Investigation of nitrogen- and sulfur-containing heterocyclic compounds

The halogenation of 2,3-dimethylpyrazino[2,3-b][1,4]thiazin-6-one with bromine or 1 mole of sulfuryl chloride gives 7-bromo-and 7-chloropyrazino[2,3-b][1,4]thiazin-6-ones, while 2 moles of sulfuryl chloride give 7,7-dichloropyrazino[2,3-b][1,4]thiazin-6-one. A number of 7-amino-and 7,7-diaminopyrazino[2,3-b][1,4]thiazin-6-ones were obtained by the reaction of the appropriate halo derivatives with amines. Some of the pyrazino[2,3-b][1,4]thiazin-6-one derivatives inhibit the growth of interweavable tumors in animals.See [3] for communication XX.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1498–1501, November, 1971.     

Cyclisation of 4-[2-Cyclofentenyl]-3-Hydroxy [1] Benzopypan-2-One

4-[2-cyclopentenyl]-3-hydroxy [1] bonzopyran-2-one(3) was cyclised to the bicyclie coumar in-1,3-ethano-2-bromo-1,2-dihydro-3H-pyrano [2,3-c] [1] benzopyran-5-one (6) by a sequence of reactions viz. acetylation of 3, addition of bromine to cyclopenteny double bond and treating the resulting acetyldibromo compound (5) with 4% alcoholic KOH, Cyclisation of compound (3) with mercuric acetate in methanol gave condensed furan derivative 7 which on reductive demercuration with zinc borohydride in dimethoxyethane gave the 1,3-propano-1,2-dihydrofuro [2,3-c] [1] benzopyran-4-one, 8. Cyclisation of compound 2 with come. H₂SO₄ furnished a mixture of bicyclic derivative 9 ad furo coumarin derivative 8.     

Nitrogen and sulfur heterocycles. 45. Dual reactivity of 1,2-dioxo-3a-alkyl-7-chloroimidazolidino[3,2-f]-pyrido[2,3-b]-1,4-thiazines

1,2-Dioxo-3a-alkyl-7-chloroimidazolidino[3,2-f]pyrido[2,3-b]-1,4-thiazines react with o- and p-nitroanilines, alkyl and acyl halides, and heterocyclic amines to give C₍₂₎- and N₍₃₎-substituted 3a-alkyl-7-chloroimidazolidino[3,2-f]pyridol[2,3-b]-1,4-thiazines.For Communication 44, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1688–1693, December, 1987.     

New sesquiterpenes from Ferula ferulaeoides (Steud.) Korovin. VI. Isolation and identification of three new dihydrofuro[2,3-b]chromones

Three novel 2-prenyl-dihydrofurochromone-type sesquiterpenoid derivatives, 2,3-dihydro-7-hydroxy-2S*,3R*-dimethyl-2-[4,8-dimethyl-3(E),7-nonadienyl]-furo[2,3-b]chromone, 2,3-dihydro-7-hydroxy-2S*,3R*-dimethyl-2-[4-methyl-5-(4-methyl-2-furyl)-3(E),7-pentenyl]-furo[2,3-b]chromone, and 2,3-dihydro-7-hydroxy-2R*,3R*-dimethyl-2-[4-methyl-5-(4-methyl-2-furyl)-3(E),7-pentenyl]-furo[2,3-b]chromone, were isolated from the roots of Ferula ferulaeoides. The structures were established by comprehensive spectral analysis. The biosynthetic pathway leading to these 2-prenyl-dihydrofurochromone-type sesquiterpenoids is proposed based on their structures.     

Acid-base properties of 2,3,4,5-tetrahydro-1H-naphtho[2,3-b]-1,4-diazepine-2,4,6, 11-tetraone

It is shown that 2,3,4,5-tetrahydro-1H-naphtho[2,3-b]-1,4-diazepine-2,4,6,11-tetraone, which has acid properties, undergoes methylation to give an N,N-di-methyl derivative, whereas it gives products of substitution of the hydrogen atoms of the methylene group in its reactions with bromine and salicylaldehyde. Treatment of 2,3,4,5-tetrahydro-1H-naphtho[2,3-b]-1,4-diazepine-2,4,6,11-tetrone with aqueous alkali or secondary aliphatic amines with heating is accompanied by opening of the diazepine ring to give hydrolysis (2-carboxyacetamido-3-hydroxy-1,4-naphthoquinones) or aminolysis (N-alkylaminomalonyl-2,3-diamino-1,4-naphthoquinones) products.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1132–1136, August, 1978.     

Regiospecific synthesis of pyrido[3,4-b]- and pyrido[4,3-b]carbazole-5,11-dione derivatives. Evaluation of their in vitro antifungal or antiprotozoological activities.

Hetero Diels-Alder reactions between 2- or 3-bromocarbazolequinones 1a or 1b and azadiene 5 afford regiospecifically pyrido[3,4-b]- and pyrido[4,3-b]carbazole-3,5,11-triones 6a and 6b. The regiochemistry of the cycloadditions is controlled by the position of the bromine atom at C-2 or C-3 of the bromoquinone. The corresponding N- and O-methyl derivatives 7 and 8 are prepared. Structural assignment of the regioisomers is made by 1H-NMR nuclear Overhauser effect difference experiments performed on a diacetoxy derivative of pyrido[4,3-b]carbazole 9b. The in vitro antifungal and antiprotozoological activities of some prepared derivatives have been evaluated against Candida albicans, Candida krusei, Cryptococcus neoformans and Trichomonas vaginalis. None of the tested compounds have shown significant activity towards the yeasts or protozoa.     

Investigation of nitrogen- and sulfur-containing heterocycles. 38. Reactions of 2-mercapto-3-ureidopyridines with halo β-diketones

The reaction of 2-mercapto-3-ureido-6-chloropyridine with chlorodibenzoylmethane in the presence of alkali leads to 2-(benzoylmethylthio)-3-benzamido-6-chloropyridine, whereas the reaction in the absence of alkali leads to 2-chloro-6-phenyl-7-benzoylpyrido[2,3-b] [1,4]thiazine. Under similar conditions 2-(diacetylmethylthio)-3-ureido-6-chloropyridine, 2-(acetylmethylthio)-3-ureido-6-chloropyridine, and 2-chloro-6-methyl-7-acetylpyrido[2,3-b][1,4]thiazine were obtained from 2-mercapto-3-ureido-6-chloropyridine and chloroacetylacetone. Treatment of 2-(diacetylmethylthio)-3-ureido-6-chloropyridine with alcoholic alkali leads to 2-(acetylmethylthio)-3-ureido-6-chloropyridine. 2-Chloro-6-phenyl-7-acetylpyrido-[2,3-b] [1,4]thiazine and 2-(benzoylmethylthio)-3-ureido-6-chloropyridine are formed in the reaction of 2-mercapto-3-ureido-6-chloropyridine with chlorobenzoylacetone in the presence of an equimolar amount of alkali, while 2-(benzoylmethylthio)-3-acetamido-6-chloropyridine is formed when excess alkali is used. See [1] for communication 37. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 787–790, June, 1980.     

Synthesis of New Pyrido[4″,3″:4″,5″]thieno[2″,3″:4,5]pyrimido[2,1-b][1,3,4]thiadiazine Derivatives

Ethyl 2-methyl-11-oxo-9, 10-dihydro-1 H , 11 H -pyrido[4",3":4',5']thieno[2',3':4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7 H )-carboxylate 7 has been synthesised by the reaction of ethyl 3-amino-4-oxo-2-thioxo-1,3,4,5,6,8-hexahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidine-7(2 H )-carboxylate 2 with allylbromide followed by treatment with bromine and subsequent dehydrobromination of the brominated product 5 with ethanolic sodium hydroxide. Its isomeric ethyl 2-methyl-11-oxo-9,10-dihydro-3 H ,11 H -pyrido[4",3Prime;:4',5']thieno[2',3':4,5]pyrimido[2,1-b][1,3,4]thiadiazine-8(7 H )-carboxylate 8 has been obtained by condensation of 2 with chloroacetone followed by cyclization of the intermediate 9 with p -toulenesulfonic acid. The thiadiazino derivatives 11 , 13 , 15 were prepared through the reaction of 2 with the appropriate f -halocarbonyl compounds followed by cyclization reactions of the intermediates 10 , 12 , 14 .     

Investigation of nitrogen- and sulfur-containing heterocycles. 44. New heterocyclic systems. Derivatives of imidazolidino-[3,2-f]pyrido[2,3-b]-and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-thiazines. Synthesis and structure

New representatives of heterocyclic systems, imidazolidino[3,2-f]-pyrido-[2,3-b]- and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-thiazines, have been obtained. Intermediate compounds of 5N-oxalamides-6-hydroxy-7H-pyrido[2,3-b]-1,4-thiazine have been isolated and characterized. Amides of N-(pyridyl-3)- and N-(pyrimidyl-5)-oxaminic acids have been obtained.For communication 43, see [1].Translated from Khimiya Geterotsiklicheskikh Soedininii, No. 7, pp. 992–997, July, 1986.     

Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

Synthesis of Fluoroalkylated Heterocycles via the Reaction of 3-(1-Hydropolyfluoroalkenyl)-1-oxo-2,4,1-benzoxazines with Dinucleophilic Reagents

The reaction of 3-(1-hydropolyfluoroalkenyl)-1-oxo-2,4,1-benzoxazines 1 with some dinucleophiles was inves-tigated.7-Fluoroalkyl-2,3-dihydro-1,4-diazepine[1,2-d]quinazolin-11-ones 2,2-fluoroalkylisoxazolo[3,2-b]quin-azolin-9-ones 3 and 2-fluoroalkylbenzoimidazoles 4 were obtained from the reaction of 1 with 1,2-diaminoethane,hydroxylamine hydrochloride and 1,2-diaminobenzene respectively.     

SYNTHESIS AND REACTIONS OF 2,3-DIHYDRO- 5-ARYL-5H,6H-THIAZOLO[3,2-b]-2,4-DIAZAFLUORENE-3,6-DIONES OF POTENTIAL BIOLOGICAL ACTIVITIES

Abstract

1,2,3,4-Tetrahydro-l-aryl-3,9-dioxo-2,4-diazafluorenes (2) and 1,2,3,4-tetrahydro-1-aryl-9-oxo-3-thi-oxo-2,4-diazafluorenes (3) were newly synthesized. Compounds 3 reacted with chloroacetic acid, α-bromopropanoic acid, or B-bromopropanoic acid in the presence of fused sodium acetate and acetic anhydride to give 2,3-dihydro-5-aryl-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (4), 2-methyl-2,3-dihydro-5-aryl-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (5) and 2,3-dihydro-6-aryl-6H,7H-thiazino[3,2-b]2,4-diazafluorene-4,7-diones (6), respectively.

2,3-Dihydro-2-arylmethylene-5-aryl-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (7) were prepared by the reaction of compounds (3) with chloroacetic acid and aromatic aldehydes in the presence of fused sodium acetate and acetic anhydride or by the reactions of (4) with aromatic aldehydes in the presence of acetic anhydride.

2-(Arylhydroazono)-5-aryl-2,3-dihydro-5H,6H-thiazolo[3,2-b]2,4-diazafluorene-3,6-diones (8) were synthesized by coupling (4) with aryldiazonium salts in the presence of pyridine.     

Synthesis of condensed structures from 3-cyano-2-pyridylacrylic acids

Ammonolysis of the methyl esters of trans--(3-cyano-2-pyridyl)acrylic (I) and trans--(6-methyl-3-cyano-2-pyridyl)acrylic (II) acids gave the amides of these acids. The addition of bromine, diazomethane, and hydrogen to the double bond of cis- and trans-acids I and II is described. Hydrogenation of the methyl esters of trans-acids I and II over Raneynickel at room temperature and atmospheric pressure occurs with intramolecular cyclization to two-ring lactams — 7-oxo-5, 6,8,9-tetrahydropyrid[3,2-c]azepine and 2-methyl-7-oxo-5,6,8,9-tetrahydropyrid[3,2-c]azepine. Under the conditons of acid hydrolysis of acids I and II the elements of water add to the nitrile group with intramolecular cyclization to give, respectively, 3-carboxymethyl-1-oxo-2,3-dihydrofuro [4,3-b]pyridine and 5-methyl-3-carboxymethyl-1-oxo-2,3-dihydrofuro[4,3-b]pyridine, whereas refluxing these acids with aqueous sodium hydroxide gives two-ring lactams — 3-carboxymethyl-1-oxo-2, 3-dihydropyrrolo[4,3-b]pyridine and its 5-methyl homolog. The structures of the compounds were confirmed by the UV, IR, PMR, and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 63–69, January, 1978.     

An efficient synthesis of 4-(phenylsulfonyl)-4H-furo[3,4-b]indoles

The fused heterocycle 4-(phenylsulfonyl)-4H-furo[3,4-b]indole, which is an indole-2,3-quinodimethane synthetic analogue, is prepared in five steps from indole in 46% yield. A similar sequence is used to synthesize C-3 derivatives (3-methyl, 3-phenyl, and 3-heptyl). Thus, indole-3-carbaldehyde (1) is protected as the N-phenylsulfonyl derivative 2 and converted to the ethylene acetal 6. Lithiation at C-2 followed by treatment with an aldehyde affords the expected hydroxy acetals 7 and 8. Exposure to acid effects cyclization to the furoindoles 5 and 9. Furthermore, C-1 lithiation of furo[3,4-b]indole 9c followed by treatment with methyl iodide affords disubstituted furo[3,4-b]indole 10.     

Condensed imidazo-1,2,4-azines. 14. Synthesis and reactivity of 3-chlorine-substituted imidazo[1,2-b]-1,2,4-triazines

When boiled with phosphorus pentachloride in phosphorus oxychloride, 2-methyl-6-phenyl-imidazo[1,2-b]1,2,4-triazin-4H-3-one gives a mixture of mono- and dichloro derivatives, whereas the action of thionyl chloride in chloroform with a catalytic amount of DMFA gives only the monosubstituted product 2-methyl-3-chloro-6-phenylimidazo[1,2-b]-1,2,4-triazine. The reactivity of the 3-chloro derivatives of imidazo[1,2-b]-1,2,4-triazine in reactions with diethylamine, piperidine, morpholine, aniline, hydrazine hydrate and thiourea was investigated.For Communication 13, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 981–985, July, 1986.     

Organometallic 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines as potential anticancer agents

Six organometallic complexes of the general formula [M(II)Cl(η(6)-p-cymene)(L)]Cl, where M = Ru (11a, 12a, 13a) or Os (11b, 12b, 13b) and L = 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3) have been synthesized. The latter are known as potential cyclin-dependent kinase (Cdk) inhibitors. All compounds have been comprehensively characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, UV-vis spectroscopy, ESI mass spectrometry, and X-ray crystallography (11b and 12b). The multistep synthesis of 3-(1H-benzimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridines (L1-L3), which was reported by other researchers, has been modified by us essentially (e.g., the synthesis of 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (3) via 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine (2); the synthesis of 1-methoxymethyl-2,3-diaminobenzene (5) by avoiding the use of unstable 2,3-diaminobenzyl alcohol; and the activation of 1H-pyrazolo[3,4-b]pyridine-3-carboxylic acids (1, 3) through the use of an inexpensive coupling reagent, N,N'-carbonyldiimidazole (CDI)). Stabilization of the 7b tautomer of methoxymethyl-substituted L3 by coordination to a metal(II) center, as well as the NMR spectroscopic characterization of two tautomers 7b-L3 and 4b'-L3 in a metal-free state are described. Structure-activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells, as well as Cdk inhibitory activity, are also reported.     

BENZOQUINOLINES II. SYNTHESIS OF SOME NEW BENZO[h] PYRIMIDO [4′,5′:4,5]THIENO[2,3-b]QUINOLINE DERIVATIVES AND RELATED FUSED HEXACYCLIC SYSTEMS

Abstract

Reaction of 8-amino-7-(2 furyl)-5,6-dihydrobenzo[h]thieno[2,3-b]quinoline-9-carbonitrile (3a) with phenyl isothiocyanate, triethyl orthoformate, ethylenediamine and/or sodium azide afforded benzo[h]thieno[2,3-b]quinolines 4,7,20 and 25 respectively. Cyclization of thiourea derivative 4 furnished thioxopyrimidine derivative 5. The dithioxopyrimidine 6 was prepared by reaction of 3a with carbon disulfide. On treatment of 7 with hydrazine hydrate, 10-amino-7-(2-furyl)-11-imino-5,6,10,11-tetrahydrobenzo[h]pyrimido[4′,5′:4,5]thieno [2,3-b]quinoline (8) was obtained. Compounds 8,20 and 25 were used as key intermediates in the synthesis of the fused hexacyclic compounds 9–19, 21–24 and 26–28 respectively. 8-Amino-7-(2-furyl)-5,6-dihydrobenzo[h]thieno[2,3-b]quinoline-9-carboxamide (3b) was reacted with some reagents, namely triethyl orthoformate, benzaldehyde, carbon disulfide, phenyl isothiocyanate, and/or acetic anhydride to give the corresponding benzo[h]pyrimido [4′,5′: 4,5]thieno[2,3-b]quinolines 29, 30, 31, 32 and 34. Compound 29 underwent some sequence reactions to give 37–42. Some of the prepared compounds were tested in vitro for their antibacterial and antifungal activities.     

Synthesis of 6-methylfuro[2,3-b]pyridine

The Claisen condensation of ethyl 2-ethoxy-6-methylpyridine-3-carboxylate with ethyl acetate gave ethyl 2-ethoxy-6-methylnicotinoylacetate, which was converted to 3-bromo-acetyl-6-niethyl-2-pyridone by heating with bromine in 48% hydrobromic acid. The cyclization of the bromoacetylpyridone by the action of silver oxide in methanol gave 3-oxo-6-methyl-2,3-dihydrofuro[2,3-b]pyridine, which was reduced to 3-hydroxy-6-methyl-2,3-dihydrofuro[2,3-b]pyridine with lithium aluminum hydride in dimethoxyethane. Acetylation of the latter gave its acetate, the pyrolysis of which in vacuo gave 6-methylfuro[2,3-b]-pyridine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1544–1546, November, 1972.     

Synthesis of dithieno[2,3-b:4',3'-d]siloles and their selective bromination

The efficient synthesis of novel unsymmetrical dithienosiloles, 7,7-dimethyl-4,6-di(trimethylsilyl)-dithieno[2,3-b:4',3'-d]silole (1) and 7,7-dimethyl-2,4,6-tri(trimethylsilyl)-dithieno[2,3-b:4',3'-d]silole (2) has been developed by intramolecular silole formation with 4,4'-dibromo-2,2',5,5'-tetrakis(trimethylsilyl)-[3,3']bithienyl (3) as the starting material in the presence of t-BuLi. Upon treatment with N-bromosuccinimide (NBS) under controlled conditions, dithieno[2,3-b:4',3'-d]silole was selectively brominated to produce mono-, di-, and tribrominated dithieno[2,3-b:4',3'-d]siloles in good yields. The crystal structures of the title compounds are described.     

Chemical and photochemical synthesis of substituted dihydro-thieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones and tetrahydro-dithieno[2,3-b:2',3'-d]thieno[2'',3''c:2'',3''c']diquinolin-6,14-dione

Some new substituted dihydrothieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones 9- 12 and tetrahydrodithieno[2,3-b: 2',3'-d]thieno[2',3'-c:2',3'-c']diquinolin-6,14-dione (17) were prepared from the corresponding new anilides 5-8 and from the corresponding dianilide 15, respectively, by a multistep combination of chemical and photochemical reactions. All the prepared compounds are of particular interest because they might serve as DNA intercalators in anticancer therapy.