Synthesis, properties, and structures of ammonium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates

The reaction of arylcyanomethylenethiocetamides with Meldrum, acid gave Michael adducts as ammonium salts. When heated in alcohol, these salts undergo cyclization to ammonium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates. The structure ofN-methylmorpholinium 4-(2′-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate was established by X-ray structural analysis. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1029–1034, May, 1997.     

Synthesis and alkylation ofN-methylmorpholinium 5-cyano-4-(3- and 4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates

The reactions of 3- or 4-hydroxybenzaldehydes with cyanothioacetamide and Meldrum's acid in the presence ofN-methylmorpholine affordedN-methylmorpholinium 5-cyano-4-(3-or 4-hydroxyphenyl)-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates, respectively. The resulting compounds were used in the synthesis of substituted 6-alkylthio-1,2,3,4-tetrahydropyridin-2-ones. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2333–2336. December, 1999.     

A study of the Claisen—Eschenmoser reaction for hydroxymethylbenzofurans and-indoles

N,N-Dimethylacetamide dimethyl acetal reacted with 5(7)-substituted 2-(hydroxy-methyl)benzofurans to give N,N-dimethyl-2-(2-methylbenzofuran-3-yl)acetamides. Analogous reactions with 3-(hydroxymethyl)indole and 1-hydroxy-6-methyl-1,2,3,4-tetrahydro-carbazole afforded N,N-dimethyl-3-(3-indolyl)propionamide and N, N-dimethyl-2-(6-methyl-1,2,3,4-tetrahydrocarbazol-1-yl)acetamide, respectively. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 314–318, February, 2007.     

Fused sulfur-containing pyridine systems. 1. Synthesis and structures of tetrahydropyridothienopyridinone and tetrahydropyridothiopyranopyridinone derivatives

The reactions of N-methylmorpholinium 4-aryl(hetaryl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates with malononitrile and acetone in ethanol afforded substituted tetrahydropyridothienopyridinones. In the absence of acetone, tetrahydropyridothiopyranopyridinones were isolated as the major reaction products. The latter were also synthesized independently by the reactions of the above-mentioned thiolates with 2-amino-1,1,3-tricyanopropene. The structure of 2,4-diamino-10-(2-chlorophenyl)-3-cyano-5-imino-8-oxo-7,8,9,10-tetrahydro-5H-pyrido[2",3":2,3]thiopyrano[4,5-b]pyridine was established by X-ray diffraction analysis.     

Synthesis of substituted N-(2,4-dioxo-1,2,3,4-tetrahydroquinazolinyl)benzamides and N-(2-thiono-4-oxo-1,2,3,4-tetrahydroquinazolinyl)benzamides

Substituted N-(2,4-Dioxo-1,2,3,4-tetrahydroquinazolinyl)benzamides ( 3a-g ) and substituted N-(2-Thiono-4-oxo-1,2,3,4-tetrahydroquinazolinyl)benzamides ( 4a-g ) were synthesized in one step from the reaction of methyl anthranilate with 2-aryl-1,3,4-oxadiazolin-5-ones ( 1a-g ) and 2-aryl-1,3,4-oxadiazoline-5-thiones ( 2a-g ), respectively, in m-cresol at 150–160°. Alternative routes leading to the formation of 3a and 4a are also reported.     

Synthesis of 6-Amino-5-R2-7-(6-R1-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

It has been found that malonodinitrile and 2-(6-R¹-oxo-3,4-dihydro-2-quinazolyl)acetonitrile in the presence of triethylamine undergo hetarylation by 5,6-dichloro-2,3-pyrazinedicarbonitrile at the active methylene group to give the triethylammonium salt of 2-(3-chloro-5,6-dicyano-2-pyrazinyl)malononitrile or 5-chloro-6-cyano(6-R¹-4-oxo-1,2,3,4-tetrahydro-2-quinazolylidene)methyl-2,3-pyrazinedicarbonitriles. Reaction of these with primary amines leads to annelation of the pyrrole ring at the pyrazine [b] edge to give 6-amino-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3,7-tricarbonitriles and 6-amino-5-R²-7-(6-R¹-4-oxo-3,4-dihydro-2-quinazolyl)-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles respectively.     

Synthesis and alkylation of n<Subscript>(3)</Subscript>-aryl-n<Subscript>(5)</Subscript>-phenyl-6-amino-4-aryl(2-furyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamide

N₍₃₎-Aryl-N₍₅₎-phenyl-6-amino-4-aryl(2-furyl)-2-thioxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides have been obtained by the interaction of N-phenyl-3-aryl(2-furyl)-2-cyanoacrylamides with 3-amino-3-thioxopropananilides under the conditions of the Michael reaction. N₍₃₎-Aryl-N₍₅₎-phenyl-2-alkylthio-6-amino-4-aryl(2-furyl)-3,4-dihydropyridine-3,5-dicarboxamides and N₍₃₎, N₍₅₎-diphenyl-6-benzylthio-4-(2-furyl)-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarboxamides were synthesized by alkylation of the products. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1018–1023, July, 2008.     

Synthesis of 3-(α-chlorophenylhydrazono)heteroarylmethyl-2-oxo-1,2-dihydroquinoxalines with antimicrobial activity

The reactions of 3-(α-chlorophenylhydrazono)hydrazinocarbonylmethyl-2-oxo-1,2-dihydroquinoxalines 4a,c with triethyl orthoesters resulted in the intramolecular cyclization to give the 3-(α-chlorophenylhydrazono-1,3,4-oxadiazol-2-ylmethyl)-2-oxo-1,2-dihydroquinoxalines 5a-d , but not the 1,2,4,5-tetrazepinylquinoxalines 6a-d . The cyclization mode into the 1,3,4-oxadiazole ring was confirmed by the alternate syntheses of 5a,c from the reactions of the 3-(1,3,4-oxadiazol-2-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxalines 7a,b with o-chlorobenzenediazonium chloride. Moreover, the reactions of 3-(benzimidazol-2-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline hydrochloride 8 with o-, m- and p-chlorobenzenediazonium chlorides afforded the 3-(α-chlorophenylhydrazonobenzimidazol-2-ylmethy])-2-oxo-1,2-dihydroquinoxa]ine hydrochlorides 9a-c , respectively. Compounds 5a-d and 9a-c were found to exhibit antimicrobial activities.     

The Mannich reaction in the synthesis of N,S-containing heterocycles

Reactions of 6-aryl-5-cyano-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidines with formaldehyde and primary amines gave earlier unknown 3,4-dihydro-2H,6H-pyrimido[2,1-b]-[1,3,5]thiadiazine derivatives in 58–94% yields. In boiling AcOH, these pyrimidothiadiazines underwent the retro-Mannich reaction leading to the starting pyrimidine-2-thiones. The structure of 3-(4-ethoxyphenyl)-6-oxo-8-phenyl-3,4-dihydro-2H,6H-pyrimido[2,1-b][1,3,5]thiadiazine-7-carbonitrile was studied by X-ray diffraction analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1384–1387, July, 2007.     

Three-component condensation in the synthesis of substituted tetrahydropyridinethiolates

Multicomponent cyclocondensation of Meldrum's acid, 2-chlorobenzaldehyde, and N-(4-bromophenyl)-3-amino-3-thioxopropanamide in the presence of N-methylmorpholine afforded N-methylmorpholinium 3-[N-(4-bromophenyl)carbamoyl]-4-(2-chlorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate in 65% yield. When treated with dilute HCl, the thiolate easily transformed into N-(4-bromophenyl)-4-(2-chlorophenyl)-2-oxo-6-thioxopiperidine-5-carboxamide, which reacted with alkyl halides to give products of regioselective S-alkylation in high yields. Dedicated to Academician N. K. Kochetkov on the occasion of his 90th birthday. __________ Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1297–1298, May, 2005.     

A new method for the synthesis ofN-methylmorpholinium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates and their properties

N-Methylmorpholinium 4-aryl-5-cyano-2-oxo-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates were obtained by the condensation of aromatic aldehydes, cyanothioacetamide, and Meldrum's acid in the presence ofN-methylmorpholine. They were then used in the syntheses of substituted 6-alkylthio-3,4-dihydropyridin-2(1H)-ones and 4,5-dihydrothieno[2,3-b]pyridin-6(7H)-ones. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 1852–1856, October, 1997.     

Synthesis and conversions of 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline

The reaction of the hydrazone 3a with hydrazine hydrate in DBU/ethanol conveniently gave 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 6 . The reactions of 6 with an equimolar and 2-fold molar amount of nitrous acid afforded 3-(α-hydroxyimino-4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 9 and 3-(α-hydroxyimino-5-methyl-2H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 10 , respectively, which were converted into the 3-heteroarylisoxazolo[4,5-b]quin-oxalines 13a,b and 11 , respectively. Compound 9 was also cyclized into the 8-quinoxalinyl-1,2,4-triazolo-[3,4-f][1,2,4]triazines 14a,b .     

A new method for the synthesis of [1,4]diazepino[6,5-b]indole derivatives

Reactions of 3-[(N-aryl-N-chloroacetyl)amino]-2-formylindoles with substituted anilines gave 1,4-diaryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indol-4-ium chlorides and those with 4-aminopyridine yielded 4-amino-1-(1-aryl-2-oxo-2,5-dihydro-1H-pyrido[3,2-b]indol-3-yl)pyridinium chlorides. Reduction of 1,2,3,6-tetrahydrodiazepinoindol-4-ium chlorides afforded the corresponding hexahydro derivatives. An alternative synthesis of 1-(4-nitrophenyl)-3-oxo-4-phenyl-1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole from 3-[N-(4-nitrophenyl)amino]-2-[(phenylimino)methyl]indole was developed. The method involves the following sequence of transformations: reduction, chloroacetylation, and intramolecular alkylation. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2193–2199, December, 2006.     

Synthesis of Hexa- and Octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine.     

Reaction of 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)]-hydrazinoquinoxaline 4-oxide with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 4a with methyl or phenyl isothiocyanate gave 6-chloro-2-[1-methyl-2-(N-methylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7a or 6-chloro-2-[1-methyl-2-(N-phenylthiocarbamoyl)hydrazino]quinoxaline 4-oxide 7b , respectively, whose reaction with dimethyl acetylenedicarboxylate afforded 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-3-methyl-4-oxo-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8a or 6-chloro-2-[N-methyl-N-(5-methoxycarbonylmethylene-4-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)]aminoquinoxaline 4-oxide 8b , respectively.     

Synthesis and properties of [1,4]diazepino[6,5-b]indoles

1-Aryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole N-oxides were synthesized based on 3-(N"-aryl-N"-chloroacetyl)amino-2-formylindoles. Deoxidation of 2-oxo-1-phenyl-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole N-oxide afforded 1,2,3,6-tetrahydro- and 1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole derivatives. A new approach to the synthesis of pyrido[3,2-b]indole and pyrimido[5,4-b]indole derivatives was developed.     

Reaction of ethyl 4-aryl-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates with N-methylmorpholinium 3-cyano-1,4-dihydro- and 3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates

Alkylation of N-methylmorpholinium 4-Ar¹-3-cyano-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates using ethyl 4-Ar-6-bromomethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (10 % KOH, DMF) gives mixtures of diastereomers of ethyl 4-Ar-6-[(4-Ar¹-3-cyano-1,4,5,6-tetrahydropyridin-2-ylthio)methyl]-1-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates in overall 30-58 % yield. Under these conditions the N-methylmorpholinium 4-Ar1-5-(N-Ar²-carbamoyl)-3-cyano-6-methyl-1,4-dihydropyridine-2-thiolates undergo aromatization of the dihydropyridine ring to give ethyl 4-Ar-6-[4-Ar¹-5-(N-Ar²-carbamoyl)-3-cyano-6-methylpyridin-2-ylthio)methyl]-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates (37-51 %). In the absence of KOH, only the substituted pyridine-2(1 H)-thione is formed as a product of oxidation of the dihydropyridine ring in the starting substrate. Some of the alkylation products obtained possess weak or moderate antibacterial activity towards the specific strains of Escherichia coli and Bacillus subtilis but are inactive towards Candida albicans and Staphylococcus aureus.     

A convenient synthesis and antifungal activity of 1-aryl-1H- and 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalinesA Convenient Synthesis and Antifungal Activity

Novel 1-aryl-1H- and 1-aryl-3-heteroaryl-1H-pyrazolo[3,4-b]quinoxalines (flavazoles) 9a-c, 12, 13 were synthesized from 3-methyl-2-oxo-1,2-dihydroquinoxaline 5 and the 3-triazolylmethylene-2-oxo-1,2,3,4-tetrahydroquinoxaline 6, respectively, via a facile hydrazone synthesis using aryl diazonium salts. Some of the above flavazoles and their related compounds exhibited the antifungal activity in some extent. The above results are described.     

Synthesis and anticancer evaluation of some novel N,O,S heterocyclic compounds pendant to 3-methyl-5-cyano-6-(3,4-dimethoxyphenyl)pyrimidine and other related fused pyrimidines

The key starting compound 5-cyano-6-(3,4-dimethoxyphenyl)-2-thiouracil ( 1 ) was synthesized and allowed to undergo electrophilic substitution with methyl iodide to give the corresponding 6-(3,4-dimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile ( 2 ). Nucleophilic substitution on compound 2 with hydrazine hydrate led to the corresponding 2-hyrazinopyrimidone intermediate 3 . Compound 3 underwent several substitution and cyclization reactions with β-ketoester, β-ketone, alkyl halides, arylisothiocyanate, or aromatic aldehydes followed by cyclization reactions to give the corresponding N,O,S heterocyclic compounds incorporated into pyrimidine moiety and/or the related S-triazino[3,4-b]pyrimidine derivatives 4 - 18 . Anticancer evaluation of some representative examples of newly synthesized compounds was carried out against MCF-7, HCT116 cell lines. Some of the newly synthesized compounds showed significant activity.     

Formation of ω-(4-oxo-1,4-dihydropyridin-2-yl)alkanamides in the Beckmann rearrangement of spiro-fused cycloalkanone oximes

ω-(4-Oxo-1,4-dihydropyridin-2-yl)alkanamides were obtained from cycloalkanone oximes spirofused to 4-oxo-6-methyl-1,2,3,4-tetrahydropyridine fragment through the α-carbon atom and C², respectively, on heating in polyphosphoric acid. The resulting amides were converted to the corresponding acids and methyl esters. Methylation of 5-(6-methyl-4-oxo-1,4-dihydropyridin-2-yl)pentanamide with diazomethane gave 4-methoxypyridine derivative as the major product and a small amount of N-methyl derivative, 5-(1,6-di-methyl- 4-oxo-1,4-dihydropyridin-2-yl)pentanamide.