C H A P T E R
3 Seven-Membered Heterocycles There are mainly two types of seven-membered heterocycles: saturated and unsaturated, depending on the nature of carbocycles. The saturated heterocycles are formed by replacing one of the sp3 carbons from the cycloheptane ring mainly by a nitrogen, oxygen, and sulfur heteroatom, and the compounds thus derived are called azepane, oxepane, and thiepane, respectively.
3.1 STRUCTURAL AND REACTIVITY ASPECTS Fully unsaturated seven-membered heterocycles are formed by replacing any of the six sp2 carbons or a sp3- hybridized carbon of cycloheptatriene by N, O, or S heteroatoms; the heterocycles thus formed are known as azacycloheptatriene or azepine, oxacycloheptatriene or oxepin, and thiacycloheptatriene, or thiepin, respectively. Azepine exists in four tautomeric forms, namely 1H-azepine (I), 2H-azepine (II), 3H-azepine (III), and 4H-azepine (IV). Out of the four tautomeric forms, 3H-azepine is most stable and their degree of stability is in the order of 3H > 1H > 2H > 4H. The stability of the tautomers is greatly influenced by the presence of electron-withdrawing substituents linked to the ring nitrogen or by annelation with benzene or a heterocycle. In the case of densely substituted azepine the existence of a new valency tautomer (V) has been observed.
All fully unsaturated seven-membered heterocycles possess 8π electrons and are antiaromatic because they do not meet the criteria of (4n + 2)π electrons for aromaticity as well as delocalization of the 8π electrons around the ring, and are mostly unstable. When one of the sp2 carbons of azacycloheptatriene is replaced by another nitrogen, they are called diazepine and exist in five tautomeric forms in which both nitrogen atoms are present at 1,2, 1,3, and 1,4 positions of the ring (VI–X). In addition, diazepine 2,3-dihydro-1H-1,4-diazepine has also been identified.
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Annelation of unsaturated seven-membered heterocycles generated molecular diversity. The most widely studied heterocycles are those that are generated by annelation of one or two benzene rings with different sites of fully unsaturated seven-membered heterocycles to produce a variety of nuclei. Generally, the benzo-annelated derivatives are more stable than their parent monocyclic molecules.
Analogously, annelation of fully unsaturated seven-membered heterocycles with two heteroatoms such as iazepine, dioxepin, etc. generate a variety of compounds. Diazepines on annelation with one or two benzene rings d generate benzodiazepines and dibenzodiazepines. These compounds are nonplanar and potentially antiaromatic because the ring possesses 8π electrons.1,2 The parent thiepine is highly unstable, but its oxidized derivative, thiepine1,1-dioxide, is stable. The preferred conformation of parent thiepine is a flat boat. The criteria for aromaticity of a compound requires (1) planarity of the ring, (2) (4n + 2)π electrons, and (3) delocalization of the π electrons around the ring. The seven-membered unsaturated heterocyclic ring is nonaromatic, but heteropines (XNH, O, S) are isoelectronic with 8π electrons and thus antiaromatic. Thiepine was reported as antiaromatic on the basis of negative resonance energy (−29.7 kJ mol−1) obtained by simple and advance calculations. It was found that heteropines exhibited boat conformation, which allows π-delocalization of the double bond. The proton nuclear magnetic resonance (NMR) spectra of 1-R-azepine and 1,2- and 1,4-diazepine showed peaks in the range of 5.0–7.0 ppm, which is a typical range for alkene and explains the nonaromatic nature of these compounds. Annular prototrophy is another property exhibited by large ring compounds that determines the instability of 1H-azepine. The demethoxycarbonylation of functionalized methyl azepine-1-carboxylate provides a mixture of 2H-, 3H-, and 4H-azepines in the ratio 13:56:1, respectively, and it was proposed that the ratio of the isomer is proportional to its thermal stability as shown in the following scheme.
Because these compounds are antiaromatic, electrophilic substitutions are not observed as aromatic compounds. Due to large ring size, intramolecular electrocyclization also occurs to give bicyclic compounds. Isomerization is a very common reaction in this class of compounds, which depends on the stability of isomer and reaction conditions.
3.2 IMPORTANCE IN NATURAL PRODUCTS, MEDICINES, AND MATERIALS In 1960, during a trail of structural misassignment, Hoffmann-La Roche and coworkers discovered the powerful sedative and anxiolytic action of some 1,4-benzodiazepines.2b Thereafter researchers became interested in Librium
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and other benzo- and dibenzo-annelated seven-membered ring-based heterocycles.2c–e Seven-membered heteroaromatics are also present in various natural products such as muscaflavin,2f benzazepine, rhoeadine, cephalotaxine,2g and 1,6-benzodiazepine anthramycin2h skeletons. Various drugs possess dibenzo[b,f]azepine2i–j and dibenzo[b,f]thiepine (2)3a as a substructure. The dibenzazepine group occurred in carbamazepine and opipramol. Carbamazepine is an anticonvulsant mainly used for the treatment of seizures, nerve pain, and bipolar disorder, while opipramol is a tricyclic antidepressant and is used for the treatment of generalized anxiety disorders. Schizophrenia can be treated with antipsychotic dibenzothiepine and zotepine.3b Various approaches were developed for the construction of 5H-dibenzo[b,f]azepines3c–h and dibenzo[b,f] thiepines.3i–k 5H-Dibenzo[b,f]azepines were synthesized under palladium-catalyzed conditions.3l–o Numerous fully unsaturated naturally occurring seven-membered heterocycles with N, O, and S heteroatoms displaying a broad range of pharmacological activities are listed in the following scheme.
3.3 SEVEN-MEMBERED ISOLATED AND BENZO-FUSED HETEROCYCLES WITH ONE AND MORE NITROGEN ATOMS Various natural seven-membered nitrogen-containing heterocycles are known and obtained by various synthetic approaches. Most known heterocycles contain either one or two nitrogen atoms in the ring. If one nitrogen is present in the ring it is termed azepine. Depending on the position of the sp3 carbon, the compound can be called 1H-, 2H-, 3H-, and 4H-azepine. When two nitrogen atoms are present in the ring they are called diazepines. If two nitrogens
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are present in the ring there are three possible arrangements of nitrogen in the ring such as 1,2 or 1,3 or 1,4 positions with respect to each other and they can be named accordingly.
3.3.1 1H-1-Azepine
Azepines exist in four tautomeric forms such as 1H-, 2H-, 3H-, and 4H-azepines, and out of these 1H- and 3Hsystems are more accessible and important.
Parent 1H-azepine is unstable and very few derivatives are known. This compound exists as red oil at −78°C, and under very mild conditions 1H-azepine isomerizes to more stable 3H-azepine via double bond rearrangement. It was observed that the electron-withdrawing group at nitrogen enhances the stability of the 1H-azepines, probably by avoiding the role of lone pair of electrons. One of the compounds, 1-(p-bromophenylsulfonyl)-1H-azepine, exists as a boat-shaped seven-membered ring containing alternate Csp (2)-Csp (2) single and double bonds.
Structure showing bond length (Å) and bond angle (degrees) of the 1H-azepine system.
The 1H NMR spectrum of the parent compound in CCl4 shows three sets of peaks at δ 5.22 for H-2/H-7, 4.69 for H-3/H-6, and 5.57 for H-4/H-5. All protons appear in the vinylic region, which indicates that 1H-azepine does not behave as a planar and 8π-antiaromatic compound. 1H-Azepines behave as nonplanar atrophic cyclopolyenes. 2-Functionalized-3H-azepines are conformationally mobile and show a two-boat structure through inversion, and the inversion barrier of 2-anilino-3H-azepine was found to be ∆G* = 42.7 kJ mol−13.
Synthesis 1. By nitrene insertion to benzene: At higher temperature and pressure, intermolecular insertion of nitrene across a benzene double bond occurred and the ring-expanded product N-sulfonyl-1H-azepine was isolated. The thermolysis of toluene-9-sulfonyl azide is performed in excess of benzene under nitrogen pressure at 155–160°C yields desired product along with functionalized benzene.4
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2. By reaction of stilbenes with amine: The syntheses of azepine were achieved using the Pd-catalyzed double amination reactions of suitably functionalized stilbenes. Stilbene with a halogen group at the ortho position reacts with aliphatic amine in the presence of palladium catalyst under basic conditions to afford the desired product.
3. By reaction of secondary formamide and nitroalkene: The conjugate addition of secondary formamide to nitroalkene gives INOC precursors within 2–4 h. These precursors on exposure to phenyl isocyanate under basic conditions deliver the smooth generation of nitrile oxide that immediately reacts with internal alkene entities to give bicyclic isoxazole-fused azepine in a fair yield.5
4. From benzylic propargyl esters: The secondary benzylic propargyl esters afforded single diastereomers of azepine products in good yields. On the other hand, use of tertiary propargyl esters also participated in the cycloaddition reactions to afford fused azepines.6
5. Reaction of pyrrole and furan with alkyne: The synthesis of oxepin and azepine derivatives was achieved by using substituted furans or pyrroles with diethyl acetylenedicarboxylate in boiling toluene in the dark.
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6. From reaction of alkyne, amine, and tetrahydrofuran: Synthesis of N-arylated azepines is achieved under catalyst-free conditions in excellent yields in polyethylene glycol (PEG).7
7. From β-aminoester: The α-substituted β-aminoesters and allyl bromide are important precursors for the reaction. The ester was deprotonated by employing lithium bis(trimethylsilyl)amide (LiHMDS), followed by the addition of a suitable electrophile-like allyl bromide to achieve substitution products in good yields.8
In a further step, ring-closing metathesis reactions were performed by employing 5 mol% Grubbs catalysts in dichloromethane (DCM) at 40°C to afford partially reduced azepines.9 8. From 1,4-cyclohexadiene: The iodine isocyanate added to l-4-dihydrobenzenes in refluxing methanol afforded trans-iodocarbamate in 54% yield. The intermediate obtained cyclized under basic conditions to produce aziridine, which on bromination provided crude dibromide. This dibromide provided the N-carbomethoxyazepine under basic conditions. This can alternatively be prepared from the reaction of benzene with methyl azidoformate.10
9. By insertion of nitrene to benzene: In situ-generated phenyl nitrene undergoes addition reaction to benzene to form an intermediate that undergoes an insertion reaction to afford N-phenyl-1H-azepine.11
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10. Synthesis of partially reduced 1H-azepines: Azatrienes undergo lithium-induced cyclization followed by N-acylation afforded dihydroazepines.12
11. Through ring closure metathesis: Ring closure metathesis of α,ω-diene or -ene-yne systems13 also provides tetrahydroazepines.14 One of the derivatives, pyrrolidinoazepinone, can be synthesized from the pyrrolidine-derived α,ω-diene.
12. From 6-(dimethylamino)fulvene: 6-(Dimethylamino)fulvene reacts with vinylogous amide to afford a protected 2,6-bifunctional fulvene. Further treatment of isolated masked fulvene with sodium hydroxide provided the sodium salt of dialdehyde, which reacted with aqueous ammonia to afford cyclopent[c]azepine.15
13. From 2-vinyl-2H-azirine: Treatment of dimethyl acetylenedicarboxylate with 2-vinyl-2H-azirine provided 4H-azepine in excellent yield.16 Mechanistically, the reaction might be going through aminoazirinium ions.
14. From azadiene: Alkynylcarbene-chromium complexes react with azadienes to provide air-stable addition products.17 The obtained addition product undergoes formal [4 + 3] cycloaddition and provides the chromium-η2azepine complexes. Then ring opening of the metalacyclopropane occurs to provide chromium-azepine complexes. This complex readily converts to azepin-2-ones.
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15. From conjugated phosphorane: The conjugated phosphorane undergoes Wittig reaction with 3-phenyl-2H- azirine-2-carbaldehyde and affords 2-(methoxycarbonyl)-1H-azepine. The azepine probably formed by the ring closure of vinylnitrene forms as an intermediate.18
Chemical Reactivity 1. Isomerization of 1H-azepine: Methyl 2,5- and 3,6-di-tert-butyl-1H-azepine-l-carboxylate can be isomerized through demethoxycarbonylation to 2H- or 3H-azepines under mild basic conditions. This reaction afforded 3Hazepine along with thermodynamically less stable 2H- and 4H-azepine.19
2. Rearrangement of 1H-azepine: Azepines can act as polyenes and substrates in pericyclic reactions. They can be used for cycloadditions, cheletropic and sigmatropic rearrangements, and dimerization reactions. The syn-1H- azepine can be converted to anti-1H-azepine in the presence of aluminum oxide.
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3. Electrocyclization of 1H-azepine: 1H-Azepines undergo (4n + 2)π-electrocyclization to yield 7-azabicyclo[4.1.0] hepta-2,4-dienes (dihydrobenzazirines).20 If positions 2 and 7 are bridged with trimethylene and tetramethylene chains, then formation of dihydrobenzazirine and other bridge azepines is observed.
4. Synthesis of 2-azabicyclo[3.2.0]hepta-3,6-dienes: If nitrogen of 1H-azepines contains an electron-withdrawing group, they can provide 2-azabicyclo[3.2.0]hepta-3,6-dienes under photochemical reaction conditions.21 Interestingly, 2-azabicyclo[3.2.0]hepta-3,6-dienes undergo thermal ring opening to afford the 1H-azepines.
5. Acetylation and formylation reaction: Tricarbonyl[η4-1-(ethoxycarbonyl)-1H-azepine]iron(0) complex can be acetylated by using a mixture of tetrafluoroboric acid and acetic anhydride. Alternatively, acetylation can also be achieved by acetic anhydride using tin(IV) chloride. Formylation of the complex can also be achieved by phosphoryl chloride in dimethylformamide.
6. Alkylation reaction: Alkylation of tricarbonyl[η4-1-(ethoxycarbonyl)-1H-azepine]iron(0) complex can be performed through a Friedel-Crafts-like approach by using 2-oxyallyl cation generated by the reaction of 2,4-dibromo-2,4-dimethylpentan-3-one and Fe(CO)9.22
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7. N-Acylation and mesylation: Acetylation of 1H-azepine can be achieved by reaction with ketene in chloroform in 20% yield. Alternatively, mesylation can be achieved by treatment of 1H-azepine with methanesulfonyl chloride.23
8. Formation of complex: Azepine can also act as a ligand and make complexes with different metals. Reaction of suitably functionalized azepine with pentacarbonyliron(0) provides a tricarbonyliron complex.24
9. Synthesis of dialdehyde: Oxidation of methyl 2,7-dimethyl-1H-azepine-1-carboxylate mediated by selenium oxide yields the corresponding dialdehyde.25
3.3.2 1,2-Diazepine
There are five possible tautomeric forms of 1,2-diazepines, such as 1H-, 3H-, 4H-, and 5H-1,2-diazepines, along with 3,4-diazabicyclo[4.1.0]hepta-2,4-diene. The 5H-1,2-diazepine tautomeric form is only of theoretical interest and has not been isolated so far. However, 5H-1,2-diazepine exists only as the valence tautomer, 3,4-diazabicyclo[4.1.0] hepta-2,4-diene. 1H-1,2-Diazepine exists in boat conformation.
Synthesis 1. From N-imidopyridine: Pyridine-1-imide is photochemically transformed to 1,2-(1H)-diazepine. Analogously, irradiation of N-carbethoxyaminopyridine, N-acylaminopyridine, or N-p-toluenesulfonylaminopyridine afforded 1,2-diazepine via photorearrangement.26
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2. From 1,4-diaryltetrazine: 3,6-diphenyl-s-tetrazine on reaction with triphenylcyclopropene in refluxing benzene provided 1,2-diazepines with evolution of nitrogen gas, involving a bicyclic intermediate that rearranged to 1H-1,2-diazepine.27
3. From cyclization of diazo compounds: Thieno[3,2-d][1,2]diazepine and thieno[2,3-d][1,2]diazepine have been synthesized by cyclization of 3-diazomethyl-2-styryl-thiophene and 2-diazomethyl-3-styryl-thiophene, respectively.28
4. From thiapyrilium salts: Other derivatives like 3,5,7-triphenyl-1,2(4H)-diazepines and 1-methyl-3,5,7- triphenyl-1,2(1H)-diazepines have been synthesized by the reactions of thiapyrilium salt and hydrazine or methyl hydrazine. Depending on the reaction conditions, 1H-1,2-diazepine or arylated pyrazole can be synthesized.29
5. From δ-chloroketone: Partially reduced diazepine intermediates were synthesized from reaction of aryl-δ-chlorobutyl ketones and hydrazine. Use of o-substituted aryl ketones provides higher annulation yields.30
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6. From enal: Formal [4 + 3] annulation reaction of azoalkenes with enals provides a mixture of 1,2-diazepine regio- and enantioselectively in good yields (often 99% ee).31
7. Base-induced condensation of malonic ester and α-bromoazine afforded 5,6-dihydro-4H-1,2-diazepine in good yields.32
8. From α,β-γ,δ-unsaturated ketones: The condensation reaction of α,β-γ,δ-unsaturated ketones and Nsulfonylhydrazines provides 3H-1,2-diazepines. In the first step, 1-tosyl-6,7-dihydro-1,2-diazepines were synthesized by reaction of dienone and tosylhydrazine in the presence of concentrated hydrochloric acid.33–36 Treatment of the isolated compound with sodium ethoxide and toluene at higher temperature provides 3H-1,2-diazepine tautomers.
Chemical Reactivity 1. Ring contraction reaction: Treatment of 1H-1,2-diazepines with an alkoxide base provides ring-opening product (2,Z)-dienaminonitrile.37 Probably, proton abstraction from CN is the key step. If (2,Z)-dienaminonitrile was treated with ethoxide for longer time, formation of 2-aminopyridine was observed.
2. Thermolysis of diazapine: N-Acyldiazapine on thermolysis undergoes cleavage of a weak NN bond to afford 1,7-diazanorcaradienes, which provides 2-aminopyridines.
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3. Various reactions of 1,2-(1H)-diazepines: 1H-1,2-Diazepines act as excellent substrates for various cycloaddition reactions.38 The reaction of 1H-1,2-diazepines with dienophiles like tetracyanoethane (TCNE) and 4-phenyl-1, 2,4-triazoline-3,5-dione provides normal Diels-Alder cycloadducts.39 On the other hand, cycloaddition with singlet oxygen provides stable epidioxides.40 1-(Ethoxycarbonyl)-1H-1,2-diazepines provide endo Diels-Alder dimers in the presence of formic acid or boron trifluoride etherate.41 1H-1,2-Diazepines and diazoalkanes react to afford 1-pyrazoline, which tautomerizes to afford corresponding 2-pyrazolines and can be used as a precursor for the synthesis of tetraaza-azulenes.42 Homodiazepines were obtained by thermolysis of 1-pyrazolines.43 Tosylmethyl isocyanide anion provides pyrrolodiazepines.44 1,3-Dipolar cycloaddition of nitrile oxides with both olefins and imines of 1H-1,2-diazepines provides site-specific cyclized oxadiazoline.45 β-Lactam diazepines were achieved by (2 + 2) π-cyclization of an imine bond with ketene.46
3.3.3 2,3-Dihydro-1H-1,4-diazepine
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3. Seven-Membered Heterocycles
Seven-membered 2,3-dihydro-1,4-diazapine is a nitrogen heterocycle in which both nitrogen atoms are present at the 1,4 position of the ring with a reduced olefinic bond between the 2 and 3 positions. The presence of two sp3 carbons and one nitrogen makes the molecule nonplanar.
3.3.4 Synthesis 1. From reaction of ethylenediamine and fluoroalkylaldehyde: 5-Per(poly)fluoroalkyl-2,3-dihydro-1,4- diazepines can be achieved by reaction of ethylenediamine and α-per(poly)fluoroalkyl aldehydes in one pot. The required starting material, α-per(poly)fluoroalkyl aldehydes, can be synthesized by addition of RfCF2I to alkenes.48
2. By condensation of 1,3-diketone and ethylenediamine: Condensation of an equivalent amount of 1,3-diketone and ethylenediamine in acetic acid provides 2,3-dihydro-1H-1,4-diazepine in good yield.49
3. By condensation of 1,2-diaminocyclopropane and aldehyde: Condensation of 1,2-diaminocyclopropane with aryl aldehyde initially forms a Schiff’s base, which on thermal cope rearrangement followed by migration of hydrogen afforded 2,3-diphenyldihydro-1,4-diazepine.
Chemical Reactivity 1. Diastereoselective synthesis of [1,2,4]oxadiazolo[4,5-d][1,4]diazepine-8-spiro-5′-isoxazolines and [1,2,4]oxadiazolo-[4,5d][1,4]-diazepines can be achieved by adding mesitonitrile oxide to 1,7-dimethyl-2,3-dihydro-1H-1,4- diazepines via a 1,3-dipolar cycloadditions approach.50
2. Enantioselective syn- or anti-aldol adducts can be achieved by using Evans oxazolidinone chiral auxiliary methodology. Through multiple steps involving various enantioselective aldol reactions and substitution reactions afforded functionalized 2,3-dihydro-1,4-diazapine.47
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3.3.5 1,4-Benzodiazepine
`
1,4-Benzodiazepine-based systems51 are pharmaceutically important and also known for tranquilizer and antidepressant properties. Various methods have been developed for construction of 1,4-benzodiazepine. Synthesis 1. From 2-aminobenzophenones: 2-Aminobenzophenones are used as a precursor for the synthesis of 2,3dihydro-1H-1,4-benzodiazepin-2-ones through a base-catalyzed cyclocondensation of o-aminobenzophenones with amino esters, or by acylation using halo acid chlorides followed by cyclization using ammonia.
2. From o-azidobenzophenones: [l,2,3]Triazolo[l,5-a][l,4]benzodiazepines were synthesized from the reaction of o-azidobenzophenones and propargylamine. They react under catalytic conditions to provide 1,3-dipolar cycloaddition and afforded aryltriazole, which cyclizes further to give the desired product. Alternatively, pyrrolo[2,1-c][1,4] benzodiazepines were synthesized by reaction of 1H-benzo[d][1,3] oxazine-2,4-dione and proline.
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3. From 2-(chloromethyl)quinazoline-3-oxides: 2-(Chloromethyl)quinazoline-3-oxides react with ammonia or primary amine to afford 2-amino-1,4-benzodiazepine-4-oxides. Mechanistically, ring expansion was started by addition of the N-nucleophile to C-2 followed by elimination of the halide via 1,2-shift in the nitrone to afford amidinium, which underwent deprotonation to yield the desired product. 2-(Chloromethyl)-quinazoline-3-oxides were synthesized by reaction of 2-aminobenzophenone oximes via N-acylation using chloroacetyl chloride followed by cyclodehydration under acidic conditions.
Diazepam (Valium) and chlordiazepoxide (Librium) are 1,4-benzodiazepine-based compounds and are prepared from 5-chloro-2-aminobenzophenone by using the following approach.52
Chemical Reactivity 1. Chlordiazepoxide yields 7-methyl-4-oxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one under mild alkaline hydrolysis. Treatment of 7-methyl-4-oxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one with acetic anhydride afforded acetic acid 7-chloro-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl ester by a Polonovski reaction.
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Interestingly, reaction of 7-methyl-4-oxy-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one with toluenesulfonyl chloride provides the ring contraction product tetrahydroquinoxaline. On the other hand, acid-catalyzed rearrangement of 3-hydroxybenzazepin-2-one leads to quinazoline-2-carbaldehyde.53
3.3.6 Dibenzo[d,f]-1,3-Diazepine
1,3-Diazepine fused with two benzene rings at the “d” and “f” sites resulted in dibenzo[d,f]-1,3-diazepine. This molecule is not completely planar and two benzene rings exist in different planes with respect to each other. Synthesis 1. Synthesis from 2-pyranone: Various substituted 5,7-dihydro-6H-dibenzo[d,f][1,3]diazepin-6-ones are prepared54 by ring transformation of suitably functionalized 2H-pyran-2-ones with indolin-2-one. Solvent/base combinations such as potassium tert-butoxide in tert-butanol and sodium methoxide in methanol work efficiently. At higher temperature in the presence of sodium methoxide, SMe was replaced by OMe.
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One of the compounds, 1-phenyl-3-methylthio-5,7-dihydro-6H-dibenzo[d,f][1,3]-diazapin-6-one, was crystallized and the structure was confirmed by single crystal X-ray. 2. From N1,N2-di-(4-methoxyphenyl)- or N1,N2-di-(4-hydroxyphenyl)-amidines: N1,N2-di-(4-methoxyphenyl)or N1,N2-di-(4-hydroxyphenyl)-amidines and 3,4,5,6-tetrachloro-1,2-benzoquinone react at room temperature in ethyl acetate and produce 3,4,5-trichloro-6-(2-hydroxy-6-methyldibenzo[d,f][1,3]diazepin-5-yl[1,2]-benzoquinones along with other side products in addition to N-aryl-N′-(6,7,8,9-tetrachloro-4-hydroxydibenzo-[1,4]dioxin-2-yl) acetamidines.55
3. From indole: Reaction of 2-methyl or -phenyl-indole and N-aryltrifluoroacetimidoyl chlorides provides the functionalized guanidine moiety, which cyclized under palladium-catalyzed conditions to afford the functionalized dibenzo[d,f][1,3]diazepine.56
4. From cyclization of suitably diarylated guanidine: Reaction of suitably functionalized guanidine and 2,2′-diaminobiphenyl under acidic conditions provided dibenzo[d,f][1,3]diazepine.57
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5. By cyclization of benzimidazolium salt: Treatment of benzimidazolium salt in dimethyl sulfoxide (DMSO) with Pd(OAc)2 and sodium iodide at 90 °C for 2 h provided cyclic guanidine and dibenzo[d,f][1,3]diazepine in moderate yield. Benzimidazolium salt was synthesized in multiple steps using N2-(2-nitro-phenyl)-[1,1′]binaphthalenyl2,2′-diamine as a precursor.58
6. By reaction of o,o′-diaminobiphenyl and S-methylthioamide: Treatment of iodomethane and thioamide provides imines, which react with o,o′-diaminobiphenyl or bipyridyl and provide 6-substituted-5H-dibenzo- or dipyrido[1,3]diazepines in good yields.59
3.4 SEVEN-MEMBERED ISOLATED AND BENZO-FUSED OXYGEN AND SULFUR HETEROCYCLES Various seven-membered heterocycles containing oxygen and sulfur are also known. Like azepine oxygen and sulfur heterocycles do not isomerize and stabilize.
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3.4.1 Oxepin
Oxepin is a seven-membered ring heterocycles comprised of one oxygen and six carbon atoms. It was observed that monocyclic oxepins show equilibrium with isomeric bicyclic benzene oxides60 (1,2-epoxybenzenes) as shown in the following diagram.
The presence of both oxepin and benzene oxide isomer was observed by low temperature. Proton NMR of the compound at −130 °C showed peaks at 4.0 (1H) and 6.3 (2H) ppm for benzene oxide and 5.1 (2H) and 6.3 (1H) ppm for oxepin. In UV spectra the λmax for oxepin and benzene oxide was found at 305 nm and 271 nm, respectively. Spectroscopic data demonstrated the polyolefinic structure with localized CC bonds. It was also found that monocyclic oxepin exhibited nonplanar boat conformation, which can provide other isomers through inversion.61 Inversion of the ring can be slowed down if the oxepin ring is fused with benzene rings. Racemization of 13-methyltribenzoxepin-11-carboxylic acid is very slow and can be isolated into its enantiomers.62
Various natural products containing oxepin are also studied, e.g., senoxepin, strychnine, brucine, brassinosteroids, etc.
Synthesis 1. From 3,4-dibromo-7-oxabicyclo[4.1.0]heptanes: The first synthesis of 3,4-dibromo-7-oxabicyclo[4.1.0]heptanes was carried out from cyclohexa-1,4-dienes in two steps. In the first step, epoxidation of 1,4-cyclohexadiene was performed followed by the addition of bromine to the double bond. In the next step, base-induced double dehydrobromination of 3,4-dibromo-7-oxabicyclo[4.1.0]heptanes yielded benzene oxide/oxepin.
3.4 Seven-Membered Isolated and Benzo-Fused Oxygen and Sulfur Heterocycles
413
2. Synthesis of oxepan-2-one: Cyclohexanone was used as a precursor for the synthesis of oxepan-2-one. This product was obtained by a Bayer-Villiger oxidation of cyclohexanone.
3. From alkyne: 1-Benzoyl-2-propylcyclopropene and hex-1-yne react in the presence of bis[dicarbonyl(chloro) rhodium] catalyst afforded 2-butyl-7-phenyl-4-propyloxepin in 62% yield and 2-butyl-6-phenyl-4-propylphenol in 8% yield.63,64
4. From hexa-2,4-diene-1,6-diol: Direct cyclization reactions of hexa-2,4-diene-1,6-diol in the presence of tert- butyllithium and 4-toluenesulfonyl chloride formed an O-C bond with the formation of 2,7-dihydrooxepins.65
5. From bicyclo[2.2.0]hexa-2,5-diene: Bicyclo[2.2.0]hexa-2,5-diene on treatment with 3-chloroperoxybenzoic acid provides its epoxide, which after thermolysis (115 °C) or photochemical irradiation provided a mixture of the valence tautomers oxepin and benzene oxide.66,67
6. From 3-oxaquadricyclanes (3-oxatetracyclo[3.2.0.02,7.04,6]heptanes): Thermal isomerization of numerous substituted 3-oxaquadricyclanes (3-oxatetracyclo[3.2.0.02,7.04,6]heptanes) provides oxepins.68–75 The obtained oxepin undergoes equilibrium with the corresponding benzene oxides.76,77
7. From oxanorbornadienes: Oxanorbornadienes under photochemical transformation change to oxepins through ring opening.78,79
8. From cyclohexa-2,5-diene-1,4-diols: Treatment of sterically hindered cyclohexa-2,5-diene-1,4-diols with trifluo roacetic acid provides the ring expansion reaction to afford a seven-membered oxepin along with the side product cyclohexa-2,4-dien-1-ones.80–82
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3. Seven-Membered Heterocycles
Chemical Reactivity 1. Cycloaddition with alkynes and oxygen: Valency isomerization of oxepin plays an important role in the various reactions.83 Diels-Alder cycloaddition of activated alkynes with benzene oxide (isomer of oxepin) provides epoxybicyclo[2.2.2]octatriene. On the other hand, peroxide was isolated by treatment with singlet oxygen, which undergoes thermal isomerization and provides trans-benzene trioxide.
2. Synthesis of phenol: Oxepin can be converted to phenol under acid-catalyzed conditions. The reaction mechanism was demonstrated by isotopic labeling experiments, which showed that a 1,2-hydride shift from carbon to oxygen plays a key role (this shift was termed the NIH shift) in the reaction.
Enzyme-catalyzed hydroxylation of arenes occurs through the NIH shift.84
3.4.2 Benzoxepin
Benzoxepin is a bicyclic nonplanar oxygen heterocycle with a 10π ring electron system comprised of fusion of benzene with the “b” site of the oxepin ring. It is also known as benzo[b]oxepin. For biosynthesis and metabolism of various mono- and polycyclic aromatic compounds, oxepins and benzoxepins play very important roles. Both of these compounds are of great pharmacological significance. Oxepin and 2,3-benzoxepin were isolated from wood-rotting fungus Phellinus tremulae and the mammalian metabolite of dibenz[a,j]anthracene, respectively.
Synthesis 1. From oxygen-bridged [10]annulene: Base-mediated reaction of tetrabromodecahydronaphthalene epoxide provided benzo[b]oxepin and oxygen-bridged [10]annulene85 through ring expansion of formed intermediate 9,10-epoxynaphthalene.
3.4 Seven-Membered Isolated and Benzo-Fused Oxygen and Sulfur Heterocycles
415
2. From phenol: First of all, 3,4-dihydrobenzo[b]oxepin-5-(2H)-one was synthesized by acid-catalyzed cyclization of the 4-phenoxy butyric acids obtainable by the reaction of corresponding phenols and ethyl bromobutyrate. To optimize the cyclization, various acidic reagents such as methane sulfonic acid, polyphosphoric acid, trifluoromethane sulfonic acid, and hafnium triflate were used.86 Among all the reagents used for cyclization, polyphosphoric acid was found the most suitable and efficient reagent for cyclization. 5-Arylbenzoxepin was synthesized by Suzuki cross-coupling with 4-hydroxyphenylboronic acid under p alladium-catalyzed conditions. The synthesis of benzoxepin was further modified through a sequence of reactions.
3. From 4-chromone: Chromone was also used as a precursor for the synthesis of benzoxepin. In the first step, o-silylation was performed by Me3SiOTf. In the next step, stereoselective synthesis of cyclopropane was achieved under copper(II)-catalyzed conditions using silylated chromone. Under the influence of trifluoroacetic acid, cyclopropane underwent ring expansion to afford 2,3-benzoxepin.87
416
3. Seven-Membered Heterocycles
4. From benzyne: Treatment of benzyne with pyridazine-1-oxides provides the corresponding 1-b enzoxepins in moderate yields as well as a by-product, 3-(2-hydroxyphenyl)pyridazines as a minor product constituent. 88
5. From resorcinol: The reaction of resorcinol with ethyl (2-oxocyclohexyl)acetate under strong acidic conditions provided 3-hydroxy-8,9,10,11-tetrahydrodibenz[b,d]oxepin-6(7H)-one in only 19% yield.89
6. From 8-hydroxy-4-methoxy-1-naphthaldehyde: Treatment of 8-hydroxy-4-methoxy-1-naphthaldehyde with N,N-dimethylformamide and phosphoryl chloride followed by perchloric acid provides 2-(dimethylamino)-7- methoxynaphth[1,8-b,c]oxepinium perchlorate.90
7. From phthaldehyde: Treatment of phthaldehyde with the bis(ylide) generated from the bis(triphenylphosphonium) salt provides 3-benzo[d]oxepin in 55% yield. Reaction of bis(bromomethyl)ether and triphenylphosphine provides the desired salt for the reaction.91,92
3.4 Seven-Membered Isolated and Benzo-Fused Oxygen and Sulfur Heterocycles
417
8. From methyl 4-(2-formylphenoxy)but-2-enoate: Methyl 1-benzoxepin-4-carboxylate is obtained by stirring methyl 4-(2-formylphenoxy)but-2-enoate in N,N-dimethylformamide in the presence of potassium carbonate for 100 h at room temperature through a methyl 5-hydroxy-4,5-dihydro-1-benzoxepin-4-carboxylate intermediate.93
9. From N-{2-[(3-phenylprop-2-ynyl)oxy]phenyl}methylidenepropan-2-amine: N-Isopropyl-4-phenyl1-benzoxepin-5-amine was synthesized from N-{2-[(3-phenylprop-2-ynyl)oxy]phenyl}methylidenepropan2-amine in the presence of n-butyllithium. A minor side product 2-(phenylethynyl)benzo[b]furan was also isolated.94
Chemical Reactivity 1. Reaction with 2-pyranones: Reaction of 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-one with suitably functionalized 2-pyranone provides benzo[b]pyrano[2,3-d]oxepines and dibenzo[b,d]oxepines depending on the substituent at position 4 of the pyran ring.95 Pyran having a methylthio group at position 4 reacted with 3,4-dihydro-2H-benzo[b] oxepin-5(2H)-one under basic conditions and provided an isomeric mixture of (E)- and (Z)-2-(4-aryl-5,6-dihydro-2Hbenzo[b]pyrano[2,3-d]oxepin-2-ylidene)acetonitriles.
However, 4-sec.amino-2H-pyran-2-ones on reaction with 3,4-dihydro-2H-benzo[b]oxepin-5(2H)-ones afforded 10-sec.amino-8-phenyl-6,7-dihydrodibenzo[b,d]oxepine-11‑carbonitriles. 2. Synthesis of polycyclic oxygen heterocycles: Treatment of 3,4-dihydro-2H-benzo[b]oxepin5(2H)-ones with methyl 2-cyano-3,3-dimethylthioacrylate provided 4-methylthio-2-oxo-5,6-dihydro-2Hbenzo[b]pyrano[2,3-d]oxepine-3‑carbonitriles in the presence of powdered KOH in DMSO and was aminated by reaction with various secondary amines under reflux conditions in ethanol to afford 4-s.Amino-2-oxo-5, 6-dihydro-2H-benzo[b]pyrano[2,3-d]oxepine-3‑carbonitriles. Further treatment of 4-methylthio-2-oxo5,6-dihydro-2H-benzo[b]pyrano[2,3-d]oxepine-3‑carbonitriles with aryl methyl ketone provided 5-aryl-2, 3-dihydro-7H,8H-naphtho[1,2-b]pyrano[4′,3′:4,5]pyrano[2,3-d]oxepin-7,8-diones, while the reaction of 4-s. Amino-2-oxo-5,6-dihydro-2H-benzo[b]pyrano[2,3-d]oxepine-3‑carbonitriles with aryl methyl ketone afforded functionalized dibenzoxepin.95,96
418
3. Seven-Membered Heterocycles
The mechanistic pathway for the synthesis of naphtho[1,2-b]pyrano[4′,3′:4,5]pyrano[2,3-d]oxepin-7,8-diones is reported in the following scheme.
3.4.3 Thiepin
Thiepins are fully unsaturated seven-membered compounds containing one sulfur atom. They contain 8π electrons and are reported as an antiaromatic system. Through computational methods, the antiaromatic character of thiepins was also observed.97–103 It has been reported that the antiaromatic resonance energy of thiepins can be reduced by the presence of electron-withdrawing substituents in the ring. 97 It was also suggested that the steric influence of alkyl and ester substituents plays a significant role in the stability of the molecule.98 Synthetically, thiepin is of great interest104 and stabilization of multifunctional thiepins is higher only at low temperatures.104
3.4 Seven-Membered Isolated and Benzo-Fused Oxygen and Sulfur Heterocycles
419
Synthesis 1. From the reaction of alkyne and thiophene: Functionalized thiepin can be achieved by the reaction of thiophenes and activated alkynes. Reaction proceeds through [2 + 2] cycloaddition and electrocyclic fission of cyclobutene formed during the cycloaddition.
2. From Thiinium salt: Reaction of thiinium salt and lithiodiazoacetic ester provided the intermediate product through C-4 addition, which yielded thiepins by ring expansion reaction under palladium-catalyzed conditions.105
3. From benzaldehyde acetal: In the first step, bis(aryl)sulfide derivatives were synthesized by the reaction of benzaldehyde acetals106,107 and bis(phenylsulfonyl)sulfide in the presence of n-butyllithium. The bis(aryl)sulfides obtained were converted to dialdehyde108 through deacetalization. The isolated product was treated under intramolecular McMurry coupling109 conditions to afford dibenzo[b,f]thiepin.
4. By reaction of phthalide and thiophenol: A reaction with potassium salt of thiophenol with 3H-isobenzofuran-1one provided 2-phenylsulfanylmethyl-benzoic acid, which after cyclodehydration yielded 6,11-dihydrodibenzo[b,e] thiepin-11(6H)-one.
5. From [2-(phenylsulfanyl)phenyl]acetic acid: [2-(Phenylsulfanyl)phenyl]acetic acid was used as a precursor for the construction of dibenzo[b,f]thiepins in the presence of POCl3 probably through an intermediate dihydrothiepinone.
420
3. Seven-Membered Heterocycles
6. From stilbene: Azepines and thiepines can also be synthesized by double amination or thiolation reactions of stilbenes, respectively, under palladium catalysis.110
7. From thiophen-2-amines: Fused thiepins are synthesized by reaction of fused thiophen-2-amines with an electron-deficient acetylenic dienophile.111
8. From triene: Thiepin 1,1-dioxide was synthesized by introducing sulfur dioxide to Z-hexatriene to yield 2,7-dihydrothiepin-1,1-dioxide.112 Bromination of one of the double bonds followed by base-mediated elimination of hydrogen bromide gave thiepin-1,1-dioxide.113
9. From diazomethane: The reaction of 2 equivalents of vinyl diazomethane and sulfur dioxide provides 4,5-dihydrothiepin-1,1-dioxide.114 Radical-mediated bromination followed by dehydrohalogenation provided thiepin.114
Cycloaddition reaction of divinyl sulfone with trimethylsilylacetylenedicobalt hexacarbonyl provided a dihydrothiepin dioxide. A one-pot bromination followed by dehydrobromination furnished 4-trimethylsilylthiepin-1,1-dioxide.115
10. From 2,6-diphenyl-4H-thiopyran-4-one 1,1-dioxide: A photochemical treatment of 2,6-diphenyl-4Hthiopyran-4-one 1,1-dioxide and alkyne provided 2,4,7-triphenylthiepin 1,1-dioxides in 20%–60% yield.116
3.4 Seven-Membered Isolated and Benzo-Fused Oxygen and Sulfur Heterocycles
421
11. From 1-bromo-2-(4-substituted-but-1-en-3-ynyl)-benzene: Treatment of monolithium species of 1-bromo-2(4-substituted-but-1-en-3-ynyl)-benzene with elemental sulfur provided 1-benzothiepins.117
Chemical Reactivity 1. Photochemical rearrangement reactions: Photochemical rearrangement of benzo[b]thiepin is reported by Hofmann and Meyer. This rearrangement provided ring contraction of the thiepin ring.118
2. Thermal rearrangement reactions: Thermal treatment of benzo[b]thiepins in benzene provided the corresponding naphthalene. During this reaction sulfur was eliminated. However, thermal rearrangement of 3,4-di(methoxycar bonyl)-5-hydroxybenzo[b]thiepin provides 4-mercaptonaphthol.118
422
3. Seven-Membered Heterocycles
3. Synthesis of benzene: Through valency isomerization, thiepin provides benzo-fused thiiran, which undergoes desulfurization to afford benzene.
3.5 MISCELLANEOUS SEVEN-MEMBERED HETEROCYCLES 3.5.1 1,4-Oxazepines Seven-membered heterocycles with one nitrogen and one oxygen or sulfur atom in the ring at the 1 and 4 positions are designated as 1,4-oxazepines and 1,4-thiazepines. Synthesis 1. 1,4-Oxazepine was synthesized by dehydrative cyclization of 3-((-hydroxyethyl) (phenyl)amino)propan-1-ol. However, 7-methyl 3,4-dihydro-1,4-ozaazepin-5(2H)-one has been synthesized through dehydrative cyclization of N-(2-hydroxyethyl)-3-oxobutanamide.
2. 7-Ethyl 5,6-dimethyl 4-ethoxyoxepino[3,2-d]isoxazole-5,6,7-tricarboxylate has been synthesized in 77% yield by the reaction of ethyl diazo-(4-ethoxycarbonyl-3-methylisoxazol-5-yl)acetate with dimethyl acetylenediacetate in the presence of dirhodium tetraacetate. The reaction probably proceeds through a vinyl carbene–cyclopropene valence tautomerization mechanism.119
3. 3-Amino-4H-thieno[3,4-c]chromen/thiochromen-4-one undergoes cycloaddition with electron-deficient acetylenic dienophile to yield a cycloadduct that readily succumbs to a series of rearrangements and affords tricyclic thiepin derivative120 in the final step after electrocyclization.
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