Cyclic homologs of xanthines. I. Imidazo[4,5-e][1,4]diazepine-5,8-diones

A useful synthetic approach to variously alkylated 4,5,7,8-tetrahydro-6.H-imidazo[4,5-e][1,4]diazepine-5,8-diones is reported. These compounds are potentially interesting cyclic homologs of pharmacologically important alkylxanthines.     

Synthesis and molecular structure of 1,4-dimethyl-4,5,7,8-tetrahydro-6H-imidazo[4,5-e][1,4]-diazepine-5,8-dithione

1,4-dimethyl-4,5,7,8-tetrahydro-6H-imidazo[4,5-e][1,4]-diazepine-5,8-dithione was synthesized by boiling 1,4-dimethyl-4,5,7,8-tetrahydro-6H-imidazo[4,5-e][1,4]-diazepine-5,8-dione (a cyclic homolog of theobromine) with P₂S₅. Its molecular and crystal structures were determined by X-ray structure analysis, PMR spectroscopy and the calculations using the MM2 program. The crystals are monoclinic, sp. gr. P2 ₁ /n with a=9.305(4), b=9.464(3), c=11.628(3) Å, -90.49(3)^o, Z=4 for C₈H₁₀N₄S₂. M.p. 268–269 °C. The 7-membered heterocycle has a boat conformation in the crystal, while in solution at room temperature it undergoes interconversion. The geometrical parameters of the molecule obtained by X-ray structure analysis, by PMR spectroscopy below the coalescence temperature (290 K), and by MM2 calculations are in good agreement.A. V. Bogatsky Physico-Chemical Institute, Ukrainian Academy of Sciences. Translated fromZhurnal Struktumoi Khimii, Vol. 34, No. 3, pp. 86–90, May–June 1993.Translated by T. Yudanova.     

Reactions of ring-expanded xanthines containing the imidazo[4,5-e][1,4]diazepine ring system

4,5,7,8-Tetrahydro-6H-imidazo[4,5-e][1,4]diazepine-5,8-dione underwent bromination at the 2-position with or without substituents at the 3-, 4- or 7-position, using bromine, N-bromosuccinimide, or acetyl hypobro-mite. The activation of position 6 with an ester functionality, as in 7 , did not alter the site of bromination. The base-catalyzed bromination of the ring-open precursor, diethyl 2-[N-(1-benzyl-5-nitroimidazolyl-4-carbon-yl)amino]malonate ( 5 ), resulted either in introduction of an alkoxy functionality in the above aminomalonate side-chain, yielding 17 when the reaction was quenched with an alcohol, or in degradation of the side-chain, yielding 1-benzyl-5-nitroimidazole-4-carboxamide ( 19 ) when the reaction was quenched with water. Both 17 and 19 are formed by oxidative bromination of 5 via the bromo intermediate 15 . An indirect evidence for the latter was obtained by base-catalyzed methylation of 5 which gave diethyl 2-methyl-2-[N-(1-benzyl-5-nitroimid-azolyl-4-carbonyl)amino]malonate ( 21 ). The base-catalyzed bromination of 5 with N-bromosuccinimide gave rise to two products, the dimer 24a and the monomer 24b that contained the substituted 2,2-diaminomalon-ate side-chain. The structure of 24b was confirmed by single-crystal X-ray diffraction analyses. Reduction of the 5-nitro group of 17 to the corresponding amino derivative 25 , followed by ring-closure with sodium meth-oxide/methanol, yielded three products, a 5:6-fused system 26 and two 5:7 fused systems 27 and 28 . The structures of 26 and 27 were confirmed by single-crystal X-ray diffraction analyses. A tentative reaction pathway for the formation of all three products has been proposed. Hydrolysis of 27 with aqueous hydrochloric acid resulted in ring-opening to form 5-amino-1-benzylimidazole-4-carboxamide ( 40 ). A mechanism for the hydrolysis reaction has been proposed. Catalytic hydrogenation of 5 in acetic acid yielded the aminoimidazo-lone derivative 11 which upon ring-closure with sodium methoxide in methanol produced imidazo[4,5-e][1,4]-diazepine-2,5,8-trione ( 12 ).     

Synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-b][1,4]diazepine-6,8-diones

The sodium ethoxide catalyzed condensation of 4,5-diaminopyrimidine ( 3 ) with diethyl malonate afforded 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ). Methylation of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) using sodium hydride and two equivalents of iodomethane gave 5,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 5 ) which on further methylation using sodium hydride and one equivalent iodomethane yielded 6,7,8,9-tetrahydro-5,7,9-trimethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 6 ). Reaction of 6,7,8,9-tetrahydro-5H-pyrirnido[4,5-b][1,4]diazepine-6,8-dione ( 4 ) with 4.2 equivalents of sodium hydride and 4.1 equivalents of iodomethane afforded 6,7,8,9-tetrahydro-5,7,7, 9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ). 6,7,8,9-Tetrahydro-5,7,7,9-tetramethyl-5H-pyrimido[4,5-b][1,4]diazepine-6,8-dione ( 7 ) exhibited weak anticonvulsant activities in the subcutaneous pentylenetetrazole and maximal electroshock anticonvulsant screens indicating it is a partial bioisostere of the anticonvulsant drug clobazam ( 2 ).     

Novel synthesis of 4,5,7,8-tetrahydro-6H-imidazo[4,5-e]-[1,4]diazepine-5,8-dione. A cyclic xanthine homolog

The xanthine homolog 4,5,7,8-tetrahydro-6H-imidazo[4,5-e][1,4]diazepine-5,8-dione has been synthesized in four stages from cyanoacetamide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 511–512, April, 1992.     

Isofuranonaphthoquinones from ventilago maderaspatana: Crystal structure of ventilone-C

From the root bark of Ventilago maderaspatana (Rhamnaceae) five isofuranonaphthoquinones have been isolated. Ventilone-A is 4,9-dihydro-5,8-dihydroxy-6,7-methylenedioxy-1-methylnaphtho[2,3-c] furan-4,9-dione and B is the 5-methyl ether. Ventilone-C has the structure 1,3,4,9-tetrahydro-8-hydroxy-5-methoxy-6, 7-methylenedioxy-1-methylnaphtho[2,3-c]furan-4,9-dione, D is the isomeric 8-methyl ether, and E is the 5,8-dimethyl ether. Structures were determined by spectroscopic methods, and X-ray crystallographic analysis of ventilone-C.     

Synthesis and properties of copper and cobalt phthalocyanine complexes fused with the nitrogen heterocyclic quinones

Copper and cobalt complexes of tetra[4,5]([8,9](benzo[f]quinoline-7,10-dione)phthalocyanine, tetra[4,5]-([6,7]1-acetyl-2H-naphtho[2,3-d][1,2,3]triazole-5,8-dione) phthalocyanine, and tetra[4,5]([6,7]3-methylquinoline-5,8-dione)phthalocyanine were synthesized and their spectral properties were investigated.     

A convenient synthesis of new pyrido[3,2-e][1,4]diazepine-2,5-diones and pyrido[2,3-e][1,4]diazepine-2,5-diones

A convenient synthesis of a series of pyrido[3,2-e][1,4]-diazepine-2,5-diones 8 and pyrido[2,3-e][1,4]diazepine-2,5-diones 9, is reported using the condensation of α-amino acid methyl ester derivatives with 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione and 1H-pyrido[2,3-d][1,3]oxazine-2,4-dione. Compounds 8 and 9 were also synthesized by peptide coupling of α-amino acid methyl ester derivatives with β-amino acids (2 or 3) followed by the cyclisation in tetrahydrofuran with sodium hydride (NaH).     

Synthesis of some novel 2-phenylpyridazino[4,5-b][1,5]thiazepines

Synthesis of some derivatives of the pyridazino[4,5-b][1,5]thiazepine ring system is reported. Thus, 5-benzyl-8-methyl-2-phenyl-2,3.4,5-tetrahydro-5H-pyridazino[4,5-b][1,5]thiazepin-9(8H)-one ( 5 ) was prepared by an intramolecular S-alkylation reaction, whereas the thiazepine ring of sulfone analogue 21 , and that of the novel tricyclic pyrrolidino fused ring system 22 was elaborated by an intramolecular C-alkylation reaction. Unexpected formation of bicyclic pyrido- and thiazine fused pyridazine systems are also discussed.     

Über Heterocyclen, 22. Mitt.: 3,4,6,7-Tetrahydro-5H-pyrrolo[3,4-d]pyrimidin-2(1H), 5-dione

Zusammenfassung Tetrahydro-6-brommethyl-2-oxopyrimidin-5-carbonsäureester reagieren mit Ammoniak bzw. Benzylamin zu Tetrahydro-5H-pyrrolo[3,4-d]pyrimidin-2(1H), 5-dionen. Mit 2-Aminopyridin (A) bilden sich Tetrahydro-6-(2-pyridylaminomethyl)-2-oxopyrimidin-5-carbonsäureester, Tetrahydro-5H-pyrrolo[3,4-d]pyrimidin-2(1H), 5-dione sowie 5-Äthoxycarbony]-2,3,5,6-tetrahydro-2-oxospiro(pyrimidin-4(1H), 2(3H)-1H-imidazo[1,2-a]pyridinium)bromide.

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Heterocycles XXII: 3.4.6.7-Tetrahydro-5H-pyrrolo [3.4-d]-pyrimidine-2(1H)-5-diones

Tetrahydro-6-bromomethyl-2-oxopyrimidine-5-carboxylates react with ammonia and benzylamine, resp., to give tetrahydro-5H-pyrrolo[3.4-d]pyrimidin-2(1H), 5-diones. With 2-aminopyridine (A) tetrahydro-6-(2-pyridylaminomethyl)-2-oxopyrimidine-5-carboxylates, tetrahydro-5H-pyrrolo[3.4-d]pyrimidine-2(1H). 5-diones as well as 5-ethoxycarbonyl-2.3.5.6-tetrahydro-2-oxospiro(pyrimidin-4(1H)-2(3H)-1H-imidazo[1.2-a]-pyridinium) bromides are formed.

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Herrn Prof. Dr.O. Hromatka zum 65. Geburtstag gewidmet.     

Enhanced reactivity of secondary hydroxyl groups in the O-alkylation of carbohydrate-related primary-secondaryvic-glycols. Regioselective 2-O-benzylation of 1,3:2,4-di-O-ethylidene-D-glucitol

Partial O-alkylation of 1,3:2,4-di-O-ethylidene-D-glucitol (1a), 1,2-O-isopropylidene-3-O-methyl--D-glucofuranose (1b), andR-(+)-1-O-benzylglycerol (1c) with benzyl chloride in a KOH/DMSO system results in products of monoalkylation at the secondary (4a–c) and at the primary hydroxyl (2a–c) in ratios of over 955 (a), 21 (b), and 11 (c), whereas (±)propane-1,2-diol (1d) gives only the product of 1-O-benzylation (2d). A qualitatively similar result is observed upon O-alkylation of diols (1a–e) with 2-methoxyethanol tosylate.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 776–781, April, 1993.     

Synthese neuer Derivate des 2-Amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonitrils: basische Substitutions-produkte und anellierte Thieno-[1,2,4]-triazolo-pyrimidine

A group of N-substituted 2-aminoacylamino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carbonitriles (1) was prepared from 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-carbonitrile (A ¹).Cyclisation reactions usingA ¹ and N-heterocyclic analogues thereof (A ² andB ³) as starting materials gave derivatives of the following two new heterocyclic ring systems: [1]benzo-thieno[3,2-e][1,2,4]-triazolo[2,3-c]pyrimidine (B) and pyrido-[4,34,5]thieno[3,2-e][1,2,4-triazolo][2,3-c]pyrimidine (C).

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Unserem verehrten Lehrer, Herrn o. Prof. Dr.O. Hromatka, in Dankbarkeit zum 70. Geburtstag gewidmet.     

Synthesis of some novel fused tetracyclic quinolonecarboxylic acids via 7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinoline and 6-methyl-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinoline

A series of fused tetracyclic quinolonecarboxylic acids was prepared for biological evaluation. These compounds were synthesized by a route involving a regiospecific functionalization of 5-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline to obtain a series of new substituted 7-methyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinolines and 6-methyl-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolines as convenient precursors of quinolones.     

Synthesis of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-diones

A convenient method was developed for the combinatorial synthesis of substituted (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]-diazepine-5,10-diones. The structure and the most probable conformation of (5aS)-2-benzylthio-3-cyano-4,5a,6,7,8,10-hexahydro-5H-pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-5,10-dione in solution was established by NMR spectroscopy and calculations using the Gaussian program.

     

A Convenient Synthesis of 1-Amino-4-methyl-4H-3-thia-4,5a,10-triazacyclopenta[a]fluoren-5-ones and Some New 2,3-Dihydro-1,3,4-thiadiazoles

1-amino-4-methyl-4H-3-thia-4,5a,10-triazacyclopenta-[a]fluoren-5-one and 6-methyl-6H-,9H-thia-4b,6,9,11,12-pentaazaindeno[1,2-a]-fluorene-5,8-dione derivatives were prepared from 2-methyl-1-oxo-3-thioxo-2,4,9b-trihydropyrimidino[1,6-a] benzimidazole-4-carbonitrile. Also, 2,3-dihydro-1,3,4-thidazoles were synthesized via a reaction of hydrazonoyl chlorides with 3-(methylamino)-2-substituted 3-thioxopropanenitrile. Structures of newly synthesized compounds were elucidated on the basis of elemental analyses, spectral data, and alternative methods synthesis whenever possible.     

Synthesis of New Heterocyclic Systems on the Basis of 7-Benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthiridine-4-carbonitrile

Methods have been developed for the synthesis of new 8-amino-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine starting from 7-benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile. 8-Hydrazinyl-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine has been converted to isomeric pentacyclic structures with a triazole ring fused through the [c] side of the pyrimidine ring, and their Dimroth rearrangement has been accomplished in both acidic and basic media. New heterocyclic systems containing pyrrolo[1,2-a]pyrimidinone and pyrimido[1,2-a]azepinone fragments were obtained on the basis of the thieno-[2,3-c][2,7]naphthyridine derivative.     

Synthesis and structure of novel derivatives of thieno[2,3-b]thiocine. An unusual product of intramolecular cycloaddition of 2-homomethallylthio-5-methyl-3-thiophenecarbonitrile oxide

9-Methyl-3,3a,4,5-tetrahydro-6H-thieno[2,3-b]thiocino[4,5-c]isoxazole and 9-hydroxyimino-2-methyl-7-methylene-6, 7,8,9-tetrahydro-5H-thieno[2,3-b]thiocine have been prepared for the first time by the oxidation of 2--alkenylthio-3-thiophenecarbaldoximes with NaOCl. X-ray structural investigations of thieno[2,3-b]thiocine and 2-homomethallylthio-5-methyl-3-thiophenecarbaldoxime have been carried out.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1262–1266, July, 1993.     

Nitration of 1,3-dihydro-2<Emphasis Type="Italic">H</Emphasis>-imidazo[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-2-one derivatives

Nitration of 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one and its N-methyl derivatives at 0–5°C and 60°C gives 5-nitro-and 5,6-dinitro-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones, respectively. The latter can also be obtained by nitration of 5-mononitro derivatives under similar conditions. The nitration of 6-chloro-and 6-bromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones and their N-methyl-substituted analogs leads to the formation of the corresponding 6-chloro(bromo)-5-nitro compounds. The same products are formed in the nitration of 5,6-dichloro-and 5,6-dibromo-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones. In this case, the process involves replacement of the halogen atom in position 5 of the pyridine fragment by nitro group. The nitration of 6-bromo-5-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one is accompanied by oxidation of the 5-methyl group to carboxy.     

α-Thioureidoalkylation of urea heteroanalogs

α-Thioureidoalkylation of urea heteroanalogs such as thiosemicarbazide, amino-guanidine, sulfamide, and sulfonamides with 4,5-dihydroxyimidazolidine-2-thiones has been studied. Previously unknown 4,5-bis[thiosemicarbazido(guanidinoamino)]imidazolidine-2-thiones, 5,7-dialkylperhydroimidazo[4,5- e][1,2,4]triazine-3,6-dithiones, 4,6-diethyl-5(3H)-thioxotetrahydro-1 H-imidazo[4,5- c][1,2,5]thiadiazole 2,2-dioxide, and 1,3-dialkyl-4-[guanidinoimino(arylsulfonylimino)]imidazolidine-2-thiones have been synthesized.     

Fusion of 2-(furan-2-yl)thiazole to 1-methyl-1<Emphasis Type="Italic">H</Emphasis>-benzimidazole

Methylation of 5(6)-nitro-1H-benzimidazole with methyl iodide in the presence of potassium hydroxide and N-methylpyrrolidin-2-one gave a mixture of isomeric 1-methyl-5-nitro- and 1-methyl-6-nitro-1H-benzimidazoles which were reduced with tin in concentrated aqueous HCl on heating. The resulting amines reacted with furan-2-carbonyl chloride in N-methylpyrrolidin-2-one to give furan-2-carboxamides which were treated with excess P₂S₅ in pyridine. Oxidation of isomeric furan-2-carbothioamides with K₃[Fe(CN)₆] in alkaline medium afforded a mixture of intramolecular cyclization products, 2-(furan-2-yl)-6-methyl-6H-imidazo[4,5-g][1,3]benzothiazole and 2-(furan-2-yl)-8-methyl-8H-imidazo[4,5-g][1,3]benzothiazole which were separated by column chromatography and identified.