Synthesis of 7H-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines and their reductive ring cleavage to 4-aminopyrrolo[2,3-d]pyrimidines

Some new 7,9-disubstituted 7H-1,2,3,4-tetrazolo[1,5-c]pyrrolo[3,2-e]pyrimidines 5 have been synthesized either by diazotization of 4-hydrazino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 4 obtained by hydrazinolysis of 4-chloro-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 3 or via a substitution reaction between 3 and sodium azide. 5,7-Disubstituted-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-ones 2 were obtained by cyclocondensation of 2-amino-3-cyano-1,4-disubstituted pyrroles 1 with formic acid which on chlorination using phosphorus oxychloride afforded 3 . A novel route for the synthesis of 4-amino-5,7-disubstituted-7H-pyrrolo[2,3-d]pyrimidines 6 by the reductive ring cleavage of 5 has been reported.     

On the bromination of thieno[c]-fused 1,5-naphthyridines and their isomeric N-oxides using dibromoisocyanuric acid in fuming sulfuric acid

Thieno[2,3-c]-1,5-naphthyridine ( 3 ), thieno[2,3-c]1,5-naphthyridine 5-oxide ( 7 ), thieno[3,2-c]-1,5-naphthyridine ( 5 ) and thieno[3,2-c]-1,5-naphthyridine 5-oxide ( 9 ) could conveniently be brominated at room temperature using dibromoisocyanuric acid in fuming sulfuric acid. Bromination occurred in good to moderate yields at the β position in the thiophene ring. Thieno[2,3-c]-1,5-naphthyridine 9-oxide ( 12 ) and thieno[3,2-c]-1,5-naphthyridine 9-oxide ( 13 ) also gave substitution in the thiophene ring at 95°. It was also found that 12 was deoxygenated under these reaction conditions. Direct oxidation of the brominated thieno[c]naphthyridines with m-chloroperbenzoic acid gave the 5-oxides in high yield.     

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).     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.     

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 new thienocyclopenta[3,2-d]-oxazole and thiazole derivatives

Synthesis of thieno[2′,3′:5,4]cyclopenta[3,2-d]oxazole and thiazole derivatives are achieved by insertion of carbon dioxide and disulfide into 4-amino-5-chloro-5,6-dihydro-4H-cyclopenta[b]thiophen-6-one.     

[1]Benzothienopyrimidines. I. Etude de la 3H-benzothieno[3,2-d]pyrimidone-4

3H-benzothieno[3,2-d]pyrimidin-4-one (3) was synthesized by bimolecular cyclising the 3-amino-2-carbethoxybenzothiophene (1) with formamide. The electrophilic substituion of 3 afforded N-methylated lactam derivavtives, the structure of which was assigned by 'H nmr and unequivocal synthesis. The sysnthesis of benzothieno[3,2-d]pyrimidine (7) was achieved by desulphurization of the 3H-benzothieno[3,2-d]-[3,2-d]pyrimisine-4-thione (6) or by oxydation of the 4-hydrazinobenzothieno[3,2-d]primidine (5).     

Synthesis and S-methylation of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidin-4(3H)-ones with and without a phase transfer catalyst

A number of 2-thioxopyrido[3′,2′:4,5]thieno[3,2-H]pyrimdin-4(3H-ones (5) have been synthesized by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-b]pyridines (3) with various isothiocyanates. Compounds 5 were S-methylated routinely and the reactions compared under solid-liquid phase transfer conditions to obtain 2-methylthiopyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-^ones (6). The new triheterocyclic pyridothienopyrimidines were prepared with the objective to study their pharmacological properties.     

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.     

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.     

Annelated piperazinyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidines

Tricyclic analogs of piperazinylthiopyrano[3,2-d]pyrimidine hypoglycemic agents were prepared. The angular tricyclic systems, 8,9-dihydro-7H-thiopyrano[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine and 8,9-dihydro-7H-tetrazolo[1,5-a]thiopyrano[2,3-e]pyrimidine derivatives were synthesized from 2,4-dichloro-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine in three step sequences. Derivatives of the linear tricyclic system, 5,6-dihydro-7H-thiopyrano[3,2-d][1,2,4]triazolo[2,3-a]pyrimidine, were prepared by condensation of 3-amino-1,2,4-triazole with ethyl 3-oxo-tetrahydropyran-2-carboxylate. The tricyclic heteroaryl-piperazines lacked significant hypoglycemic activity.     

The synthetic utility of heteroaromatic azido compounds. Part VII. Preparation of some 2- and 4-substituted thieno[3,2-d]pyrimidines

Synthetically useful scission reactions of some 1H-1,2,3-triazolo[1,5-a]thieno[3,2-d]pyrimidines have been studied. The net result of these reactions is an elimination of nitrogen, and a 1,1-addition of the cleaving agent, forming 2-substituted thieno[3,2-d]pyrimidines. The mechanism of the scission is discussed, and a concomitant nucleophilic attack and expulsion of nitrogen is proposed. An unusual reaction between the unsubstituted triazole-fused parent compound ( 1 ) and bromine in alkaline medium is also reported.     

Die Synthese von 2,3,4,5-1H-Tetrahydroimidazo[2,1-b]chinazolin-2,5-dionen und analogen 2,3,4,5-1H-Tetrahydroimidazo[1,2-a]thieno[2,3-d] (bzw. [3,2-d])-pyrimidin-2,5-dionen

The Synthesis of 2,3,4,5-1H-Tetrahydroimidazo[2,1-b]quinazolin-2,5-diones and analogous 2,3,4,5-1H-Tetrahydroimidazo[1,2-a]thieno[2,3-d] (or [3,2-d])-pyrimidin-2,5-diones The syntheses of various imidazo [2, 1-b]quinazolinediones and their thiophene analogs are described.     

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.     

Synthesis of New Fused Pirano[4,3-b]pyridine Derivatives

A method was developed for the synthesis of pyrano[4,3-b]thieno[3,2-e]pyridine derivatives based on the reaction of 3-amino-7-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]pyridine-2-carboxylic acid ethyl ester with chloroacetic acid chloride, triethyl orthoformate, hydrazine hydrate, and also phenyl chloroformate. The synthesis of various new representatives of pyrano[2″,3″:5′,6′]pyrido[3′,2′:4,5]thieno[3,2-dl-pyrimidine series was carried out.

     

Studies on the chemistry of 5-propynyloxy- and 5-propynylthiopyrimidines: New syntheses of furo- and thieno[3,2-d]pyrimidines

The utility of certain 5-alkynyloxy-, 5-alkynylthio, and 5-alkynylsulfinyl-pyrimidines as precursors of 7-substituted furo[3,2-d]- and thieno[3,2-d]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3-dimethyl-5-(2-propynyloxy)uracil ( 6 ) cyclizes to afford 1,3,7-tri-methylfuro[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 12 ) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5-(2-butynyloxy)pyrimidine ( 7 ), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8-methylpyrano[3,2-d]pyrimidine 8 in methyl sulfoxide and the 6,7-dimethylfuro[3,2-d]pyrimidme 11 in dimethylformamide. The 5-(2-propynylthio)pyrimidine 15 affords the allene 19 and the 1-propyne 22 when treated with various bases, but none of the 7-methylthieno[3,2-d]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio-Claisen rearrangement process to afford the 6-methylthieno[3,2-d]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7-thiomethoxymethyl substituent derived from the solvent. Heating the 5-(2-propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3-dimethyl-7-formylthieno[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 29 ) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′-proton of 23 . This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma-tropic rearrangements, and the intermediacy of a dihydrothieno[3,2-d]pyrimidine such as compound 30.     

Synthesis of two novel bicyelic systems,imidazo[1,5-D]-as-triazine and imidazo[1,2-d]-as-triazine

4-Imidazolecarboxyaldehyde was condensed with methyl dithiocarbazinate and with ethyl carbazate, the resulting hydrazones were subjected to thermolysis in diphenyl ether at 175–240, to give imidazo[1,5-d]-as-triazine-4(3H)thione and imidazo[1,5-d]-as-triazin-4(3H)one, respectively. A number of 2-, 5-, and 2,5-substituted 4-imidazolecarboxaldehydes were also carried through this scheme. The same sequence of reactions with 2-imidazolecarboxaldehyde gave the novel system imidazo[1,2-d]-αs-triazine-5-(6H)-thione. Upon treatment with sodium hydride and methyl iodide, imidazo[1,5-d]-as-triazine-4(3H)thione and imidazo[1,2-d]-as-triazine-5(6H)-thione gave 4-methylthioimidazo[1,5-d]-as-triazine and 5-methylthioimidazo[1,2-d]-as-triazine, respectively. Displacement of the thiomethyl group was achieved with a selection of amine reagents in both of the above cases.     

Synthesis and antimicrobial testing of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone

Synthesis of 2-amino-6-hydroxymethyl-4-(3H)pyrido[3,2-d]pyrimidinone ( 5 ) from 2-amino-6-methyl-4-(3H)-pyrido[3,2-d]pyrimidinone ( 2 ) was accomplished by selenium dioxide oxidation of 2 to the aldehyde 4 followed by sodium borohydride reduction. Compound 2 was available in four steps from 5-aminouracil or in two steps from 5-nitroisocytosine ( 3a ). Catalytic reduction of 4 or 5 gave a mixture of 2-amino-6-methyl-5,6,7,8-tetrahydro-4-(3H)pyrido[3,2-d]pyrimidinone ( 6a ) and the 6-hydroxymethyl compound 6b . These compounds showed only weak inhibitory activity in the coupled reactions catalyzed by 7,8-dihydro-6-hydroxymethylpterin pyrophosphokinase and 7,8-dihydropteroate synthetase from E. Coli. No significant antibacterial activity was observed.     

New polyheterocyclic series based on 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

4,8-Dimethyl-6,7,8,9-tetrahydropyrido[4′,3′:4,5]thieno[2,3-e][1,2,4]triazolo[3,4-a]-4H-pyrimidin-5-ones, 7-methyl-2,3,6,7,8,9-hexahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrrolo[1,2-a]-1H, 10H-pyrimidin-10-one, 8-methyl-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:4,5]thieno[2,3-d]-11H-pyrimidin-11-one, and 9-methyl-2,3,4,5,8,9,10,11-octahydro[4′,3′:4,5]thieno[2,3-d]azepino-[1,2-a]-1H, 12H-pyrimidin-12-one which consist four new heterocyclic ring systems were synthesized from 2-amino-3-carbethoxy-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.     

New syntheses of 7-substituted-2-aminothieno- and furo[3,2-d]pyrimidines

In a recent publication, we have the described the synthesis of 7-substituted-2-amino-1,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-ones which are potent inhibitors of the enzyme Purine Nucleoside Phosphorylase from the corresponding 3-aminopyrroIe-2-carboxylate esters. A key step in the synthesis is condensation of the amino group with the highly reactive guanylating reagents 3 or 4 followed by annulation. The furo[3,2-d]pyrimidin-4-one and thieno[3,2-d]pyridin-4-one are closely related rings systems. However, these rings have not been reported in the literature with a 2-amino, substituent which would arise from such guanylation reactions. In this report, the syntheses of the novel furans 5 are described based on our improved pyrrole synthesis (Scheme 1). The syntheses of the novel thiophenes 6 are described. The guanylation of 5 and 6 were studied and compared to 2. The 3-amino group of 5 and 6 failed to react with 3 or 4 under mild acid catalysis; conditions under which 2 easily condensed. Guanylation was finally achieved by generating the carbodiimide intermediate of 3 under mercury catalysis affording the guanylated adducts which were converted to the novel 2-aminothieno- and furo[3,2-d]pyrimidin-4-ones 16.