The synthetic utility of heteroaromatic azido compounds. Part VI. Preparation of some 1H-1,2,3-triazolo[1,5-a]thieno[3,2-d]pyrimidines

Some 1,2,3-triazolo[1,5-a]thieno[3,2-d]pyrimidines have been prepared by the reaction of active methylene nitriles with 3-azido-2-substituted thiophenes. Thus, for example the 3-carboxy derivative 5 was prepared by condensation of 3-azido-2-formylthiophene dimethyl acetal ( 1 ) with ethyl cyanoacetate, followed by intramolecular cyclization. Decarboxylation of 5 led to the unsubstituted parent compound 6 . The structure of the triazole-fused compounds is discussed.     

The synthesis and transformations of 2-ethoxycarbonyl-3-isothiocyanatopyridine. Pyrido[3,2-d]pyrimidines and some azolopyrido[3,2-d]pyrimidines

2-Ethoxycarbonyl-3-isothiocyanatopyridine ( 2 ), prepared from 3-amino-2-ethoxycarbonylpyridine ( 1 ) by the thiophosgene method, was converted with nucleophiles into pyrido[3,2-d]pyrimidine derivatives 6–11 and 25–30 either directly, or through thiourethane 3 . Tricyclic systems 18 and 19 were obtained from 3 , and tricyclic systems 12–17 from pyrido[3,2-d]pyrimidine derivative 11 . Pyrrole reacted with 2 at C₂ to give 20 , and by further cyclization 21 and 22 .     

Syntheses of functionalized thieno[3,4-d]imidazoles and thieno[3,2-d]pyrimidines from chlorine-containing enamidonitriles

Enamidonitriles of the general formula Cl(X)C=C(CN)NHCOR readily react with methyl sulfanylacetate to give tri-or tetra-substituted thiophenes, which can be converted into new functional derivatives of thieno[3,2-d]pyrimidine and thieno[3,4-d]imidazole.     

Synthesis of 2-mercaptothieno[3,2-d]- and 2-mercaptobenzo[4, 5]thieno[2,3-d]thiazoles

2-Mercaptothieno[3,2-d]- and 2-mercaptobenzo[4, 5]thieno[2,3-d]thiazoles were synthesized by reduction of bis(3,3′-nitro-2,2′-thienyl) and bis(2,2′-nitrobenzo[b]thien-3,3′-yl) disulfides, respectively, with sodium hydrosulfite or sodium sulfide in the presence of carbon disulfide.     

Synthesis of thiopyrano[2,3-d] pyrimidines and thieno[2,3-d]pyrimidines

The reaction of 4-chloro-5-cyano-2-methylthiopyrimidine (I) with ethyl mercaptosuccinate (II) in refluxing ethanol containing sodium carbonate has afforded diethyl 3-amino-2-(methyl-thio)-7H-thiopyrano[2,3-d]pyrimidine-6,7-dicarboxylate (IV). Displacement of the methylthio group in IV with hydrazine gave the corresponding hydrazino derivative which underwent Schiff base formation with benzaldehyde or 2,6-dichlorobenzaldehyde. Treatment of IV in refluxing acetic anhydride afforded the corresponding diacetylated amino derivative. Partial saponification of IV with sodium hydroxide gave 5-amino-2-(methylthio)-7H-thiopyrano-[2,3-d]pyrimidine 6,7-dicarboxylic acid 6 ethyl ester (VIII). The reaction of 4-amino-6-chloro-5-cyano-2-phenylpyrirnidine (XI) with II resulted in the formation of ethyl 4-amino-6-(ethoxy-carbonyl)-5,6-dihydro-5-amino-2-phenylthieno[2,3-d]pyrimidine-6-acetate (XIII) which when subjected to hydrolysis gave ethyl 4,5-diamino-2-phenylthieno[2,3-d]pyrimidine-6-acetate isolated as the hydrochloride (XIV). Diazotization of IV with sodium nitrite in acetic acid unexpectedly afforded diethyl 5-(acetyloxy)-6,7-dihydro-6-hydroxy-2-(methylthio)-5H-thio-pyrano[2,3-d]pyrimidine-6,7-diearboxylate (XV). Several structural ambiguities were resolved by ir and pmr spectra.     

Preparation of reissert compounds derived from the thieno[3,2-c]pyridine,thieno[2,3-d]pyridazine and the thieno[2,3-d]pyrimidine ring systems

The use of tributyltin cyanide, trimethylsilyl cyanide and potassium cyanide in the Reissert reaction is contrasted in the furo[3,2-c]pyridine, thieno[3,2-c]pyridine, thieno[2,3-dpyridazine, and thieno[2,3-d]pyrimidine ring systems.     

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.     

Studies on the synthesis of 2-(2-arylvinyl)thieno[2,3-d]pyrimidines and 5-(2-arylvinyl)triazolothieno[3,2-e]pyrimidines

Synthesis of 2-(2-arylvinyl)thienopyrimidines, by the acid catalyzed condensation of nitriles with thiophene o-aminocarbonyl compounds, the condensation of aldehydes with thiophene o-aminoamides, the base catalyzed condensation of aldehydes with 2-methylthienopyrimidines and by the Wittig condensation of 2-thieno-pyrimidinylmethylphosphonium salts with aldehydes is described. Isomeric 5-methyltriazolothienopyrimidines were found to react, under basic condition, with aldehydes yielding 5-(2-arylvinyl)triazolo[2,3-c]thieno-pyrimidines. While 5-styryltriazolo[4,3-c] isomers resisted acid catalysed isomerization, they were found to isomerize to triazolo[2,3-c]pyrimidines under base catalysis.     

Thiazolo(oxazolo)thieno[b]pyrimidines. Preparation from 2-allylthio(oxy)thieno[2,3-d]pyrimidines and hydrolysis

Heterocyclization of 5,6-disubstituted 2-allylthio(oxy)-4-oxothieno[2,3-d]pyrimidines by treatment with halogens affords thieno[3,2-e]thiazolo[3,2-a]pyrimidine iminium salts. Treatment of these salts with aqueous sodium acetate results in cleavage of the thiazoline ring.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 413–418, March, 1989.     

Synthesis of some new thieno[3,4-d]pyrimidines and their C-nucleosides

The synthesis of several new thieno[3,4-d]pyrimidine C-nucleosides 5-8 is described. The known 5-ribosyl-ated methyl 4-(formylamino)thiophene-3-carboxylate key intermediate 20 was obtained as a mixture of anomers in significantly improved yield by condensation of the sugar 15 with methyl 4-(formylamino)thio-phene-3-carboxylate 19 in nitromethane at 60° in the presence of stannic chloride. Attempts to prepare the C-7 ribosylated compound 21 β by direct condensation of the bicyclic base 10 with 15 gave instead the N-1 ribosylated nucleoside 16 . The synthesis of the corresponding and previously unknown thieno[3,4-d]pyrimi-dine bases 12 and 13 is described along with stability studies on the 4-methylthio derivative 12 . Preliminary biological studies indicate that adenosine analogue 7 is a potent growth inhibitor of several mammalian tumor cell lines.     

Synthèse des pyrido[2,3-d] el [3,2-d] -s-triazolo[3,4-f] pyrimidines el de (pyrazolyl-1')-4 pyrido[2,3-d] et [3,2-d] pyrimidines

The synthesis of two new heterocycles is described: pyrido-[2,3-d]-.s-triazolo[ 3,4-f] pyrimidine and pyrido[3,2-d]-.s-triayzolo-[3,4-f] pyrimidine. 4-[I'-Pyrazolyl]pyrido[2,3-d]pyrimidines and 4-[1′-pyrazoly1] pyrido[ 3,2-d] pyrimidine are obtained by the action of 4-hydrazinopyrido[2,3-d]pyrimidine and 4-hydrazinopyrido-[3,2-d]pyrimidine with several β-diketones.     

Aminoethyl derivatives of 4-substituted pyrazolo[3,4-d]pyrimidines

New 3-aminoethyl derivatives of pyrazolo[3,4-d]pyrimidine were synthesized by reduction of 3-cyanomethylpyrazolo[3,4-d]pyrimidines with hydrazine hydrate in the presence of Raney nickel in alcohol.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 846–847, June, 1972.     

Synthesis of 2-mercapto-substituted thieno[2,3-d]thiazoles and ben zothieno[3,2-d] thiazoles

2-Mercaptothieno[2, 3-d]thiazoles were synthesized from bis(2-nitro-3-thienyl) disulfide by successive reduction of, initially, the disulfide bond and the nitro group in the presence of carbon disulfide without isolation of the intermediate 2-nitro-3-mercaptothiophene. 2-Mercaptobenzo-[b]thieno[3, 2-d]thiazole was synthesized by reaction of 3-aminobenzo[b]thiophene hydrochloride with sulfur monochloride and cleavage of the resulting benzo[b]thienothiazothionium chloride with sodium sulfide in the presence of carbon disulfide.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1355–1356, October, 1976.     

Syntheses of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidines from methyl tetrahydro-4-oxo-3-thiophenecarboxylate and methyl tetrahydro-3-oxo-2-thiophenecarboxylate,respectively

A general synthesis of 10-Oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidines and 10-Oxo-10H-pyrido[1,2-a]-thieno[3,2-d]pyrimidines is described. Methyl tetrahydro-4-oxo-3-thiophenecarboxylate ( 13 ) was condensed with 6-aminonicotinic acid ( 18 ) to give 3,10-dihydro-10-oxo-1H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 19 ). Treatment of 19 successively with chlorotrimethylsilane, N-chlorosuccinimide and water gave 10-oxo-10H-pyrido[1,2-a]thieno[3,4-d]pyrimidine-7-carboxylic acid ( 17 ). Methyl tetrahydro-3-oxo-2-thiophenecarboxylate ( 21 ) was converted to 10-oxo-10H-pyrido[1,2-a]thieno[3,2-d]pyrimidine-7-carboxylic acid ( 25 ) by an analogous route.     

New syntheses of pyrido[3,2-d]pyrimidines

New synthetic routes to pyrido[3,2-d]pyrimidines starting with 5-amino-1,3,6-trimethyluracil (I) or 1,3,6-trimethyl-5-nitrouracil (X) are described. Thus, condensation of I with arylaldehydes gave 5-arylideneamino-1,3,6-trimethyluracils (IIa-h), which upon heating with dimethylformamide dimethylacetal afforded 6-aryl-1,3-dimethylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-diones (Va-h) via 5-arylideneamino-1,3-dimethyl-6-(2-dimethylaminovinyl)uracils (IIIa-h). On the other hand, reaction of X with phenylacetaldehyde in the presence of base yielded Va and its 5-oxide (XI).     

Thienopyrimidines. VII. Reactions of the 4-hydrazinothieno[2,3-d]pyrimidines

The cyclization reactions of the 4-hydrazinothieno[2,3-d]pyrimidines give s-triazolo[1,2-c]-thieno[3,2-e]pyrimidines and tetrazolo[1,5-c]thieno[3,2-e]pyrimidines.     

Synthesis of substituted thieno[2,3-d]thiazoles and indolo[3,2-d]thiazoles

Alkylene-, halo-, and aryl-substituted 2-methylthieno[2,3-d]thiazoles were obtained by the action of phosphorus pentasulfide on the corresponding 2-acetylamino-3-bromo- or 2-acetylamino-3-hydroxythiophenes in an organic solvent with heating. 2-Oximes of halo- and methyl-substituted isatins were converted by reduction and acylation into 2-hydroxy-3-acetylaminoin-doles, from which 2-methylindolo[3,2-d]-thiazoles were obtained by the action of phosphorous pentasulfide with heating in xylene.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 410–417, March, 1987.     

Convenient synthesis and anticancer evaluation of novel pyrazolyl-thiophene,thieno[3,2-b]pyridine,pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine derivatives

The newly synthesized 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was utilized as a precursor for the synthesis of pyrazolyl-thiophene derivative, which undergoes cyclization upon treatment with benzaldehyde derivatives to provide pyrazolo[3,4-d]thieno[3,2-b]pyridines. Basic treatment of pyrazolyl-thiophene derivative with phenyl isothiocyanate followed by subsequent addition of chloroacetone and/or ethyl bromoacetate yielded the thiazolylidene-pyrazolyl thiophenes. In addition, the building block 3-(3-amino-5-(phenylamino)-4-(phenylcarbamoyl)thiophen-2-yl)-3-oxopropanoate was converted into the corresponding thieno[3,2-b]pyridine compounds through its reactions with (DMF-DMA) and/or heating in sodium ethoxide. Moreover, the reaction of 7-hydroxy-5-oxo-N-phenyl-2-(phenylamino)-4,5-dihydrothieno[3,2-b]pyridine-3-carboxamide with 2-arylidenemalononitrile produced the new annulated pyrano[2,3-d]thieno[3,2-b]pyridines. The prepared thiophene-based compounds were evaluated against HepG2, PC3, and MCF-7 cancer cells, and normal fibroblast cell (WI38). The pyrazolo[3,4-d]thieno[3,2-b]pyridine and pyrano[2,3-d]thieno[3,2-b]pyridine compounds substituted with chlorophenyl group presented promising cytotoxic activities against HepG2 cancer cell line without any human toxicity. Docking study for the synthesized thiophene compounds delivered valuable insights about the binding interactions with the crystal structure of NS5B enzyme with PDB ID (4TLR).