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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
12.06 Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1 M. P. Mahajan, G. Bhargava, and C. Mohan Guru Nanak Dev University, Amritsar, India ª 2008 Elsevier Ltd. All rights reserved. 12.06.1
Introduction
327
12.06.2
Theoretical Methods
330
12.06.3
Experimental Structural Methods
330
12.06.3.1
X-Ray Crystallography
330
12.06.3.2
NMR Spectroscopy
330
12.06.3.3
Mass Spectrometry
332
12.06.3.4
IR Spectroscopy
332
12.06.3.5
UV Spectroscopy
332
12.06.4
Thermodynamic Aspects
12.06.5
Reactivity of Fully Conjugated Rings
332
12.06.6
Reactivity of the Nonconjugated Rings
333
12.06.7
Reactivity of the Substitutents Attached to the Ring Carbon Atom
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12.06.8
Reactivity of the Substitutents Attached to the Ring Heteroatom
333
12.06.9
Ring Synthesis Classified by the Number of Ring Atoms in Each Component
333
12.06.10
332
Ring Synthesis from Derivatives of One of the Rings
12.06.10.1
Synthesis from Heterocycles Containing Two Heteroatoms
12.06.10.1.1 12.06.10.1.2 12.06.10.1.3 12.06.10.1.4
12.06.10.2
Synthesis Synthesis Synthesis Synthesis
from fused pyrimidinone derivatives from hydrazino intermediates from amino intermediates using other intermediates
Synthesis from Heterocycles Containing Three Heteroatoms
12.06.10.2.1 12.06.10.2.2 12.06.10.2.3 12.06.10.2.4
Synthesis Synthesis Synthesis Synthesis
using acetylenic esters using dibromopropane using epichlorohydrin using other ring systems
333 333 333 333 334 335
336 337 337 337 338
12.06.11
Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available
338
12.06.12
Important Compounds and Applications
338
References
338
12.06.1 Introduction There have been a reasonable number of literature reports concerning bicyclic 6-6 heterocycles with a nitrogen atom at the bridgehead position and three extra heteroatoms all in the same ring <1996CHEC-II(8)713>. Such ring systems reported previously are numbered 1–27; during the last decade bicyclic 6-6 systems and their fused benzo-derivatives containing one ring junction nitrogen atom with the rings containing nitrogen and sulfur as the other heteroatoms have been most explored in the literature. Examples of such heterocyclic systems reported
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
during the last decade are: 3,4-dihydroxyoctahydropyridazino[1,6-d][1,2,4]triazine 28; 3a,9a-dihydro-1,8-dithia4a,5,9-triazacyclopenta[b]naphthalene 29; 8,9-dihydropyridazino[6,1-c][1,2,4]triazine 30; 2,3,4,9-tetrahydropyrimido[1,2-a][1,3,5]triazine 31; 3,4-dihydro-2H-pyrimido[6,1-c][1,2,4]triazine 32; pyrimido [2,1-c][1,2,4]triazine 33; 2,3,4,9-tetrahydropyrimido[1,6-a][1,3,5]triazine 34; 1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene 35; 2H-1thia-4,4a,9-triaza-anthracene 36; 3a,7,8,9a-tetrahydro-4H-1-thia-4a,6,7,9-tetra-azacyclopenta[b]naphthalene 37; 3,4hydro-2H,9H-1-thia-4a,5,9,10-tetra-azaphenanthrene 38; 3,4-dihydro-2H,10H-1-thia-4a,9,10-triaza-anthracene 39; 4H,9H-1-thia-4a,9,10-triazaphenanthrene 40; 7,8-dihydro-6H-[1,3]thiazino[2,3-c][1,2,4]triazine 41; 3H-3,4,9,10atetra-azaphenanthrene 42; 2,3-dihydro-1H-1,4,9,10a-tetra-azaphenanthrene 43; 3,4-dihydro-2H,9H-1-thia-4a,9,10triazaphenanthrene 44; 12H-quinoxalino[1,2-c][1,2,3]benzotriazin-5(6H)-one 45.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
12.06.2 Theoretical Methods Theoretical methods have not been applied to these heterocyclic systems.
12.06.3 Experimental Structural Methods Since these heterocyclic systems are diverse in nature, different methods have been adopted for their synthesis; a detailed discussion of the experimental techniques has not been attempted.
12.06.3.1 X-Ray Crystallography The X-ray crystallography of only one system has been reported during the period 1995–2006. Previous studies for compounds 6, 23, 26, 27, and 28 are discussed in CHEC-II(1996) <1996CHEC-II(8)713>. Thus, for example, crystals of 10-benzyl-1,3-diphenyl-1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene-2,4-dione 46 <2000EJO2105> were shown to be monoclinic having space group of P21/c with cell dimensions of a ¼ 1124.19 (8), b ¼ 1106.63(10), c ¼ 1890.29 (15), ¼ 95.56 (6). In this structure the tetrahydroquinazoline moiety exists in a half chair; the chiral carbon atom C-4 is positioned under the molecular plane of the benzene ring and atoms C-9 and N-5. Except for the chiral carbon atom, all atoms of the triazine ring are nearly planar. The regression surface of these five atoms being twisted by 43.4 around the C-7 and N-5 bond axis against the plane of the benzene ring.
12.06.3.2 NMR Spectroscopy Almost all the reported compounds have been characterized with the help of various nuclear magnetic resonance (NMR) techniques. For previous studies of the compounds, refer to CHEC-II(1996) <1996CHEC-II(8)713>.The 1H NMR spectrum (300 MHz) of 2,3,7-trimethyl-3a,9a-dihydro-1,8-dithia-4a,5,9-triazacyclopenta[b]naphthalene-4,6dione 47 <2000JHC1161> showed the presence of one quartet at 4.23 corresponding to the CH. Another broad singlet corresponds to the presence of the N–H proton.
Similarly, the compound 6-benzyl-3-methyl-9-phenyl-8,9-dihydro-pyridazino[6,1-c][1,2,4]triazine-4,7-dione 48 <1997JHC389> in its 1H NMR spectrum (300 MHz) showed the presence of two multiplets at 3.40–3.75 and 4.62–4.84 corresponding to the endocyclic CH2 and CH of the diazine ring. Two additional doublets appeared at 5.08 and 5.29 due to the benzylic protons.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
The 1H NMR spectrum (500 MHz) of 3-(4-chloro-phenyl)-7-ethyl-7,9-dimethyl-2,3,4,9-tetrahydropyrimido[1,2-a][1,3,5]triazine-6,8-dione 49 <2002JHC663> showed the presence of quartets (AB pattern) at 4.99 and 5.12 corresponding to the methylene protons of the triazine ring.
The 1H NMR spectrum (200 MHz) of 10-benzyl-1,3-diphenyl-1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene2,4-dione 46 <2000EJO2105> showed the presence of a singlet at 6.14 corresponding to C(4)–H. In the 1H NMR spectrum of 3,4-dihydro-2H,9H-1-thia-4a,5,9,10-tetra-azaphenanthrene 50 <1999IJH75>, two triplets at 3.3 and 4.4 correspond to the SCH2 and NCH2, respectively, and a multiplet at 2.5 corresponds to the CH2 protons.
Similarly, the 1H NMR spectrum (90 MHz) of 4-oxo-4H, 9H-1-thia-4a,9,10-triazaphenanthrene-2-carboxylic acid methyl ester 51 <1998IJH303> displayed two singlets at 8.1 and 7.28 corresponding to Ha and Hb, respectively. The compound 3,4-dihydro-2H, 9H-1-thia-4a,9,10-triazaphenanthren-3-ol 52 <2003PS797> in its 1H NMR spectrum (200 MHz) showed the presence of two dd at 3.08 and 3.96 corresponding to two CH2 protons. The spectrum also showed one multiplet at 4.27 corresponding to CH and one doublet at 5.55 assigned to the OH proton.
The 1H NMR spectrum (300 MHz) of 8,9-dimethyl-12H-quinoxalino[1,2-c][1,2,3]benzotriazin-5(6H)-one 53 <2003JHC357> showed the presence of two broad singlets at 11.27 and 13.32 corresponding to the N(6)–H
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
and N(12)–H protons and the 13C NMR spectrum (300 MHz) showed one peak at 153.1 a characteristic of C-5 (CTO). Its 15N NMR spectrum (500 MHz) showed four peaks at 177.6, 126, 119.5, and 301.5 corresponding to N-12, N-11, N-6 and N-13, respectively.
12.06.3.3 Mass Spectrometry The mass spectra of all the compounds showed the presence of molecular ion peaks. The fragmentation pattern of pyrimidotriazines has been discussed previously in CHEC-II(1996) <1996CHEC-II(8)713>.
12.06.3.4 IR Spectroscopy The infrared (IR) spectra of these compounds were mostly studied in the solid state which showed all the basic peaks characteristic of various functionalities attached to such bicyclic heterocycles with bridgehead nitrogen atoms. The difference in the frequency of carbonyl and carbon nitrogen double bond in tautomers of compound 18 (R ¼ H) has been discussed previously in CHEC-II(1996) <1996CHEC-II(8)713>.
12.06.3.5 UV Spectroscopy The presence of tautomeric structures in compound 32 has been determined from ultraviolet (UV) spectra in ethanol. Compound 32 showed two absorption bands (due to its tautomeric forms 32a and 32b) at 288.6 and 241.0 nm attributed to an n–p* and p–p* bands, respectively <1997IJB269>. Previous studies are discussed in CHEC-II(1996) <1996CHEC-II(8)713>.
12.06.4 Thermodynamic Aspects No information is available in the literature.
12.06.5 Reactivity of Fully Conjugated Rings The heterocyclic compounds containing ring junction nitrogen atom are nonaromatic, thus lacking extensive conjugation. Consequently, there is no information available regarding the reactivity of fully conjugated compounds.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
12.06.6 Reactivity of the Nonconjugated Rings No information is available in the literature during the period 1995–2006. Previous studies are discussed in CHECII(1996) <1996CHEC-II(8)713>.
12.06.7 Reactivity of the Substitutents Attached to the Ring Carbon Atom No information is available in the literature.
12.06.8 Reactivity of the Substitutents Attached to the Ring Heteroatom No information is available in the literature.
12.06.9 Ring Synthesis Classified by the Number of Ring Atoms in Each Component Synthesis of these compounds is not discussed in this section, but is given below.
12.06.10 Ring Synthesis from Derivatives of One of the Rings The reports concerning the synthesis of bicyclic, ring junction nitrogen heterocycles containing three additional heteroatoms are divided into three categories. In category I the parent molecule is a heterocyclic ring containing two heteroatoms, in category II, the parent heterocyclic ring has three heteroatoms, and other synthetic methods fall into category III. In the present chapter the synthesis reported during period of 1995–2006 has been discussed, while the synthesis reported earlier has been discussed in <1996CHEC-II(8)713>.
12.06.10.1 Synthesis from Heterocycles Containing Two Heteroatoms 12.06.10.1.1
Synthesis from fused pyrimidinone derivatives
5-Benzyl-1-buta-1,3-diynylsulfanyl-6H-3-thia-4,5a,8,9-tetra-azacyclopenta[a]naphthalen-7-ylamine 55 <1999JCR(S)646> was prepared by the treatment of 2-benzyl-5-buta-(1,3-diynylsulfanyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)acetonitrile 54 with hydrazine (Equation 1).
ð1Þ
12.06.10.1.2
Synthesis from hydrazino intermediates
The use of a hydrazine group attached to different heterocycles having two heteroatoms was successfully exploited for the synthesis of various bicyclic and fused bicyclic heterocyclic systems having bridgehead nitrogen atoms. The 3-methylpyrimido[2,1-c][1,2,4]triazin-4-one 57 <1998JHC325> and 6-benzyl 3-methyl-9-aryl-8,9-dihydropyridazino[6,1-c][1,2,4]triazine-4,7-dione 59 <1997JHC389> have been prepared from the corresponding hydrazine derivatives 56 and 58, respectively, as depicted in Scheme 1.
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
Scheme 1
Refluxing of hydrazine 60 in acetic acid in the presence of sodium acetate resulted in the formation of 6-methyl-3oxo-8-phenyl-3,4-dihydro-2H-pyrimido[6,1-c][1,2,4]triazine-9-carbonitrile 61 in good yield <1997IJB269> (Equation 2).
ð2Þ
12.06.10.1.3
Synthesis from amino intermediates
The reaction of potassium 3-amino-4-oxo-3,4-dihydroquinazoline-2-thiolate 62 with -bromophenylacetic acid 63 resulted in the formation of (3-amino-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-phenyl-acetic acid methyl ester 64 which on alkali treatment and subsequent acidification resulted in the synthesis of 2-phenyl-1-thia4,4a,9-triaza-anthracene-3,10-dione 65 <1999JCR(S)86>. Similarly, the reaction of potassium 3-amino-5,6dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3-d]pyrimidine-2-thiolate 66 with -bromo-ester 67 resulted in the formation of 2-(3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3-d]pyrimidin-2-ylsulfanyl)-propionic acid ethyl ester 68. Subsequent treatment with alkali followed by acidification resulted in the formation of 2,3,7-trimethyl-3a,9a-dihydro-1,8-dithia-4a,5,9-triazacyclopenta[b]naphthalene-4,6-dione 69 <2000JHC1161> (Scheme 2).
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
Scheme 2
Compound 7-ethyl-7-methyl-3-phenyl-2,3,4,9-tetrahydropyrimido[1,2-a][1,3,5]triazine-6,8-dione 71 <2002JHC663> was prepared by the one-pot condensation reaction of 6-amino-3-ethyl-3-methyl-5H-pyridine-2,4-dione 70 with aromatic amines and formaldehyde (Equation 3).
ð3Þ
12.06.10.1.4
Synthesis using other intermediates
3-Methyl-3,4-dihydroquinazoline 72 <2000EJO2105> when treated with phenyl isocyanate resulted in the formation of 10-methyl-1,3-diphenyl-1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene-2,4-dione 73 (Equation 4).
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
ð4Þ
Displacement of the 3-hydroxyl group of 74 was carried out with Et2NSF3 (DAST) (DAST – diethylaminosulfur trifluoride) in dichloromethane. The expected fluorinated product 75 on treatment with aqueous perchloric acid led to regioselective epoxide ring opening to give 76, which on treatment with hydrazine hydrate at 100 C for 18 h yielded 3,4-dihydroxy-8-oxo-octahydropyridazino[1,6-d][1,2,4]triazine-1-carboxylic acid phenylamide 77 (Scheme 3) <1997T9357>.
Scheme 3
The compound 10a,10b-dihydro-5H,12H-4b,5,6,12-tetraaza-chrysen-11-one 81 <2003JHC357> was prepared through diazotization of the corresponding amine derivative 3-(2-aminophenyl)-1H-quinoxalin-2-one 78. The reaction proceeded through intermediates 79 and 80 (Scheme 4).
12.06.10.2 Synthesis from Heterocycles Containing Three Heteroatoms There are very few reports concerning the use of heterocycles containing three heteroatoms for the synthesis of the target bicyclic systems.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
Scheme 4
12.06.10.2.1
Synthesis using acetylenic esters
The treatment of 1,4-dihydro-2H-pyrido[2,3-e][1,2,4]triazine-3-thione 82 with dimethyl acetylenedicarboxylate (DMAD) in methanol at room temperature leads to the formation of 5-oxo-8,8a,9,10-tetrahydro-5H-4,4b,9,10-tetraazaphenanthrene-7-carboxylic acid methyl ester 83 <1998IJH303> (Equation 5).
ð5Þ
12.06.10.2.2
Synthesis using dibromopropane
The pyridotriazine 84 on treatment with dibromopropane resulted in the formation of 3,4,10,10a-tetrahydro-2H,9H1-thia-4a,5,9,10-tetra-azaphenanthrene 85 <1999IJH75> (Equation 6).
ð6Þ
12.06.10.2.3
Synthesis using epichlorohydrin
Refluxing of benzo[1,2,4]triazine-3-thione 86 with epichlorohydrin in the presence of triethylamine in methanol for 14 h resulted in the formation of 3,4-dihydro-2H,9H-1-thia-4a,9,10-triaza-phenanthren-3-ol 87 <2003PS797> (Equation 7).
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
ð7Þ
12.06.10.2.4
Synthesis using other ring systems
The treatment of (2-benzoylamino-5-iodobenzoyl-amino)acetic acid ethyl ester 88 with hydrazine hydrate for 4 h yielded hydrazine derivative 2-benzoylamino-N-hydrazinocarbonylmethyl benzamide 89, which on refluxing with sodium acetate and acetic acid for 8 h resulted in the formation of 6-iodo-10-phenyl-3H-3,4,9,10a-tetra-azaphenanthren2-one 90 <2000IJH59> (Scheme 5).
Scheme 5
12.06.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available No examples were found suitable to carry out comparative studies of these systems.
12.06.12 Important Compounds and Applications Many of these bicyclic heterocyclic systems were found to be biologically active. Compounds 91 <2002JHC663>, 92 <2002FES109>, exhibited good antifungal activity and compound 93 showed average affinity for serotoninergic 5-HT1A and 5-HT1B receptors <2002JHC663>. For more examples of such heterocyclic biologically important compounds, refer to CHEC-II(1996) <1996CHEC-II(8)713>.
References 1996CHEC-II(8)713 S. N. Mazumdar and M. P. Mahajan; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 8, p. 713. 1997IJB269 M. A. Megid, Indian J. Chem., Sect. B, 1997, 26, 269. 1997JHC389 J. Lange, J. Karolak-Wojciechowska, E. Pytlewska, J. Plenkiewicz, T. Kulinski, and S. Rump, J. Heterocycl. Chem., 1997, 34, 389.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
1997T9357 1998IJH303 1998JHC325 1999IJH75 1999JCR(S)86 1999JCR(S)646 2000EJO2105 2000IJH59 2000JHC1161 2002FA109 2002JHC663 2003JHC357 2003PS797
I. Thomsen, B. Ernholt, and M. Bols, Tetrahedron, 1997, 53, 9357. M. M. Haveri, H. A. Oskooie, Y. S. Beheshtiha, N. Nami, and S. Ghoresishi, Indian J. Heterocycl. Chem., 1998, 303. S. Nagai, T. Ueda, S. Sugiura, A. Nagatsu, N. Murakami, and J. Sakakibara, J. Heterocycl. Chem., 1998, 35, 325. M. M. Haveri, M. Rahimizadeh, E. Iravani, M. Ghassemzadeh, and K. Aghapoor, Indian J. Heterocycl. Chem., 1999, 75. A. Santagati, M. Modica, L. M. Scolaro, and M. Santagati, J. Chem. Res. (S), 1999, 86. H. M. Hosni, W. M. Basyouni, and H. A. El-Nahas, J. Chem. Res. (S), 1999, 646. H. Tiez, O. Rademacher, and G. Zahn, Eur. J. Org. Chem., 2000, 2105. S. G. Abdel-Hamide, Indian J. Heterocycl. Chem., 2000, 59. A. Santagati, M. Modica, and M. Santagi, J. Heterocycl. Chem., 2000, 37, 1161. A. Ghaib, S. Menager, V. Philippe, and L. Olivier, Farmaco, 2002, 57, 109. L. Lucry, F. Enoma, F. Estour, H. Oulyadi, S. Menager, and O. Lafont, J. Heterocycl. Chem., 2002, 39, 663. I. Wiedermannova, J. Slouka, O. Humpa, and K. Lemr, J. Heterocycl. Chem., 2003, 40, 357. M. M. Heravi, M. Rahimizadeh, E. Iravani, and M. Ghassemzadeh, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178, 797.
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Biographical Sketch
Mohinder P Mahajan was born in 1947 at Gurdaspur, Punjab (India), and obtained his PhD in 1975 from Punjabi University, Patiala, under the supervision of Prof. N. K. Ralthan. He was a postdoctoral associate with Prof. M. V. George at the Indian Institute of Technology, Kanpur, Alexander-Von Humboldt Fellow with Prof. Rolf Huisgen at Munich. He was later associated with Prof. Gordon Kirby at Glasgow University, United Kingdom. He started his independent academic carrier in 1979 as lecturer at North–Eastern Hill University, Shillong, where he was promoted to full professor in 1991. In 1996 he shifted to Guru Nanak Dev University, Amritsar and at presently is professor in the department of Applied Chemistry of this University. In 2002, he was elected as fellow of National Academy of Science (FNASc) Allahabad, India. His research interests include the chemistry of heterodienes, the applications of cycloaddition reactions in synthesis of novel heterocyclic compounds, biologically potent heterocyclic molecules, and studies of reaction mechanisms.
Chander Mohan was born in 1975 at Dhariwal, Punjab, India. He received his B. Pharm and M. (Tech) Pharm. in Bulk Drugs from Guru Nanak Dev University and the National Institute of Pharmaceutical Education and Research (NIPER) Mohali. After that he worked as senior chemist at Dr. Reddy’s Research Foundation, Hyderabad. He then joined Prof. M. P. Mahajan’s research group in 2002 for his doctoral studies. His research is focused on the synthesis and chemical transformation of C-5/C-6 substituted pyrimidinones. His research interest includes synthesis of medicinally important molecules, transition metal-induced transformations in organic synthesis, reaction mechanism, and total synthesis of natural products.
Introduction
327
12.06.2
Theoretical Methods
330
12.06.3
Experimental Structural Methods
330
12.06.3.1
X-Ray Crystallography
330
12.06.3.2
NMR Spectroscopy
330
12.06.3.3
Mass Spectrometry
332
12.06.3.4
IR Spectroscopy
332
12.06.3.5
UV Spectroscopy
332
12.06.4
Thermodynamic Aspects
12.06.5
Reactivity of Fully Conjugated Rings
332
12.06.6
Reactivity of the Nonconjugated Rings
333
12.06.7
Reactivity of the Substitutents Attached to the Ring Carbon Atom
333
12.06.8
Reactivity of the Substitutents Attached to the Ring Heteroatom
333
12.06.9
Ring Synthesis Classified by the Number of Ring Atoms in Each Component
333
12.06.10
332
Ring Synthesis from Derivatives of One of the Rings
12.06.10.1
Synthesis from Heterocycles Containing Two Heteroatoms
12.06.10.1.1 12.06.10.1.2 12.06.10.1.3 12.06.10.1.4
12.06.10.2
Synthesis Synthesis Synthesis Synthesis
from fused pyrimidinone derivatives from hydrazino intermediates from amino intermediates using other intermediates
Synthesis from Heterocycles Containing Three Heteroatoms
12.06.10.2.1 12.06.10.2.2 12.06.10.2.3 12.06.10.2.4
Synthesis Synthesis Synthesis Synthesis
using acetylenic esters using dibromopropane using epichlorohydrin using other ring systems
333 333 333 333 334 335
336 337 337 337 338
12.06.11
Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available
338
12.06.12
Important Compounds and Applications
338
References
338
12.06.1 Introduction There have been a reasonable number of literature reports concerning bicyclic 6-6 heterocycles with a nitrogen atom at the bridgehead position and three extra heteroatoms all in the same ring <1996CHEC-II(8)713>. Such ring systems reported previously are numbered 1–27; during the last decade bicyclic 6-6 systems and their fused benzo-derivatives containing one ring junction nitrogen atom with the rings containing nitrogen and sulfur as the other heteroatoms have been most explored in the literature. Examples of such heterocyclic systems reported
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
during the last decade are: 3,4-dihydroxyoctahydropyridazino[1,6-d][1,2,4]triazine 28; 3a,9a-dihydro-1,8-dithia4a,5,9-triazacyclopenta[b]naphthalene 29; 8,9-dihydropyridazino[6,1-c][1,2,4]triazine 30; 2,3,4,9-tetrahydropyrimido[1,2-a][1,3,5]triazine 31; 3,4-dihydro-2H-pyrimido[6,1-c][1,2,4]triazine 32; pyrimido [2,1-c][1,2,4]triazine 33; 2,3,4,9-tetrahydropyrimido[1,6-a][1,3,5]triazine 34; 1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene 35; 2H-1thia-4,4a,9-triaza-anthracene 36; 3a,7,8,9a-tetrahydro-4H-1-thia-4a,6,7,9-tetra-azacyclopenta[b]naphthalene 37; 3,4hydro-2H,9H-1-thia-4a,5,9,10-tetra-azaphenanthrene 38; 3,4-dihydro-2H,10H-1-thia-4a,9,10-triaza-anthracene 39; 4H,9H-1-thia-4a,9,10-triazaphenanthrene 40; 7,8-dihydro-6H-[1,3]thiazino[2,3-c][1,2,4]triazine 41; 3H-3,4,9,10atetra-azaphenanthrene 42; 2,3-dihydro-1H-1,4,9,10a-tetra-azaphenanthrene 43; 3,4-dihydro-2H,9H-1-thia-4a,9,10triazaphenanthrene 44; 12H-quinoxalino[1,2-c][1,2,3]benzotriazin-5(6H)-one 45.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
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Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
12.06.2 Theoretical Methods Theoretical methods have not been applied to these heterocyclic systems.
12.06.3 Experimental Structural Methods Since these heterocyclic systems are diverse in nature, different methods have been adopted for their synthesis; a detailed discussion of the experimental techniques has not been attempted.
12.06.3.1 X-Ray Crystallography The X-ray crystallography of only one system has been reported during the period 1995–2006. Previous studies for compounds 6, 23, 26, 27, and 28 are discussed in CHEC-II(1996) <1996CHEC-II(8)713>. Thus, for example, crystals of 10-benzyl-1,3-diphenyl-1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene-2,4-dione 46 <2000EJO2105> were shown to be monoclinic having space group of P21/c with cell dimensions of a ¼ 1124.19 (8), b ¼ 1106.63(10), c ¼ 1890.29 (15), ¼ 95.56 (6). In this structure the tetrahydroquinazoline moiety exists in a half chair; the chiral carbon atom C-4 is positioned under the molecular plane of the benzene ring and atoms C-9 and N-5. Except for the chiral carbon atom, all atoms of the triazine ring are nearly planar. The regression surface of these five atoms being twisted by 43.4 around the C-7 and N-5 bond axis against the plane of the benzene ring.
12.06.3.2 NMR Spectroscopy Almost all the reported compounds have been characterized with the help of various nuclear magnetic resonance (NMR) techniques. For previous studies of the compounds, refer to CHEC-II(1996) <1996CHEC-II(8)713>.The 1H NMR spectrum (300 MHz) of 2,3,7-trimethyl-3a,9a-dihydro-1,8-dithia-4a,5,9-triazacyclopenta[b]naphthalene-4,6dione 47 <2000JHC1161> showed the presence of one quartet at 4.23 corresponding to the CH. Another broad singlet corresponds to the presence of the N–H proton.
Similarly, the compound 6-benzyl-3-methyl-9-phenyl-8,9-dihydro-pyridazino[6,1-c][1,2,4]triazine-4,7-dione 48 <1997JHC389> in its 1H NMR spectrum (300 MHz) showed the presence of two multiplets at 3.40–3.75 and 4.62–4.84 corresponding to the endocyclic CH2 and CH of the diazine ring. Two additional doublets appeared at 5.08 and 5.29 due to the benzylic protons.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
The 1H NMR spectrum (500 MHz) of 3-(4-chloro-phenyl)-7-ethyl-7,9-dimethyl-2,3,4,9-tetrahydropyrimido[1,2-a][1,3,5]triazine-6,8-dione 49 <2002JHC663> showed the presence of quartets (AB pattern) at 4.99 and 5.12 corresponding to the methylene protons of the triazine ring.
The 1H NMR spectrum (200 MHz) of 10-benzyl-1,3-diphenyl-1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene2,4-dione 46 <2000EJO2105> showed the presence of a singlet at 6.14 corresponding to C(4)–H. In the 1H NMR spectrum of 3,4-dihydro-2H,9H-1-thia-4a,5,9,10-tetra-azaphenanthrene 50 <1999IJH75>, two triplets at 3.3 and 4.4 correspond to the SCH2 and NCH2, respectively, and a multiplet at 2.5 corresponds to the CH2 protons.
Similarly, the 1H NMR spectrum (90 MHz) of 4-oxo-4H, 9H-1-thia-4a,9,10-triazaphenanthrene-2-carboxylic acid methyl ester 51 <1998IJH303> displayed two singlets at 8.1 and 7.28 corresponding to Ha and Hb, respectively. The compound 3,4-dihydro-2H, 9H-1-thia-4a,9,10-triazaphenanthren-3-ol 52 <2003PS797> in its 1H NMR spectrum (200 MHz) showed the presence of two dd at 3.08 and 3.96 corresponding to two CH2 protons. The spectrum also showed one multiplet at 4.27 corresponding to CH and one doublet at 5.55 assigned to the OH proton.
The 1H NMR spectrum (300 MHz) of 8,9-dimethyl-12H-quinoxalino[1,2-c][1,2,3]benzotriazin-5(6H)-one 53 <2003JHC357> showed the presence of two broad singlets at 11.27 and 13.32 corresponding to the N(6)–H
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and N(12)–H protons and the 13C NMR spectrum (300 MHz) showed one peak at 153.1 a characteristic of C-5 (CTO). Its 15N NMR spectrum (500 MHz) showed four peaks at 177.6, 126, 119.5, and 301.5 corresponding to N-12, N-11, N-6 and N-13, respectively.
12.06.3.3 Mass Spectrometry The mass spectra of all the compounds showed the presence of molecular ion peaks. The fragmentation pattern of pyrimidotriazines has been discussed previously in CHEC-II(1996) <1996CHEC-II(8)713>.
12.06.3.4 IR Spectroscopy The infrared (IR) spectra of these compounds were mostly studied in the solid state which showed all the basic peaks characteristic of various functionalities attached to such bicyclic heterocycles with bridgehead nitrogen atoms. The difference in the frequency of carbonyl and carbon nitrogen double bond in tautomers of compound 18 (R ¼ H) has been discussed previously in CHEC-II(1996) <1996CHEC-II(8)713>.
12.06.3.5 UV Spectroscopy The presence of tautomeric structures in compound 32 has been determined from ultraviolet (UV) spectra in ethanol. Compound 32 showed two absorption bands (due to its tautomeric forms 32a and 32b) at 288.6 and 241.0 nm attributed to an n–p* and p–p* bands, respectively <1997IJB269>. Previous studies are discussed in CHEC-II(1996) <1996CHEC-II(8)713>.
12.06.4 Thermodynamic Aspects No information is available in the literature.
12.06.5 Reactivity of Fully Conjugated Rings The heterocyclic compounds containing ring junction nitrogen atom are nonaromatic, thus lacking extensive conjugation. Consequently, there is no information available regarding the reactivity of fully conjugated compounds.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
12.06.6 Reactivity of the Nonconjugated Rings No information is available in the literature during the period 1995–2006. Previous studies are discussed in CHECII(1996) <1996CHEC-II(8)713>.
12.06.7 Reactivity of the Substitutents Attached to the Ring Carbon Atom No information is available in the literature.
12.06.8 Reactivity of the Substitutents Attached to the Ring Heteroatom No information is available in the literature.
12.06.9 Ring Synthesis Classified by the Number of Ring Atoms in Each Component Synthesis of these compounds is not discussed in this section, but is given below.
12.06.10 Ring Synthesis from Derivatives of One of the Rings The reports concerning the synthesis of bicyclic, ring junction nitrogen heterocycles containing three additional heteroatoms are divided into three categories. In category I the parent molecule is a heterocyclic ring containing two heteroatoms, in category II, the parent heterocyclic ring has three heteroatoms, and other synthetic methods fall into category III. In the present chapter the synthesis reported during period of 1995–2006 has been discussed, while the synthesis reported earlier has been discussed in <1996CHEC-II(8)713>.
12.06.10.1 Synthesis from Heterocycles Containing Two Heteroatoms 12.06.10.1.1
Synthesis from fused pyrimidinone derivatives
5-Benzyl-1-buta-1,3-diynylsulfanyl-6H-3-thia-4,5a,8,9-tetra-azacyclopenta[a]naphthalen-7-ylamine 55 <1999JCR(S)646> was prepared by the treatment of 2-benzyl-5-buta-(1,3-diynylsulfanyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-yl)acetonitrile 54 with hydrazine (Equation 1).
ð1Þ
12.06.10.1.2
Synthesis from hydrazino intermediates
The use of a hydrazine group attached to different heterocycles having two heteroatoms was successfully exploited for the synthesis of various bicyclic and fused bicyclic heterocyclic systems having bridgehead nitrogen atoms. The 3-methylpyrimido[2,1-c][1,2,4]triazin-4-one 57 <1998JHC325> and 6-benzyl 3-methyl-9-aryl-8,9-dihydropyridazino[6,1-c][1,2,4]triazine-4,7-dione 59 <1997JHC389> have been prepared from the corresponding hydrazine derivatives 56 and 58, respectively, as depicted in Scheme 1.
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Scheme 1
Refluxing of hydrazine 60 in acetic acid in the presence of sodium acetate resulted in the formation of 6-methyl-3oxo-8-phenyl-3,4-dihydro-2H-pyrimido[6,1-c][1,2,4]triazine-9-carbonitrile 61 in good yield <1997IJB269> (Equation 2).
ð2Þ
12.06.10.1.3
Synthesis from amino intermediates
The reaction of potassium 3-amino-4-oxo-3,4-dihydroquinazoline-2-thiolate 62 with -bromophenylacetic acid 63 resulted in the formation of (3-amino-4-oxo-3,4-dihydroquinazolin-2-ylsulfanyl)-phenyl-acetic acid methyl ester 64 which on alkali treatment and subsequent acidification resulted in the synthesis of 2-phenyl-1-thia4,4a,9-triaza-anthracene-3,10-dione 65 <1999JCR(S)86>. Similarly, the reaction of potassium 3-amino-5,6dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3-d]pyrimidine-2-thiolate 66 with -bromo-ester 67 resulted in the formation of 2-(3-amino-5,6-dimethyl-4-oxo-3,4,4a,7a-tetrahydrothieno[2,3-d]pyrimidin-2-ylsulfanyl)-propionic acid ethyl ester 68. Subsequent treatment with alkali followed by acidification resulted in the formation of 2,3,7-trimethyl-3a,9a-dihydro-1,8-dithia-4a,5,9-triazacyclopenta[b]naphthalene-4,6-dione 69 <2000JHC1161> (Scheme 2).
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
Scheme 2
Compound 7-ethyl-7-methyl-3-phenyl-2,3,4,9-tetrahydropyrimido[1,2-a][1,3,5]triazine-6,8-dione 71 <2002JHC663> was prepared by the one-pot condensation reaction of 6-amino-3-ethyl-3-methyl-5H-pyridine-2,4-dione 70 with aromatic amines and formaldehyde (Equation 3).
ð3Þ
12.06.10.1.4
Synthesis using other intermediates
3-Methyl-3,4-dihydroquinazoline 72 <2000EJO2105> when treated with phenyl isocyanate resulted in the formation of 10-methyl-1,3-diphenyl-1,9,10,10a-tetrahydro-1,3,4a,10-tetra-azaphenanthrene-2,4-dione 73 (Equation 4).
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ð4Þ
Displacement of the 3-hydroxyl group of 74 was carried out with Et2NSF3 (DAST) (DAST – diethylaminosulfur trifluoride) in dichloromethane. The expected fluorinated product 75 on treatment with aqueous perchloric acid led to regioselective epoxide ring opening to give 76, which on treatment with hydrazine hydrate at 100 C for 18 h yielded 3,4-dihydroxy-8-oxo-octahydropyridazino[1,6-d][1,2,4]triazine-1-carboxylic acid phenylamide 77 (Scheme 3) <1997T9357>.
Scheme 3
The compound 10a,10b-dihydro-5H,12H-4b,5,6,12-tetraaza-chrysen-11-one 81 <2003JHC357> was prepared through diazotization of the corresponding amine derivative 3-(2-aminophenyl)-1H-quinoxalin-2-one 78. The reaction proceeded through intermediates 79 and 80 (Scheme 4).
12.06.10.2 Synthesis from Heterocycles Containing Three Heteroatoms There are very few reports concerning the use of heterocycles containing three heteroatoms for the synthesis of the target bicyclic systems.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
Scheme 4
12.06.10.2.1
Synthesis using acetylenic esters
The treatment of 1,4-dihydro-2H-pyrido[2,3-e][1,2,4]triazine-3-thione 82 with dimethyl acetylenedicarboxylate (DMAD) in methanol at room temperature leads to the formation of 5-oxo-8,8a,9,10-tetrahydro-5H-4,4b,9,10-tetraazaphenanthrene-7-carboxylic acid methyl ester 83 <1998IJH303> (Equation 5).
ð5Þ
12.06.10.2.2
Synthesis using dibromopropane
The pyridotriazine 84 on treatment with dibromopropane resulted in the formation of 3,4,10,10a-tetrahydro-2H,9H1-thia-4a,5,9,10-tetra-azaphenanthrene 85 <1999IJH75> (Equation 6).
ð6Þ
12.06.10.2.3
Synthesis using epichlorohydrin
Refluxing of benzo[1,2,4]triazine-3-thione 86 with epichlorohydrin in the presence of triethylamine in methanol for 14 h resulted in the formation of 3,4-dihydro-2H,9H-1-thia-4a,9,10-triaza-phenanthren-3-ol 87 <2003PS797> (Equation 7).
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ð7Þ
12.06.10.2.4
Synthesis using other ring systems
The treatment of (2-benzoylamino-5-iodobenzoyl-amino)acetic acid ethyl ester 88 with hydrazine hydrate for 4 h yielded hydrazine derivative 2-benzoylamino-N-hydrazinocarbonylmethyl benzamide 89, which on refluxing with sodium acetate and acetic acid for 8 h resulted in the formation of 6-iodo-10-phenyl-3H-3,4,9,10a-tetra-azaphenanthren2-one 90 <2000IJH59> (Scheme 5).
Scheme 5
12.06.11 Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available No examples were found suitable to carry out comparative studies of these systems.
12.06.12 Important Compounds and Applications Many of these bicyclic heterocyclic systems were found to be biologically active. Compounds 91 <2002JHC663>, 92 <2002FES109>, exhibited good antifungal activity and compound 93 showed average affinity for serotoninergic 5-HT1A and 5-HT1B receptors <2002JHC663>. For more examples of such heterocyclic biologically important compounds, refer to CHEC-II(1996) <1996CHEC-II(8)713>.
References 1996CHEC-II(8)713 S. N. Mazumdar and M. P. Mahajan; in ‘Comprehensive Heterocyclic Chemistry II’, A. R. Katritzky, C. W. Rees, and E. F. V. Scriven, Eds.; Pergamon, Oxford, 1996, vol. 8, p. 713. 1997IJB269 M. A. Megid, Indian J. Chem., Sect. B, 1997, 26, 269. 1997JHC389 J. Lange, J. Karolak-Wojciechowska, E. Pytlewska, J. Plenkiewicz, T. Kulinski, and S. Rump, J. Heterocycl. Chem., 1997, 34, 389.
Bicyclic 6-6 Systems with One Bridgehead (Ring Junction) Nitrogen Atom: Three Extra Heteroatoms 2:1
1997T9357 1998IJH303 1998JHC325 1999IJH75 1999JCR(S)86 1999JCR(S)646 2000EJO2105 2000IJH59 2000JHC1161 2002FA109 2002JHC663 2003JHC357 2003PS797
I. Thomsen, B. Ernholt, and M. Bols, Tetrahedron, 1997, 53, 9357. M. M. Haveri, H. A. Oskooie, Y. S. Beheshtiha, N. Nami, and S. Ghoresishi, Indian J. Heterocycl. Chem., 1998, 303. S. Nagai, T. Ueda, S. Sugiura, A. Nagatsu, N. Murakami, and J. Sakakibara, J. Heterocycl. Chem., 1998, 35, 325. M. M. Haveri, M. Rahimizadeh, E. Iravani, M. Ghassemzadeh, and K. Aghapoor, Indian J. Heterocycl. Chem., 1999, 75. A. Santagati, M. Modica, L. M. Scolaro, and M. Santagati, J. Chem. Res. (S), 1999, 86. H. M. Hosni, W. M. Basyouni, and H. A. El-Nahas, J. Chem. Res. (S), 1999, 646. H. Tiez, O. Rademacher, and G. Zahn, Eur. J. Org. Chem., 2000, 2105. S. G. Abdel-Hamide, Indian J. Heterocycl. Chem., 2000, 59. A. Santagati, M. Modica, and M. Santagi, J. Heterocycl. Chem., 2000, 37, 1161. A. Ghaib, S. Menager, V. Philippe, and L. Olivier, Farmaco, 2002, 57, 109. L. Lucry, F. Enoma, F. Estour, H. Oulyadi, S. Menager, and O. Lafont, J. Heterocycl. Chem., 2002, 39, 663. I. Wiedermannova, J. Slouka, O. Humpa, and K. Lemr, J. Heterocycl. Chem., 2003, 40, 357. M. M. Heravi, M. Rahimizadeh, E. Iravani, and M. Ghassemzadeh, Phosphorus, Sulfur Silicon Relat. Elem., 2003, 178, 797.
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Biographical Sketch
Mohinder P Mahajan was born in 1947 at Gurdaspur, Punjab (India), and obtained his PhD in 1975 from Punjabi University, Patiala, under the supervision of Prof. N. K. Ralthan. He was a postdoctoral associate with Prof. M. V. George at the Indian Institute of Technology, Kanpur, Alexander-Von Humboldt Fellow with Prof. Rolf Huisgen at Munich. He was later associated with Prof. Gordon Kirby at Glasgow University, United Kingdom. He started his independent academic carrier in 1979 as lecturer at North–Eastern Hill University, Shillong, where he was promoted to full professor in 1991. In 1996 he shifted to Guru Nanak Dev University, Amritsar and at presently is professor in the department of Applied Chemistry of this University. In 2002, he was elected as fellow of National Academy of Science (FNASc) Allahabad, India. His research interests include the chemistry of heterodienes, the applications of cycloaddition reactions in synthesis of novel heterocyclic compounds, biologically potent heterocyclic molecules, and studies of reaction mechanisms.
Chander Mohan was born in 1975 at Dhariwal, Punjab, India. He received his B. Pharm and M. (Tech) Pharm. in Bulk Drugs from Guru Nanak Dev University and the National Institute of Pharmaceutical Education and Research (NIPER) Mohali. After that he worked as senior chemist at Dr. Reddy’s Research Foundation, Hyderabad. He then joined Prof. M. P. Mahajan’s research group in 2002 for his doctoral studies. His research is focused on the synthesis and chemical transformation of C-5/C-6 substituted pyrimidinones. His research interest includes synthesis of medicinally important molecules, transition metal-induced transformations in organic synthesis, reaction mechanism, and total synthesis of natural products.