,4-dihydro derivatives using a variety of oxidizing agents.
The most commonly used oxidizing agents are nitrous acid, halogens, ferric chloride, nitric acid, hydrogen peroxide, chromic oxide, and isoamyl nitrite.830 2. Pinner synthesis831: There are several methods for the synthesis of s-tetrazine derivatives. However, the first synthesis was reported by Pinner. The method involves reaction of hydrazine with benzonitrile forming a dihydrotetrazine derivative, which on oxidation yields the aromatic 3,6-diphenyl-1,2,4,5-tetrazine.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
217
However, Pinner method was applicable for aromatic nitriles that are not sterically hindered. This protocol was not suitable for aliphatic nitriles and the process was modified by replacing nitriles by aldehydes to obtain hexahydro-s-triazines, which on oxidation delivered volatile alkyl-substituted s-tetrazines.832, 833
The yields of the 1,2-dihydro derivatives in all reactions were not good but these have been improved by using sulfur as catalyst.834
The improved synthesis of the 1,2-dihydro derivative with the addition of sulfur is proposed to take place by the following mechanism.835
Recently, one-pot synthesis of s-tetrazines directly from aliphatic nitriles and hydrazines has been reported. The method involves reaction of benzyl cyanide with hydrazine in the presence of Lewis acid metal salts like ZnBr2, ZnCl2, Zn(OTf)2, Cu(OTf)2, MgBr2, MnBr2, CuBr2, etc., without involving isolation of the 1,2-dihydro derivative, which is oxidized by NaNO2 in the presence of HCl.836
3. Hantzsch and Lehmann synthesis: Base-catalyzed dimerization of ethyl diazoacetate afforded 1,2-dihydro1,2,4,5-tetrazine salt, which was neutralized, oxidized, and subsequently decarboxylated to yield s-tetrazine.837
218
2. Six-Membered Heterocycles
4. [4 + 2] condensation reaction: Dichloromethylhydrazines have also been used for the synthesis of tetrazines. The method involves reaction of dichloromethylhydrazines with hydrazine forming the dihydro derivative, which was oxidized to 1,2,4,5-tetrazine.
Dichloromethylhydrazines can be prepared by reaction of 1,2-diacylhydrazines with PCl5 or chlorination of 2-acylhydrazones with thionyl chloride and chlorine.838 5. One-pot synthesis of unsubstituted s-tetrazine was reported for the first time in 1980 by reaction between commercially available formamidine acetate and hydrazine acetate.839, 840
6. Many carboxylic acid derivatives like imidates, hydrazides, thioamides, and thiohydrazides also react with hydrazine to afford 1,2-dihydrotetrazine, which on oxidation yields tetrazine.841, 842
7. Green chemistry: An efficient green procedure was used for the synthesis of both symmetric and asymmetric 3,6-disubstituted 1,2,4,5-tetrazine in moderate yield by the reaction of gem-difluoroalkenes with hydrazine under aerobic conditions at room temperature.843
8. Substituted hydrazines like 1-benzylidine-2-alkylhydrazine have also been employed for the synthesis of 1,2,4,5-tetrazine derivatives. The process involves treating the substituted hydrazine derivative with iodine and sodium hypochlorite.844
9. Synthesis by ring enlargement: On heating 3-azido-5-substituted 1,2,4-triazol-4-amine in chlorobenzene at 110°C liberates nitrogen to yield 6-substituted 1,2,4,5-tetrazine-3-amine.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
219
10. Dichlorotetrazine is a versatile synthon obtained by the sequence of reaction of guanidine with hydrazine followed by reaction with 1,3-dicarbonyl compounds and chlorine. It is used for the synthesis of a wide variety of tetrazine derivatives by nucleophilic displacement of chlorine by various nucleophiles like alcohols, thiols, and amines. Monosubstitution takes place readily at room temperature, whereas disubstitution requires forcing conditions. The method involves synthesis of bis(3,5-dimethyl-1H-pyrazol-1-yl)-s-tetrazine, which can subsequently be converted to 3,6-dichloro-s-tetrazine in two steps.
Physical Properties 1,2,4,5-Tetrazines are usually red, bluish red, or violet-red in color. They are quite unstable and can be stored only out of contact with air or at reduced temperatures. 1,2,4,5-Tetrazine itself is soluble in water and in most organic solvents. Chemical Reactivity 1. Aromatic nucleophilic substitution reaction: Due to the presence of four electron-withdrawing groups in the tetrazine core, it reflects a high degree of electrophilicity. Thus the groups present at positions 3 and 6 are capable of leaving as anions, and opening a new pathway by which modifications can be made in the s-tetrazine core by means of aromatic nucleophilic substitution reactions. The most common groups that are capable of leaving as anions are halogens, the methylsulfanyl group, and the 3,5-dimethylpyrazolyl group. The aromatic nucleophilic substitution reaction in s-tetrazine takes place by the following pathway.
Aromatic nucleophilic substitution in s-tetrazine.
Butan-1,4-diol reacts with 3,6-dichloro-1,2,4,5-tetrazine in the presence of 2,4,6-collidine at room temperature to give the monosubstituted derivative. Similarly, unsymmetrical-substituted tetrazine was synthesized by reacting 3,6-dichloro-1,2,4,5-tetrazine with excess ammonia.845
220
2. Six-Membered Heterocycles
3,6-Dichloro-1,2,4,5-tetrazine condenses with 2 equivalents of sodium salt of 5-aminotetrazole to yield the disubstituted 3,6-bis(1H-1,2,3,4-tetrazol-5-ylamino)-1,2,4,5- tetrazine.846
1,2,4-Trizole in acetone reacts with 3,6-dichloro-1,2,4,5-tetrazine to yield 3,6-bis-(1,2,4-triazol-1-yl)-1,2,4,5- tetrazine. Similarly, 3,5-diamino-1,2,4-triazole in DMF reacts with a solution of dichlorotetrazine in acetonitrile to yield 3,6-bis-(3,5-diamino-1,2,4-triazolyl-1-yl)-1,2,4,5-tetrazine.847
2. N-oxidation: Oxidation of 1,2,4,5-tetrazine-3,6-diamine with performic acid affords 1,4-dioxide as the major product with 1-oxide as the minor product. However, oxidation with trifluoroperoxyacetic acid yields 1-oxide as the major product and 1,5-dioxide as the by-product.
3. Reduction: s-Tetrazine can easily be reduced by 1,2-dihydrotetrazines or dihydropyridazines to 1,4-dihydro-1,2,4,5-tetrazine.
Reduction of 3,6-diphenyl-1,2,4,5-tetrazine with lithium aluminum hydride leads to isolation of benzalazine.
2.5 Six-Membered Heterocycles With Three and More Nitrogen Atoms
221
However, reduction with sodium borohydride yields 1,6-dihydro-1,2,4,5-tetrazine as the product.
4. Amination: Reaction of 3-alkyl/aryl-1,2,4,5-tetrazine derivative with liquid ammonia between −45 and −35°C affords homoaromatic σ adducts, which are ionic and this has been confirmed on the basis of 1H and 13C NMR spectroscopy.848
5. Cycloaddition reaction: Tetrazines due to the presence of four electron-withdrawing nitrogen atoms in the ring are commonly used as azadiene in a [4+2] cycloaddition reaction. 3,6-Bis-(polyfluoroalkyl)-s-tetrazine reacts with a variety of unsaturated compounds like styrene, acetylene, aliphatic and alicyclic olefin, and allene with ease to yield pyridazines. However, 3,6-diphenyl and 3,6-dimethyl-s-tetrazine reacts similarly but less readily.849
s-Tetrazine undergoes [4+2] cycloaddition reaction with open chain alkenes like ethylene to initially form 4,5-dihydropyridazine, which undergoes trimerization to give a mixture of stereoisomers with respect to the central triazine ring system.
An inverse demand Diels-Alder reaction of unsubstituted s-tetrazine was reported for the first time in 1987. The method involves reaction of s-tetrazine with 4,5-dihydro-1-methyl-2-(methythio)pyrrole yielding 2,3-dihydro-1methylpyrrolo[2,3-d]pyridazine.850
1,2,4,5-Tetrazine reacts with electron-rich dienophile to produce the pyridazine derivative. This IED-DA reaction proceeded via a bridged intermediate, which after loss of nitrogen yields the desired pyridazine.851
222
2. Six-Membered Heterocycles
Similarly, a cycloaddition reaction of 1,2,4,5-tetrazine with alkynylboronate ester yielded boronic ester, which undergoes a Suzuki coupling reaction to generate the pyridazine derivative.852, 853
s-Tetrazine undergoes an electron demand Diels-Alder process with simple alkenes to dihydropyridazine, which on oxidation forms the pyridazine derivatives.
This method has been used for the synthesis of a derivative of the natural isolate epibatidine.854 The reaction commences with the cycloaddition of tetrazine with enol ether forming an intermediate, loss of nitrogen, and subsequent methanol elimination yields the product.
s-Tetrazine on reaction with thietanone undergoes a series of condensations-fragmentations and cyclization to yield pyrazol-4-ol.
2.6 Six-Membered Heterocycles With One Oxygen Atom
223
Tetrazine undergoes a [4+2] cycloaddition reaction with epoxy naphthalene derivative yielding an intermediate, which undergoes a retro[4+2] reaction to yield isobenzofuran, which rapidly reacts with a C60 molecule to yield a [4+2] cycloaddition product.855
2.6 SIX-MEMBERED HETEROCYCLES WITH ONE OXYGEN ATOM 2.6.1 Pyrans Pyrans or oxines are monocyclic six-membered oxygen heterocycles with two double bonds. There are two isomeric forms of pyran designated as 2H- and 4H-pyran, which differ only in the location of the double bonds. 2HPyran has a saturated carbon at the C-2-position, whereas 4H-pyran has a saturated carbon at C-4. Since both of them lack the conjugated double bond characteristic of benzene and pyridine, as a consequence both pyrans are unsaturated closed chain compounds lacking aromatic properties.
2.6.2 2H-Pyran 3
4
2 O 1
5 6
Structural and Reactivity Aspects856 The IR spectrum of 2H-pyran shows typical CC stretching bands at 1600–1650 cm−1. In the 1H NMR spectrum of a 2H-pyran derivative in CCl4, 3H and 4H olefinic protons were observed at δ 4.89 and δ 5.60, respectively. Importance in Natural Products, Medicines, and Materials 2H-Pyran derivatives constitute a class of rare compounds and there are only a few examples in which this nucleus is present in a natural product. Among them is versicolin, an antibiotic that has been isolated from Aspergillus versicolor.857
Synthesis So far there has been no evidence for the existence of parent 2H-pyran. However, due to the importance of this nucleus, a number of its polyfunctionalized derivatives have been synthesized.
224
2. Six-Membered Heterocycles
1. Palladium-catalyzed cycloisomerization of enynols through a 6-endo-dig cyclization leads to 2H-pyran derivative.
2. Methylmagnesium bromide when added to pyrylium ion forms the 2H-pyran derivative, which on heating tautomerizes to dienones.
3. Addition of metal hydride complexes such as sodium borohydride to pyrylium salt takes place at the C-2position leading to the generation of 2H-pyran derivative.
4. An efficient and divergent one-pot synthesis of substituted 2H-pyran involving intermolecular cyclization of βoxo amides was mediated by N,N,N′,N′-tetramethylchloroformamidinium chloride (TMC).858
5. Reaction of α-halo carbonyl compound with dimethyl aceylenedicarboxylate (DMAD) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as catalyst at room temperature yields a furan derivative (minor product) and highly functionalized 2H-pyran as the major product.859
6. One-pot synthesis of highly stable 2H-pyran from propargyl vinyl ethers has been reported. The process proceeds via an Ag(I)-catalyzed propargyl-Claisen rearrangement, followed by base-catalyzed isomerization and 6π-oxaelectrocyclization leading to the formation of the 2H-pyran derivative.860
Chemical Reactivity 1. It has been observed that 2H-pyran undergoes electrocyclic ring opening to dienone.861
2.6 Six-Membered Heterocycles With One Oxygen Atom
225
2. 2,2,4,6-Tetramethyl-2H-pyran undergoes regioselective Diels-Alder reaction with propiolic ester to give a bicyclo adduct, which on cycloreconversion and acetone elimination yields 2,4-dimethylbenzoate.
3. 2,4,6-Triphenylpyrylium ion on reaction with butylamine, cyclohexylamine, etc. yields corresponding ringopened divinylogous amides. This reaction is thought to proceed with the formation of a charged 2H-pyran reaction intermediate.862
Similarly, on heating 2,2,4,6-tetramethyl 2H-pyran the heterocyclic ring is opened yielding a product that on reaction with LiAlH4 yields a reduced product.
4. Polyfunctionalized 2H-pyrans, which in aqueous solution are in equilibrium with their pyrylium cation, readily undergo a ring-opening process leading to the generation of diketones.863, 864
2.6.3 3,4-Dihydro-2H-Pyran 4 3
5 6
O
2
1
3,4-Dihydro-2H-pyran, also known as 2,3-dihydro-4H-pyran, is a six-membered nonaromatic heterocycle with one oxygen atom and one double bond in the ring. It is chiefly used as a protecting agent.
226
2. Six-Membered Heterocycles
Structural and Reactivity Aspects865 The 1H and 13C NMR spectra of 3,4-dihydro-2H-pyran suggest it to be a cyclic enolic ether. H and 13C NMR spectral data of 3,4-dihydro-2H-Pyran
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.97; H-3/4, 1.90; H-5, 4.65; H-6, 6.37
C-2, 65.8; C-3, 22.9; C-4, 19.6; C-5, 100.7; C-6, 144.2
Examination of the Raman spectra suggests that the dihydropyran moiety exists predominantly in the half chair conformation with a twist angle of 23 degrees. Groups present at the 2-position may be either equatorially or axially oriented, but out of the two the conformer in which the group is axially oriented predominates due to an anomeric effect. OR H
O
RO
O H
Conformations of dihydropyran.
Importance in Natural Products, Medicines, and Materials A 3,4-dihydro-2H-pyran skeleton is present in a number of natural products like carbohydrates, iridoid alkaloids, and antibiotics. A number of drugs containing this skeleton have been reported. For example, zanamivir and laninamivir, the two drugs that are recommended for the treatment of influenza caused by influenza A and B viruses, contain this skeleton.
Drugs containing 3,4-dihydro-2H-Pyran skeleton.
Synthesis 1. 3,4-Dihydro-2H-pyran is synthesized by catalytic dehydration of tetrahydrofuryl alcohol with alumina at higher temperatures.866
2. [4 + 2] cycloaddition reaction: This is a reaction of synthetic importance because substituted dihydropyran derivatives are synthesized by this method. The reaction involves heating crotonaldehyde with methyl vinyl ether at 200°C in an autoclave in the presence of a catalytic amount of hydroquinone.867
3. 4-Acyloxylbutylphosphonium salt obtained by reaction of 1,4-dibromobutane with triphenylphosphine undergoes intramolecular Wittig reaction yielding 6-methyl-3,4-dihydro-2H-pyran.868
2.6 Six-Membered Heterocycles With One Oxygen Atom
227
4. Substituted dihydropyran derivatives were synthesized by the reaction of Baylis-Hillman acetate with 2,4-pentanedione869 in the presence of DABCO in aqueous THF at 42–50°C.
Physical Properties 3,4-Dihydro-2H-pyran, a cyclic vinyl ether, is a colorless, flammable liquid with a bp of 86°C. It is soluble in water and ethanol. Chemical Reactivity 1. Addition of hydrogen: 3,4-Dihydro-2H-pyran on hydrogenation in the presence of nickel yields tetrahydro-2H-pyran.870
2. Addition of halogen acid: Hydrochloric and hydrobromic acid adds across the reactive double bond forming corresponding 2-halotetrahydro-2H-pyran, which readily undergoes dehydrohalogenation. This property has thus been used for the synthesis of 2-substituted tetrahydro-2H-pyran. For example, 3,4-dihydro-2H-pyran on reaction with hydrogen bromide forms 2-bromotetrahydro-2H-pyran, while on reaction with mercuric cyanide or silver cyanide 2-cyanotetrahydro-2H-pyran is the product.871
3. Addition of halogen: Halogens adds across the reactive double bond forming the 2,3-dihalo derivative. Halogen at the 2-position can easily be substituted by a reactive group. 3,4-Dihydro-2H-pyran reacts with bromine to form 2,3-dibromotetrahydro-2H-pyran, which on reaction with silver cyanate yielded 3-bromo-2isocyanatotetrahydro-2H-pyran .872
4. Addition of bromine fluoride: Bromine fluoride generated in situ by reaction of bromine with silver fluoride added across the reactive double bond yielded a trans-derivative as the major product.873
228
2. Six-Membered Heterocycles
5. Hydroboration: Hydroboration takes place regioselectively leading to the generation of tetrahydro-2H-pyran-3-ol.874
6. Reaction of 3,4-dihydro-2H-pyran with diethyl hydroxymethylphosphonate and phosphorous oxychloride yields diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate.
7. Cycloaddition reaction: The addition of carbene to alkene to give a cyclopropane derivative is one of the characteristic reactions of carbene. Carbene generated by reaction of methylene iodide with a zinc-copper couple reacts with 3,4-dihydro-2H-pyran to yield the cyclopropane derivative.875
Dichlorocarbene, the halogen derivative of carbene, has been generated by a variety of methods by the use of chloroform and alkali metal alkoxide, sodium trichloroacetate, butyllithium, and bromotrichloromethane. However, dichlorocarbene generated by using trichloroacetic acid and an alkali metal alkoxide gives a higher yield of adduct.876 The adduct on dehydrohalogenation results in opening of the cyclopropane ring to give a 2,3-dihydrooxepine system.
Diphenylketene undergoes cycloaddition reaction with 2,3-dihydropyran to yield the cyclobutanone derivative.877
Diphenylacetylene on reaction with an excess of 3,4-dihydro-2H-pyran yielded the cyclobutene derivative878 on irradiation at 2537 Å.
8. When 3,4-dihydro-2H-pyran is stirred with dilute hydrochloric acid, ring opening takes place leading to the generation of 5-hydroxypentanal.879
2.6 Six-Membered Heterocycles With One Oxygen Atom
229
9. As protecting group: In organic synthesis, in the presence of acid catalyst, 3,4-dihydro-2H-pyran is used as a protecting group for alcohols. Reaction of alcohols with dihydropyran forms dihydropyranyl ether. These ethers are stable to alkali, organolithium, Grignard reagent, LiAlH4, and acetic anhydride, yet they undergo hydrolysis with dilute acid to regenerate the alcohol.
A mixture of camphorsulfonic acid, propargyl alcohol, and 3,4-dihydro-2H-pyran in dichloromethane when stirred for 2 h yields 2-propargyloxytetrahydropyran.880
In addition, 3,4-dihydro-2H-pyran has also been effectively used for the protection of the carboxylic group, secondary amines, and amides.
10. Hypohalogenation of3,4-dihydro-2H-pyran was effected by the use of trichloroisocyanuric acid in the presence of water. In addition to trans-2-hydroxy-3-chlorotetrahydro-2H-pyran,2,2'-oxybis(3-chlorotetrahydro-2H-pyran) was also formed.881
11. A stereoselective synthesis of (E)-4-hexen-1-ol involves chlorination of 3,4-dihydro-2H-pyran to yield 2,3-dichlorotetrahydro-2H-pyran, which underwent coupling with methylmagnesium bromide and afforded 3-chloro-2-methyltetrahydro-2H-pyran, which on treatment with an ethereal suspension of sodium, followed by hydrolysis of the sodium salt solution with water.882
12. Oxidation: Oxidation of 3,4-dihydro-2H-pyran with nitric acid yields glutaric acid while oxidation with osmium tetraoxide provided tetrahydro-2H-pyran-2,3-diol.Ozonolysis of 3,4-dihydro-2H-pyran yielded hydroperoxide which on treatment with tributoxyphosphine yields aldehyde while reaction with toluenesulfonyl chloride provided methyl 4-(formyloxy)butanoate.
230
2. Six-Membered Heterocycles
2.6.4 Tetrahydropyran 4 3
5 6
O
2
1
Tetrahydropyran is a saturated six-membered heterocyclic compound composed of five sp3-hybridized carbon atoms and one sp3-hybridized oxygen atom. In fact, it is considered to be a cyclohexane derivative in which one of the carbon atoms of cyclohexane has been replaced by oxygen, hence it is also known as oxacyclohexane. Structural and Reactivity Aspects883a The structure of tetrahydropyran was determined in the gaseous state by electron diffraction and microwave spectroscopy. These studies suggest that this six-membered oxygen heterocyclic compound like cyclohexane exists in chair conformation with Cs symmetry. In chair conformation, tetrahydropyran exits in two isomeric forms, specified as 1C4 and 4C1. The letter C stands for chair and the number indicates the carbon atoms, which are located above or below the reference plane of the chair conformation. The energy barrier for this ring flipping is about 10 kcal/mol. 1
4
O
O 4
4
C1
1
C4
1
Conformations of tetrahydropyran.
The free energy of activation for ring inversion was calculated to be 42.3 kJ mol−1 (at 212 K) and this value was quite similar to cyclohexane (43.0 kJ mol−1) but lower than that of piperidine (46.1 kJ mol−1). The bond angles and bond lengths of tetrahydropyran in the gas phase as determined by electron diffraction and microwave spectroscopy are given in the following diagram.
Bond lengths and bond angles of tetrahydropyran.
The 1H and 13C NMR spectra of tetrahydropyran are quite similar to that of a cyclic ether. H and 13C spectral data of tetrahydropyran
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2/H-6, 3.65; H-3/H-4/H-5, 1.65
C-2/C-6, 68.6; C-3/C-5, 27.4; C-4, 24.3
231
2.6 Six-Membered Heterocycles With One Oxygen Atom
Importance in Natural Products, Medicines, and Materials The tetrahydropyran nucleus has been found to be present in a number of natural products that have shown significant biological and pharmacological activities, for example, antifungal, cytotoxic macrolides, Phorboxazole A and B,883b antileishmanial agent, (−)-centrolobine,884 microbial product with antitumor activity, and GEX1A (herboxidiene).885 R1
O
R2
N OMe OMe
O
O N
Br
O OH
OH
O
O
O
O
Phorboxazole A,
R1= H, R2 = OH
Phorboxazole B,
R1= OH, R2 = H Me
OH
MeO (-)-Centrolobine
OMe
O
O
Me
O COOH
Me
Me
Me
Me
OH
GEX1A (herboxidiene)
Natural products containing tetrahydropyan nucleus.
A number of tetrahydropyran derivatives have been used as materials in photographic films886 and host-guest chemistry.887 Synthesis 1. Hydrogenation: 3,4-Dihydro-2H-pyran on hydrogenation in the presence of nickel yields tetrahydropyran.888
2. Intramolecular Williamson synthesis: When hydroxy and halogen groups are part of the same molecule they undergo cyclization on heating in the presence of NaH in THF. 5-Bromopentan-1-ol on heating with NaH in THF cyclized to afford tetrahydro-2H-pyran.
Similarly, heating a mixture of pentane-1,5-diol with sulfuric acid yields tetrahydro-2H-pyran.
3. Acid-catalyzed cyclization of δ-substituted aldehydes leads to the generation of tetrahydro-2H-pyran derivatives.889
The reaction is thought to proceed with the protonation of aldehyde to form carbocation I. This carbocation undergoes intramolecular exchange to give a more stable carbocation II, followed by cyclization leading to the generation of tetrahydropyran derivative.
232
2. Six-Membered Heterocycles
4. Prins reaction890: Tetrahydro-2H-pyran derivatives have been synthesized by the reaction of alkenes with aldehydes. Buten-1-ol reacts with a variety of aldehydes or ketones in the presence of acid to yield a variety of tetrahydro-2H-pyran derivatives.891
Prins-cyclization reaction has been used in the synthesis of tetrahydro-2H-pyran odorants, including commercial Florol and Clarycet, by grinding an aldehyde and a homoallylic alcohol in the presence of a catalytic amount of p- toluenesulfonic acid (p-TSA) on silica under solvent-free conditions.892
5. 3-Hydroxy-3,7-dimethyloct-6-enoic acid in the presence of an acid catalyst such as boron trifluoride diethyl etherate, or iodine underwent cyclization to yield a tetrahydro-2H-pyran derivative.893
6. [4 + 2] cycloaddition reaction: Reaction of triethylsilylaldehyde with allyl silane in the presence of BF3-etherate afforded a tetrahydropyran derivative as a single diastereoisomer.894
2.6 Six-Membered Heterocycles With One Oxygen Atom
233
7. Reaction of hex-5-en-1-ol with peracid leads to the generation of 4-hydroxybutyloxirane, which on acidcatalyzed cyclization leads to the generation of 2-hydroxymethyltetrahydro-2H-pyran.
Physical Properties Tetrahydropyran is a colorless, volatile, mobile liquid with a pungent sweetish odor with a bp of 88°C. It is highly flammable and irritating to eyes and skin. It is soluble in water but miscible with alcohol and ether. Chemical Reactivity 1. Reaction with aryl amines: Tetrahydropyran when heated with aniline and toluidines over activated alumina at higher temperatures yielded N-phenylpiperidine and N-tolylpiperidine in excellent yield. However, yields with o-toluidine were much lower.895, 896
2. Ring-opening reactions (a) Heating tetrahydropyran with trimethylbromosilane and trimethylchlorosilane separately at higher temperature yields 1-bromo-5-trimethylsilyoxypentane and 1-chloro-5-trimethylsilyoxypentane, respectively.897
(b) Reaction with HBr: Tetrahydropyran when heated with hydrobromic acid and concentrated sulfuric acid underwent ring opening to yield 1,5-dibromopentane.898
(c) Reaction with nitric acid: Oxidation takes place leading to the generation of glutaric acid.
(d) Reaction of tetrahydropyran with acetyl chloride in presence of zinc chloride yields 5-chloropentyl acetate.
(e) When heated in the vapor phase with carbon monoxide in the presence of nickel catalyst, pimelic acid is obtained.
234
2. Six-Membered Heterocycles
(f) Reaction of tetrahydropyran with ethyl iodide and mercury(II) acetate result in the ring opening and yields of 5-ethoxypentyl acetate.899
3. Photolysis: Photolysis of liquid tetrahydropyran at 185 nm yields 2-(5′hydroxypentyl)tetrahydropyran, valeraldehyde, pent-4-en-1-ol, and pentan-1-ol as the major products. These products are thought to be formed via biradical (I) and through intramolecular and intermolecular photoreaction.900
2.6.5 4H-Pyran
4H-Pyran is a six-membered, unsaturated, nonconjugated, nonaromatic oxygen heterocycle with two double bonds and an sp3-hybridized carbon at position 4 of the ring. Structural and Reactivity Aspects901 The IR spectrum of 4H-pyran, in contrast to 2H-pyran, shows typical CC stretching bands at ≈ 1700 and ≈1600 cm−1. The 1H and 13C NMR of 4H-pyran (in CCl4) are given the following table. H and 13C NMR spectral data of 4H-pyran
1
1
H NMR (δ values in ppm)
13
C NMR (δ values in ppm)
H-2/H-6, 6.16; H-3/H-5, 4.63; H-4, 2.65
C-2/C-6, 141.1; C-3/C-5, 101.1
Importance in Natural Products, Medicines, and Materials The chemistry of 4H-pyran has been a subject of research for centuries902a because of its biological and pharmacological activities. They constitute a structural unit of a number of natural products. Compounds containing this nucleus have been reported to possess a wide range of biodynamic properties such as antimicrobial,902b antiviral,903 antiallergic, antibacterial, diuretic, anticoagulant, antianaphylactic,904 and antitumor.905 Synthesis 1. A Diels-Alder adduct formed by reaction of acrolein with vinyl acetate is decomposed on a column of glass beads at 350°C leading to the generation of 4H-pyran and acetic acid.906 This compound was unstable in air and hence disproportionate to dihydropyran and pyrylium ion.
2.6 Six-Membered Heterocycles With One Oxygen Atom
235
Synthesis of 4H-pyran has also been reported by heating a mixture of glutaraldehyde and hydrochloric acid in methylene dichloride at 90°C and 40 mm Hg.907 2. Stable polyfunctionalized 4H-pyrans are synthesized by the reaction of formaldehyde with ethyl acetoacetate in the presence of piperidine, yielding diketone, which on reaction with zinc chloride cyclized to a 4H-pyran derivative.908
3. Mesityl oxide condenses with ethyl acetoacetate to yield 4H-pyran.
4. Stable and polyfunctionalized 4H-pyran derivative was synthesized by one-pot condensation of an active methylene diketo compound with an aldehyde and malononitrile using basic Mg/La mixed oxide as catalyst.909
5. Polyfunctionalized 4H-pyrans have also been synthesized by cyclocondensation of aryl aldehydes with malononitrile and β-dicarbonyls in dimethylacetamide in the presence of baker’s yeast.910
6. An efficient method has been developed for the synthesis of 4H-pyran derivatives by cyclocondensation of aldehydes, malononitrile, and ethyl acetoacetate using silica-supported ammonium acetate as recyclable catalyst, promoted by ultrasonic irradiation.911
7. Benzylmagnesium chloride on reaction with pyrylium ion forms a 4H-pyran derivative.
236
2. Six-Membered Heterocycles
8. Neutral alkynes in the presence of a nickel catalyst undergo a [4+2] cycloaddition reaction with α,β-unsaturated carbonyl compound to yield a 4H-pyran derivative.912
9. One-pot, three-component coupling of an aldehyde, malononitrile, and reactive methylene compound in the presence of Amberlyst A21, an ion exchange polystyrene resin led to the synthesis of polyfunctionalized 4Hpyrans. The process is simple, requires no chromatographic purification, and no hazardous solvent has been used.913
10. 2H-Pyrans could be converted into substituted 4H-pyrans by treating them with sodium hydroxide in ethanol at room temperature.914
Physical Properties 4H-Pyran has a bp of 80°C and an nD20 of 1.4559. Chemical Reactivity 1. Pyrylium tetraborate is obtained as a crystalline solid by reaction of 4H-pyran with triphenylmethane tetrafluoroborate.
2. Lithium aluminum hydride reduction of 3-carbethoxy-2,4,4,6-tetramethyl-4H-pyran afforded 3-hydroxymethyl2,4,4,6-tetramethyl-4H-pyran. Reaction of this alcohol with chromic trioxide oxidizes it to an aldehyde. Basecatalyzed aldol condensation of the aldehyde with acetone yields an unsaturated ketone.915
2.6 Six-Membered Heterocycles With One Oxygen Atom
237
3. When 2,4-dinitrophenylhydrazine (DNP) reacts with 4H-pyrans, a ring-opening reaction takes place leading to the generation of bis-2,4-dinitrophenylhydrazone derivatives.
4. Reaction of 2,4,6-trimethylpyrylium perchlorate with sodium borohydride yields 2,4,6-trimethyl-4H-pyran and 4-methyl-cis-3-trans-5-heptadien-2-one. It was experimentally proved that the open chain structure formation takes place with the intermediate formation of a 2H-pyran derivative.916
5. Photochemical reaction: On UV irradiation, 2,4,6-triphenyl-4-benzyl-4H-pyran isomerizes to 2-benzyl-2H-pyran, which on further reaction with hydrochloric acid yields 1,2,3,5-tetraphenylbenzene in quantitative yield.
4-Benzyl-2,4-diphenyl-6-alkyl-4H-pyran on reaction with perchloric acid yields 1,3-diphenylnaphthalene. The reaction is thought to proceed by the following mechanism.
2.6.6 Pyrylium Salt
Pyrylium cation is a six-membered heterocyclic compound consisting of five carbon atoms and one positively charged oxygen atom.
238
2. Six-Membered Heterocycles
Structural and Reactivity Aspects917 The X-ray analysis of 3-acetyl-2,4,6-trimethylpyrylium salt shows that the molecule is a planar, slightly distorted hexagon with CC and CO bonds of almost equal length. The bond length (in pm) and bond angles (in degrees) are shown in the following diagram.
Bond lengths and bond angles of a derivative of pyrylium salt.
The 1H and 13C NMR spectral data of pyrylium ion are given in the following table. H and 13C NMR spectral data of pyrylium ion
1
1 H NMR (CF3COOD) δ (ppm)
13
C NMR (CD3CN) δ (ppm)
H-2/6, 9.22; H-3/5, 8.08; H-4, 8.91
C-2/6, 169.2; C-3/5, 127.7; C-4, 161.2
The 1H NMR of unsubstituted pyrylium salt was also recorded. The most deshielded were the α-protons at δ 8.6 followed by γ-protons at δ 7.5, and the least deshielded protons were at δ 7.1. The pyrylium ion is represented by a number of resonating structures with the positive charge delocalized over the whole ring.
Resonationg structures of pyrylium ion.
Importance in Natural Products, Medicines, and Materials The most important application of pyrylium salts is in the photographic industry where they are used as photosensitive layers in films and papers. Pyrylium salts, because of their fluorescent properties, are used as internal labeling agents for photographic films. These films are identified by the fluorescence of specific pyrylium salts and their respective color when they are exposed to UV light.918 Besides, pyrylium salts are also used as fluorescent dyes and dye lasers. Some pyrylium salts have been reported to function as plant growth stimulants and as anticorrosion agents.918 Synthesis 1. Pyryliumtetrafluoroborate has been prepared by hydride abstraction from the corresponding 4H-pyran using triphenylcarbeniumtetrafluoroborate.919
2. 2,6-Di-tert-butyl-4-methylpyrylium trifluoromethanesulfonate was synthesized by heating pivaloyl chloride, anhydrous tert-butyl alcohol, and trifluoromethanesulfonic acid920 at 95–105°C.
3. 2,4,6-Triphenylpyrylium tetrafluoroborate, a versatile, useful, stable starting material for the synthesis of substituted nitrobenzene derivatives, has been prepared by heating benzalacetophenone and acetophenone in dichloroethane with a 52% ethereal solution of fluoroboric acid.921
2.6 Six-Membered Heterocycles With One Oxygen Atom
239
4. 2,4,6-Trimethylpyrylium tetrafluoroborate, 2,4,6-trimethylpyrylium perchlorate, and 2,4,6-trimethylpyrylium trifluoromethanesulfonate were synthesized by reaction of acetic anhydride and tert-butyl alcohol with 40% fluoroboric acid, 70% perchloric acid, and trifluoromethanesulfonic acid, respectively.922–924
5. Balaban-Nenitzescu-Praill reaction: Diacylation of alkenes that have three or more carbon atoms in the presence of strong acids afforded pyrylium salts.
Electrophilic diacylation of isobutene or α-methylstyrene with acetic anhydride in the presence of sulfuric acid affords 2,4,6-trimethylpyrylium or 2,6-dimethyl-4-phenylpyrylium sulfoacetates, respectively.925
6. Hantzsch-type synthesis: This process involves the reaction of an aldehyde with 2 moles of aryl methyl ketone in acetic anhydride affording a 1,5-diketone, which cyclizes to pyran. Oxidation of pyran yielded pyrylium salt.926, 927
Chemical Reactivity 1. Reaction with ammonia and other amines: Pyrylium salt reacts with ammonia and other amines to give pyridine or pyridinium derivatives. This is one of the best methods for preparing nitrogen heterocycles.
Reaction of 2,6-di-tert-butyl-4-methylpyrylium trifluoromethanesulfonate with ammonium hydroxide yields 2,6-di-tert-butyl-4-methylpyridine.928
240
2. Six-Membered Heterocycles
2. 2,4,6-Trimethylpyrylium salt reacts with warm alkali resulting in the formation of 2-hydroxypyran, which immediately undergoes a ring-opening process. The acyclic intermediate undergoes aldol-type condensation to form 3,5-dimethylphenol.
3. 2,4,6-Triphenylpyrylium ion reacts with methoxide to produce methoxy-substituted 2H- and 4H-pyrans.
4. Reaction of 2,4,6-triphenylpyrylium tetrafluoroborate with nitromethane in the presence of triethylamine in absolute ethanol yields triphenylnitrobenzene.929
5. Reaction of 2,4,6-trimethylpyrylium salt with sodium cyanide afforded a conjugated acyclic 5-cyano-2,4-dienone by α-addition of the cyanide anion to the pyrylium cation followed by electrocyclic ring opening of 2H-pyran. Dienone on reaction with HCl afforded 5-cyanosorbic acid.930
The same reaction has been reinvestigated by reacting 2,4,6-trimethylpyrylium perchlorate with sodium cyanide at room temperature in a stirred mixture of water and ethyl ether. The major product was 2-Z,4-Z,2,4-dimethyl6-oxo-2,4-heptadienonitrile and 2-E,4-Z,2,4-dimethyl-6-oxo-2,4-heptadienonitrile was the minor product. When treated with concentrated hydrochloric acid under similar reaction conditions, 2-Z,4-E,2,4-dimethyl-6-oxo-2,4heptadienonitrile and 2-E,4-E,2,4-dimethyl-6-oxo-2,4-heptadienonitrile, respectively,931 were formed.
2.6 Six-Membered Heterocycles With One Oxygen Atom
241
6. Reaction with organometallics: The addition of organometallic compounds normally takes place at the α-position, whereby ring opening takes place leading to the formation of dienones or aldehydes. However, reaction with benzylmagnesium chloride is an exception because it leads to the formation of a 4H-pyran derivative.
2,4,6-Trimethylpyrylium ion reacts with methylmagnesium bromide leading to the generation of a pyran derivative, which undergoes a ring-opening process to give 4,6-dimethylhepta-3,5-dien-2-one.
Pyrylium perchlorate undergoes reaction with butyllithium at −78°C, and ring opening takes place leading to the formation of nona-2,4-dienal.932
7. Photochemical reaction: Photolysis of pyrylium perchlorate in acetic acid containing acetic anhydride yields triacetates in a 5:2 ratio.933
However, when photolysis is carried out in wet acetonitrile, a single oxazoline derivative was obtained, which was identified by X-ray crystallography. Oxazoline formation takes place by hydration of initially formed nitrilium ion, followed by cyclization and opening of the epoxide.
8. Reaction of 2,4,6-triphenylpyrylium with hydroxylamine affords the monoxide of a pseudobase. It readily isomerizes into 3,5-diphenyl-5-phenacyl-2-isoxazoline, which on reaction with mineral acid splits into acetophenone and 1,3-diphenylisoxazole.934
242
2. Six-Membered Heterocycles
9. Azulene: A simple and general method of azulene synthesis involves reaction of 2,4,6-trimethylpyrylium perchlorate with cyclopentadienyl sodium. 4,6,8-Trimethylazulene formed during the reaction is crystallized935 from ethanol with mp of 80–81°C.
Pyranones Pyrones or pyranones are unsaturated, six-membered, oxygen heterocycles comprised of one oxygen atom and a carbonyl group in the ring. They exist in two isomeric forms, 2-pyrone or α-pyrone and 4-pyrone or γ-pyrone, assigned on the basis of the position of the carbonyl group relative to the oxygen atom within the ring system. They are also known as 2H-pyran-2-one and 4H-pyran-4-one, respectively.
2.6.7 2H-Pyran-2-One (2-Pyranone)
2-Pyranone, also known as α-pyrone, 2H-pyran-2-one, or pyran-2-one, is an unsaturated lactone that exhibits aromatic as well as aliphatic characters. The 2-pyrone skeleton is more readily found in nature as part of coumarin, the benzo derivative of 2-pyrone. Structural and Reactivity Aspects936 2-Pyrone is well presented as a resonance hybrid between two structures, an enol lactone (1) and a betaine (2). From IR spectrum studies, the presence of an absorption band around 1730 cm−1, which is characteristic for ketonic groups, suggested that structure (2) does not play an important part in the description of the 2-pyran-2-one system.
Resonance structures of 2-Pyrone.
Microwave spectroscopic studies further suggest that 2-pyrone possesses bond parameters of an enol-lactone system with a localized CC double bond and single bonds.
Bond lengths and bond angles in 2-pyrone.
2.6 Six-Membered Heterocycles With One Oxygen Atom
243
The 1H and 13C NMR spectral data of 2-pyrone are given in the following table. H and 13C NMR spectral data of 2-pyrone
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H3, 6.38; H-4, 7.58; H-5, 6.43; H-6, 7.77
C-2, 162.0; C-3, 116.7; C-4, 144.3; C-5, 106.8; C-6, 153.3
The IR spectrum for 2-pyran-2-one shows carbonyl group stretching vibration at ≈1730 cm−1 and suggests that betaine structure (2) has a minor role to play in describing the 2-pyran-2-one ring system. In the mass fragmentation pattern of the 2-pyran-2-one system, furan and cyclopropenylium ion are the main fragments.
Mass fragmentation pattern of 2-pyran-2-one.
Importance in Natural Products, Medicines, and Materials The 2-pyrone nucleus is present in a wide variety of natural products isolated from animals, plants, bacteria, fungi, etc. and they are reported to possess a wide spectrum of biological activity such as antibacterial, antifungal, anti-Alzheimer’s disease, anticancer, cholesterol lowering, and cardiotonic.937–939 The diverse biological activity expressed by 2-pyranone is thought to be as a result of enzyme inhibition.940–942 In July 2013, α-pyrones were identified as a new class of signaling molecule in bacterial communication, similar to quorum sensing.
Natural products containing 2-pyranone skeleton.
Synthesis 1. 2-Pyrone in good yield is obtained by heating coumalic acid at higher temperature over fine copper turnings.943 2-Pyrone in low yield have earlier been obtained by pyrolysis of heavy metal salts of coumalic acid944 and pyrolysis of its carboxylic acid derivative of coumalic acid over copper.945
Coumalic acid has been prepared by heating cheap and easily available malic acid with oleum. The reaction is believed to proceed by initial dehydration/decarboxylation of malic acid, yielding an aldehyde acid enol (A), which then condenses by Michael addition to the enol of the corresponding enone yielding product B, which after dehydration and lactonization yields coumalic acid.946, 947
244
2. Six-Membered Heterocycles
2. 2-Pyrone is also synthesized by a reaction of formaldehyde with 3-butenoic acid.
3. Condensation of 3,3-dichloropropenal with a reactive methylene compound like methyl ethyl ketone afforded 2-pyrone.
4. Claisen condensation between diethyl oxalate and α,β-unsaturated ester results in the formation of an intermediate, which undergoes ring closure via keto enol to produce 2-pyrone.948
5. 5,6-Difunctionalized 2-pyrones were easily synthesized by reaction of ene-ynoic acid with iodine followed by either a Stille or Negishi cross-coupling reaction.949, 950
6. Improvements were made in the use of the Stille reaction for the synthesis of 2-pyrones, which could be formed in one step by reaction of acyl chloride with a distannane.951
2.6 Six-Membered Heterocycles With One Oxygen Atom
245
7. Sonogashira coupling reaction between iodo-substituted unsaturated ester and terminal alkyne leads to the generation of (Z)-2-alken-4-ynoate, which undergoes electrophilic cyclization in the presence of ICl or I2 affording 2-pyrone.952
Fluorinated 2-pyrone derivative was synthesized by the reaction of (2E)-2,3-difluoro-3-iodoacrylic acid with terminal alkynes under Sonogashira alkynylation conditions using PdCl2(PPh3)2 in combination with CuI as a co-catalyst.953
8. Palladium-catalyzed coupling of terminal alkyne with haloacrylic acid leads to the formation of (Z)-5-alkyl-2-en4-ynoic acid, which undergoes lactonization in the presence of zinc bromide to form 2-pyrones.954a
9. Highly functionalized 2-pyrones have been synthesized by stirring an equimolar mixture of ketenedithioacetals such as methyl 2-cyano-3,3-(dimethylthio)acrylate or dimethyl 2-(bis(methylthio)methylene)malonate and aliphatic or arylmethyl ketone using more than 1 equivalent of powdered KOH in dry DMF/DMSO at room temperature for 4–5 h. Usual workup provided 6-aryl-4-methylthio-2H-pyran-3-carbonitrile/carboxylate in moderate yield.954b, c
Physical Properties 2-Pyrone is a colorless liquid with a bp of 208°C, miscible with water. Chemical Reactivity 1. Electrophilic substitution reaction: 2-Pyrone has an aromatic character, which is reflected by its reactions toward electrophilic substitution reaction. The substitution preferably takes place at either the 3- or 5-position, i.e., ortho or para to the carbonyl group. (a) 2-Pyrone on reaction with bromine in carbon tetrachloride initially forms an unstable adduct, which on warming yields 3-bromo-2-pyrone. The reaction takes place by addition-elimination sequence rather than by direct electrophilic substitution.955
246
2. Six-Membered Heterocycles
However, when photobromination is carried out at a lower temperature than the addition product, trans-dibromide is obtained, which in the presence of base undergoes dehydrobromination. (b) Nitration with nitronium tetrafloroborate, initially attacks the carbonyl oxygen forming o-nitro salt (pyrylium salt), which slowly rearranges to 5-nitro-2-pyrone.956
However, with an electrophilic reagent like trimethyloxonium tetrafluoroborate (Meerwein’s reagent) the attack takes place only at the carbonyl oxygen forming pyrylium salts.
2. Nucleophilic substitution reaction: 2-Pyrone can readily be attacked by nucleophilic reagents at the C-4- and C-6-positions. The intermediates formed during the process are readily stabilized by resonance.
(a) 2-Pyrone, which possesses an unsaturated lactone ring system on reaction with the base, underwent a ringopening process.
(b) Depending on the type of nucleophile, 2-pyrone can easily be attacked by nucleophilic reagents. Weak nucleophiles attack at the C-2-position, whereas strong nucleophiles attack at the C-6-position. 2-Pyrone reacts with ammonia with the initial attack at C-6, followed by rearrangement to yield pyridin-2(1H)-one.
2.6 Six-Membered Heterocycles With One Oxygen Atom
247
(c) 2-Pyrone reacts with sodium cyanide in DMF to yield a product that on acidification yields 5-trans-cyano-2-cis4-pentadienoic acid.957
The mechanism of the reaction involves the attack of the cyanide ion at position C-6 of pyrone, leading to the generation of resonance-stabilized carbanion intermediate A, which cleaves to give the stable carboxylate anion B.
(d) Grignard reagent is first added to the carbonyl group followed by ring opening of the 2-pyrone. The second molecule of the Grignard reagent reacts with either of the two carbonyl groups in the intermediate. Protonation and dehydration lead to the generation of an aldehyde and ketone.
3. Cycloaddition reactions: 2-Pyrone has some aromatic character, hence it undergoes Diels-Alder [4+2] cycloaddition reaction less readily in comparison to cyclic-conjugated dienes. 2-Pyrone undergoes cycloaddition reaction with maleic anhydride. The adduct formed undergoes thermal decarboxylation to 1,2-dihydrophthalic anhydride.
2-Pyrone undergoes cycloaddition reaction with bis(trimethylsilyl)acetylene with 2-pyrone acting as diene and alkyne as dienophile. Initially, a highly strained bicyclooctadiene is formed, from which expulsion of a two-atom bridge takes place to yield the aromatic compound. The presence of a trace amount of acid was responsible for isomerization of the product.958
Similarly, reaction of 2-pyrone diene with bis(pentamethyldisilanyl)acetylene and diphosphyrylacetylene dienophile yielded the desired 1,2-bis(pentamethyldisilanyl)benzene959 and 1,2-diphosphorylbenzene,960 respectively.
248
2. Six-Membered Heterocycles
Tetrasilyl diyne dienophile undergoes cycloaddition with 2 equivalents of 2-pyrone in toluene (containing triethylamine) to afford [2.2] orthocyclophane (1). When the reaction was carried out in bromobenzene, [2.2] metacyclophane (2) was isolated.961
In the foregoing cycloaddition reactions, elimination of carbon dioxide from the initially formed bicyclo product led to aromatization; however, if the olefin contains such groups, which are unable to be eliminated after the formation of the bicyclo product, then this would lead to the formation of dihydrobenzenes. Dihydrobenzene (A) as a single product was obtained by cycloaddition of 2-pyrone with the endocyclic double bond of the tricyclic diene (B).962
The cycloaddition of 1,2,3-triphenylcyclopropene with 2-pyrone leads to the generation of cycloadduct product (A). Elimination of a molecule of carbon dioxide with the spontaneous ring enlargement led to the generation of 1,6,7-triphenylcyclohepta-1,3,5-triene.963
Reaction of 2-pyrone with the reactive 1,4-dihydronaphthalene-1,4-endo-oxide resulted in the formation of a regioisomeric mixture of Diels-Alder cycloadduct, which after a few transformations resulted in the formation of biologically active anthracycline 7-deoxydaunomycinone.964
A number of complex natural products were synthesized involving tandem pericyclic reactions. The reaction involves intermolecular Diels-Alder cycloaddition reaction of 2-pyrone with α,ω-diene followed by expulsion of carbon dioxide from bicyclic lactone (A) and intramolecular Diels-Alder reaction of cyclohexadiene (B) to afford the polycyclic structure.965
2.6 Six-Membered Heterocycles With One Oxygen Atom
249
4. Photochemical Reaction (a) When a cold solution of 2-pyrone in methylene chloride is irradiated by visible light, photobromination takes place possibly by an ionic mechanism as well as by a radical pathway yielding dl-trans-5,6-dibromo-5,6dihydro-2-pyrone as the exclusive product.955
(b) Photochemical reactions of 2-pyrone have been widely investigated and have been found to give interesting products. Direct photolysis of an ethereal solution of 2-pyrone leads to the generation of bicyclic β-lactone (A) as the exclusive product. However, when photolysis is carried out in the presence of 10% added methanol, methyl trans-4-formyl-3-butenoate is the product.966 Continued irradiation of bicyclic β-lactone (A) yields cyclobutadiene.967
Irradiation of 2-pyrone in the presence of a triplet sensitizer results in dimerization, leading to the formation of a tricyclic structure. (c) Photodimerization: Pressurization of a 50% solution of 2-pyrone in toluene or nitromethane at 7 kbar at 70°C in the presence of 1% hydroquinone yields dimer 1. However, photosensitization of 2-pyrone968 leads to a mixture of dimers 2 and 3.
Ring transformation by nitrogen nucleophiles: Suitably functionalized 2H-pyran-2-ones such as 6-ary-4-methylthio2H-pyran-3-carbonitriles/carboxylates smoothly undergo ring transformation reactions by different nitrogen
250
2. Six-Membered Heterocycles
nucleophiles such as ammonia, heterocyclic primary and sec.amine, hydrazine, cyanamide, and generated molecular diversity by stirring a mixture of 2-pyranone with different nitrogen nucleophiles in DMF at room temperature or by heating neat or in different solvents.969
Ring transformation reactions by carbanion: Numerous aromatic and heterocyclic compounds have been prepared by ring transformation reactions of 6-aryl-4-methylthio-2H-pyran-3-carbonitriles by carbanion generated from acetophenone, 1-substituted 4-piperidone, terahydrothiophene-3-one, 2-ethoxycarbonyl-4-cyclopentan-4-one, nitromethane, and 1-aryl-3-methylpyrazol-5-one in DMF using powdered KOH as a base at room temperature. Usually, reaction is initiated with carbanion attack at C-6 followed by cyclization. Usual workup and purification yielded a variety of compounds.969
2.6 Six-Membered Heterocycles With One Oxygen Atom
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2.6.8 4H-Pyran-4-One (4-Pyranone)
4-Pyranone, also known as γ-pyrone or pyran-4-one or simply 4-pyrone, is an unsaturated, nonconjugated, nonaromatic, six-membered oxygen heterocycle. This skeleton is more readily found in naturally occurring compounds such as chromone, maltol, and kojic acid. Structural and Reactivity Aspects970 4-Pyrone is well presented as a resonance hybrid of two structures. However, the dipole moment of 4-pyran-4-one is ≈4 D and its greater basicity (pKa = 0.1) suggests that the betaine canonical structure (2) makes little contribution to the resonance hybrid.
Resonating structures of 4-pyrone.
The structure of 4-pyrone as a cross-conjugated, localized cycloenone system on the basis of its bond parameters has been established on the basis of microwave spectroscopy.
Bond length and bond angles of 4-pyrone.
The 1H and 13C NMR spectral data of 4-pyrone suggest it to be an α,β-unsaturated carbonyl system. H and 13C NMR spectral data of 4-pyrone
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H2, 7.88; H-3, 6.38
C-2, 155.6; C-3, 118.3; C-4, 179.9
Importance in Natural Products, Medicines, and Materials 4-Pyrone is of great value because this structural subunit is present in a number of natural products like onchitriols I and II, and verticipyrone.971 Besides, a number of natural products and synthetic molecules possessing this skeleton have been reported to display various biological activities such as flavoring agents in the food industry, skin whitening agent, treatment of melismas, alixinas as an antitumor agent, and phenoxan as an anti-HIV agent.
252
2. Six-Membered Heterocycles
Natural products and drugs containing 4-pyrone nucleus.
Synthesis 1. Decarboxylation of chelidonic acid and orcomanic acid yields 4-pyrone. Decarboxylation, however, takes place smoothly in the presence of copper powder. Chelidonic acid is, however, prepared by reaction of acetone with ethyl oxalate.
2. From Meldrum’s acid: Meldrum’s acid on reaction with acetyl chloride in the presence of pyridine yields the acylated product, which on reaction with butyl vinyl ether yields pyrandione as intermediate. On treatment of pyrandione with p-toluenesulfonic acid, decarboxylation and loss of butanol led to the formation of 4-pyrone.972
2.6 Six-Membered Heterocycles With One Oxygen Atom
253
3. A new environmentally friendly (metal-free) synthetic strategy for the synthesis of 4-pyrones with high efficacy has been reported.973 The process involves heating 1,5-diphenylpenta-1,4-diyn-3-one with Brønsted acid like pTsOH in methanol at 90°C.
4. Benzoylation of acetyl and benzoylacetones at the terminal methyl group leads to the formation of 1,3,5-triketones, which in the presence of sulfuric acid is cyclized to 4-pyrones.974
5. Synthesis of aryl- and alkyl-disubstituted 4-pyrones from β-keto acids in the presence of trifluoromethanesulfonic anhydride has been reported. The reaction proceeds via decarboxylative autocondensation of β-keto acids.971
6. Symmetrically substituted 4-pyrones are synthesized by heating alkanoic acids or their anhydrides with polyphosphoric acid975 at 200°C.
7. Dehydroacetic acid, an important 4-pyrone derivative, is synthesized by Claisen condensation of two molecules of ethyl acetoacetate followed by cyclization.
Physical Properties 4-Pyrone is a low-melting colorless crystalline solid mp 32°C. Chemical Reactivity 1. 4-Pyrone reacts with Grignard reagent with the attack preferentially at carbonyl carbon (C-2), forming tertiary alcohol, which undergoes dehydration with acid to form 4-substituted pyrylium salt.976
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2. Six-Membered Heterocycles
2. 4-Pyrone, which possesses an unsaturated lactone ring system on reaction with the base, undergoes a ringopening process leading to the generation of oxopentanedial.
3. 4-Pyrone in comparison to 2-pyrone is more basic and on alkylation with dimethyl sulfate gave 4-methoxypyrylium salt.
4-Pyrone also reacts with trialkyl derivatives of silyltrifluoromethanesulfonate forming 4-silyloxypyrylium triflate.
4. Formylation: 4H-Pyrones are formylated by using a carbon monoxide-hydrochloric acid mixture in the presence of trifluoroacetic acid as a catalyst.977
5. Reaction with hydroxylamine: 4-Pyrone reacts with hydroxylamine hydrochloride to afford 1-hydroxy-4pyridone or 4-hydroxyaminopyridine-N-oxide.978
6. Reaction with amino acid: 4-Pyrone reacts with 3-aminopropanoic acid to yield N-carboxyethyl-4-pyridone. The reaction is proposed to take place by a ring-opening and ring-closure process.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
255
7. Photochemical reaction: Irradiation of a trifluoroethanol solution of 3,5-dimethyl-4-pyrone at 254 nm yields 3,6-dimethyl-2-pyrone. The reaction takes place with the intermediate formation of 2,5-dimethylcyclopentadienone epoxide.979
8. Cycloaddition reaction: 2,6-Diethyl-4-pyrone on reaction with tosylisocyanate undergoes [2+2] cycloaddition reaction followed by loss of carbon dioxide to afford a 4-imine derivative, which on reaction with aqueous ammonia at 60°C gave a 1,4-dihydropyridine derivative. The pyridine derivative on reaction with sulfuric acid yielded 4-amino-4,6-diethylpyridine.980, 981
2.7 SIX-MEMBERED BENZO-FUSED OXYGEN HETEROCYCLES 2.7.1 Benzopyrans Benzopyrans are bicyclic oxygen-containing heterocycles in which the benzene ring is fused to the pyran ring. However, in older literature such compounds are called chromenes and according to the latest IUPAC nomenclature this name is retained. There are two isomers of benzopyran: 1-benzopyran (chromene) and 2-benzopyran (isochromene).
2.7.2 2H-1-Benzopyran (2H-Chromene)
2H-1-Benzopyran is a bicyclic-conjugated oxygen heterocycle constituted by fusion of the “b” site of the pyran ring with the benzene ring. All the carbons except C-2 (sp3) are sp2 hybridized and an oxygen atom at position 1 is part of the chromene ring.
256
2. Six-Membered Heterocycles
Structural and Reactivity Aspects The ultraviolet spectrum of 2H-1-benzopyran in hexane shows two bands at λmax (hexane) 266.5 and 314 nm due to π→π* transition. The IR spectrum of 2H-1-benzopyran showed the following peaks: 3040, 2970, 2840, 1644, 1610, 1613, 1570, 1495, 1480, 1360, 1230, 1110, 930, and 750 cm−1. The peaks at 1644 and 1230 cm−1 are for the carbon-carbon double bond of the pyran ring and CO stretching of the cyclic ether. The most reliable and characteristic information regarding the structure of 2H-1-benzopyran is provided by 1H NMR. The assignment is as follows: δ 4.53 (q, 2H, 2-H), 5.38 (m, 1H, 3-H), 6.20 (m, 1H, 4-H), 6.60–7.13 (m, 4H, Ar-H). The pyran ring protons exhibited the following coupling: J1,2 = 3Hz; J4,2 = 2 Hz; J3,4 = 10 Hz. The 13C NMR data of 3,3-dimethyl-2H-chromene are as follows.982 13
C NMR (CDCl3) δ (ppm)
C-2, 76.05; C-3, 130.66; C-4, 122.29; C-5, 126.26; C-6, 120.65; C-7, 129.01; C-8, 116.28; C8a, 152.91; C4a, 121.24; 2CH3, 27.98
The mass spectrometry of 2H-1-benzopyran along with its fragmentation pattern is depicted in the following diagram. The base peak is the benzopyrylium cation, formed by loss of the hydrogen radical.
Mass fragmentation of 2H-1-benzopyran.
Importance in Natural Products, Medicines, and Materials A number of natural products like acetovanillochromene, ageratochromene, alloevodione, alloevodionol, euproeioxheomwnw, evodione, arahypin, xanthyletin, calanone, etc., isolated from plants, are 2H-chromene derivatives. The 2H-chromene nucleus, which is also present in a number of natural products like tannins and polyphenols,983 has been reported to possess antitumor984 and antibacterial activity.985 Although a large number of natural products with a 2H-chromene nucleus have been isolated and various synthetic derivatives have been prepared, this bicyclic heterocyclic received significant attention when two important 2H-chromene derivatives, precocene I and precocene II, isolated from Ageratum houstonianum were reported to induce precocious metamorphosis in a variety of insects.986 Since then a large number of natural products having a 2Hchromene nucleus have been isolated and identified. For example, acronycine is an antitumor drug,987 inophyllum B36 is an HIV-1 reverse transcriptase inibibitor,988 and robustic acid is a c-AMP inhibitor.989
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
257
Natural products containing 2H-Chromene nucleus.
A number of pharmaceuticals and some newly synthesized biologically active compounds have been reported to possess a 2H-chromene nucleus. For example, icaprim, an antibiotic used for skin infection,990 daurichromenic acid, a highly potent anti-HIV agent,991 and 6-fluoro-2H-chromene, exhibited the highest 5-HT1A receptor affinity among a series of 6-chromane derivatives.992 Similarly, a 4′-dehydroxyphlorizin derivative with a 6-substituted-2H-chromene unit was tested for potential antidiabetic activity as a Nac-glucose cotransported inhibitor.
Drugs containing 2H-chromene nucleus.
Synthesis993 1. Reaction of salicylaldehyde with triphenylvinylphosphonium yields 2H-chromene. The reaction involves Michael addition followed by Wittig reaction.994, 995
Reaction of sodium salt of salicylaldehyde with substituted allyltriphenylphosphonium bromide yielded 2H-1benzopyran derivative.996 The reaction involves the initial formation of a butadienyl phenolic product by Wittig reaction. This phenolic product undergoes nonreversible sigmatropic shift of phenolic hydrogen to give an intermediate methylene quinonoid compound, which undergoes instantaneous ring closure to give a benzopyran derivative.
258
2. Six-Membered Heterocycles
Ortho-formylation of p-hydroxybenzaldehyde after acetalization of the aldehyde followed by reaction with triphenylvinylphosphonium bromide yielded 2H-1-benzopyran-6-carboxyaldehyde.997
2. Petasis condensation: This reaction involves condensation of vinylic or aromatic boronic acid, aromatic aldehydes, and amines in the presence of a resin-bound amine yielding 2H-chromenes.998
3. Reaction of Grignard reagent with coumarin: Synthesis of 2,2-disubstituted 2H-1-benzopyran derivatives was reported by reaction of alkyl magnesium halide with coumarin. The reaction is thought to proceed by following the reaction pathway.999
The formation of pyrylium salt during the course of reaction was proved by reacting coumarin with 1 equivalent of Grignard reagent; pyrylium chloride was isolated after neutralization with hydrochloric acid.1000 However, the normal Grignard path was disapproved and a new mechanism was proposed, according to which reaction of Grignard reagent with coumarin led to opening of the ring, yielding an intermediate that undergo 1,4-addition before ring closure to chromene.1001
4. Dehydrohalogenation of 3,4-dihalochromans by treatment with sodium alkoxide in solvent under reflux condition yields 4-halo-2H-1-benzopyran.1002
Halogenation of chroman is accomplished with bromine in carbon tetrachloride or N-bromosuccinimide. Dehydrohalogenation is accomplished by heating of halochroman over sodium alkoxide or by treating with alkoxide in benzene under reflux conditions yielding 2H-1-benzopyran.1003, 1004
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
259
5. Dehydration: 4-Chromanones on reaction with Grignard reagent yields an alcoholic compound, which on dehydration with anhydrous copper acetate yields 2H-1-benzopyran along with alkylidene chroman as a side product.1005, 1006
6. Condensation reaction: Isobutylene and 2-chloro-2-methylpentane react with salicylaldehyde in the presence of silica-alumina (150°C) or zinc chloride (75°C) to yield 2H-1-benzopyran derivative. The reaction is thought to proceed with the formation of chromanol, which is then dehydrated.1007
7. Thermal rearrangement: Thermal cyclization of aryl propargyl ethers (prepared by alkylation of appropriate phenol with halogenated alkyne) effected regioselective orthocyclization yielding 2H-chromene derivatives.1008
8. 1,3-Michael-Claisen annulation reaction: Precocene II, a molecule showing antijuvenile activity was synthesized from α-methylene-δ,δ-dimethyl-δ-valerolactone. Michael addition of thioacetal anion to lactone followed by cyclization of the resulting adduct with ZnCl2 afforded tetrahydrochroman. Transacetalization was carried out using Fujita’s condition, yielding a product that was aromatized with p-TsOH. Methylation of the resulting phenol with methylsulfate and dehydrogenation with DDQ yielded precocene II.1009
260
2. Six-Membered Heterocycles
9. Ring-closing metathesis: Substituted phenol was initially converted to its corresponding aryl allyl ether which undergoes thermal Claisen rearrangement to afford o-allylphenol. In the next step, terminal alkene was isomerized to internal alkene in the presence of ruthenium-based catalyst yielding a mixture of E and Z isomers, in which the E isomer predominates. O-Allylation afforded the 1-alloyloxy-2-(prop-1-enyl)benzene. This compound underwent ring-closing metathesis in the presence of Grubbs second-generation catalyst yielding the 2H-chromene derivative.1010
An atom-economical and environmentally friendly FeCl3-catalyzed intramolecular alkyne-aldehyde metathesis process for the synthesis of functionalized 2H-chromene derivatives from readily available alkynyl ethers of salicylaldehyde derivatives has been reported.1011
A Novel cobalt-catalyzed reaction between salicyl-N-tosylhydrazones and terminal alkynes that led to the generation of 2H chromenes has been reported.1012
An efficient gold-catalyzed method for the synthesis of 2H-chromene has been reported. Monoallylic diols (prepared from salicylaldehyde) undergo exo-cyclization in the presence of Au(I) catalyst yielding the title compound.1013
Gold-catalyzed cycloisomerization of substituted aryl propargyl ethers yields substituted 2H-chromenes. According to the proposed mechanism, a hydroarylation reaction is initiated by addition of gold(I) catalyst. As a result of high aurophicity of alkyne moiety the aryl propargyl ether is activated by gold(I) metal to form the auropropargyl complex (I), which undergoes endo-selective hydroarylation to form the Wheland-type intermediate (II). Release of gold (I) catalyst affords the 2H-chromene derivative.1014–1016
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
261
An aldol-type condensation reaction between 3-methoxyphenol, 3,3-dimethylacrylaldehyde, and phenylboronic acid afforded cyclic borate, which on heating undergoes elimination reaction to yield o-quinone methide, which undergoes electrocyclization reaction to produce 2H-chromene derivative.1017, 1018
10. Enantioselective organocatalytic 2H-chromene synthesis: The first organocatalytic asymmetric synthesis of benzopyrans via one-pot oxa-Michael addition followed by intramolecular aldol condensation between salicylaldehyde and α,β-unsaturated aldehyde was reported by Ardidsson et al. The reaction used diphenylprolinol trimethylsilyl ether as catalyst.1019
Synthesis of 2-substituted 2H-chromene-3-carbaldehyde was carried out by adopting a domino oxa-Michael/ aldol condensation reaction using diphenylprolinol trimethylsilyl ether as catalyst.1020 Synthesis of chiral chromenes employing (S)-diphenylprolinol triethylsilyl ether as chiral organocatalyst and benzoic acid as co-catalyst works well with salicylaldehyde and trans-cinnamaldehyde.1021 The nitrochromenes were synthesized by one-pot enantioselective oxa-Michael/aza-Henry condensation between salicylaldehyde and nitro-olefins using chiral secondary amine as organocatalyst and salicylic acid as co-catalyst.1022
Palladium-catalyzed asymmetric allylic alkylation of phenol allyl carbonates in an intermolecular fashion led to enantioselctive formation of the allylic CO bond, followed by cyclization to provide chiral chromans, which on subsequent oxidation yield chiral chromene.1023
262
2. Six-Membered Heterocycles
Synthesis of 3-nitro-2H-chromene via enantioselective tandem oxa-Michael/Henry reaction using chiral amine is established1024 Another effective method for synthesis of optically active 2H-chromene derivative involving kinetic resolution has been reported.1025 The reaction involves the use of chiral thiourea-derived Takemoto’s catalyst, which undergoes selective asymmetric formal [2+2] cycloaddition of azomethine ylide with one enantiomer of nitrochromene leaving behind the other enantiomer.
Physical Properties 2H-1-Benzopyran is a liquid with a bp of 92°C/15 mm and nD251.5551, d4161.0993. Chemical Reactivity 1. Oxidation: Treatment of 2H-chromene with [hydroxyl(toxyloxy)iodo]benzene (HTIB) in methanol introduced a methoxy group at the C-4-position yielding a 4H-chromene derivative.1026
Reaction of 2H-chromene with osmium tetroxide and peroxide in anhydrous ether or cold (−15 to −20°C) dilute potassium permanganate afforded cis-glycol,1027, 1028 while treatment with hydrogen peroxide in formic acid produced trans-glycol.1029
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
263
Reaction of 2H-chromene derivative with 5% perbenzoic acid in chloroform over a period of 4 h causes epoxidation.1030
Epoxidation of 2H-1-benzopyran can be achieved in chloroform by using perbenzoic acid.1031–1033
2. Reduction: Hydrogenation of a nonaromatic double bond of the pyran ring has been accomplished with a variety of reagents. The most commonly used catalysts are palladium on charcoal, platinum, and Raney nickel. Palladium on charcoal has been used with methanol, ethanol, acetic acid, and ethyl acetate as solvent. When hydrogenation is carried out with palladium on charcoal in ethanol, debenzylation of the ether group also takes place.1034
Lithium aluminum hydride in tetrahydropyran reduces the pyran double bond as well as amide group of 2H-1-benzopyran-3-carboxamide.1035
Reaction of 3-nitrochromene with sodium borohydride and hydrazine hydrate in the presence of Raney nickel and propyl iodide yielded 3-N,N-dipropylaminochromane, which showed anxiolytic activity.1036
Birch reduction of a 2H-chromene derivative by series of single electron transfer processes led to opening of the ring to yield o-prenylated phenols.1037
3. Addition reactions: Addition of chlorine is accomplished by bubbling chlorine gas through an ice-cold solution of 2H-chromene derivative in chloroform.1038
264
2. Six-Membered Heterocycles
Treating 2,2-dimethyl 2H-1-chromene with saturated bromine water solution led to the synthesis of bromo derivative 4-bromo-3-hydroxy-2,2-dimethyl chroman.1039
Addition of MeOBr also takes place when methyl 2H-1-benzopyran-3-carboxylate is treated with a methanolic solution of N-bromosuccinimide.1040
Isobutyraldehyde added to 3-nitrochromene in the presence of racemic proline and sodium acetate yielded trans-chromanes.1041
The addition of benzyl-2-ketopentanoate to 2H-1-chromene in the presence of Takemoto’s chiral catalyst yields an antiisomer of keto ester with 97% enantiomeric excess.1042
The asymmetric nucleophilic addition of dimethylmalonate to 2H-chromene in the presence of Takemoto’s chiral reagent provides trans-diastereomer in high yield and in high enantiomeric excess.1043, 1044
Carbene addition: When 2-methyl-2H-1-benzopyran is treated with sodium methoxide and ethyl trichloroacetate, addition of dichlorocarbene from a less hindered side takes place leading to the generation of a dichlorocyclopropane derivative of benzopyran.1045, 1046
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
265
4. Nitration: Selective nitration of the double bond in 2H-chromene is achieved by successive treatment with nitrogen monoxide at room temperature, followed by dehydration of the intermediate nitrochromanol by boiling over acidic alumina for 30 minutes in dichloroethane.1047
5. Photochemical reaction: Irradiation of 2,2-dimethyl-2H-1-benzopyran in methanol yielded o-quinoneallide, which is unstable and decomposes to give different phenolic products depending on the reaction conditions.1048
2.7.3 4H-1-Benzopyran (4H-Chromene)
4H-Benzo[b]pyran is a bicyclic, nonconjugated, unsaturated oxygen heterocycle, constituted by fusion of the benzene ring with the “b” site of the 4H-pyran ring. Because the benzene ring is not in conjugation with the pyran ring and does not meet the criteria of Hückel’s rule of the (4n+2π) electron system for aromaticity it is neither a true aromatic nor aliphatic. Structural and Reactivity Aspects Since the carbon-carbon double bond of the pyran ring of 4H-1-benzopyran is not in conjugation with the benzene ring, its ultraviolet spectrum should be similar to that of substituted benzenes. The ultraviolet spectrum of substituted 4H-1-benzopyran showed three absorptions at 212, 278, and 284 nm. All these bands are due to π→π* transition.1049 The infrared spectrum of 4H-1-benzopyran showed absorptions at 1665, 1580, 1490, 1273, 1050, and 755 cm−1. The carbon-carbon double bond stretching at 1665 cm−1 is observed at a higher frequency in comparison to 2H-1benzopyran. Pyran aromatic ether1050 CO stretching is also observed at higher frequencies of 1273 and 1050 cm−1. The most reliable and characteristic information on the structure of 4H-1-benzopyran is provided by the 1H NMR spectrum.1051 The assignment is as follows: δ 3.36 (q, 2H, 4-H, J4,4 = 0.6 Hz), 4.83 (sextet, 1H, 3-H, J3,4 = 2.0 Hz, J2,3 = 6.4 Hz), 6.44 (sextet, 1H, 2-H, J2,4 = 3.6 Hz), and 6.90 (4H, Ar-H).
266
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials A large number of natural products with a 4H-chromene nucleus have been isolated and a large number of their synthetic derivatives have been prepared. For example, 7-hydroxy-6-methoxy-4H-chromene, which was isolated from the plant Wisteria sinensis along with related compound 6,7-dimethoxy-4H-chromene, was reported to be having interesting organoleptic properties.1052 This compound has also been efficiently synthesized.
Natural products containing 4H-chromene nucleus.
Another naturally occurring 4H-chromene is uvafzlelin, isolated from the stems of Uvaria ufielii, which show broad-spectrum antimicrobial activity against Gram-positive and acid-fast bacteria.1053 In recent years a number of 4H-chromenes and their derivatives have attracted great interest because a number of these compounds have exhibited diverse pharmacological properties such as antimicrobial, antiangiogenesis, antioxidant, antitumor, and anticancer activities.1054–1059
Different biological activity exhibited by differently functionalized 4H-chromene skeleton.
Synthesis 1. When 2-hydroxymethylcoumaran is heated at 300–400°C, 4H-chromene is obtained along with 2-methylcoumarone.1060
2. Chromone-2-carboxylic acid on boiling with an excess of thionyl chloride gives 4,4-dichloro-4H-chromene.1061
3. From phenols: o-Allyl phenol was initially obtained from its corresponding aryl allyl ether by thermal Claisen rearrangement. This compound in the presence of copper acetate was then converted to its respective aryl vinyl ether. Then ruthenium-mediated ring-closing metathesis yielded the 4H-chromene derivative.1062
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
267
Phenols substituted with a 3-keto substituent on heating with a catalytic amount of acid catalyst in acetic anhydride yield 4H-chromene derivative.1063, 1064
Reaction of resorcinol with acetylacetone in the presence of concentrated hydrochloric acid or sulfuric acid yields 4-methylene-4H-1-benzopyran.1065, 1066
4. 2-Amino-3-cyano-4H-chromene scaffold has received increasing attention during the last few years due to diverse biological activities. One-pot, three-component reaction of aromatic aldehyde, malononitrile, and resorcinol in refluxing ethanol in the presence of Rochelle salt as a novel green heterogeneous and reusable catalyst led to the synthesis of 4H-chromene derivative. This compound has also been synthesized by using modified mesolite-type natural zeolite as green catalyst.1067
Atom-efficient condensation reaction between malononitrile and 2-hydroxybenzaldehyde in the presence of triethylamine or indium chloride yields an imine intermediate, which can be trapped with thiophenol to yield 2-amino-4-(phenylsulfanyl)-4H-chromene-3-carbonitrile or reduced with Hantzsch dihydropyridine ester to yield unsubstituted 2-amino-3-cyano-4H-chromene.
Enantioselective synthesis of a 4-substituted chromene derivative has been reported. The process involves treating E-2-(2-nitrovinyl)phenol with malononitrile in diethyl ether at room temperature in the presence of thiourea-based catalyst, which yields the 4H-chromene derivative in moderate enantiomeric excess.1068
268
2. Six-Membered Heterocycles
A number of methods have been reported for increasing the yield of the title compound.1069–1072 5. Reduction of the double bond and carbonyl group of coumarin with H2/Pd-C followed by DIBAL-H yielded an alcoholic derivative, which on dehydration with oxalic acid yielded a 4H-chromene derivative.1073
Reaction of coumarin with sodium ethoxide yields 2-hydroxycinnamate. Conjugate addition of ethyl cyanoacetate generates an intermediate that undergoes cyclization to ethyl 2-amino-3-ethoxycarbonyl-4H-4-chromenylacetate.
Heating acetyloxychromans in a vacuum at high temperature (450–700°C) yields 4H-1-benzopyran.1074
Similarly, pyrolysis of acetate ester of 2- or 3-chromanol yielded 4H-1-benzopyran.1050, 1051
Heating 3-chromanol or its methyl ester with a catalytic amount of polyphosphoric acid yields 4H-1-benzopyran.1075
Physical Properties 4H-1-Benzopyran is a liquid with a bp of 77°C/9 mm, 44°C/1.3 mm, and nD25 1.5551. Chemical Reactivity 1. Addition reaction (a) Addition of halogen: Addition of bromine to 4H-chromene takes place to yield dibromo derivative, but this product could not be isolated because it decomposes spontaneously to yield halobenzopyran.1060, 1076, 1077
(b) Addition of alcohol: By treatment of a solution of 4H-chromene in alcohol with a trace of acid, carbocation is formed as an intermediate, which reacts further with alcohol to yield an ether derivative.1060, 1076
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
269
(c) Addition of water takes place by treating 4H-chromene derivative with 1N H2SO4 solution. The addition takes place according to the Markovnikov rule.1076
(d) Reaction of 4H-chromene with diborane followed by alkaline oxidation led to the addition of water by following the anti-Markovnikov rule.1078
(e) Addition of carbene: Reaction of 4H-chromene with dichlorocarbene affords 1,1-dichloro-1a,7a-dihydro-4Hbenzo[b]cyclopropa[e]pyran in good yield.
2. Reaction with Grignard reagent: 4H-Chromene on reaction with bromine followed by treatment with phenyl magnesium bromide yields 2-bromo-1-(2-hydroxyphenyl)-3-phenylpropan-3-ol, which on heating with p-toluenesulfonic acid yielded trans-3-bromo-flavan. This on treatment with methanolic KOH afforded 2H-chromene.1079
3. Oxidation: Reaction of 2-phenyl-4H-chromene with potassium permanganate in acetone affords 2-phenyl-4H-chromone.
2.7.4 Benzopyrylium Salts Benzopyrylium salts are pyrylium salt derivatives in which a benzene ring is fused to a pyrylium cation. All together there are two benzopyrylium derivatives, namely benzo[b]pyrylium (chromylium or 1-benzopyrylium) and benzo[c]pyrylium (isochromylium or 2-benzopyrylium) salts.
270
2. Six-Membered Heterocycles
Structural and Reactivity Aspects1080a The positive charge of the 1-benzopyrylium salt is distributed unevenly over the heterocyclic ring. As a result, the following resonance structures are possible.
Resonanting structures of 1-benzopyrylium salt.
2-Benzopyrylium salt is represented by the following two mesomeric structures.
Resonanting structure of 2-benzopyrylium salt.
The 1H NMR data of 1-benzopyrylium trifluoromethanesulfonate are given in the following table. H spectral data of 1-benzopyrylium salt
1
1-Benzopyrylium H-1, 9.87; H-3, 8.13; H-4, 9.72
The 13C NMR data of 2-phenyl 1-benzopyrylium perchlorate and 2-benzopyrylium salt are given in the following table. C NMR spectral data of 1- and 2-benzopyrylium salt
13
1-Benzopyrylium
2-Benzopyrylium
C-2, 176.8; C-3, 118.6; C-4, 150.0; C-4a, 127.5; C-8a, 157.7
C-1, 174.0; C-3, 149.7; C-4, 116.4; C-4a, 140.7; C-8a, 118.0
Because 1-benzopyrylium salts are colored, their UV/Vis maxima are usually quite intense and observed around >350 nm. Importance in Natural Products, Medicines, and Materials 1-Benzopyrylium is of great value because this structural subunit is the aglycon part (commonly called anthocyanidins) of the anthocyanins—the plant pigments responsible for the large variety of colors of flowers, fruits, and leaves. The most common 1-benzopyrylium derivative present in plants is its 2-phenyl derivative commonly called flavylium chloride. Some selected anthocyanidins and the color they impart to flowers/fruits are shown in the following table. Anthocycnidins and the colour they impart Anthocyanidin
Color
Cyanidin
Magenta
Delphinidin
Purple, blue
Pelargonidin
Orange
Malvidin
Purple
Peonidin
Magenta
Structures of some common 1-benzopyrylium salts.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
271
2-Benzopyrylium salts are not found in nature. However, their application lies in their transformation to isoquinoline derivatives. Synthesis 1. Unsubstituted 2-benzopyrylium cation was synthesized in two steps. In the first step, oxidation of indene affords homophthalic dialdehyde. In the second step, the dialdehyde is cyclized to 2-benzopyrylium tetrachloroferrate by treating it with hydrochloric acid and ferric chloride.1080b
2. Reaction of dialkoxycarbocation (formed by reaction of acetals with triphenylmethyl perchlorate) with benzyl ketone leads to the generation of 2-benzopyrylium salt.1081
3. Reaction of resorcinol with acetylacetone in the presence of hydrochloric acid affords 1-benzopyrylium ion.1082
4. Condensation of o-hydroxybenzaldehyde with reactive methylene compounds such as acetophenone in ethyl acetate solution, which is saturated with hydrogen chloride, affords an important benzopyrylium ion-flavylium chloride.1083 The reaction is thought to proceed with the formation of o-hydroxychalcone as intermediate.
5. Condensation of resorcinol with α,β-ethylenic ketone like cinnamyl phenyl ketone in the presence of oxidizing agent such as chloranil affords 1-benzopyrylium salt.
1-Benzopyrylium salts are also synthesized by condensation of resorcinol with phenyl ethynyl ketone in the presence of hydrochloric acid.1084
272
2. Six-Membered Heterocycles
6. Refluxing 1,1,3,3-tetraethoxypropane (bis-acetal of malondialdehyde) with o-cresol in the presence of stannic chloride in toluene affords acetal ether, which in the presence of acetic acid and perchloric acid yields hetero ring-unsubstituted benzopyrylium salt.
7. Addition to carbonyl oxygen: Carbonyl oxygen of chromone undergoes protonation to produce hydroxybenzopyrilium salt. Thus reaction of chromone in ether with hydrogen chloride leads to the precipitation of chromone hydrochloride (4-hydroxy-1-benzopyrilium chloride).
In comparison to chromone the carbonyl oxygen of coumarin is less readily protonated. However, reactive electrophiles like Meerwein’s salt ([Et3O]BF4) attack carbonyl oxygen of coumarin, yielding 2-alkylated benzopyrylium ion.
Coumarin reacts with aromatic compounds in the presence of phosphoryl chloride alone or with zinc chloride to yield benzopyrylium ion.1085, 1086
Coumarin reacts with Grignard reagent to form benzopyrylium ion.
Chemical Reactivity 1. Ring-opening reaction: Benzopyrylium salt on heating in aqueous alkali resulted in the ring opening of the heterocyclic ring followed by carbon-carbon bond cleavage.
2. Reaction with amines: 2-Benzopyrylium salt reacts with ammonia to afford isoquinoline derivative or isoquinolium salts.1087
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
273
Reaction of 2-benzopyrylium ion with aniline resulted in the formation of 2-phenyl-3-methyl-6,7- dimethoxyisoquinolinium perchlorate. However, on reaction with ethylenediamine, bis-cations are formed.1088
1-Benzopyrylium salts on reaction with amines form C-2 and C-4 derivatives. For example, 1-benzopyrylium salt reacts with piperidine to form 2H and 4H adducts. This reaction is, however, reversible in acidic medium.
1-Benzopyrylium salt reacts with an ethereal solution of dimethylaniline to afford a colorless compound N,Ndimethyl-4-(2-phenyl-4H-chromen-4-yl)aniline, which on oxidation yielded carbinol.1089
3. Reduction: Catalytic reduction of 1-benzopyrylium salts results in saturation of the double bond in the heterocyclic ring.
4. Oxidation: Ozonolysis of 3-methoxy-4′-bromoflavylium chloride in glacial acetic acid followed by decomposition of the ozonide with water and zinc dust afforded salicylaldehyde, p-bromobenzoic acid, and methyl 2-(2-methoxy-2-oxoethyl)phenyl 4-bromobenzoate.1090
274
2. Six-Membered Heterocycles
5. Benzopyrylium salt on reaction with tertiary benzenoid amine forms flavylium salts, which on warming with pyridine forms flavones.
6. Reaction with carbon nucleophiles: Malononitrile adds to 1-benzopyrylium salts in the presence of triethylamine affording 4-substituted chromene derivatives.
When benzopyrylium salt is generated by O-silylation of chromone on reaction with silyl enol ethers or allylsilanes, addition takes place at the C-2-position.
2-Benzopyrylium perchlorate on reaction with aqueous sodium cyanide in the presence of diethyl ether yielded stable, colorless cyanoisochromene derivatives.1091
2.7.5 Chroman (2,3-Dihydro-2H-1-Benzopyran)
Chroman or 3,4-dihydro-2H-1-benzopyran or benzodihydropyran is a bicyclic oxygen heterocycle resulting from the fusion of the benzene ring with the “b” (2,3) site of dihydropyran. Structural and Reactivity Aspects1092 The 1H and 13C NMR spectral data of chroman are given in the following table.1092 H and 13C NMR spectral data of chroman
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.82; H-3, 1.70; H-4, 2.28
C-2, 74.0; C-3, 32.8; C-4, 22.6; C-5a, 121.7; C-8a, 147.5
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
275
Importance in Natural Products, Medicines, and Materials Though chroman as an independent unit it is not found in nature; however, this important scaffold is present in many natural products like vitamin E (all tocopherol, tocotrienol, and tocomonoenol derivatives). This nucleus is also present in many clinically used drugs like troglitazone, nebivolol, Trolox, and ormiloxifene.
Vitamin and drugs containing chroman nucleus.
Chromans are also important synthons that are associated with a wide variety of biological activities like neuroprotective,1093 antiestrogen,1094 antioxidant,1095 anti-HIV,1096 and antibreast cancer agents.1097 Synthesis1098a 1. Chroman was first prepared by warming an alkaline solution of 2-(3-chloropropyl) phenol.1098b However, chroman in high yield and in purified form by distillation from sodium was obtained by cyclization of 1-phenyl-3-chloropropoxybenzene.1099
2. Heating coumarin over copper chromate at 250°C yields 2-(3-hydroxypropyl)phenol, which on reaction with phosphorous tribromide in benzene yields 2-(3-bromopropyl)phenol. Warming an aqueous sodium hydroxide solution of 2-(3-bromopropyl)phenol yields chroman.1100
3. Freshly prepared 1,3-diphenoxypropane, when heated with aluminum chloride in boiling benzene, gives chroman.
Similarly, 6-methylchroman was also obtained by reaction of appropriate 1,3-di(p-tolyloxy)propane with aluminum chloride in boiling benzene.1101
276
2. Six-Membered Heterocycles
4. Reaction of an acetyl derivative of allyl phenol with hydrogen bromide in the presence of benzoyl peroxide yields chroman.
5. Grignard reagent on reaction with 3,4-dihydrocoumarin afforded tert-alcohol through ring fission, which underwent ring closure to generate 2,2-dialkyl chroman.1102
6. Domino reaction: The synthesis of chroman derivative involves a reaction of salicyl N-thiophosphinylimines and ethyl 2,3-pentadionate in the presence of triphenylphosphine or (2′-hydroxylbiphenyl-2-yl)diethylphosphane (LBBA) as catalyst. The reaction is the first example of ϒ-CH3 of allenoate undergoing cyclization to chroman derivatives.1103a
7. Allenylidene-ene process: A novel method for the synthesis of chiral chromanes has been reported.1103b The process involves heating propargylic alcohol bearing an (E)-alkene moiety in 1,2-dichloroethane in the presence of an optically active thiolate-bridged diruthenium complex and NH4BF4 yielding 4-ethynyl-3-(1-phenylethenyl) chromane as a mixture of two diastereomers, the syn-isomer with 93% enantiomeric excess being the major and the anti-isomer being the minor.
8. A new method for the synthesis of 2-substituted and 2,2-disubstituted chromans using a Pd-catalyzed carboetherification reaction between aryl/alkenyl halides and 2-(but-3-en-1-yl)phenols has been reported. In this reaction, formation of a new CO and CC bond takes place leading to the generation of chroman in good yield.1104a
Palladium-catalyzed asymmetric allylic alkylation of phenol allyl carbonates in an intermolecular fashion led to enantioselective formation of the allylic CO bond, which was followed by cyclization to provide chiral chromans.1104b
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
277
9. A novel method for direct access to chromans has been accomplished by carrying out allylic oxidation of phenols with terminal olefins in the presence of a combination of Pd(II)/bis-sulfoxide CH activation and Lewis acid co-catalysis.1105
Physical Properties Chroman is a colorless, steam volatile, oily liquid with a bp of 214°C/742 mm, d20 1.0610, and nD20 1.544, with a peppermint-like odor. It is soluble in nearly all organic solvents. Chroman gives a red color with sulfuric acid. Chemical Reactivity 1. Alkylation: A number of 4-alkylchromans have been synthesized by reacting 4-bromochroman with appropriate Grignard reagent. 4-Bromochroman is, however, prepared by treating chroman with N-bromosuccinimide.
2. Friedel-Crafts acylation: Reaction of chroman with veratroyl chloride (3,4-dimethoxybenzoyl chloride) in the presence of Lewis acid catalyst yields 6-veratroyl chroman.1106
3. Reduction: Chroman is reduced with lithium in 1:1 (by volume) of dry ethylamine and dimethylamine to 3,4,5,6,7,8-hexahydrochroman in 85% yield, which reacts with perphthalic acid in moist ether to give trans diol, which is cleaved with lead tetraacetate to yield 6-oxononanolide.1107
4. Gas-phase pyrolysis of chroman at 413°C gave a mixture of o-cresol, benzofuran, and styrene in a ratio of 4:2:1.1108
278
2. Six-Membered Heterocycles
However, pyrolysis of chroman over alumina at 250°C gave only 2,3-dihydro-2-methylbenzo[b]furan in 10% yield.
5. Thermal decomposition: Gas-phase thermal decomposition of chroman has been studied between 760 and 1110 K. Decomposition starts with the elimination of ethene leading to the formation of 6-methylene-2,4-cyclohexadien1-one (o-quinone methide). Quinone methides are important intermediates in the chemistry of lignin. At high temperature (860–980 K) quinone methide decomposes into CO, benzene, and a small amount of fulvene.1109
2.7.6 Coumarin
Coumarin is a fragrant chemical compound belonging to the benzopyrone family. The term coumarin comes from the French term coumarou meaning tonka beans, from which it was first isolated. Structural and Reactivity Aspects1110a X-ray analysis of coumarin suggests it to be a planar compound. The bond angles (in degrees) and bond lengths (in pm) of coumarin as derived from X-ray analysis are given in the following diagram.
Bond lengths and bond angles of coumarin.
The UV absorption spectrum of coumarin is quite helpful in distinguishing it from other chromones. Chromones show one strong absorption band at 240–250 nm (log ε 3.8), whereas coumarins show two strong absorption bands at 274 and 311 nm (log ε 4.03 and 3.72), which are attributed to the benzene and pyrone rings.1110b The δ-lactone carbonyl stretching frequency of coumarin is usually observed in the region 1720–1750 cm−1. In contrast to other isomeric chromones, the IR spectrum of coumarin normally shows three strong absorption bands in the region 1600–1660 cm−1, due to CC stretching.1111, 1112
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
279
The 1H and 13C NMR data of coumarin confirm it to be a 2H-pyran-2-one derivative. The 1H NMR data further suggest that coumarin has an enol lactone character rather than that of heteroarene. The 1H and 13C NMR data of coumarin are given in the following table. H and 13C NMR spectral data of coumarin
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-3, 6.43; H-4, 7.80; H-5, 7.36; H-6, 7.22; H-7, 7.45; H-8, 7.20
C-2, 159.6; C-3, 115.7; C-4, 142.7; C-4a, 118.8; C-8a, 153.1
The mass fragmentation pattern of coumarin is shown in the following diagram. It involves loss of CO from the carbonyl group, a characteristic feature of coumarins. The benzofuran ion is further decomposed by consecutive loss of CO and the hydrogen atom.1113
Mass fragmentation pattern of coumarin.
Importance in Natural Products, Medicines, and Materials Coumarins constitute a class of naturally occurring oxygen ring compounds that are structural subunits of a number of more complex natural products. Coumarin itself was first isolated in 1822 from tonka beans, coumarins, which have been found to play an important role in plant biochemistry and are also involved in the actions of plant growth hormones and growth regulators, control of respiration, photosynthesis, as well as defense against infections.1114 A number of naturally occurring organic compounds containing coumarin moiety have been found to exhibit useful applications. Calanolide A1115, 1116 is a novel nonnucleoside reverse transcriptase inhibitor with potent activity against HIV-1. Inophyllum B has also been found to be an active component for inhibition against HIV-reverse transcriptase.1117 (+)-Cordatolide A is also a novel coumarin, and its structure and properties are similar to (+)-calanolide.1118Ayapin, also a coumarin derivative, has been reported to have pronounced blood thinning or anticoagulant property.1119
Biologically active natural products containing coumarin nucleus.
Molecules possessing the coumarin nucleus have been found to display a wide range of interesting properties—a number of them are highly colored, strongly absorbing in the UV region and exhibiting potent fluorescence and luminescence.1120–1122 Besides, a number of biological activities have been attributed to this nucleus and it is thus considered an attractive drug scaffold used in the treatment of viral infection,1123 neurodegenerative diseases,1124, 1125 edema,1126 inflammation, and as a hepatoprotective and antioxidant agent.1127 A number of coumarin derivatives are already being used as drugs, for example, vitamin K antagonists (warfarin), anticoagulants (phenprocoumon), antibiotics (novobiocin), antispasmodics (hymecromone), and coronary vasodilators (carbochromen).
280
2. Six-Membered Heterocycles
Drugs containing coumarin nucleus.
Synthesis1128 1. Perkin reaction: Coumarin was synthesized by the Perkin method by heating salicylaldehyde with acetic anhydride and anhydrous sodium acetate.
2. Pechmann coumarin synthesis: Pechmann reaction involves condensation of phenol with β-keto ester in the presence of sulfuric acid or Lewis acid yielding coumarin.1129, 1130
The reaction proceeds by the following mechanism.
A method has been developed for the synthesis of coumarin via Pechmann reaction catalyzed by montmorillonite K-10 or KSF in yields up to 96%. The advantage of this procedure is that it is environmentally friendly and inexpensive, with easy separation of the product and recyclability of the catalyst.1131
The use of cation exchange resins Zeokarb 225 and Amberlite IR 120 as condensing agents in the synthesis of coumarins has been reported. The reaction takes place in the following steps: (1) addition across the double bond of the enolic form of β-keto ester, (2) ring closure, and (3) dehydration.1132, 1133
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
281
Microwave-assisted Pechmann reaction has been developed for the synthesis of coumarins from substituted phenols and methylacetate in the presence of sulfuric acid. This protocol reduced the reaction period from several hours to a few minutes.1134 A convenient microwave-assisted one-pot synthesis of coumarin under Pechmann reaction conditions using different catalysts like FeF3, Sm(NO3)3, and TiCl4 under solvent-free conditions has also been reported.1135–1137 3. Claisen rearrangement: To overcome the difficulties encountered with Pechmann synthesis, a new application of Claisen rearrangement was developed using allyl or propargyl aryl ethers, in which allylic or propargylic αcarbon was oxygenated. This method has been applied in cases where coumarin synthesis could not be achieved by Pechmann reaction. The reaction involves rearrangement of α-oxygenated allyl aryl ethers. The intermediate alkoxychroman obtained was then oxidized to coumarin.1138
4. Knoevenagel reaction: Condensation of 2-hydroxybenzaldehyde with compounds having active methylene groups (like malonic acid, malonic ester, cyanoacetic ester) in the presence of amine resulted in the formation of coumarins.1139, 1140
Two different mechanisms have been proposed for this reaction.1141 According to first mechanism, the formation of imine or iminium salt with amine, followed by reaction with the enolate of a reactive methylene compound and elimination of amine, followed by ring closure, yields coumarin.
In the second mechanism, carbanion produced by deprotonation of the reactive methylene compound by amine attacks the carbonyl group to yield an intermediate. Proton transfer and ring closure via acyl substitution, followed by dehydration, yields coumarin.
282
2. Six-Membered Heterocycles
The yield of coumarin derivatives by Knoevenagel condensation reaction is low. Attempts have been made by increasing the yield up to 94% by carrying out Knoevenagel condensation under microwave conditions.1142 A procedure for preparing coumarin-3-carboxylic acid by stirring salicyladehyde and Meldrum’s acid using a catalytic amount of potassium phosphate has been reported.1143 Coumarin-3-carboxylic acid has also been synthesized by reacting malononitrile with an aldehyde or ketone in the presence of piperidine.1144
A solid-phase synthesis of coumarin-3-carboxylic acid derivatives using Knoevenagel condensation between ethyl malonate bound to Wang resin and o-hydroxybenzaldehydes in the presence of pyridine and piperidine at room temperature has been discovered.1145
Iodocoumarin derivatives were synthesized by condensation of 3,5-diiodosalicylaldehyde with active methylene compounds (ethyl acetoacetate, malononitrile, ethyl cyanoacetate) in the presence of piperidine as catalyst. In this reaction, 3-substituted coumarins were obtained in excellent yield. When acetic acid was used as an active methylene compound in the presence of sodium acetate, unsubstituted coumarin was obtained.1146
Ultrasound-promoted synthesis of coumarin-3-carboxylic acid by reaction of substituted o-hydroxybenzaldehyde with Meldrum’s acid has also been reported.1147 5. Wittig reaction: A novel one-pot synthesis of coumarins via intramolecular Wittig cyclization involving reaction of o-hydroxybenzaldehydes with phosphonium ylides [phosphorane, (ethoxycarbonymethylene)triphenylphosphorane] has been reported. The reaction primarily takes place through a betaine and/or oxyphosphetane intermediate.1148, 1149
A novel Wittig reaction involving an ortho-carbonyl compound and triphenyl(α-carboxymethylene)phosphorane imidazolide has also been reported.1150
A novel route to the synthesis of 4-carboxymethylcoumarin involving electrophilic substitution reaction between the conjugate base of a substituted phenol and the betaine formed by the addition of triphenylphospine to dimethyl acetylenedicarboxylate (DMAD) has also been reported.1151 Coumarins have also been synthesized by involving a one-pot reaction of o-hydroxy- benzaldehyde, ethyl 2-bromoacetate, and triphenylphosphine in the presence of a catalytic amount of triethylamine in ethyl acetate, water, or under solvent-free conditions.1152 A simple, efficient, and inexpensive method involving intramolecular
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
283
Wittig reaction of substituted 2-formylphenyl 2-bromoacetate with triphenylphosphine in saturated aqueous sodium bicarbonate at ambient temperature has been developed.1153
6. Reformatsky reaction: Condensation of aldehydes or ketones with an organozinc derivative of α-halo esters yielding β-hydroxy esters is known as Reformatsky reaction. However, under appropriate conditions, lactonization could take place leading to the formation of coumarins.
Sodium telluride-triggered cyclization of the bromoacetate of salicylaldehyde to coumarin via modified Reformatsky reaction has been achieved. The cyclization proceeds by formation of the phenolate ester enolate, which attacks the ortho-carbonyl group leading to cyclization.1154
7. Palladium-catalyzed synthesis: Reaction between substituted phenol and an alkyne in the presence of palladium(0) complex as catalyst has been reported. In the presence of formic acid, palladium(II) acetate is reduced to Pd(0), which then catalyzes the reaction. Cis addition initially affords (E)-cinnamic ester, and E-Z isomerization accounts for the isolation of coumarin rather than E-cinnamete.1155
3-Substituted coumarins have been synthesized by adopting Heck’s reaction conditions. The reaction involves treating 3-bromocoumarin with alkenes and alkynes in the presence of palladium catalyst.1156
284
2. Six-Membered Heterocycles
Physical Properties Coumarin is a colorless or white crystalline solid with a vanilla beanlike odor, mp 71°C. It is soluble in chloroform, ethanol, and ether. Chemical Reactivity 1. Compared to chromone the carbonyl oxygen of coumarin is less readily protonated. However, reactive electrophiles like Meerwein’s salt ([Et3O]BF4) attack the carbonyl oxygen of coumarin, yielding benzopyrylium ion.
Coumarin reacts with aromatics containing electron-withdrawing groups in the presence of phosphoryl chloride alone or with zinc chloride to yield benzopyrylium ion.1157, 1158
2. Coumarin on reaction with bromine undergoes addition reaction to give 3,4-dibromo-3,4-dihydrocoumarin, which on reaction with KOH undergoes Perkin-type rearrangement to give benzo[f]furan. Treating coumarin dibromide with alcoholic potassium hydroxide followed by acidification with hydrochloric acid yielded coumarilic acid.1159 The dibromo derivative also undergoes elimination of HBr by the action of a base leading to the formation of 3-bromocoumarin.1159
Chloromethylation of coumarin, carried out by treating it with a solution of coumarin in acetic acid with formaldehyde and hydrogen chloride, produced 3-chloromethyl coumarin.1160
3. Electrophilic substitution (a) Sulfonation: Coumarin on reaction with hot chlorosulfonyl chloride yields 6-sulfonyl chloride.1161 This sulfonyl derivative on reaction with N,N-dimethylhydrazine and hydrazine hydrate-triethylamine yielded hydrazone derivatives.
(b) Nitration: Coumarin on reaction with 1 equivalent of ceric ammonium nitrate (CAN) gave 6-nitrocoumarin as the sole product in excellent yield.1162
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
285
4. Reaction with nucleophilic reagents: Coumarin, being a lactone on reaction with aqueous alkali solution, is readily hydrolyzed to give yellow solutions of the corresponding salts of cis-cinammic acid, which cannot be isolated (because the acid reverts immediately to coumarin) and on prolonged alkali treatment leads to isomerization and formation of a stable trans-acid (coumaric acid) salt.
A simple and effective synthetic route to various coumarin-fused heterocycles like pyrazoles, isoxazoles, and pyrimidine, adhering to the green chemistry principle has been reported. The process involves microwave irradiation of α,β-unsaturated ketone of the coumarin ring with different nucleophiles in aqueous medium in the presence of a green catalyst.1163
5. Reaction with Grignard reagent: Coumarin reacts with methyl magnesium iodide affording tertiary alcohol and 2,2-alkylchromenes giving a mixture of products.1164, 1165
Coumarin on reaction with phenyl magnesium bromide yields 3-(2-hydroxyphenyl)-1,1-diphenylprop-2-en-1-ol and 3-(2-hydroxyphenyl)-1,3-diphenylprop-1-one. Both the compounds on boiling with acetic acid yield 2,2-diphenyl2H-chromene and 2,4-diphenyl-4H-chromene, respectively.1166
286
2. Six-Membered Heterocycles
However, a new protocol for the Cu-catalyzed asymmetric conjugate addition of Grignard reagent to coumarin has been developed. The corresponding products are formed in high yield and enantioselectively. The process involves copper-catalyzed asymmetric conjugate addition of Grignard reagent to coumarin in the presence of ferrocenyl- based biphosphine ligand leading to the generation of 4-alkylchroman-2-ones.1167
Asymmetric 1,4-addition of alkylboronic acid to coumarins takes place with high enantioselectivity in the presence of rhodium catalyst generated from Rh(acac)(C2H4)2 and (R)-SEGPHOS to yield (R)-4-arylchroman-2-ones in over 99% enantiomeric excess. This reaction has been applied for the synthesis of (R)-tolterodine, an antimuscarinic drug.1168
6. Fries rearrangement: 4-Methyl-7-hydroxycoumarin on reaction with acetic anhydride yields 4-methyl7-acetoxycoumarin. This esterified derivative in the presence of aluminum chloride undergoes Fries rearrangement to yield 4-methyl-7-hydroxy-8-acetylcoumarin.1169
7. Claisen rearrangement: 4-Methyl-7-allyloxy coumarin undergoes Claisen rearrangement to yield 8-allyl-7-hydroxy-4-methylcoumarin.1170
8. Heterocyclic ring fission: Heating 4-methyl-7-hydroxy-8-acetylcoumarin with sodium hydroxide followed by acidification led to ring opening to yield 2,6-dihydroxyacetophenone.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
287
9. Reduction: Lithium aluminum hydride not only saturates the CC double bond, it also attacks the carbonyl carbon giving a mixture of products.
10. Cycloaddition reaction: Under forcing conditions, coumarin serves as a dienophile in Diels-Alder reaction and undergoes cycloaddition reaction with 2,3-dimethyl-1,3-butadiene at 260°C to give a tetrahydrobenzocoumarin derivative.1171, 1172
11. Photochemical reaction: Coumarin on prolonged illumination in the solid state or in solution is converted to its dimer, with head-to-head cis-cyclobutane structure. The trans-head-to-head dimer is obtained by irradiating coumarin in ethanol in the presence of photosensitizer benzophenone.1173–1175
Photodimerization of coumarin was also carried out in solid inclusion complexes with β- and ϒ-cyclodextrins.1176 [2+2] Photodimerization of coumarin to an optically active antihead-to-head dimer in the presence of an optically active host compound in cyclohexane solution has been found to proceed with high enantioselectivity.1177
12. Transformation to other heterocycles: Coumarin can be transformed to 4H-chromene by sequential reduction of the double bond and carbonyl group by H2, Pd/C, and DIBAL-H, respectively, yielding a hydroxyl chroman derivative, which on dehydration with oxalic acid yields a 4H-chromene derivative.
288
2. Six-Membered Heterocycles
Coumarin on reaction with sodium ethoxide yields 2-hydroxycinnamate, which on conjugate addition with ethyl cyanoacetate undergoes cyclization to yield a 4H-chromene derivative.
Coumarin on reaction with phosphorous pentasulfide gives thiocoumarin.1178
2.7.7 Isocoumarin
Isocoumarin, also known as 1H-2-benzopyran or 3,4-benzopyrone, is an isomer of coumarin in which the orientation of lactone is reversed. Thus isocoumarin is an unsaturated, nonconjugated oxygen heterocycle constituted by fusion of the benzene ring with the 3,4-position (“c” site) of the 2-pyrone ring. It is neither a true aromatic nor a true aliphatic compound because it shows the properties of aliphatic and aromatic compounds. Structural and Reactivity Aspects The structure of unsubstituted isocoumarin has been proved on the basis of 1H NMR spectroscopy.1179 1
H NMR spectral data of isocoumarin
1
H NMR (CDCl3)
δ 8.31 (br d, J = 7.5 Hz Ar-H), 7.28–8.0 (m 3H, Ar-Hs); 7.28 (d 1H, J = 5.7 Hz); 6.49 (d 1H, J = 5.7 Hz, vinylic H)
The IR spectrum shows two prominent bands at 1728 and 1638 cm−1 for CO and CC stretching vibrations. Importance in Natural Products, Medicines, and Materials Isocoumarin represents an important class of compound that exhibits a wide range of pharmacological activities. A large number of isocoumarins have been isolated from plants and have been explored for antifungal, antimicrobial, anticancer, antiallergic, antiinflammatory, anti-HIV, and anticoagulant activities.1180 Some of the promising isocoumarin derivatives are capillarin and artemidin, which have potential antifungal activity. Thunberginol A and B exhibit antiallergic and antimicrobial activity. Ruticulol and cytogenin are known for their antitumor activity.
Natural products containing isocoumarin skeleton.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
289
Synthesis1181a 1. One of the most convenient synthetic methods of isocoumarin involves ozonization of indene in ethyl alcohol followed by decomposition of cyclic ester to 2-carboxyphenylacetaldehyde, which on treatment with mineral acid yields isocoumarin.1181b
2. Claisen condensation: Condensation of diethyl homophthalate with methyl formate in the presence of sodium ethoxide affords isocoumarin-5-carboxylic acid, which on decarboxylation with phosphoric acid yields isocoumarin.1182
Condensation of diethyl homophthalate with diethyl oxalate in the presence of sodium metal affords triester, which when heated loses ethanol to give diethyl isocoumarin-3,4-dicarboxylate. Heating the dicarboxylate with hydrochloric acid in a sealed tube at 180–190°C, yields isocoumarin-3-carboxylic acid.1183
3. Heating homophthalic acid with aryl or acyl chlorides yields isocoumarins.1184
4. Condensation of phthalaldehydic acid with nitromethane in the presence of sodium hydroxide in methanol gave (nitromethyl)isobenzofuranone, which on treatment with sodium borohydride in dimethylsulfoxide afforded 2-(2-nitroethyl)benzoic acid. Nitro acid was converted to keto acid by applying Nef procedures. Keto acid on intramolecular cyclization followed by dehydration yielded isocoumarin.1179
290
2. Six-Membered Heterocycles
5. Acid-catalyzed selective intramolecular cyclization of enynecarboxylic acid to isocoumarin derivative has been reported.1185
6. Reaction of o-iodobenzoic acid with 1-hexyne in the presence of Pd(PPh3)4, Et3N, and ZnCl2 in DMF at 100°C gave isocoumarin.1186
7. Tandem Stille reaction: Reaction of 2-iodobenzoic acid with allenyltributyltin reagent in the presence of palladium acetate, triphenylphosphine, and tetrabutylammonium bromide in dimethylformamide afforded 3-substituted isocoumarins via tandem Stille reaction and 6-endo-dig oxacyclization.1187
8. Cross-coupling reaction of o-bromobenzoate with n-tributyl vinyl tin in the presence of palladium catalyst affords isocoumarin.1188
9. The reaction between 4-hydroxycoumarin and a benzyne precursor in the presence of CsF as fluoride source in acetonitrile at room temperature affords isocoumarin.1180
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
291
10. A multicomponent reaction between terminal alkynes, arynes, and carbon dioxide yields isocoumarin.
Physical Properties Isocoumarin is a low-melting solid with mp of 45–46°C. Chemical Reactivity1189 1. Hydrolysis: Isocoumarin on alkaline hydrolysis undergoes a ring-opening process to give homophthaldehydic acid. However, isocoumarin containing alkyl group at position 3 provides ketone under same reaction conditions.
2. Reaction with nitrogen nucleophiles: Ammonia and its derivatives add to isocoumarins to yield isocarbostyrils.1190
This process has been used in the synthesis of indole alkaloid yobyrine. The process involves treating isocoumarin with tryptamine and the product obtained is converted to yobyrine.
3. Reaction with Phosphorous pentasulphide: Isocoumarin on reaction with phosphorous pentasulfide affords 1-thioisocoumarin, which on treatment with ammonium sulfide or aniline yields isoquinoline.
4. Reaction with Grignard reagent: Reaction of isocoumarins with Grignard reagent yields an alcoholic derivative, which on dehydration with strong acid affords 1-substituted 2-benzopyrylium salt.
292
2. Six-Membered Heterocycles
5. Reduction: Reduction of isocoumarin was carried out with sodium borohydride, leading to the generation of 3,4-dihydroisocoumarin. On reaction with alkali the heterocyclic ring was opened yielding 2-(2-oxoalkyl) benzoic acid, which was reduced by sodium borohydride to a corresponding alcohol. The intermediate alcohol was cyclized to 3,4-dihydroisocoumarin1191 in the presence of acidic reagents (sulfuric acid solution, acetic anhydride).
6. Oxidation: Oxidation of 3,4,6,7-tetraphenyl isocoumarin with chromium trioxide affords 2-benzoyl-4,5diphenylbenzoic acid.
7. Photocycloaddition reaction1192: Irradiation of isocoumarin (λ = 350 nm) in the presence of 10-fold molar excess of tetrachloroethene in acetonitrile afforded a cis-fused cyclobutane derivative.
However, irradiation of isocoumarin (λ = 350 nm) in the presence of 10-fold molar excess of 2,3-dimethyl-but-2ene in acetonitrile afforded a mixture of cis- and trans-fused cyclobutane derivative.
Benzopyrones Benzo[b]pyrone is a bicyclic, unsaturated, nonconjugated oxygen heterocycle constituted by fusion of the benzene ring with the 2,3-position (“b” site) of the pyran-4-one ring. It is neither a true aliphatic nor a true aromatic compound because it exhibits the properties of aliphatic as well as aromatic compounds. There are two structural isomers: (1) α-benzopyrone, commonly referred to as coumarin and (2) γ-benzopyrone, commonly referred to as chromone.
2.7.8 Chromone
Chromone, also known as 4-chromone, 1-benzopyran-4-one, 4H-chromen-4-one, or 4H-benzo[b]pyran-4-one, is an isomer of coumarin and consists of a substituted keto group at the 4-position of the 4H-pyran ring. The word chromone is derived from the Greek word chroma meaning color. The word chromone was first used by Bloch and Kostanecki for several naturally occurring colored compounds like brazilin and hydroxyflavones that contained a benzopyran-4-one structure. Some important chromone derivatives are flavone, flavanol, and isoflavone.
293
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
Some important chromone derivatives.
Structural and Reactivity Aspects Chromones can be identified on the basis of their color tests. Chromones in ethanol produced a crimson to blue color when an aqueous 0.001 N iodine solution was added to them.1193 2-Methylchromone gave a red to violet color when an aqueous solution of chromone was poured over pellets of potassium hydroxide on a watch glass.1194 2-Methychromones are also identified by adding sodium nitroprusside in ethanol to an ethanolic solution of chromone. A drop of 30% sodium hydroxide solution is added followed by acidification with two drops of acetic acid. 2-Methylchromone if present produces a reddish violet coloration.1195 Synthetic methods often lead to a mixture of chromones and coumarins which can be separated by a chemical method. To a mixture of chromone and coumarin was added a solution of sodium ethoxide in ethanol, whereby the 2- and 4-pyranone rings were opened to give phenolic diketone and carboxylic acid, respectively. The carboxylic acid was recyclized by acid at 18°C to yield coumarin, while the β-ketoester was extracted with aqueous sodium hydroxide and cyclized to the chromone in the presence of acid.1196
Another method of differentiation between chromone and coumarin is their behavior toward bromine. Chromone, when treated with bromine in chloroform or glacial acetic acid, forms perbromide, whose solubility is very low in solvent. Coumarin under similar reaction conditions forms a 3-bromo derivative.1197 Spectral methods are quite helpful in distinguishing chromones from coumarins. The chemical shifts of 1H NMR of chromone1198 and coumarin are given in the following table (δ ppm from TMS in CDCl3). Comparative 1H NMR spectral data of chromone and coumarin C-2
C-3
C-4
C-5
C-6
C-7
C-8
Chromone
7.88
6.34
-
8.21
7.42
7.68
7.47
Coumarin
-
6.45
7.80
7.63
7.22
7.45
7.20
One of the major differences between the two benzopyrans is the paramagnetic shift suffered by the C-5 proton of chromone because of the effect of the adjacent carbonyl group. The 13C NMR spectral data of chromone is given in the following table.1199 The NMR was taken in a 50:50 (v/v) mixture of CDCl3 and (CD3)2SO. C NMR spectral data of chromone
13
Chromone
C-2
C-3
C-4
C-5
C-6
C-7
C-8
8a
4a
145.5
113.0
177.6
125.3
125.8
133.8
118.3
156.6
125.0
294
2. Six-Membered Heterocycles
The structure of chromone is well established on the basis of its mass fragmentation pattern.1200–1202
Mass fragmentation pattern of chromone.
Importance in Natural Products, Medicines, and Materials The bicyclic rigid chromone fragment has been a privileged scaffold in drug discovery processes because several biological properties have been attributed to some of its derivatives, namely antiallergic, antiinflammatory, antioxidant, anticancer, antiviral, and antifungal activities.1203, 1204 Besides this, a number of chromone derivatives are found highly effective in the treatment of cystic fibrosis.1205–1207 There are numerous chromone derivatives that have been used as therapeutic agents. Khellin extracted from the seeds of the plant Ammi visnaga has previously been used as a diuretic to relieve renal colic,1208 and in the treatment of angina pectoris and asthma. However, the present use of khellin focuses on the treatment of vitiligo, a pigmentation disorder.1209 Nevertheless, due to the secondary effects of khellin like headaches or intestinal disorders, sodium chromoglycate (Lomudal), a derivative of khellin was developed, which finds use as a mast cell stabilizer in allergic rhinitis, asthma, and allergic conjunctivitis. Diosmin (Daflon) is used for the treatment of venous diseases, whereas flavoxate is used as a muscle relaxant to treat urge incontinence.1210, 1211
Therapeutic agents containing chromone skeleton.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
295
Taking into account the therapeutic potential of chromone derivatives, researchers have tried to elucidate the possible structure-activity relationship that might lead to new drug discovery. Structural modification along with biochemical activity is listed in the following diagram.1212
Structure activity potential of chromone.
Synthesis 1. The first synthesis of chromone was reported in 1900 and it involved heating 4-oxo-4H-1-benzopyran-2carboxylic acid in a vacuum.1213
2. Under heating conditions, 2-hydroxy-benzoylpyruvic acid in acetic anhydride undergoes decarboxylation followed by cyclization yields chromone.
3. Claisen condensation: Claisen condensation between o-hydroxyaryl allyl ketone with a carboxylic acid ester in the presence of a strong base delivered diketones, which on heating in acidic medium cyclized to chromones.
The first example was reported by Kostanecki et al., who synthesized 7-ethoxy-4H-1-benzopyran-2-carboxylic acid from 2′ethoxy-4′-hydroxyacetophenone via diketone intermediate which cyclized in the presence of HCl.1214
The ester group of the Claisen condensation product obtained by reaction of 2-hydroxyacetophenone with diethyloxalate is susceptible to transesterification. When the sodium salt of this compound is suspended in methanol at 0°C and acidified with dilute sulfuric acid, the methyl ester formed is cyclized to chromone methyl ester. However, cyclization in acidic ethanol yields a chromone ethyl ester derivative.1215
296
2. Six-Membered Heterocycles
Claisen condensation of o-hydroxyacetophenone with an ester in the presence of sodium hydride yielded 1,3-dione, which was cyclized to 2-(2-phenylethyl)chromone.1216
4. Kostanecki reaction: The reaction of o-hydroxyaryl ketones with aliphatic acid anhydride in the presence of sodium or potassium salt of corresponding acid provides chromones is known as the Kostanecki reaction.1217
This reaction was further elaborated by Allan and Robinson1218 who synthesized flavones by reacting 2,4-dihydroxyacetophenone with benzoic anhydride in the presence of sodium benzoate. Thus synthesis of chromones is known as the Kostanecki reaction, whereas synthesis of flavones is known as the Allan-Robinson reaction.
Mechanism: The most likely mechanism of Kostanecki reaction is one proposed by Baker.1219–1221 According to the mechanism hydroxyaryl ketone is first acylated to yield an ester, which undergoes enolization followed by acylation of the enolate to yield enolacetate. Cyclization followed by loss of water yields the chromone.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
297
To increase the yield of the product, a number of modifications in the Kostanecki reaction were introduced. The process involves reacting o-hydroxyacetophenone with ester (ethyl propionate) in the presence of metallic sodium. The resulting sodium enolate was quenched with acetic acid to give the diketone, which on heating with acetic acid and hydrochloric acid yielded ethylchromone in 75% yield.1222
Usually, the Kostanecki reaction is carried out at high temperatures (>160°C), and modifications were developed where acetic formic anhydride was used at room temperature instead of acetic anhydride.1223, 1224
Another variation adopted for the Kostanecki reaction was the use of a stoichiometric amount of 1,8-diazabicyclo[5.4.0]undec-7-ene instead of sodium acetate.1225 Calanolide A, a potent nonnucleosidal-specific reverse transcriptase inhibitor, was synthesized first by converting propiophenone to a chromone derivative by the Kostanecki reaction, which after several steps was converted to (+)-calanolide.1226
298
2. Six-Membered Heterocycles
5. Baker-Venkataraman rearrangement: The dione prepared by Claisen condensation can also be prepared from o-acyloxy ketones. The base-catalyzed rearrangement of o-acyloxy ketones to β-diketones is known as the BakerVenkataraman rearrangement.1227, 1228
The diacetate of resacetophenone reacts with sodium to afford dioxophenol, which cyclized to form 7-hydroxy-2methylchromone under acidic conditions.1229
2′-Acyloxyacetophenone in the presence of potassium tert-butoxide underwent Baker-Venkataraman rearrangement to yield 1-(2-hydroxyaryl)-1,3-diketone. The diketone was subsequently cyclized in methanol or trifluoroethanol containing a cobalt (salen) complex [CoIII(salpr)OH] at 60°C to chromone in good yield.1230, 1231
6. Simonis reaction: The reaction of a phenol with 3-oxoester in the presence of sulfuric acid yields coumarin. The reaction is known as Pechmann condensation. However, cyclization by phosphorous pentoxide afforded chromone, which is called the Simonis reaction.1232
7. One-pot synthesis of 2-methylchromone by condensation of 3,5-dimethoxyphenol with 5-(1-methoxyalkylidene), Meldrum’s acid, in the presence of Yb(OTf)3 catalyst has also been reported.1233
8. Vilsmeier-Haack reaction1234: This one-pot synthesis has chiefly been used for the synthesis of chromone-3carbaldehyde by reaction between o-hydroxyalkylarylketone and a formylating agent known as Vilsmeier-Haack reagent.1235, 1236
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
299
The reaction, however, suffered from a number of drawbacks like long reaction time, unexpected side reactions, and unsatisfactory yield. The problem was overcome by using boron trifluoride etherate with formation of an intermediate1237–1239 and making a variation in the Vilsmeier-Haack reagent like triphosgene (bistrichloromethyl)carbonate/DMF, phosgene iminium chlorides, or DMF-dimethylacetal.1240
Vilsmeier reagent prepared from phthaloyl chloride and DMF was very helpful in converting 2-hydroxyacetophenone to chromone. Ready availability and low cost of phthaloyl dichloride and DMF, high activity of Vilsmeier reagent, shorter reaction time, and mild reaction conditions are some of the advantages of this new method.1241
The first step of the mechanism involves reaction of boron trifluoride complex with o-hydroxyacetophenone, which is then attacked by Vilsmeier reagent, followed by nucleophilic attack of the hydroxyl group; finally, deamination takes place to form chromone.
9. Ruhemann reaction: The reaction of phenol with chlorofumaric acid or acetylenic dicarboxylic acid esters under basic conditions yields an intermediate, which undergoes cyclization in the presence of sulfuric acid, perchloric acid, or hydrogen fluoride to afford chromones. This method has largely been used for the synthesis of chromone-2-carboxylic acid derivatives.1242
300
2. Six-Membered Heterocycles
10. Nucleophilic displacement of ethyl salicylate by anion derived from DMSO produced sulfinylketone, which on cyclization with formaldehyde yielded chromanone, which after thermal elimination of MeSOH gave chromone.1243, 1244
Salicylic acid or its substituted derivative was converted to its O-acyl(aroyl) by reaction with corresponding acid chloride or anhydride, which when treated with tert-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole furnished the corresponding silyl ester. The silyl derivative and (trimethylsilyl)-methylenetriphenylphosphorane when heated in refluxing THF undergoes intramolecular Wittig cyclization to yield the desired chromone.1245
Reaction of activated salicylic acid derivative with diethyl malonate yields an intermediate, which after hydrolysis and decarboxylation yields 2-methylchromone.1246
2-Methylchromone is also obtained by reaction of methylsalicylate with dimethylpentan-2,3-dienedionate1247 in the presence of KOtBu/BuOH. 11. 2-Hydroxyacetophenone on reaction with triethyl formate in the presence of perchloric acid was converted to benzopyrylium salt, which on heating with water yielded 7-hydroxychromone.1248, 1249
12. A transition metal-catalyzed reaction provides one of the most attractive methodologies for the synthesis of chromone derivatives. A one-pot Sonogashira carbonylation-annulation reaction has been developed that involves a reaction of o-iodophenol with terminal alkynes under a carbon monoxide atmosphere in the presence of secondary amine and a catalytic amount of palladium complex and yields 2-substituted chromone.1250
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
301
Use of a microwave has been found to speed up the reaction process and the yield of the chromone derivative.1251 Synthesis of 2-substituted chromone by a Sonogashira coupling reaction by palladium catalysis was also carried out by reaction of o-methoxybenzoyl chloride with terminal alkyne and o-methoxybenzaldehyde with lithium acetylide.1252 Direct palladium-catalyzed aerobic dehydrogenation of chroman-4-one using O2 as oxidant yields chromone.1253
13. Treatment of a benzofuran derivative with osmium tetroxide followed by hydrolysis yields chromone. The reaction involves oxidation of a double bond, followed by opening of the furan ring and recyclization yielded chromone.
14. The 3-formyl chromone synthesized previously has been used for the synthesis of other chromones. Reduction of the formyl group of chromone with a suspension of basic alumina in isopropanol,1254 and oxidation with sodium chlorite in the presence of aminosulfonic acid,1255 led to the formation of 3-hydroxymethylchromone and chromone-3-carboxylic acid, respectively.
Physical Properties Chromone is a colorless crystalline compound with mp of 59°C. Chemical Reactivity 1. Carbonyl oxygen of chromone undergoes protonation to produce hydroxyl benzopyrylium salt. Thus treatment of chromone in ethereal HCl produced 4-hydroxy-1-benzopyrylium chloride.1256
Benzopyrylium salts have been converted into important derivatives. Benzopyrylium salt on reaction with tertiary benzenoid amine forms flavylium salts, which on warming with pyridine forms flavones.
302
2. Six-Membered Heterocycles
Benzopyrylium salt generated by silylation of chromone reacts with silyl enol ethers or allylsilanes. The addition takes place at the C-2-position.1257
2. Electrophilic substitution reaction (a) Nitration: Chromone readily undergoes a substitution reaction in acidic medium via hydroxyl benzopyrylium cation, which is then attacked by the electrophile yielding a 6-nitro derivative.1258,1259
(b) Bromination: Chromone also undergoes bromination at the 6-position by treating it with dibromoisocyanuric acid (1,3-dibromo-1,3,5-triazine-2,4,6-trione) in the presence of sulfuric acid.
3. Substitution in the heterocyclic ring: Substitution at position 3 of the pyran ring takes place when chromone is refluxed in ethanol with dimethylamine, formaldehyde, and hydrochloric acid, aminomethylation takes place under Mannich conditions.1260
4. Reaction with nucleophiles: The chromone nucleus behaves as a Michael acceptor toward nucleophiles. The pyran ring is opened by alkali due to addition of water, leading to the generation of o-hydroxyphenyl-1,3diketone, which on reaction with acid produced o-hydroxyphenyl ketone and carboxylic acid or salicylic acid and ketone.
Chromone reacts with cold sodium hydroxide solution. The attack takes place at C-2 leading to a ring-opening process.
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
303
Secondary amines also attack chromones at the C-2-position leading to a ring-opening process.
In some cases, chromone reacts with secondary amines to yield enamines.1261, 1262
3-Iodo chromone reacts with imidazole to yield a 2-substituted product probably via addition-elimination sequence.1263
5. The carbonyl group of the pyran ring of chromone does not react with hydroxylamine or hydrazine to form oxime or hydrazone; instead the products were isoxazole and pyrazole, respectively.1264, 1265
However, reaction of phenylhydrazine with chromone at 0°C formed phenylhydrazone in good yield along with enamine as the minor component. The unstable enamine was readily transformed into 5-(2-hydroxyphenyl)-1-phenylpyrazole.
Reaction of chromone with anthrone leads to the generation of an anthraquinone derivative.1266
304
2. Six-Membered Heterocycles
When chromone was refluxed with thionyl chloride in an atmosphere of carbon dioxide or with dichloromethyl methyl ether, the carbonyl group was substituted by two chlorine atoms yielding 4,4-dichlorochromen.1267, 1268 On addition of a small amount of benzoyl peroxide to this reaction a mixture of chromone and thionyl chloride, trichlorochromen, was obtained.
6. Addition reaction: Reaction of chromone with sulfuryl chloride yielded an addition product, 2,3-dichlorochromanone.
Reaction of chromone with NBS in aqueous dimethyl sulfoxide leads to the addition of hypobromite across the C-2 and C-3 double bond. However, when reaction of NBS is carried out in methanolic dimethyl sulfoxide, then 3-bromo-2-methoxy chromanone is obtained.1269
A novel and readily prepared C2-symmetric chiral bis-sulfoxide ligand and its successful use in the rhodium- catalyzed asymmetric 1,4-addition of tetraarylborate acid to chromone is reported1270 with high enantioselectivity.
7. Cycloaddition reaction: Heating chromone with tert-butyldimethylsilyl trifluoromethane sulfonate (TBDMSOTf) at 80°C results in the formation of 4-tert-butyldimethylsilyloxy-1-benzopyrylium triflate. The silylated chromone derivative undergoes cycloaddition reaction with α,β-unsaturated ketone in the presence of TBDMS triflate and 2,6-lutidine.1271, 1272
3-Acylchromones, chiefly 3-formyl chromone, undergo hetero Diels-Alder reaction with vinyl ethyl ether to provide a cycloaddition product, which on reaction with sulfuric acid undergoes a ring-opening process to yield 4-oxo-4H- chromen-3-yl-acrolein.1273, 1274
2.7 Six-Membered Benzo-Fused Oxygen Heterocycles
305
Chromone-3-ester also undergoes a cycloaddition reaction but serves as a dienophile under Diels-Alder reaction conditions.1275
Chromone on reaction with trimethylsilyl triflate yields benzopyrylium salt, which on reaction with ethyl diazoacetate yields a cycloproponation adduct. On acidification the cyclopropane ring is opened leading to a benzoxepine derivative.1276
8. Photocycloaddition reaction: Chromones undergo [3+2] and [2+2]π cycloaddition reaction quite readily.1277 The photoaddition reaction involves electrophilic attack by C-3 of chromone involving n→π* triplet excitation.
Irradiation of a solution of chromone with 1,1-dimethoxyethylene1278, 1279 gave two products: A and B. Studies revealed that product B was a secondary photolysis product of A.
9. Reaction with Grignard reagent: Enantioselective copper-catalyzed conjugate addition of dialkylzinc reagent to chromone led to the synthesis of optically active 2-alkylchromanones.1280
306
2. Six-Membered Heterocycles
However, a direct enantioselective synthesis of chiral 2-alkylchromanones has been reported. The process involves copper-catalyzed asymmetric conjugate addition of Grignard reagent to chromone in the presence of ferrocenyl-based biphosphine ligand.1281
10. Alkenylation of chromone: A general method for introducing the vinyl group into chromone involves a reaction between 3-halochromone and alkene. However, a direct alkenylation method has also been reported. The process involves a cross-coupling reaction of chromone with alkene in the presence of Cu(OAc)2/Ag2CO3 associated with the use of pivalic acid.1282
2.8 SIX-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH MIXED HETEROATOMS 2.8.1 Oxazines Six-membered heterocycles containing one oxygen and one nitrogen in a doubly unsaturated ring have systematically been named as oxazines. Depending on the relative position of the heteroatom and double bonds, there are number of isomers of oxazines.
2.8.2 1,2-Oxazine Monocyclic 1,2-oxazines with two double bonds can exist in three 4H, 2H, and 6H isomeric forms. Besides the three isomers, several oxo, thioxo, imino, di, and tetrahydro derivatives are also known.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
307
Structural and Reactivity Aspects1283 X-ray crystal analysis of tetramethyl-1,2-oxazinium cation has been helpful in confirming the 1,2-oxazine s tructure. The bond lengths (in Å) are shown in the following figure.
The 13C NMR spectral data of tetramethyl-1,2-oxazinium salt and 5-methyl-3-phenyl-1 and 2-oxazine are given in the following table. 13
C NMR spectral data of two 1,2-oxazine derivatives Tetramethyl-1,2-oxazinium salt
5-Methyl-3-phenyl-1,2-oxazine
C-3
165.1
156.8
C-4
157.3
110.9
C-5
139.7
141.4
C-6
197.5
66.5
Importance in Natural Products, Medicines, and Materials 1,2-Oxazines constitute a versatile class of N and O heterocycles, which are useful intermediates in the synthesis of γ-lactams, γ-amino acids, amino alcohols, aziridines, pyrrolizidines, and pyrrolidine derivatives. Synthesis 1. Reaction of arylmethylketoxime with ethyl magnesium bromide yields aryl-substituted 6H-1,2-oxazine.1284
2. Action of weak acid on the monoxime of 1,3,4-triphenylbutane-1,2,4-trione yields 5-hydroxy- 6-methoxy-3,4,6-triphenyl-6H-1,2-oxazine.
The reaction is reversible and on boiling with water the oxime is regenerated. 3. Refluxing 1,4-diphenyl-3-nitro-3-buten-1-one with hydroxylamine in pyridine-ethanol yields 3,6-diphenyl-6H-1,2-oxazine.1285
308
2. Six-Membered Heterocycles
4. Cycloaddition reaction of 2-chloro-2-nitrosopropane with butadiene affords an adduct, which on reaction with aqueous alkali yields 3,6-dihydro-2H-1,2-oxazine.1286
5. Reaction of ketones with hydroxylamine hydrochloride in the presence of sodium acetate afforded oximes, which on treatment with chloramine-T gave α-nitrosoolefins, which subsequently underwent hetero-Diels-Alder reaction with terminal acetylenes to give 6H-1,2-oxazines in excellent yield.1287
6. Hydroboration of 2,3-dimethylbuta-1,3-diene afforded 2,3-dimethylbutane-1,4-diol, which on bromination is subsequently converted to 1,4-dibromobutane. Cyclization to N-methyloxazines is affected on treatment of 1,4-dibromobutane with N-hydroxyurethane under basic conditions.1288
7. On reaction of lithiated methoxy allenes with D-glyceraldehyde-derived nitrones, [3+3] cyclization takes place leading to the generation of enantiopure 1,2-oxazine derivatives.1289
Chemical Reactivity 1. During reaction of 5-hydroxy-6-methoxy-3,4,6-triphenyl-6H-1,2-oxazine with phenyl magnesium bromide the methoxy group is substituted by the phenyl group yielding 5-hydroxy-3,4,6,6-tetraphenyl-6H-1,2-oxazine, which on alkylation with ethyl bromide yields 2-ethyl-5-oxo-3,4,6,6-tetraphenyl-5,6-dihydro-6H-1,2-oxazine.1290
2. 6H-1,2-Oxazine derivatives in concentrated halogen acid rearrange to form 2,4-diarylpyrroles.1291
3. When 3-phenyl-6H-1,2-oxazine reacts with benzyl alcohol in the presence of hydrochloric acid, conjugate addition takes place leading to the generation of a 5-ether derivative.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
309
4. Reduction of 3,6-dihydro-2H-1,2-oxazine normally takes place with the NO bond. Depending on the type of reducing agent used, a variety of products are formed.
5. The enantiomeric pure 1,2-oxazine derivatives have been converted to highly functionalized compounds, most of them being similar to carbohydrates. The process involves acid treatment of 1,2-oxazine whereby cleavage of the acetonide ring takes place. Subsequent reaction with enol ether forms bicyclic ketal, which on exhaustive hydrogenolysis provides furan derivatives, which are equivalent to the depicted ulose.1289
6. The enol ether double bond of 1,2-oxazines has been employed to react with other electrophiles. Hydroboration proceeds regio- and stereoselectively leading to the introduction of the hydroxyl group at C-5. This hydroxyl derivative is then used for the preparation of aza sugars, amino sugars, azetidine, or pyrrolidine (imino sugar derivatives). Polyhydroxylated pyrrolidines are moderately strong α-l-fucosidase inhibitors.1292
310
2. Six-Membered Heterocycles
7. The NO bond of 5,6-dihydro-3-phenyl-4H-1,2-oxazine is readily cleaved by retro-Diels-Alder process under mild conditions to give 2-phenyl pyrrole.
8. 5,6-Dihydro derivatives possessing a substituent at C-6 capable of stabilizing a positive charge are readily cleaved under acidic conditions. Thus 6-ethoxy-3-phenyl-5,6-dihydro-4H-1,2-oxazine is readily converted to pyrroline N-oxide on reaction with HCl in methanol.
2.8.3 1,3-Oxazine Monocyclic 1,3-oxazines are also known as metoxazine (or mazoxin). The 1,3-oxazines with two double bonds can exist in three 4H, 2H, and 6H isomeric forms. Besides three isomeric forms, several oxo, thioxo, imino, di, and tetrahydro derivatives are also known.
Structural and Reactivity Aspects The 1H and 13C NMR data of 2-ethoxycarbonyl-4,6-diphenyl-2H-1,3-oxazine are given in the following table.1293 H and 13C NMR spectral data of 1,3-oxazine derivative
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 6.1; H-5, 6.6
C-2, 86.6; C-5, 95.5; C-4, 161.4; C-6, 163.6
UV absorption spectra of 1,3-oxazine shows absorption maxima in the range of 210–260 nm due to the presence of CC and CN chromophoric groups. On the basis of NMR spectral data it has been proved that various dihydro derivatives of 1,3-oxazines exist in half chair conformations and tetrahydro derivatives as chair conformations as depicted in the following diagram.1294–1297
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
311
Importance in Natural Products, Medicines, and Materials Because of their biological and pharmaceutical activities the chemistry of 1,3-oxazines has been a subject of research. They constitute a structural unit of a number of natural products. For example, geissospermine was found to contain this ring. A number of derivatives were also evaluated for their analgesic, antibacterial,1298 and anticonvulsant activities. Numerous 1,3-oxazine derivatives are drugs. Efavirenz, an antiretroviral drug used for the treatment and prevention of HIV/AIDS, 3-oxauracil, an antimetabolite for its activity against E. coli and L121 leukemia cells, and oxazinomycin, an antibiotic.
Drugs containing 1,3-oxazine nucleus.
Synthesis1296 1. The first synthesis of the 1,3-oxazine derivative was reported by Kohn1299 and consisted of cyclizing 3-aminopropan-1-ol derivative with aldehyde.
2. The first example of the synthesis of 1,3-4H-oxazine was reported by Wohl1300 by the reaction of an aqueous solution of oxalic acid with diethyl acetal of γ-benzoylamino propionaldehyde.
3. A general method for the synthesis 1,3-4H-oxazine was reported by Gabriel and Miyamichi1301 by the reaction of β-(N-acylamine) derivatives of ketones and carboxylic acid esters with PCl5 or P2O5, respectively.
312
2. Six-Membered Heterocycles
4. Reaction of an acetylenic compound with Schiff’s base and acyl chloride in the presence of stannous chloride yielded a 4H-1,3-oxazine derivative.1302
5. 2H-1,3-Oxazine is synthesized by the action of alkali on isoxazolium salts.1303
6. When 4-amino-1-azadienes were treated with esters of glyoxylic acid at 20–50°C, substituted 2H-1,3-oxazines were isolated in excellent yields.1304
7. 1,4-Cycloaddition of unactivated olefins with N-acyliminiums (obtained from benzotriazole precursors) afforded polysubstituted 5,6-dihydro-4H-1,3-oxazines.1305
8. Treating 3-aminopropan-1-ol with acetylene under pressure yields 2-methyl tetrahydro-1,3-oxazine.1306
9. 3-Aminopropan-1-ol also undergoes cyclization with vinylbutoxyethyl ether in the presence of mercuric salts to yield 2-methyl tetrahydro-1,3-oxazine.1306
10. Reacting vinyl ether of 3-aminopropanol with N,N-dimethylcarbamyl chloride in the presence of potassium carbonate yields a 1,3-oxazine derivative.1307
11. Benzoylation of 3-bromopropylamine in the presence of a base yields 2-phenyl-5,6-dihydro-4H-1,3-oxazine. The reaction is proposed to take place with the intermediate formation of N-benzoyl-3-propylamine.1308
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
313
12. Reaction of 3-aminopropanol with tert-butylisocyanide in the presence of silver cyanide leads to the formation of 5,6-dihydro-4H-1,3-oxazine.1309
13. 3-Propanolamines on reaction with acetylenic ethers afford 1,3-oxazines.1310
14. A novel method for the synthesis of oxazines involves reaction of 3-azidopropanol with aromatic aldehydes.1311
Chemical Reactivity 1. 1,3-Oxazines act as bases and react with acids to form salts, which vary with regard to their solubility in water and their stability. 4H-1,3-Oxazine on reaction with trityl perchlorate in acetonitrile forms 3-azapyrylium salts.1300
2. Ring-opening reaction: A common reaction of 1,3-oxazines is their ability to be hydrolyzed with a ring-opening process. This process takes place in the presence of dilute mineral acids. (a) 5-Nitrotetrahydro-1,3-oxazine is readily hydrolyzed to a 3-amino-2-nitropropanol derivative.1312, 1313
(b) Hydrobromide of 2-phenyl-5,6-dihydro-1,3-oxazine is hydrolyzed in water to form 3-aminopropylbenzoate, which is rearranged to 3-benzamidopropanol.1314
(c) 1,3-4H-Oxazine is also hydrolyzed by water particularly in the presence of acids.1314
3. 6-Aryl-6-alkyltetrahydro-1,3-oxazines when warmed with concentrated hydrochloric acid undergo rearrangement to piperidinols.1315, 1316
4. In basic medium, 5-nitro-5-hydroxymethyltetrahydro-1,3-oxazine couples with aryl diazonium salt to afford an arylazo compound with elimination of a molecule of formaldehyde.
314
2. Six-Membered Heterocycles
5. Catalytic hydrogenation of oxazine in the presence of Adam’s catalyst in ethanol at atmospheric pressure led to an amide.1317
Reduction of 2H-1,3-oxazine derivative with NaBH3CN in THF/AcOH at 20–50°C after basic hydrolysis yielded 1,3-aminoalcohol as a single stereoisomer, which on further reduction with LiAlH4 yielded an aminodiol derivative. Cyclocondensation of aminoalcohol with aqueous formaldehyde afforded tetrahydroxazine.1318
6. 1,3-Oxazines by hydride abstraction are readily converted to oxazinium cations, which are stable species and can readily be attacked by nucleophiles to yield a variety of products.1319–1321 By reacting oxazinium cation with ammonia and benzyl magnesium bromide, ring opening takes place followed by cyclization.
2.8.4 1,4-Oxazine
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
315
In the 1,4-oxazine series, only the 4H and 2H isomers are known and they are in equilibrium with each other. Besides the two isomers there are several other oxo, thioxo, imino, di, and tetrahydro derivatives, which are known. 1,4-Oxazines are not aromatic and they exist in boat conformation. Structural and Reactivity Aspects1322 X-ray crystal analysis of tert-butylmethyl 4H-1,4-oxazine-3,4-dicarboxylate suggests the flat boat conformation of this original antiaromatic system. The bond lengths of tert-butylmethyl 4H-1,4-oxazine-3,4-dicarboxylate and tert- butyl 4H-1,4-oxazine-4-carboxylate are shown in the following figure confirming the structure of the molecule.
Bond lengths of 1,4-oxazine derivatives.
The 1H and 13C NMR of the parent 4H-1,4-oxazine were recorded, which further proved the complete structure. H and 13C NMR spectral data of 4H-1,4-oxazine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-2, 5.29; H-3, 5.19; N-H, 2.9
C-2, 126.4; C-3, 114.5
Importance in Natural Products, Medicines, and Materials The 1,4-oxazine scaffold is a structural unit of a number of naturally occurring and synthetic compounds and they have been reported to have diverse biological activities like antiulcer, antihypertensive, antifungal, and a nticancer.1323 A number of tricyclic 1,4-oxazines have been evaluated as dopamine agonists with selectivity for D2 receptors thereby making them therapeutically important candidates for the treatment of Parkinson’s disease.1324 A number of drugs are available in the market with the presence of the 1,4-oxazine skeleton. Reboxetine is a drug used as an antidepressant,; timolol, as an eye drop, is used to treat high pressure inside the eye during ocular hypertension and glaucoma, and when taken orally it is used to treat high blood pressure; aprepitant is used to treat nausea and vomiting associated with highly emetogenic cancer chemotheraphy; phendimetrazine is used as an appetite suppressant; and dextromoramide is a powerful opioid analgesic.
Drugs containing 1,4-oxazine skeleton.
316
2. Six-Membered Heterocycles
Synthesis 1. Synthesis of the parent 1,4-4H-oxazine was reported for the first time by Aitken et al. The monosubstituted oxazine synthesized by Coudert et al. was subjected to flash vacuum pyrolysis (FVP) at 450°C yielding the parent 4H-1,4-oxazine.1322
2. Fusing diglycolic acid with ammonium carbonate yields morpholine 3,5-dione, which was converted to an N-protected derivative, the N-Boc morpholine 3,5-dione. Treatment of N-Boc derivative with potassium bis(trimethylsilyl)amide (KHDMS) in the presence of hexamethylphosphoramide (HMPA) at −78°C afforded the bisvinylphosphate derivative, which on reduction in the presence of palladium acetate yielded 4-(tert-butoxycarbonyl)-[1,4]-oxazine.1325
3. A metal- as well as solvent-free protocol for hydroalkoxylation of alkynyl alcohols with sodium hydride leads to stereospecific synthesis of 1,4-oxazines with one as well as two chiral carbon centers. The desired alkynyl alcohol was obtained by reaction of aldehyde with Grignard reagent by following Cram’s rule.1326
4. Partial hydrogenation of N-phenacylideneaniline in the presence of palladium on carbon afforded N-3,4,6-tetraphenyl-4H-1,4-oxazin-2-amine.
5. Cyclodehydration of N,N-diphenacylaniline with excess phosphoryl chloride affords 2,4,6-triphenyl- 4H-1,4-oxazine.
6. Diphenacyl ether reacts with ammonia in ethanol to form 3,5-diphenyl-2H-1,4-oxazine.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
317
Chemical Reactivity 1. Tautomerism: Heating 3,5-diphenyl-2H-1,4-oxazine with acetic anhydride in pyridine at 100°C results in tautomerization to the 4H- form, which is trapped by N-acetylation to yield 3,5-diphenyl-4H-1,4-oxazine.1327
2. Metalation: Treatment of 4-substituted 4H-1,4-oxazine with butyllithium at −78°C leads to regioselective deprotonation at C-3, resulting in the formation of a 3-lithio derivative, which subsequently reacts with different electrophiles to form 3,4-disubstituted-4H-1,4-oxazines.1325
3. Stille or Suzuki reaction: Bisvinylphosphate was subjected to Stille or Suzuki reaction with a tin reagent in the presence of catalytic Pd-(PPh3)4 and anhydrous LiCl in refluxing THF yielding the 3,5-disubstituted vinyl derivative.1325
4. tert-Butyl 2-formyl-3,5-diphenyl-4H-1,4-oxazine-4-carboxylate was subjected to Wittig reaction, which resulted in the formation of conjugated diene in good yield.1325
5. tert-Butyl 2-iodo-3,5-diphenyl-4H-1,4-oxazine-4-carboxylate undergoes a Sonogashira coupling reaction with prop-2-yn-1-ol in the presence of palladium catalyst to yield an alkynyl derivative.
6. Michael addition reaction: 1,4-Oxazine underwent a Michael-type nucleophilic addition reaction with 4-methoxyphenol and thiophenol, resulting in the formation of a single diastereomeric product in good yield. The 2,3-trans-stereochemistry was confirmed on the basis of NMR spectroscopy.1328
318
2. Six-Membered Heterocycles
7. Nucleophilic addition: A secondary amine on reaction with α,β-unsaturated methyl ester resulted in the opening of the heterocyclic ring via an addition-elimination process and delivered enamines as a mixture of Z- and Eisomers in good yield.
Nucleophilic addition of benzylamine to α,β-unsaturated methyl ester afforded the tetrahydropyrazinol in quantitative yield. The structure of tetrahydropyrazinol was confirmed by X-ray analysis.
8. William-Ben Ishai Amino acid synthesis: Synthesis of α-amino acid takes place through the intermediate formation of 1,4-oxazine-2-one. The process involves nucleophilic addition of tert-butyldimethylsilylketene acetal followed by hydrogenolysis to afford the amino acid.1329
2.8.5 Morpholine
Morpholine also referred to as 1-oxa-4-aza-cyclohexane, tetrahydro-1,4-oxazine, or diethylenimide oxide and is thought to be derived from tetrahydropyran by replacing one methylene group by NH. Structural and Reactivity Aspects1330 Like cyclohexane, morpholine prefers the chair conformation. In the stable chair conformation the hydrogen atom bonded to nitrogen can occupy either the axial or equatorial position. However, on the basis of X-ray analysis the H-atom bonded to nitrogen preferably exists in equatorial conformation.1331
Conformations of morpholine.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
319
Primary bond distances (in Å) and angles (in degrees) are given in the following table. Bond length
Bond angle
O1C2: 1.432
C6O1C2: 110.32
C2C3: 1.516
O1C2C3: 111.31
C3N4: 1.466
C2C3N4: 108.69
N4H: 0.89
C3N4C5: 109.25
N4C5: 1.468
N4C5C6: 108.43
C5C6: 1.510
C5C6O1: 111.41
O1C6: 1.424
The 1H and 13C NMR spectral data of morpholine are given in the following table. H and 13C NMR spectral data of morpholine
1
1
H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H2, 3.65; H-3, 2.80; N-H, 1.92
C-2, 68.1; C-3, 46.7
Importance in Natural Products, Medicines, and Materials Morpholine and its derivatives have received worldwide attention due to their remarkable and wide variety of applications. The morpholine nucleus is present in a wide variety of natural products.1332 For example, alkaloid polygonapholine isolated from the rhizome of Polygonatum altelobatum is used as a tonic by the Taiwanese.1333 Two alkaloids, chelonin A and chelonin C, were isolated from the marine sponge Chelonaplysilla sp., while chelonin A was found to exhibit antimicrobial activity against Bacillius subtilis and also has antiinflammatory effects.1334 Two spiroalkaloids, acortatarin A and acortatarin B, isolated from the rhizome of Acorus tatarinowii were presumed to be valuable starting compounds for designing new antidiabetic and anticancer drugs.1335
Natural products containing morpholine skeleton.
A number of morpholine-based compounds are of commercial interest because they are easily available in the market as drugs and fungicides. For example, viloxazine and reboxetine are effective antidepressants, linezolid is an antibiotic for the treatment of Gram-positive bacteria, gefitinib is used for the treatment of breast and lung cancer, and dextromoramide is an analgesic.
320
2. Six-Membered Heterocycles
Drugs containing morpholine skeleton.
A number of morpholine derivatives like amorolfine, fenpropimorph, and tridemorph find use as agricultural fungicides.
Agricultural fungicides possessing morpholine skeleton.
Synthesis 1. On an industrial scale, morpholine is produced by dehydration of diethanolamine with sulfuric acid. It is also prepared by reaction of dichlorodiethyl ether with ammonia at 50°C and 1750 psi pressure.1336
2. Disubstituted morpholines are prepared by reaction of N-benzyl-2-aminoethanol with oxirane in the presence of 70% sulfuric acid followed by catalytic debenzylation.
3. (R)-2-Benzylmorpholine, an appetite suppressant agent, was synthesized from 2-bromo-3-phenylacrylaldehyde. The process involves reduction of 2-bromo-3-phenylacrylaldehyde with baker’s yeast to 2-bromo-3phenylpropanol. Bromo alcohol on treatment with a base gave 2-benzyl oxirane, which on treatment with ethanolamine sulfonate under basic conditions resulted in the opening of the oxirane ring to sulfate ester. Sodium hydroxide treatment of sulfate ester afforded (R)-2-benzylmorpholine.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
321
An alternate method for the synthesis of (R)-2-benzylmorpholine employing Sharpless asymmetric epoxidation has also been reported.1337 4. Enantiomerically pure morpholine-3,4-dimethyl-2-phenylmorphine has been synthesized by reaction of 2-methylamino-1-phenyl-propan-1-ol (L-ephedrine) with chloroethanol.1338
5. Synthesis of cis-3,5-disubstituted morpholines from enantiomerically pure amino alcohols has been reported. The key step of the reaction is generation of the substrate by a Pd-catalyzed carboamination reaction between N-protected amino alcohol with NaH and allyl bromide; cleavage of the Boc group followed by Pd-catalyzed Narylation of the resulting amine trifluoroacetate salt provided the substrate. The desired morpholine heterocycle is obtained through Pd-catalyzed coupling with an aryl or alkenyl halide.1339
6. Petasis coupling reaction: A three-component coupling reaction between protected amino alcohol with glyoxal and phenyl boronic acid afforded 2-hydroxymorpholines.1340
7. A one-step protocol for the synthesis of morpholine involving reaction of diphenyl vinyl sulfonium salts with protected amino alcohols has been reported.1341
Physical Properties Morpholine is a colorless, hygroscopic liquid with a bp of 128.3°C. It is soluble in water in all proportions but not in strong alkali. Chemical Reactivity 1. Enamine formation: A general method for the synthesis of enamines from secondary amine involves refluxing morpholine with cyclohexanone and p-toluenesulfonic acid in toluene yielding 1-morpholino-1-cyclohexene.1342
322
2. Six-Membered Heterocycles
The enamines formed have been utilized for carrying out acylation, for example, acylation of cyclopentanone through enamine formation.1343
2. N-alkylation and arylation: Morpholine can be alkylated and arylated by several methods. Dialkyl sulfates, trialkyl phosphates, alkyl halide, and aryl halide are the effective reagents.
3. Morpholine undergoes Michael-type nucleophilic addition across α,β-unsaturated compounds (1) in the presence of a catalytic amount of silica-supported aluminum chloride at 60°C under solvent-free conditions or (2) under solvent- and catalyst-free conditions to afford β-amino compounds in excellent yield.1344, 1345
4. Reaction with epoxides: Morpholine reacts with oxirane rings to give corresponding β-4-morpholine alkanols.
Regio- and stereoselective epoxide ring opening of N,N-disubstituted-1,2-epoxy-3-aminocyclopentane using Lewis acid catalyst resulted in the formation of diaminocyclopentanols.1346
5. Nitration: N-Nitromorpholine is prepared by heating morpholine with acetone cyanohydrin nitrate.1347
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
323
6. Willgerodt-Kindler reaction: The reaction of aryl alkyl ketone with elemental sulfur and an amine like morpholine yields a thioacetamide, which on hydrolysis yields amide.1348, 1349
7. Mannich reaction: Morpholine like other secondary amines reacts with aldehydes to give Mannich-type condensation reactions.1350
8. Morpholine on reaction with sodium hypochlorite yields N-chloromorpholine, which on reaction with 2-chloromethoxybenzene in the presence of 80% sulfuric acid gave 2,4-dichloromethoxybenzene.1351
9. Leuckart-Wallach reaction: Addition of formic acid to a mixture of aldehyde and morpholine results in reductive alkylation of morpholine.
10. 4-Nitrophenyltriflate under high pressure undergoes an addition elimination reaction with morpholine.1352
11. Excess of morpholine on treatment with glyoxal or its monohydrate produced 1,1,2,2-tetramorpholine.1353 It is an exothermic reaction.
12. 6-Aryl-methylthio-2H-pyran-2-one-3-carbonitrile on reaction with morpholine in refluxing ethanol provided 6-aryl-4-morpholino-2H-pyran-3-carbonitrile.1354
324
2. Six-Membered Heterocycles
Thiazines Thiazine is a six-membered, unsaturated, nonconjugated heterocycle containing four carbons, one sulfur, and one nitrogen atom with two olefinic bonds in the ring. There are three isomeric thiazines: 1,2-thiazine, 1,3-thiazine, and 1,4-thiazine, which differ by the arrangement of sulfur and nitrogen atoms in the ring.
2.8.6 1,3-Thiazine
Structural and Reactivity Aspects The 1H and 13C NMR spectral data of thiasporin A, a 1,3-thiazine derivative are given in the following table.1355 1 H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
H-3, 6.79 (d); H-4, 7.10 (t); H-5, 6.56 (t); H-6,7.51 (d)
C-1, 114.4; C-2, 146.5; C-3, 116.1; C-4, 130.2; C-5, 115.2; C-6, 128.4; C-7, 166.4; C-9, 118.7; C-10, 164.2; C-11, 157.7
Importance in Natural Products, Medicines, and Materials 1,3-Thiazine is an unsaturated heterocyclic compound with sulfur and nitrogen at the 1- and 3-positions of the ring. Because an NCS linkage is present in the molecule, it has been reported to be useful in the field of pharmaceutical and medicinal chemistry. Recently, a natural product, thiasporine A, containing this nucleus, isolated from a marine-derived Actinomycetospora chlora, showed cytotoxicity1355 against the nonsmall-cell lung cancer cell line H2122 with an IC50 value of 5.4 μM. 1,3-Thiazine is also part of the framework of cephalosporins—an important class of β-lactam antibiotics, xylazine-agonist at the α-2 class of adrenergic receptor, which is used for sedation, anesthesia, and as a muscle relaxant. Chlormezanone-marketed as trancopal, used as anxiolytic and a muscle relaxant.
Drugs containing 1,3-thiazine nucleus.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
325
Synthesis 1. From thiourea or thioamides: Acetophenone on Claisen-Schmidt condensation reaction with aryl aldehydes yields chalcones, which on treatment with thiourea undergo cyclocondensation in a basic medium to yield a 1,3-thiazine derivative.
Heating 2-nitropropane-1,3-diol with thiourea yields 5-nitro-2H-1,3-thiazine-2-imine.
Reaction of 4-methylpent-3-en-2-one with thiourea in the presence of hydrogen bromide yields 4,6,6-trimethyl-3H-1,3-thiazine-2(6H)-imine.
Reaction between thiourea and acetylene monocarboxylates in methanol yields 1,3-thiazin-4-one in good yield.1356
Thioacetamide reacts with aromatic aldehyde to form a N-thiacyl imine heterodyne derivative, which undergoes hetero Diels-Alder reaction with alkenes to form a 1,3-thiazine derivative.
2. Hetero-Diels-Alder reaction: Reaction of 3-aza-4-dimethylamino-1-thiabutadienes with acrylates by heating or under high pressure results in the formation of substituted 5,6-dihydro-4H-1,3-thiazine.
326
2. Six-Membered Heterocycles
Thiazines are also obtained by reaction of alkynes with heterodienes.1357–1359
3. Allylamine derivatives react with arylisothiocyanate to form an allyl thiourea derivative, which undergoes intramolecular cyclization by Sulfa-Michael reaction to yield 2-amino substituted-5,6-dihydro-4H-1,3-thiazine.
4. 5,6-Dihydro-4H-1,3-thiazines were synthesized by a boron trifluoride etherate-catalyzed reaction of α,β-unsaturated ketones with thiobenzamide. The synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv(ATCC 27294) using Alamar blue susceptibility assay.1360
5. A three-component reaction involving thiobenzamide, benzaldehyde and 1-hexene resulted in the formation of 1,3-thiazine derivatives. The reaction takes place via a hetero-Diels-Alder reaction affording two diastereoisomers—endo- and exo-1,3-thiazines.1361
Chemical Reactivity 1. Rearrangement: By heating 2-amino-1,3-thaizine to 145°C, it rearranges to 3,4-dihydropyrimidine-2-thione.1362
2. Dimroth rearrangement: 2-Amino-6H-1,3-thiazines with an ester group at C-5 undergo Dimroth rearrangement to 3,4-dihydropyrimidine-2-thiones. The rearrangement was carried out under microwave conditions employing either toluene or 1-methyl-2-pyrrolidone as solvent.1363
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
327
3. Staudinger reaction: The diastereoisomeric endo- and exo-1,3-thiazines on reaction with chloroacetyl chloride in the presence of triethylamine in refluxing toluene were transformed by stereoselective Staudinger reaction into corresponding chloro-β-lactam-condensed-1,3-thiazine. However, the endo-chloro-β-lactam-condensed-1, 3-thiazine was obtained under basic conditions.1361
2.8.7 1,4-Thiazine
1,4-Thiazine is an unsaturated, six-membered, nonconjugated heterocyclic compound with four carbon atoms, one nitrogen atom and one sulfur atom at the 1,4-position (opposite corners) of the ring. Structural and Reactivity Aspects Conformational studies of tetrahydro-1,4-thiazine-1,1-dioxides using 1H and 13C NMR studies suggest that the molecule exists in chair conformation with equatorial orientation of the substituents.1364
The 1H and 13C NMR spectral data of 5-acetyl-2,3-dihydro-1,4-thiazine is given in the following table. 1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.01; H-3, 3.51; H-6, 6.19
C-2, 26.6; C-3, 40.9; C-5, 135.6; C-6, 106.5
Importance in Natural Products, Medicines, and Materials The 1,4-thiazine derivative chondrine and 1,4-thiazine-1,1-dioxide have been isolated from the red alga Chondria crassiacaulis and marine sponge Anchinoe tenacior, respectively. Besides a novel thiazine derivative, 5-acetyl-2,3- dihydro-1,4-thiazine with an intense popcorn-like odor has been isolated from an aqueous ribose/cysteine solution.
Natural products containing 1,4-thiazine skeleton.
328
2. Six-Membered Heterocycles
Synthesis 1. Heating ammonium 2,2′-thiodiacetate affords 3,5-dihydroxy-2H-1,4-thiazine, which is passed over alumina on pumice at 450°C to yield 2H-1,4-thiazine.1365
2. L-1,4-Thiazine-3-carboxylic acid has also been synthesized. The process involves reaction of bromoethanol and l-cysteine in the presence of sodium in liquid ammonia to give S-(2-hydroxyethyl)-l-cysteine, which on heating with hydrochloric acid gave S-(2-hydroxyethyl)-l-cysteine hydrochloride. Cyclization in the presence of dimethylformamide-triethylamine afforded the thiazine derivative.1366
3. When benzyl (S)-N-benzyloxycarbonyl-2-aziridine carboxylate is reacted with 2-chloroethanol in dichloromethane in the presence of a catalytic amount of BF3-etherate, ring opening takes place and the intermediate N-benzyloxycarbonyl-O-(2-chloroethyl)cysteine benzyl ester was obtained. The benzyloxycarbonyl and benzyl ester group were removed by catalytic hydrogenation followed by cyclization in the presence of triethylamine to afford tetrahydro-2H-1,4-thiazine-3-carboxylic acid.1367
4. Reaction of substituted 3-aminoacrylates with S2Cl2 or SCl2 affords bis(2-aminovinyl)sulfides, which on cyclization forms diethyl 3-amino-3,5-bis(trifluoromethyl)-2H-1,4-thiazine-2,6-dicarboxylate. Loss of ammonia yields diethyl 3,5-bis(trifluoromethyl)-2H-1,4-thiazine-2,6-dicarboxylate.1368
5. Reaction of a solution of chloroacetone in methyl ethyl ketone with thioglycolamide in the presence of triethylamine affords 5-methyl-2,3-dihydro-4H-1,4-thiazine-3-one, which on reaction with phosphorous pentasulfide in pyridine afforded thiolactam. Alkylation of thiolactam with triethyloxonium tetrafluoroborate afforded 3-ethylthio-5-methyl-2H-1,4-thiazine.1369
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
329
Chemical Reactivity 1. 3,5-Disubstituted-2H-1,4-thiazine, when heated in ethanol solution containing picric acid or nitrobenzene, underwent oxidative coupling at the 2-position giving 2,2′-bithiazines.1370
2. Treatment of diethyl 3,5-bis(trifluoromethyl)-2H-1,4-thiazine-2,6-dicarboxylate with triethylamine provided corresponding pyrroles in good yield.
3. Reaction of 3-ethylthio-5-methyl-2H-1,4-thiazine with p-toluidine in the presence of a trace of acid afforded 3-p-tolylamino-5-methyl-2H-1,4-thiazine.1369
4. Reaction of 4,5-dimethyl-2,3-dihydro-1,4-thiazine-4-one with methyl iodide in anhydrous acetone afforded 3-methylthio-4,5-dimethyl-2H-1,4-thiazinium iodide, which on treatment with potassium tert-butoxide followed by reaction with an excess of methyl iodide resulted in the formation of 3-methylthio-4,4,5-trimethyl-1,4thiazinium iodide.1369
+
330
2. Six-Membered Heterocycles
2.8.8 Phenoxazine
Phenoxazine or 10H-phenoxazine is a tricyclic heterocyclic compound in which oxazine is fused on each side by the benzene ring. Structural and Reactivity Aspects1371a Pheoxazine in not planar but slightly folded along the axis, which passes through the two central heteroatoms. The hydrogen atom bonded to the nitrogen may be placed either between or out of the planes of the two rings, producing two molecular geometries, which may be called H-intra and H-extra.
The 1H NMR spectrum of phenoxazine showed aromatic proton signals from δ 6.7 to 7 (m) and a singlet for the NH proton at δ 8.2. The UV spectra of phenoxazine shows bands at λmax 239 (log ε 4.66), which is due to π→π* transition, and at λmax 318 (log ε 3.93), which is due to n→π* transition. The IR spectrum of phenoxazine, besides the ring stretching modes from 1450 to 1630 cm−1, also reveals a strong NH stretching frequency at 3342 cm−1. Importance in Natural Products, Medicines, and Materials Phenoxazine is important because this nucleus is present in a large number of naturally occurring compounds like dactinomycin or actinomycin D, which is used to treat a number of types of cancer. Phenoxazine derivatives find use as drugs, sedatives, tranquilizers, central nervous system depressants, and antitumor agents. They are also used as colorants in the textile industry and as laser dyes. Synthesis 1. The classical method for the synthesis of phenoxazine is based on Bernthensen’s synthesis, which involves pyrolytic condensation of o-aminophenols with catechols.
2. Phenoxazine was synthesized in good yield by heating an equimolar mixture of o-aminophenol and its hydrochloride.1371b
The reaction was proposed to proceed through formation of o,o'-dihydroxydiphenylamine as intermediate, which was isolated and characterized.1372A better procedure for the synthesis of unsubstituted phenoxazines involves autocondensation of o-aminophenol in the presence of iodine with the elimination of ammonia and water.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
331
3. Turpin reaction: Originally the reaction is based on the condensation of 2-aminophenol with picryl chloride to give 2-nitrophenoxazine.1373 The reaction takes place with the intramolecular displacement of the 2-nitro group by the phenoxide group at the 2-position.
Turpin’s reaction has been widely used for the synthesis of substituted phenoxazines.1374–1376 4. 2-Chloronitrobenzenes react with phenols containing nitro or methoxy groups at the ortho-position to yield 2,2′-disubstituted diphenyl ethers, which were catalytically reduced and demethylated to yield phenoxazines.1377, 1378
In place of 2-methoxy phenol, 2-bromophenol may also be used, which reacts with 2-chloronitrobenzene under basic conditions to give 2,2′-disubstituted diphenyl ether. Reduction of the nitro group with stannous chloride or iron filings in acetic acid followed by ring closure by heating in DMF solution in the presence of copper and potassium carbonate offered phenoxazine.
5. Reaction of 1-halo-2-nitrobenzene with 2-chloro-3-hydroxybenzoic acid afforded diphenyl ether as intermediate. Reduction of a nitro intermediate followed by formylation and hydrolysis yielded the title compound.1379
6. Palladium-catalyzed tandem CN bond formation between aryl halide and primary amine via an intermolecular/intramolecular process allowing one-pot synthesis of phenoxazine derivative has been reported.1380
332
2. Six-Membered Heterocycles
7. 2-Chlorophenoxazine has been reported to partially reverse VLB resistance in MDR carcinoma cell line GC3/ c1 and completely reversed the 86-fold VLB resistance in MDR-1 overexpressing breast carcinoma1381 cell line BC 19/3. A new and efficient synthesis of 2-chlorophenoxazine has been reported1381, 1382 by the reaction of 2-bromophenol with 2,5-dichloronitrobenzene using KOH as a base forming an intermediate, which after reduction followed by cyclization in formic acid afforded the title compound.
Physical Properties Phenoxazine is a green-gray powder with mp of 154–159°C. It is soluble in most organic solvents. Its solution in concentrated sulfuric acid shows violet or violet-red fluorescence. Chemical Reactivity 1. Electrophilic substitution (a) Bromination: Phenoxazine on reaction with bromine in benzene afforded 3-bromo- and 3,7-dibromophenoxazine.1383
(b) Chlorination: Phenoxazine on chlorination with thionyl chloride gave tetrachlorophenoxazine.1384
(c) Nitration: Phenoxazine reacts violently with dilute nitric acid to yield tetranitrophenoxazine.1385
(d) Friedel-Crafts acylation: Condensation of phenoxazine with acetyl chloride in the presence of aluminum chloride yielded 3-acetylphenoxazine as a minor component and 10-acetylphenoxazine as a major component.1386
2. Nucleophilic substitution: Phenoxazine is slowly metalated by n-butyllithium in ether. Metalation followed by carbonylation of phenoxazine yields phenoxazine-4-carboxylic acid.1387
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
333
3. Oxidation: In acidic solution, phenoxazine is oxidized by a variety of reagents like potassium permanganate, hydrogen peroxide, bromine, etc. to form a radical cation (A), which on neutralization or basification deprotenates to radical (B). The radical either polymerizes to polyphenoxazine or oxidizes to phenoxazine3(3H)-one (C).1383, 1388
4. Vilsmeier-Haack reaction: 10-Ethylphenoxazine reacts with N-methylformanilide in the presence of phosphorous oxychloride in 1,2-dichlorobenzene to afford 3-formyl 10-ethylphenoxazine.1389
Phenoxazine reacts with tetracyanoquinodimethane (TCQD) to afford α,α′-di( 3-phenoxazinyl)-p- phenylenedimalononitrile and p-phenylenedimalonitrile. The reaction is proposed to take place in two steps. In the first step an intermediate 1,6-addition product (A) is formed, which undergoes oxidation to give radical (B). In the next step the radical then reacts with phenoxazine to give the product.1390
334
2. Six-Membered Heterocycles
2.8.9 Phenothiazine
Phenothiazine also known as 10H-dibenzo-1,4-thiazine, is a tricyclic heterocycle in which 1,4-thiazine ring is fused with two benzene rings at 2,3 and 5,6 positions. Structural and Reactivity Aspects The complete structure of phenothiazine was established by using X-ray crystallography.1391 The X-ray analysis of this heterocycle shows that the molecule has a folded configuration with the dihedral angle between the two planes of the benzene ring being 158.5°. The bond distances (in Å) and bond angles in degrees are shown in the figure given below
The 1H and 13C NMR spectral data1392,1393 of phenothiazine are given below. 1 H NMR(CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1/9: 6.62; H-2/8: 6.93; H-3/7: 6.74; H-4/6 6.89
C-1/9: 114.48; C-2/8: 127.40; C-3/7: 122.62; C-4/6: 126.82; C-1a/9a: 141.79; C-4a/6a: 118.33
Importance in Natural Product, Medicine and Materials The chemistry of phenothiazines has received a considerable importance due to their extremely important therapeutic properties. Methylene blue, an azine dye was earlier used for the treatment of malaria. Phenothiazines exhibit a complex range of action on the central nervous system (CNS). They act on CNS by inducing sedative and antiemetic effect, affecting skeletal muscles, endocrine system and also potentiating the action of analgesics. Some of the well-known drugs of this category are chlorpromazine, promazine, acetophenazine, perphenazine, thioridazine etc.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
335
Synthesis (i) Phenothiazine is synthesized by reaction of diphenylamine with sulfur in the presence of aluminum chloride as a Lewis acid catalyst.
(ii) By Smiles rearrangement: Reaction of 2-chloronitrobenzene with 2-aminobenzenethiol in an alkaline medium yields the corresponding 2-amino-2′-nitrodiphenyl sulfide, which on treatment with carboxylic acids provides an N-acetylated product. The resulting 2-acetamido-2′-nitrodiphenyl sulfide undergoes Smiles rearrangement under alkaline conditions, followed by intramolecular cyclization to yield phenothiazine.1394,1395
NO2 Cl
H2N
NO2 NH2 RCOOH
+ HS
S
NO2 NHCOR S
OH Smiles rearrangement
H N S
–HNO2
COR N NO2 S
Furthermore, a thermal Smiles rearrangement of 1′-amino-4-methyl-2-nitrodiphenyl sulfide was also carried out at 90°C to generate 3-methylphenothiazine. This reaction was thought to be proceeded by following mechanism.1396
This synthetic strategy has been successfully extended to synthesize 2-chlorophenothiazine1397 as a precursor for the synthesis of a neuroleptic drug, chlorpromazine.
(iii) Ullmann type synthesis: This synthetic protocol involves a reaction of 2-halonitrobenzene with 2-halothiophenol to yield 2-halo-2′nitrodiphenyl sulfide which on standard reduction conditions forms 2-halo-2′aminodiphenyl sulfide. Finally, phenothiazine is obtained either by Ullmann reaction or via benzyne intermediate.1398,1399
336
2. Six-Membered Heterocycles
This procedure has also been found to be useful for the synthesis of 2-chlorophenothiazine as depicted in the following scheme. Cl
NO2 Cl
Br
Br NO2
+ HS
S
Cl
Br NH2 Red
Cl
S Ullmann reaction H N Cl S
(iv) In another approach, 10-phenyl phenoxazine is synthesized in excellent yield through a palladiumcatalyzed tandem C-N bond formation reaction between 2,2′-dibromophenyl sulfide and aniline in a one-pot operation.1400 This reaction possibly proceeds via a nucleophilic aromatic substitution in the first step followed by intramolecular cyclization to afford the desired product.
Physical properties Phenothiazine is a light yellow crystalline solid with an mp 180–181°C. It is insoluble in water, sparing soluble in ethanol but easily soluble in other organic solvents. It has a faint but bitter taste. Chemical reactions (i) N-Substitution: Due to the diverse pharmacological profiles associated with 10-substituted phenothiazines, much work has been done on the functionalization of secondary amine functionality of this molecule. The replacement of amine hydrogen has been carried out by using a variety of alkylating agents1401–1403 such as alkenes, alkynes and alkyl/aryl halides and acylating agents1404 such as carboxylic acid, chlorides and anhydrides as depicted in the scheme.
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
337
Similarly, ethyl 2-(10H-phenothiazine-10-yl)acetate was prepared by heating a mixture of phenothiazine and ethyl bromoacetate in presence of potassium carbonate and copper powder.1405
Further, this N-substitution protocol has widely been adopted for the synthesis of numerous drug molecules and some representative syntheses are given in the following schemes. S +
CH2 CH2 CH2 N
Cl
N H
CH3
S
NaNH2
CH3
N CH2 CH2 CH2 N Promazine
S H3CS
S
(CH3CO)2O
N H
H3CS
H3CS O
N CH2CH2Cl CH3
N CH2CH2 H3 C Mesoridazine
N COCH3
K2CO3/CH3OH
S H3CS O
CH3
S
H2O2
N COCH3
CH3
H3CS O
NaNH2
N
S N H
(ii) Electrophilic substitution reaction: From π-electron charge densities calculation, it was established that position 3 is more reactive as compared to position 1, but due to ease of oxidation, the electrophilic substitution reaction on thiaphenozine scaffold is often complicated by the side reactions. (a) Halogenation: Phenothiazine on chlorination in dimethyl sulphoxide at 40°C affords 3,7-dichlorophenothiazine.1406 H N S
H N
Cl2, DMSO 40oC
Cl
S
Cl
However, when chlorination is carried out in presence of cupric chloride, 1,7-dichlorophenothiazine is obtained as a product.
338
2. Six-Membered Heterocycles
Additionally, bromination of 10-phenylphenothiazine in acetic acid, yields a mixture of 3-bromo-10- phenylphenothiazine and 3,7-dibromo-10-phenylphenothiazine.1407
Iodination: Bromine-lithium exchange of mono- and dibromophenothiazines on electrophilic trapping with iodine furnishes 3-iodo- and 3,7-diiodophenothiazines, respectively in excellent yields.1408
(b) Nitration: Phenothiazine on nitration with fuming nitric acid at 0°C gave 3,7-dinitrophenothiazine sulfoxides.1409
(c) Friedel Craft acylation: Reaction of phenothiazine with acetyl chloride in the presence of aluminium chloride as catalyst in boiling carbon disulphide affords 2,10-diacetylphenothiazine. When acetyl chloride is used in excess then 2,8,10-triacetylphenothiazine was isolated.1410
(iii) Reaction with nucleophiles: Phenothiazine on metallation with butyl lithium followed by treatment with carbon dioxide yields phenothiazine-1-carboxylic acid.1411
(iv) Oxidation: Phenothiazine can be oxidized by a number of oxidizing agents, which often result in a variety of products. Phenothiazine on oxidation first forms radical cation (A), which deprotonated in the presence of base to phenothiazinyl radical (B). Alternatively, phenothiazine also forms phenothiazonium cation (C) under oxidation and deprotonation conditions. In strong acidic medium, cation (C) can be converted to dication (D).1412,1413 However, the oxidation of phenothiazine is believed to proceed via comparatively more stable phenothiazinyl radical (B), which in fact dimerizes involving two resonating phenothiazine radical species to afford a stable product. Furthermore, the formation of these cationic and radical cationic species can also be observed visually via a color change in the solution. Phenothiazine gives a golden colored solution immediately when dissolves in concentrated sulfuric acid due to the formation of radical cation (A). On standing for several days the colour of solution changes to green because of the conversion of radical cation
2.8 Six-Membered Isolated and Benzo-Fused Heterocycles With Mixed Heteroatoms
339
(A) to dication (D) after the loss of one electron. Further, on dilution the color changes to red-brown which indicates the formation of phenothiazonium cation (C) in the solution.1414
Phenothiazine on oxidation with hydrogen peroxide in acetone followed by base treatment yields phenothiazine 5-oxide.1415
Phenothiazine on oxidation with aqueous acid affords phenothiazine -3(3H)-one. It was proposed that initially mesomeric phenothiazonium cation (E) was formed which on nucleophilic attack by water at C-3 gives an intermediate, which on further oxidation and deprotonation yields the desired product.1416,1417
(v) Duff formylation: Microwave assisted Duff formylation of phenothiazine with urotropine in acetic acid afforded 10(H)-3-formylphenothiazine in excellent yield.1418 This process requires shorter reaction time in comparison to conventional reaction protocol.
340
2. Six-Membered Heterocycles
2.9 SIX-MEMBERED HETEROCYCLES WITH TWO OXYGEN OR SULFUR ATOMS 2.9.1 Dioxane Dioxanes are six-membered, nonplanar, nonaromatic saturated heterocycles with two oxygen atoms replacing two methylene groups (CH2) of the cyclohexane ring. Depending on the position of both oxygen atoms in the ring there are three possible isomeric forms, designated as 1,2-, 1,3-, and 1,4-dioxane.
2.9.2 1,3-Dioxane
1,3-Dioxanes or -m-dioxanes are cyclic acetals or ketals and are considered to be methylene ethers of 1,3-diols. Structural and Reactivity Aspects1419 It has been well established that 1,3-dioxane prefers to exist in chair conformation.1420 When a heteroatom is placed in a cyclohexane ring the bond lengths and bond angles changed. Thus in 1,3-dioxane the CO bond lengths shorten and the axial 1,3-hydrogens come closer in space, therefore there is greater van der Waals strain. Thus the cyclohexane ring is more stable in comparison to 1,3-dioxane, which has two heteroatoms.
The chair conformation of 1,3-dioxane was confirmed by X-ray crystallography of one of its derivatives 2-(p- chlorophenyl)-1,3-dioxane. The bonds lengths are comparatively shorter in comparison to cyclohexane. Hence 1,3-dioxane is more compact in comparison to cyclohexane. Bond lengths (in pm) and angles (in degrees) are shown in the following figure.
Bond lengths and bond angles in 1,3-dioxane derivative.
The 1H and 13C NMR spectra of 1,3-dioxane are given in the following table. H and 13C NMR spectral data of 1,3-dioxane
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 4.70; H-4/H-6, 3.80; H-5, 1.68
C-2, 95.4; C-4/C-6, 67.6; C-5, 26.8
Importance in Natural Products, Medicines, and Materials The importance of 1,3-dioxane originates from its structural features, its application in industrial and fine organic synthesis, and also its promising physiological properties. Special mention is made regarding the industrial application of this cyclic acetal in the production of isoprene, 1,3-diol, and a number of drugs.1421 1,3-Dioxane derivatives like cis-5-hydroxy-2-methyl-1,3-dioxane and trans-5-hydroxy-2-methyl-1,3-dioxane have been reported to be present in Spanish Fino sherry.1422
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
341
Synthesis 1. Prins reaction: Basically, Prins reaction is the acid-catalyzed addition of aldehydes to alkenes yielding different products depending on the conditions of the reaction. This reaction has also been used in the synthesis of 1,3-dioxanes. Reaction of 2-methylprop-1-ene with formaldehyde in the presence of aqueous sulfuric acid yields 4,4-dimethyl-1,3-dioxane as the major product.1423
The reaction has been proposed to take place by the following mechanism.
Polyaniline (PANI)-supported PTSA/FeCl3-catalyzed Prins reaction of paraformaldehyde with different alkenes in dichloromethane at different temperatures yields 1,3-dioxanes.1424
Prins reaction for 1,3-dioxane synthesis is also illustrated by condensation of isoeugenol with paraformaldehyde in the presence of a small amount of ion-exchange cationic resin as catalyst.1425
2. β-Haloacetals and ketals have been used as alkylating agents and in the preparation of Grignard reagents. 1,3-Dioxane is considered to be acetal, and the synthesis of their bromo derivatives has been reported.1426 The process involves reaction of acrolein with 1,3-propanediol in the presence of hydrogen bromide under nitrogen conditions yielding 2-(2-bromoethyl)-1,3-dioxane.
Similarly, 2,5,5-trimethyl-2-(2-bromoethyl)-1,3-dioxane is synthesized by reaction of methyl vinyl ketone with neopentanediol in the presence of gaseous hydrogen bromide.
3. Synthesis of chloro and bromo derivatives of 1,3-dioxane has also been reported.1427 The process involves heating 1-bromo-3-chloro-2,2-dimethoxypropane with 1,3-propanediol in the presence of concentrated sulfuric acid as catalyst yielding 2-(bromomethyl)-2-(chloromethyl)-1,3-dioxane.
342
2. Six-Membered Heterocycles
4. Alkenes undergo condensation with paraformaldehyde in the presence of indium tribromide in ionic liquids such as 1-butyl-3-methyl hexafluorophosphate or 1-butyl-3-methylimidozolum tetrafluoroborate to afford 1,3-dioxane derivatives in high yield.1428
5. Meldrum’s acid (2,2-dimethyl-1,3-dioxane-4,6-dione), which is a dioxane derivative, has attracted considerable attention as a reagent and intermediate in organic synthesis and is prepared by a reaction between acetone, malonic acid, and acetic anhydride.
6. Baylis-Hillman reaction: An important method for the synthesis of 1,3-dioxanes is via Baylis-Hillman reaction. The process involves reaction of phenyl acrylate with acetaldehyde in the presence of DABCO as catalyst forming an intermediate, which cyclizes with acetaldehyde to afford a 5-methylene-1,3-dioxane-4-one derivative.1429, 1430
7. Synthesis and stereochemistry of a novel 1,3-dioxane derivative is prepared by reaction of diacetylbenzene with 1,3-diol in the presence of a catalytic amount of p-toluenesulfonic acid. The anancomeric structure of these compounds, orientation of the groups bonded to the dioxane ring, and cis- and trans-isomerism of these compounds has been discussed on the basis of NMR and X-ray crystallography.1431
Physical Properties 1,3-Dioxane is a colorless liquid with a bp of 105°C. It is readily soluble in nearly all organic solvents.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
343
Chemical Reactivity 1. Hydrolysis: 1,3-Dixoane is hydrolyzed to 1,3-diols. The rate of the reaction is determined by the rate at which the cation A is formed.1432 3-Methyl-1,3-butanediol is obtained by stirring 2,2-dimethyl-1,3-dioxane with 2% sulfuric acid solution under reflux.1423
2. Protection: A simple, selective protection of both symmetrical and unsymmetrical substituted 1,3-diols obtained after cleavage of 1,3-dioxanes has been reported. The process involves regioselective cleavage of 1,3-dioxanes with acetyl chloride followed by conversion of the resulting chloromethyl ether acetate to an alkoxy methyl ether acetate.1433, 1434
Monoprotection is achieved by carrying out hydrolysis with potassium carbonate in the presence of methanol.
3. Synthesis of cyclopropenone 1,3-propanediol ketal: Cyclopropenone 1,3-propanediol ketal is stable and has proved to be a useful equivalent of the 1,3-dipole in a regiospecific three carbon + two carbon cycloaddition reaction with electron-deficient olefins.1435 The targeted compound1427 is synthesized by stirring an ether solution of 2-(bromomethyl)-2-(chloromethyl)-1,3-dioxane with freshly prepared potassium amide at −50 to −60°C.
4. Ring contraction: During nucleophilic displacement reaction of 5-hydroxy-2-methyl-1,3-dioxane, ring contraction is observed.1436
344
2. Six-Membered Heterocycles
5. Chiral synthesis: Several systems derived from 1,3-dioxane serve as chiral building blocks for stereoselective transformations. The cationic coupling of a 4-acetoxy-1.3-dioxane derivative with allyltrimethylsilane in the presence of boron trifluoride etherate yielded a product with anticonfiguration.1437
Similarly, 4-cyano-1.3-dioxane derivative was converted into a syn-derivative.1438
2.9.3 1,4-Dioxane
1,4-Dioxane, also known as p-dioxane, diethylene oxide, or 1,4-dioxacyclohexane, is a six-membered, saturated heterocyclic compound containing two oxygen atoms present at 1,4 positions of the cyclohexane ring. Structural and Reactivity Aspects1439 The 1,4-dioxane molecule, which is centrosymmetric, exists in chair conformation and this was also confirmed by the ab initio studies.1440 The CC and CO bond lengths are 152 and 142 pm, respectively, whereas the CCC and COC bond angles are 105 and 112 degrees, respectively.
The 1H and 13C NMR spectral data of 1,4-dioxane are given in the following table. H and 13C NMR spectral data of 1,4-dioxane
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2/H-3/H-5/H-6, 3.70
C-2/C-3/C-5/C-6, 67.8
Importance in Natural Products, Medicines, and Materials The 1,4-dioxane scaffold occurs in a wide range of natural products and pharmaceutical drugs. For example, compounds 1, II, III, IV, and V exhibit antiviral, anticancer, and cardiotonic activity.1441, 1442
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
345
Biologically active compounds containing 1,4-dioxane skeleton.
Synthesis 1. It is prepared by acid-catalyzed cyclic dehydration of ethylene glycol.1443
2. Dimerization of oxirane in the presence of acid as catalyst yields 1,4-dioxane.
3. Williamson synthesis: Upon action of a base on 5-halo-3-oxopent-1-ol, cyclization takes place yielding 1,4-dioxane.
4. Cyclocondensation of ethylene glycol with oxirane in the presence of an acid catalyst yields 1,4-dioxane.
5. Asymmetric synthesis: Asymmetric synthesis of chiral 1,4-dioxanes has been developed by means of organic catalytic enantioselective desymmetrization of oxetanes. With the oxetane bearing an ethylene glycol ether at the 3-position and by using BINOL-derived chiral phosphoric acid as a catalyst, the intramolecular reaction proceeded smoothly at room temperature resulting in stereo-controlled reopening of the oxetane ring to form chiral 1,4-dioxanes.1442
Synthesis of an enantiomerically pure (R)-7 compound (1,4-dioxane derivative) has been reported to take place in three steps from commercially available epichlorohydrin (S)-4. The chiral compound (R)-7 is transformed to dithioacetal derivative (A) from which the two antiviral compounds (I) and (II) have been synthesized.1441
346
2. Six-Membered Heterocycles
Physical Properties 1,4-Dioxane is a colorless, volatile, hygroscopic liquid with a bp of 101°C and a mild ethereal odor. It is miscible with water and nearly all organic solvents. The structure of dioxane is quite stable. It is resistant to reaction with acids, oxides, and oxidizing agents. This stability, under a wide variety of conditions, makes dioxane quite suitable for use as an organic solvent. Chemical Reactivity 1. Halogenation: Thermal chlorination of 1,4-dioxane in carbon tetrachloride leads to the formation of heptochloro1,4-dioxane in good yield.
When chlorination is carried with sulfuryl chloride with UV radiation and ice cooling such that the internal temperature is 30–35°C, 2,3-dichloro-1,4-dioxane is obtained.
When chlorination is carried out at 10°C with a trace of benzoyl peroxide, trans-2,5-dichloro-1,4-dioxane was obtained.1444
2. Acetylation: Refluxing 1,4-dioxane with lead tetraacetate in a flask covered with aluminum foil and heated with a “power light” of a 500 W lamp yielded 2-acetoxy-1,4-dioxane.1445
When acetylation is carried out with acetic anhydride in the presence of ferric chloride, a ring-opening process takes place leading to the formation of bis(2-acetoxyethyl) ether and 1,2-diacetoxyethane.
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347
However, when acetylation is carried out with acetyl chloride in the presence of aluminum chloride as catalyst, 2-chloroethyl acetate is isolated.
3. Photolysis: Although dioxane is used as a solvent in many photochemical reactions, the photochemistry of dioxane has also been discussed.1446 When dioxane was irradiated using a 40 W medium pressure lamp through quartz in a nitrogen atmosphere, four products were isolated after preparative GLC.
4. Adduct formation: Dioxane acts as an n-electron donor and forms a stable adduct with Lewis acid or other acceptor molecules. These adducts find use as reagents in organic synthesis. (a) Dioxane-monochloroborane: The reagent was prepared by reaction of dioxane and dioxane-BCl3 with diborane. The adduct obtained is liquid and stable up to 25°C and is used to hydroborate simple unhindered olefins to corresponding dialkylchloroboranes.1447
(b) Dioxane-sulfur trioxide: Use of sulfur trioxide as sulfonating agent is limited because it often leads to charring. Sulfonation is therefore carried out with its adduct with dioxane. The donor/acceptor complex of dioxane with sulfur trioxide is quite stable and its crystal structure has also been studied.1448 This adduct is chiefly used for the sulfonation of alcohols, alkenes, carbonyl, and aromatic compounds.
(c) Dioxane-bromine adduct: This is chiefly used for bromination reactions. For example, bromination of furan with a dioxane-bromine complex at −5°C yields 2-bromofuran.
2.9.4 1,4-Dioxin
1,4-Dioxin, also referred to as p-dioxin or simply dioxin, is a six-membered unsaturated, nonconjugated, nonaromatic oxygen heterocycle consisting of four carbon atoms and two oxygen atoms at the 2- and 4-positions of the ring. Structural and Reactivity Aspects1449 This heterocyclic ring of 1,4-dioxin is made up of 8π electrons, is nonplanar, and is classified as nonaromatic. The 1 H NMR spectrum shows one singlet at δ 5.50 suggesting it to be a symmetrical cyclic vinyl ether.
348
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials The 1,4-dioxin nucleus has been found to be present in a number of natural products. Some lignan derivatives like eusiderin and silybin have been found to possess this skeleton.1450, 1451
Natural products containing 1,4-dioxin skeleton.
The Chinese traditional medicine “Shi Hu” prepared from the stems of several Dendrobium species is widely used as an antipyretic, and is beneficial to eyes and as a tonic. Dendrocandin B, a novel dioxin derivative, was isolated from Dendrobium candidum, one of the most popular Dendrobium species.1452 The structure of the 1,4-dioxin derivative caleteucrin isolated from Cafea prunifolia was established by single crystal X-ray diffraction.1453
Dendrocandin B one of the constituent of “Shi Hu” possess 1,4-dioxin skeleton.
Dihydro-1,4-dioxin carboxyanilide derivatives A and B have been reported to possess fungicidal activity.1454
Biological active compounds with 1,4-dioxin skeleton.
Synthesis 1. 1,4-Dioxin is synthesized by dechlorination of 2,3,5,6-tetrachloro-1,4-dioxane with magnesium and iodine in boiling dibutyl ether.
2. Reductive elimination of bromine from 2,3-dibromo-2,3-dihydro-1,4-dioxin on reaction with phenylmagnesium bromide in diethyl ether yields 1,4-dioxin.
3. Heating 2,5-dimethoxy-2,3,5,6-tetraphenyl-1,4-dioxane or 2-methoxy-2,3,5,6-tetraphenyl-2,3-dihydro-1,4-dioxin with acetic anhydride in the presence of a catalytic amount of concentrated sulfuric acid, zinc(II) chloride, or iron(II) chloride gives tetraphenyl-1,4-dioxin.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
349
4. trans-2,5-Bis(iodomethyl)-1,4-dioxane when heated with aqueous sodium hydroxide causes elimination of a molecule of hydrogen iodide and yields 2,5-bis(methylene)-1,4-dioxane, which undergoes isomerization in the presence of a palladium-on-charcoal catalyst to afford 2,5-dimethyl-1,4-dioxin.
5. Heating benzoin with methanol in the presence of hydrogen chloride gave a mixture of trans-6-methoxy-2,3,5,6tetraphenyl-1,4-diox-2-ene and trans,trans-2,5-dimethoxy-1,4-dioxane. This mixture when treated directly with zinc chloride in boiling acetic anhydride gave tetraphenyl-p-dioxin.1455
6. Reaction of methyl phenylchloropyruvate with potassium phthalimide in chlorobenzene under the conditions of Gabriel reaction yielded 2,5-dimethoxycarbonyl-3,6-diphenyl-1,4-dioxin and 2,6-dimethoxycarbonyl-3, 5-diphenyl-1,4-dioxin.1456
7. Diels-Alder reaction: Furan and maleic anhydride undergo cycloaddition reaction forming an adduct, which is converted to an epoxide. The epoxide undergoes retro-Diels-Alder reaction forming 1,4-dioxin and regenerating maleic anhydride.1457
350
2. Six-Membered Heterocycles
Physical Properties 1,4-Dioxin is a colorless, highly flammable liquid with a bp of 75°C. Chemical Reactivity 1. Halogenation: 1,4-Dioxin behaves as a typical unsaturated ether, and bromine added to one of the double bonds giving 2,3-dibromo-2,3-dihydro-1,4-dioxin. Similarly, two molecules of chlorine added across both the double bonds affords 2,3,5,6-tetrachloro-1,4-dioxane.1458
2. Oxidation: 1,4-Dioxin undergoes one electron oxidation electrochemically or chemically to give a radical cation, which further loses the second electron to give rise to Hückel 6π electron structure.1459
Electrochemical oxidation of 2-chloro-2,3-dihydro-1,4-dioxin in the presence of alcohol yields chloroacetal with addition of the alkoxy group at C-3.
3. Photolysis: Photolysis of tetraphenyl-p-dioxin in tert-butanol gave benzil as the major product and tolan as the minor product. When photolysis was carried out in benzene for 2.5 h in a nitrogen atmosphere, besides benzil and tolan, trans-dibenzoylstilbene was also formed. Photolysis in the presence of air produced benzil as the exclusive product; however, photolysis in benzene in an oxygen atmosphere again produced benzil as the exclusive product. The reaction pathways are depicted in the following diagram.1455
4. Thermolysis: On thermolysis, tetraphenyl-p-dioxin is first converted to cis-dibenzoyl stilbene, which on heating at higher temperatures is converted to 3,3,4,5-tetraphenylfuran-2(3H)-one. The reaction has been proposed to take place by the following pathway.1455
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351
2.9.5 Dibenzo-1,4-Dioxin Dibenzo-1,4-dioxin, also referred to as dibenzodioxin, dibenzo-p-dioxin, dibenzo[b,e][1,4]dioxin, or oxanthrene, is a tricyclic heterocyclic compound in which two benzene rings are connected to the 1,4-dioxin ring.
Structural and Reactivity Aspects X-ray crystal analysis of 2,7-dichlorodibenzo-1,4-dioxin suggests that the molecule is planar. The bond distances (in Å) and bond angles (in degrees) are shown in the following figure.1460
Bond length and bond angles of dibenzo-1,4-dioxin.
The 1H NMR of 1-chlorodibenzo-1,4-dioxin1461 and the 13C NMR of tetrabromodibenzo-1,4-dioxin1462 are given in the following table. 1
H and 13C NMR spectral data of dibenzo-1,4-dioxin derivatives
1 H NMR (CDCl3) δ (ppm)
13
C NMR (DMSO d6) δ (ppm)
Ar-H, 6.97–6.83 (5H); H-3, 6.81 (t), H-2, 6.74 (dd)
C-1, 145.7; C-2, 116.3; C-3, 117.9; C-4, 101.3; C-4a, 140.2; C-10, 129.7; C-5a, 138.4; C-6, 110.3; C-7, 129.7; C-8, 115.9; C-9,118.7; C-9a, 142.4
The mass fragmentation of dibenzo-1,4-dioxin is also discussed below.1463
Mass fragmentation pattern of dibenzo-1,4-dioxin.
352
2. Six-Membered Heterocycles
Importance in Natural Products, Medicines, and Materials Dibenzo-1,4-dioxins are unusual natural products that are produced by the coupling of phenoxy radicals. The biosynthesis of the halogenated derivatives of this class of compound have been reported to follow the same route as suggested for diphenyl ethers, followed by nucleophilic displacement of halogen and formation of the second bond of dioxin.
Biosynthesis of halogenated derivatives of dibenzo-1,4-dioxin.
A number of natural products bearing this skeleton have been isolated from the sponges Tedania ignis and Dysidea dendyi.
Natural products containing dibenzo-1,4-dioxin skeleton.
A number of phlorotannins such as phlorofucofuroeckol A with a dibenzo-1,4-dioxin skeleton isolated from the edible brown alga Ecklonia kurome Okamura have been reported to inhibit the action of α2-macroglobulin and α2-plasmin inhibitor.1464, 1465
A number of synthetic dibenzodioxin derivatives have been reported to possess anticancer activity.1466 Certain polychlorodibenzo-1,4-dioxins formed during the manufacture of polychlorophenols are highly toxic to humans. Synthesis 1. Dichlorobenzene is activated toward nucleophilic substitution reaction by carrying out complexation with ferrocene, whereby a cationic (cyclopentadienyl) iron complex of 1,2-dichlorobenzene is obtained. This complex reacts with benzene 1,2-diol in the presence of base to afford a cationic (cyclopentadienyl) complex of dibenzo1,4-dioxin, which on irradiation with light yields dibenzo-1,4-dioxin.1467, 1468
2. Sodium or potassium salt of 2-halophenol when heated at high temperatures in the presence of copper catalyst undergoes self-condensation to give dibenzo-1,4-dioxin.1469
353
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
3. 2-(2-Chlorophenoxy)phenolates when heated at 120–130°C in the presence of potassium carbonate in DMF undergo cyclization to give dibenzo-1,4-dioxin.
4. Benzene 1,2-diols are activated under basic conditions to give 1,2-diolate anions, which undergo condensation with 1,2,4,5-tetrachlorobenzene to give 2,3-dichlorodibenzo-1,4-dioxin.
Similarly, nitro-substituted 2-chloro-1,2,3- trinitrobenzene.
dioxins
can
be
synthesized
by
treating
benzene-1,2-diol
with
5. An improved synthesis of substituted dibenzo-1,4-dioxin by reaction of catechol with 1,2-dichloro- or 2-chloronitrobenzenes in the presence of metallic potassium in hexamethylphosphoramide has been reported.1461
Chemical Reactivity 1. Electrophilic substitution reaction (a) Nitration: Nitration of dibenzo-1,4-dioxin with nitric acid at −20°C yields a 2,7-dinitro derivative.1470
(b) Friedel-Crafts acylation: Acylation of dibenzo-1,4-dioxin with acetyl chloride or propanoyl chloride in the presence of anhydrous aluminum chloride afforded a 2,7-diacyl derivative.1471
(c) Halogenation: Dibenzo-1,4-dioxin is chlorinated by bubbling chlorine gas into a well-stirred solution of dibenzo-1,4-dioxin in glacial acetic acid. 2-Chlorodibenzo-1,4-dioxin was the major product. When chlorination was carried out under similar conditions, except photoirradiation with UV light, 2,7-dichlorodibenzo-1,4dioxin was obtained. Similarly, synthesis of 2-bromodibenzo-1,4-dioxin was achieved by treating dibenzo-1,4dioxin in glacial acetic with potassium bromide-bromate while reaction with bromine in acetic acid afforded 2,7-dibromodibezo-1,4-dioxin.1469
354
2. Six-Membered Heterocycles
2. Sandmeyer’s reaction: Sandmeyer’s reaction of chlorodibenzo-1,4-dioxinamines can be used to introduce different functional groups into the aromatic ring. Nitro-substituted chlorodibenzo-1,4-dioxins are easily converted to diazonium salt on treatment with tert-butylnitrite. Treatment of diazonium salt with copper(I) [37Cl] chloride gave 37Cl-labeled dichlorodibenzo-1,4-dioxin.
3. Nucleophilic substitution reaction: Reaction of dibenzo-1,4-dioxin with 2 equivalents of butyllithium forms 1,9-dianion, which on first reaction with carbon dioxide followed by esterification with methanol in the presence of acid yields 1,9-diester.1472
4. Photochemistry: Photochemistry of dibenzo-1,4-dioxin initially involves opening of the ring by aryl-oxygen bond homolysis to give a biradical, which on reduction by hydrogen abstraction from the medium gave 2-phenoxyphenol. Further photolysis of 2-phenoxyphenol afforded 2,2′-biphenol as the major component and 4-hydroxydibenzofuran as the minor product.1473
However, a detailed study by Rayne et al. suggested that dibenzo-1,4-dioxin initially underwent singlet-state photochemically initiated aryl-ether bond homolysis yielding 2-spiro-6-cyclohexa-2,4-dien-1-one and subsequently 2,2′-biphenylquinone, which undergo excited-state hydrogen abstraction from organic solvent to give 2,2-dihydroybiphenyls.1474
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
355
2-Nitrodibenzo-1,4-dioxin in the presence of a primary amine like propylamine in polar solvent undergoes a photosubstitution reaction to give isomeric (N-propylamino)hydroxynitrodiphenyl ethers.1475
2.9.6 1,4-Dithiin
1,4-Dithiin, also known as 1,4-dithia-2,5-cyclohexene, is 2,2-diethoxyethane-1-thiol a six-membered heterocycle that contains two carbon-carbon double bonds, four carbon atoms, and two sulfur atoms. This heterocyclic ring, which is made up of 8π electrons, is nonplanar and is classified as nonaromatic rather than antiaromatic. Structural and Reactivity Aspects1476a X-ray diffraction studies of the parent compound 1,4-dithiin revealed that the ring is nonplanar and exists in a boat conformation in solid state with a butterfly-flapping angle of 137 degrees or 141 degrees between the two SCCS planes.
Boat conformations of 1,4-dithin.
1,4-Dithiin is nonaromatic due to the absence of a diamagnetic ring current. In addition, the 1H NMR spectrum exhibits a singlet at 6.21 ppm, which is almost equal to the observed value for dihydro-1,2-dithiin. The 13C NMR of the parent compound in CDCl3 also showed a single peak at δ 121.3 ppm suggesting it to be a symmetrical molecule.1476b Importance in Natural Products, Medicines, and Materials The 1,4-dithiin skeleton is found in a number of biologically active compounds such as dimethipin, a commercial plant growth regulator. Depending on the type and number of substitutions on the ring and unsaturation in the ring, this ring structure has been found to exhibit either herbicidal or microcidal activity. 1476c
Synthesis 1. The parent compound is obtained from 2,2-diethoxyethane-1-thiol by vapor-phase dealkoxylation of 2,5-dialkoxy-1,4-dithiane1477 over alumina at 270°C.
356
2. Six-Membered Heterocycles
Distilling a mixture of 1,4-dithiane-2,5-diol in N,N-dimethylformamide in the presence of thionyl chloride and pyridine yields 1,4-dithiin in high yield.1476b
2. Bunte salt formed by the reaction of phenacyl bromide with sodium thiosulfate underwent cyclization under acidic conditions to yield 2,5-diaryl-1,4-dithiin.1478
3. Reaction of cis-1,2-dichloroethylene with disodium cis-ethylenedithiolate in DMSO yielded 1,4-dithiin.1479
4. Tetraphenyl-1,4-dithiin is obtained by condensation of benzoin with hydrochloric acid and hydrogen sulfide.1480
5. Photolysis of 1,2,3-thiadiazole leads to elimination of a molecule of nitrogen forming a diradical, which underwent dimerization to form 1,4-dithiin.
6. Upon irradiation of 4,5-diphenyl-1,3-dithiole-2-one, photodecarbonylation takes place forming tetraphenyl-1,4-dithiin.
7. [5 + 1] cyclization: 1-Alkynyl ethynyl sulfide on reaction with sodium sulfide in methanol underwent [5+1] cyclization to afford monosubstituted 1,4-dithiin.1481
Cis-1,2-ethylenedithiolate reacts with 1,3-butadiyne to afford 2-vinyl-1,4-dithiin.1482
Physical Properties 1,4-Dithiin has an mp of 99–100°C. Chemical Reactivity 1. Electrophilic substitution reaction: 1,4-Dithiin being nonaromatic does not undergo electrophilic substitution reaction. However, its diaryl derivative undergoes substitution in two steps.1483
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
357
2. Electrophilic addition reaction: 1,4-Dithiin on reaction with chlorine underwent electrophilic addition reaction to yield a dichloro derivative.
3. Reaction with nucleophiles: The presence of electron-withdrawing groups on the ring facilitates nucleophilic attack. For example, tetracyano-1,4-dithiin underwent reaction with a variety of nucleophiles to give fivemembered products.1484
Unsubstituted 1,4-dithiin on reaction with alkyllithium underwent ring opening of dithiin. Lithiation of 1,4-dithiin with butyllithium in diethyl ether at −110°C gave a 2-lithio derivative. The lithio derivative on a rise in temperature from −110 to −60°C opened the ring to give dilithium salt, which on subsequent methylation gave the sulfane derivative.
1,4-Dithiin on reaction with butyllithium in diethyl ether at −78°C yields a 2-lithio derivative, which can easily be transformed into an alkyl derivative.
4. Oxidation: Oxidation of 1,4-dithiin with 30% hydrogen peroxide in the presence of glacial acetic acid at room temperature yields 1,4-dithiin-1,1-dioxide.1485
358
2. Six-Membered Heterocycles
2-p-Methoxyphenyl-5-phenyl-1,4-dithiin on oxidation with peracid yields the monosulfone derivative, which on heating thermally yields 2-p-methoxy-4-phenylthiophene.
In the case of unsymmetrically substituted 1,4-dithiins the sulfur atom, which has the higher electron density (in terms of mesomeric effect), is oxidized.1471
5. Thermolysis: The parent unsubstituted molecule is thermally stable and can be distilled at 190°C without decomposition. However, when subjected to the action of heat, substituted 1,4-dithiins undergo ring contraction with extrusion of sulfur to yield thiophene derivatives.
Similarly, thermolysis of tetraphenyl-p-dithiin takes place with extrusion of sulfur to yield tetraphenyl thiophene.1480
6. Photolysis: Unsubstituted 1,4-dithiin on photolysis in the absence of oxygen undergoes [2+2] cyclodimerization.1486
7. Cycloaddition reaction: 1,4-Dithiin reacts as a dienophile in a thermal [4+2] cycloaddition reaction with reactive dienes like 2,5-dimethyl-3,4-diphenylcyclopentadienone to give the cycloaddition product in high yield.1487
2.9.7 1,3-Dithiane
1,3-Dithiane, also known as m-dithane or 1,3-dithiacyclohexane, is a six-membered cyclohexane derivative in which two methylenes of the cyclohexane have been replaced by two sulfur atoms. Structural and Reactivity Aspects The 1H and 13C NMR spectral data of 1,3-dithiane, which helped in the interpretation of its structure, are given in the following table.1488
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
359
H and 13C NMR spectral data of 1,3-dithiane
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-2, 3.67 (s); H-4, H-6, 2.7 (m); H-5, 2.0 (m)
C-2, 31.9; C-4, H-6, 29.8; C-5, 26.8
The mass spectral fragmentation of 1,3-dithiane has been studied by 2H labeling and metastable defocusing.1489
Mass fragmentation pattern of 1,3-dithiane.
The basic structure of 1,3-dithiane was confirmed on the basis of the X-ray crystal structure of 2-phenyl-1,3-dithane, which suggests that the molecule exists in the chair conformation.1490 The following figure shows bond angles in degrees and bond lengths in Å.
Bond length and bond angles of 1,3-dithiane.
Importance in Natural Products, Medicines, and Materials 1,3-Dithiane is one of the constituents isolated from garlic and other allium species. Dithiane-incorporated compounds have been reported to possess pesticidal,1491 insecticidal,1492 and human 5α-reductase inhibitory activity. Recently, a number of dithiane-incorporated pregnane derivatives were synthesized and evaluated for their in vitro antifungal and antibacterial activity.1493
Dithiane incorporated steroids (pregnane) derivatives.
Synthesis 1. The parent compound is synthesized by refluxing a solution of 1,3-propanedithiol and methylal (dimethoxymethane) in boron trifluoride diethyl etherate, glacial acetic acid, and chloroform.1494
This method requires special precautions to avoid side reaction. However, an improved method involving condensation of 1,3-propanedithiol with ethylal in the presence of montmorillonite KSF clay has been reported.1495
2. 2-Substituted dithiane is synthesized by the reaction of 1,3-propanedithiol with benzaldehyde in the presence of hydrogen chloride gas1496 at 0°C.
360
2. Six-Membered Heterocycles
3. A mild method for the preparation of 1,3-dithane from the reaction of aldehydes and ketones with propane-1,3thiol in the presence of lithium perchlorate as Lewis acid has been reported.1497
An environmentally friendly method for the synthesis of 1,3-dithanes by the reaction of aliphatic and aromatic carbonyl compounds with propane 1,3-thiol in the presence of a catalytic amount of tungstate-sulfuric acid under solvent-free conditions has also been reported.1498 4. A facile synthesis of 1,3-(2-13C)- and 1,3-(213C, 2-2H2)dithiane in two steps from [13C]- or [13C, 2H3]methyl phenyl sulfoxide has been reported. The process involves reaction of [13C] methyl phenyl sulfoxide with trifluoroacetic anhydride to afford (phenylthio)[13C]methyl 2,2,2-trifluoroacetate, which on reaction with 1,3-propanedithiol yielded 1,3-(2-13C)dithiane. Similarly, [13C, 2H2]methyl phenyl sulfoxide reacts with trifluoroacetic anhydride to afford (phenylthio)[13C, 2H2]methyl 2,2,2-trifluoroacetate, which on reaction with 1,3-propanedithiol yielded 1,3(2-13C, 2H2)dithiane.1499
5. Dieckmann reaction: 3,5-Dithia-1,7-heptadioic ester in the presence of sodium ethoxide afforded 5-keto-1,3-dithiane.
6. Terminal alkyne on reaction with aldehyde in the presence of H2S using boron trifluoride as a catalyst delivered 2-aryl-1,3-dithiane.
Physical Properties 1,3-Dithiane is a colorless to yellow crystalline solid with an mp of 53–54°C. It is hygroscopic, very slightly soluble in water, but easily soluble in ether, chloroform, benzene, and THF. Chemical Reactivity 1. 1,3-Dithiane derivatives are versatile intermediates in the synthesis and interconversion of monocarbonyl and dicarbonyl compounds.1500 1,3-Dithianes react with a strong base such as n-butyllithium forming lithiated 1,3-dithiane, which acts as a nucleophilic agent. This on reaction with an electrophile, usually alkyl halides, and subsequent hydrolysis with mercuric oxide or mercuric chloride yielded an aldehyde or ketone.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
361
(a) Synthesis of ketones: Aldehydes and open chain ketones have been synthesized from dithiane. Cyclobutanone, which was earlier synthesized by reaction of diazomethane with ketene Synthesis of cyclobutanone has been reported in two steps. In the first step, 5,9-dithiaspiro[3,5]nonane is synthesized by reaction of 1,3-dithiane with butyllithium followed by reaction with 1-bromo-3-chloropropane. In the second step, 5,9-dithiaspiro[3,5] nonane is refluxed at 90–110°C with triethylene glycol, mercury(II) chloride, and cadmium carbonate in a nitrogen atmosphere.1501
(b) Reaction of 1,3-dithiane with butyllithium followed by reaction with 2-cyclohexen-1-one yields 1-(1,3-dithian2-yl)-2-cyclohexen-1-ol, which on reaction with mercuric oxide and boron trifluoride etherate in THF yielded 3-hydroxy-1-cyclohexene-1-carboxaldehyde.1502
Unsaturated aldehydes have also been synthesized by the reaction of 1,1-diethoxymethyl-2.3-epoxypropane with 2-lithiodithane yielding 2-(2-acetoxy-3,3-diethoxypropyl)-1,3-dithane, which on hydrolysis with HgO-BF3 afforded 3-acetoxy-4,4-diethoxybutanal followed by reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produced 4,4-diethoxy-2-butenal.1503
(c) 2-Phenyl-1,3-dithiane on reaction with n-butyllithium followed by thiomethylation with (methylsulfinothioyl) methane delivered 2-methylthio-2-phenyl-1,3-dithiane, which on reaction with lindole in chloroform using BF3 etherate as a catalyst produced 3-(2-phenyl-1,3-dithian-2-yl)-1H-indole.1504 This on heating in acetone in the presence of CuCl2 and CuO gave 3-benzoylindole. However, reduction with lithium aluminum hydride (LAH) in the presence of ZnCl2 and CuCl2 delivered 3-phenylmethyl-1H-indole.
(d) A total and stereoselective synthesis of racemic echinolone (A), a juvenile hormone mimic, has been reported1505 using 2-methyl-1,3-dithiane as precursor.
362
2. Six-Membered Heterocycles
(e) Dioxaspiro compound (B), which is the aggregating pheromone of Pityogenes chalcographus, is prepared by sequential alkylation of 1,3-dithane with a chloro derivative and bromoperoxide. The oxirane ring was cleaved with LiBHEt to give an intermediate, which on hydrolysis yielded the diastereomeric mixture of the dioxaspiro compound (B).1506
(f) Vermiculin, a macrocytic aglycoside dilactone, which has been reported to possess antibacterial, antiprotozoal, and immunosuppressant activity and is isolated from Penicillium vermiculatum, has also been synthesized by Umpolung reaction/process.1507
2. Oxidation: Enantiomerically pure 1S(−)-1,3-dithiane-1-oxide has been synthesized in three steps. In the first step, 1,3-dithiane is made to react with 1M solution of sodium hexamethyldisilazide in THF. The resulting yellow solution is then made to react with butyllithium followed by reaction with ethyl 2,2-dimethylpropanoate. 2-(2,2-Dimethylpropanoyl)-1,3-dithiane obtained as colorless needles (mp 97–99°C) is made to react with (+)-[(8,8-dimethoxycamphoryl)sulfonyl]oxaziridine whereby a mixture of anti- and syn-1S-(2,2dimethylpropanoyl)-1,3-dithiane-1-oxide is obtained as a colorless crystalline solid (mp 103–105°C). Refluxing this enantiomeric mixture with 5% ethanolic sodium hydroxide yields the desired product.1508
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
363
3. Vinylogous acyl triflates undergo tandem nucleophilic addition reaction1509 to 2-methyl-1,3-dithiane to yield alkyne building blocks. 2-Methyl-2-(1-oxo-5-heptynyl)-1,3-dithiane is synthesized by reaction of 2-methyl-1,3dithiane with n-butyllithium and 2-methyl-3-trifluoromethanesulfonyloxy-cyclohex-2-en-1-one at −78°C.
2.9.8 Dibenzo[b,e]-1,4-Dithiin (Thianthrene)
Thianthrene, also known as 9,10-dithiaanthracene or di-σ-phenylene disulfide, is a tricyclic heterocyclic compound with two sulfur atoms connecting the two benzene rings. Earlier, on the basis of molecular weight determination (C12H8S2), the compound was named diphenylenedisulfide. However, later it was named thianthrene due to its similarity to anthracene. Structural and Reactivity Aspects On the basis of X-ray crystallography, thianthrene has a folded C2v configuration with the bond angle between the two planes defined by two aromatic rings and sulfur, being 128 degrees. The bond lengths in Å as derived from X-ray analysis are shown in the following figure.1510
Bond length (in Å) values of thianthrene.
The 1H and 13C NMR spectral data of thianthrene are given in the following table.1511, 1512 H and 13C NMR spectral data of thianthrene
1
1 H NMR (CDCl3) δ (ppm)
13
C NMR (CDCl3) δ (ppm)
H-1,4,6,9, 7.48; H-2,3,7,8, 7.23
C-3, 127.6; C-4, 128.7; C-4a, 135.5
Importance in Natural Products, Medicines, and Materials Thianthrene has been detected from the oil produced following steam distillation of the roots of the American herb Porophyllum ruderale (Bolivian coriander). An extract prepared from the powdered roots of the Indian globe thistle (Echinops echinatus Roxb.) also confirmed the presence of thianthrene. Thianthrene finds use as an ingredient of the coolant moderator fluids circulating in a nuclear reactor,1513 and also as a component of extreme pressure lubricants.1514 Mesulfen, a 2,7-dimethyl derivative of thianthrene, finds use in the treatment of scabies-producing mites and in antiacne therapy.
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2. Six-Membered Heterocycles
Synthesis 1. A convenient method for the synthesis of thianthrene involves heating benzene with sulfur monochloride in the presence of anhydrous aluminum chloride as catalyst.
It was proposed that during the reaction diphenylsulfide was formed as an intermediate, which then slowly reacts with sulfur to form thianthrene.
2. Heating benzene with sulfur dichloride in the presence of aluminum chloride as catalyst also yields thianthrene.
3. Thianthrene in higher yield is obtained by carrying out pyrolysis of diphenyldisulfide.
A free radical mechanism was proposed for the said reaction.1515
4. Reaction of diphenyl disulfide with triethyloxonium fluoroborate or diethoxycarbonium fluoroborate yields thianthrene together with aryl sulfides.1516
5. Pyrolysis of 2-mercaptodiphenyl sulfide yields thianthrene.
2.9 Six-Membered Heterocycles With Two Oxygen or Sulfur Atoms
365
6. 2,7-Difluorothianthrene is synthesized by reaction of 4-fluorobenzenethiol with fuming sulfuric acid, followed by treatment with zinc in acetic acid.1517
Physical Properties Thianthrene is a white crystalline nonhygroscopic solid with mp of 156–158°C. It is odorless with a very low pressure. It is insoluble in water but soluble in nearly all organic solvents. Chemical Reactivity 1. Electrophilic substitution reaction: Thianthrene behaves as a normal aromatic compound, and electrophilic substitution reaction takes place preferably at the para position to the sulfur atom. For example, halogenation takes place in a stepwise manner.1518, 1519
2. Alkylation: Liquid-phase tert-butylation of thianthrene with tert-butylalcohol in isooctane was carried out at moderate temperatures (below 100°C) in the presence of large pore zeolites and mesoporous aluminosilicates yielding 2-, 2,6-, and 2,7-di-tert-butyl derivatives.1520
3. Chloromethylation of thianthrene with chloromethyl methyl ether in the presence of anhydrous SnCl4 in chloroform at −20°C yields 2,7-bis(chloromethyl)thianthrene together with a polymeric product.1521
4. Oxidation: Thianthrene on treatment with benzenediazonium salt in glacial acetic acid, is oxidized to thianthrene 5-oxide. The best results are, however, obtained on reaction with 2-and 4-nitrobenzenediazonium sulfate.1522
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2. Six-Membered Heterocycles
Oxidation of thianthrene with bromine in the presence of alkoxide yields a mono(dialkoxysulfurane) derivative.
Thianthrene on reaction with dilute nitric acid in glacial acetic acid at reflux temperature results in the formation of thianthrene 5-oxide.1523
Reaction of thianthrene with excess sulfuryl chloride yields thianthrene trans-5,10-dioxide.1524
5. Metalation: Thianthrene on reaction with butyllithium in diethyl ether at room temperature afforded a 1-lithio derivative, which was easily transformed to carboxylic acid or a hydroxyl derivative by reaction with dry ice1525 and butylmagnesium iodide,1523 respectively.
Similarly, a number of other 1-substituted thianthrene derivatives were synthesized, as listed in the following diagram.1526
6. Formation of radical cation: Solution of thianthrene in 96%–97% sulfuric acid is paramagnetic and it has been proposed that this is due to the presence of radical cation.1527
Thianthrene perchlorate is of particular interest because it has been used for the synthesis of a number of derivatives.
REFERENCES 367
7. Hydrodesulfuration: Desulfuration of thianthrene in the presence of nickel complexes has been proposed. Two paths were proposed: (Path A) When reaction was carried out with THF and a soluble complex of (2,2′-bipyridyl)(1,s-cyclooctadiene) nickel, dibenzothiophene was the major product (55%) and biphenyl (15%) was the minor product. (Path B) When reaction was carried out in the presence of a novel nickel complex like LiAlH2(THF)n(bpy)Ni, then biphenyl was the major product (15%) and dibenzothiophene (5%) was the minor product.1528, 1529 Benzene was also obtained during the reaction.
8. Ring fission: In a nickel-promoted catalytic reaction, thianthrene is cleaved unsymmetrically by Grignard reagent to afford 1,2-bis(methylthio)benzene and o-xylene.
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390 1440. 1441. 1442. 1443. 1444. 1445. 1446. 1447. 1448. 1449. 1450. 1451. 1452. 1453. 1454. 1455. 1456. 1457. 1458. 1459. 1460. 1461. 1462. 1463. 1464. 1465. 1466. 1467. 1468. 1469. 1470. 1471. 1472. 1473. 1474. 1475. 1476. 1477. 1478. 1479. 1480. 1481. 1482. 1483. 1484. 1485. 1486. 1487. 1488. 1489. 1490. 1491. 1492. 1493. 1494. 1495. 1496. 1497. 1498. 1499. 1500. 1501. 1502. 1503. 1504.
2. Six-Membered Heterocycles
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1505. 1506. 1507. 1508. 1509. 1510. 1511. 1512. 1513. 1514. 1515. 1516. 1517. 1518. 1519. 1520. 1521. 1522. 1523. 1524. 1525. 1526. 1527. 1528. 1529.
FURTHER READING
Orsini, F.; Pelizzoni, F. J. Org. Chem. 1980, 45, 4726. E. Hungerbuehler; R. Naef; D. Wasuth; D. Seebach; H. R. Loosli; A. Wehrli, Helv. Chim. Acta, 63: 1960, 1980. Yus, M.; Najera, C.; Foubelo, F. Tetrahedron 2003, 59, 6147. Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.; Andrews, D. M. Org. Synth. Coll. 2004, 10, 378. Lisboa, M. P.; Hoang, T. T.; Dudley, G. B. Org. Synth. 2011, 88, 353. Rowe, I.; Post, B. Acta Crystallogr. 1958, 11, 372. Sharpless, N. E.; Bradley, R. B.; Ferretti, J. A. Org. Magn. Reson. 1974, 6, 115. Meier, H.; Konnerth, U.; Graw, S.; Echter, T. Chem. Ber. 1984, 117, 107. R. O. Bolt; B. J. Fontana; J. R. Wright. U.S. Patent 2,883,331, 1959. Hugel, G. Riv. Combust. 1955, 9, 417. Schonenberg, A.; Mustafa, A. J. Chem. Soc. 1949, 889. Miller, B.; Hans, C. H. J. Org. Chem. 1971, 36, 1513. Edson, J. B.; Knauss, D. M. J. Polymer. Sci. 2004, 42, 6353. Fries, K.; Vogt, W. Liebigs Ann. Chem. 1911, 381, 312. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1955, 77, 5944. Armengol, E.; Orma, A.; Garcla, H.; Primo, J. Appl. Catal. A Gen. 1997, 149, 411. Dronov, V. I.; Nigmatullina, R. F. Russ. Chem. Bull. 1976, 25, 2609. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1956, 78, 2163. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1957, 79, 991. Savin, E. D.; Nedelkin, V. I.; Zverev, Z. V. Chem. Hetrocycl. Compd. 1997, 33, 333. Gilman, H.; Swayampati, D. R. J. Am. Chem. Soc. 1957, 79, 208. Sheikh, M. C.; et al. Synthesis 2014, 46, 42. Murata, Y.; Shine, H. J. J. Org. Chem. 1969, 34, 3368. Eisch, J. J.; Hellenbeck, L. E.; Han, K. I. J. Am. Chem. Soc. 1986, 108, 7763. Bird, C. W.; Hollins, E. M. J. Organomet. Chem. 1965, 4, 245.
Further Reading 1530. 1531. 1532. 1533. 1534.
Paudler, W. W.; Barton, J. M. J. Org. Chem. 1966, 31, 1720. Hammond, G. S.; et al. J. Am. Chem. Soc. 1964, 86, 3103. Meng, X.; Huang, Y.; Zhao, H.; Xie, P.; Ma, J.; Chen, R. Org. Lett. 2009, 11, 991. Lee, L. F.; Howe, R. K. J. Org. Chem. 1984, 49, 4780. Tomita, M. J. Pharm. Soc. Jpn. 1934, 54, 891.
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