Condensed Pyridopyrimidines. 7. Synthesis of Condensed Triazolo[4,3-c]- and Tetrazolo[1,5-c]pyrimidines

Novel dihydro-5H-pyrano[3',4':5',6']pyrido[2,3-d]-1,2,4-triazolo[4,3-c]pyrimidines and 1,2,3,4-tetrazolo[1,5-c]pyrimidines have been synthesized from 2-amino-3-cyano-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine.     

Derivatives of Condensed Thienopyrimidimines. 13. Synthesis and Structure of Pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines

Methods for the synthesis of 5-substituted 10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines have been developed. An X-ray crystallographic study of 5-(2-ethoxymethylhydrazino)-10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidine has been carried out.     

Substituted ethyl 2-acyl-3-amino-6-methylthieno[2,3-b]pyridine-4-carboxylates as synthons for novel heterocycles

The triethylamine-catalyzed reaction of 4-substituted ethyl 2-acyl-3-amino-6-methylthieno[2,3-b]pyridine-4-carboxylates IIIa-h with 2,2,6-trimethyl-4H-1,3-dioxin-4-one IV gave 4-substituted ethyl 3-acetyl-2-hydroxy-7-methylthieno[2,3-b:4,5-b′]dipyridine-9-carboxylates Va-h. Some of the thienodipyridines ( V ) reacted with excess IV to give 5-substituted ethyl 3-acetyl-4,8-dimethyl-2-oxo-2H-pyrano[2,3-b]-pyrido[3′,2′:4,5]thieno[2,3-e]pyridine-10-carboxylates VI .     

Intramolecular 4+2 cycloaddition of thieno[2,3-e][1,2,4]triazines: routes towards condensed thieno[2,3-b]pyridines

Synthetic approaches towards new condensed thienopyridine ring systems including furo[2,3-b]thieno[3,2-e]pyridines, bisthieno[2,3-b:3′,2′-e]pyridines, 5H-chromeno[2,3-b]thieno[3,2-e]pyridines, 5H-benzo(f)chromeno[2,3-b]thieno[3,2-e]pyridines have been achieved by application of intramolecular 4+2 cycloaddition reactions of suitably designed thieno[2,3-e][1,2,4]triazines tethered with alkene or alkyne terminals.     

Synthesis of new condensed derivatives of pyrano[4,3-<Emphasis Type="Italic">b</Emphasis>]thieno[3,2-<Emphasis Type="Italic">e</Emphasis>]pyridine and pyrido[3',2':4,5]thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]pyrimidine

The reactions of 2-methyl (propyl) substituted 8,8-dimethyl-7,10-dihydro-4H,8H-pyrano[3",4":5',6']pyrido[3',2':4,5]thieno[3,2-d][1,3]oxazines with primary amines give 2-methyl (propyl) substituted 8,8-di- methyl-7,10-dihydro-8H-pyrano[3",4":5',6']pyrido[3',2':4,5]thieno[3,2-d][1,3]pyrimidin-4(3H)-ones or 3-acetyl-N-alkyl- and N-alkyl-3-butyrylamino-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]thieno[3,2-e]- pyridine-2-carboxamides depending on steric hindrance in the amines.     

Reaction of thieno[2,3-b]pyridines with sodium hypochlorite: An unusual and stereoselective one-pot approach to dimeric pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridines

The oxidation of 3-aminothieno[2,3-b]pyridine-2-carboxamides with commercially available bleach leads to the formation of dimeric pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridines (7a,14a-diamino-7,14-bis(aryl)-7,7a,14,14a-tetrahydro-6H,13H-pyrido[3″″,2″″:4?,5?]thieno[2?,3?:4″,5″]pyrrolo-[3″,4″:3′,4′]pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridine-6,13-diones) in moderate yields (37–52%).     

Synthesis and transformations of 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines

Reactions of 2,5-dimethoxytetrahydrofuran with 3-aminothieno[2,3-b]pyridines afford a number of substituted 3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridines. The possibility of the reaction and the yield of the product are determined by the character of a substituent in position 2 of thieno[2,3-b]pyridine. The Curtius rearrangement of 2-acylazido-3(1H-pyrrol-1-yl)thieno[2,3-b]pyridines yields 4,5-dihydropyrido[3",2":4,5]thieno[2,3-e]pyrrolo[1,2-a]pyrazin-4-ones. The molecular and crystal structures of ethyl 4-methoxymethyl-6-methyl-3-(1H-pyrrol-1-yl)thieno[2,3-b]pyridine-2-carboxylate were determined by X-ray diffraction analysis.     

Condensed Thienopyrimidines. 19. Study of the Heterocyclization of 2-Hydrazino-6,6-dimethyl-5,6-dihydro-8H-pyranothieno[2,3-d]pyrimidin-4-one

Novel condensed pyrano[4',3':4,5]thieno[3,2-e]triazolo[3,4-b]pyrimidine derivatives have been synthesized from 2-amino-3-carbethoxy-5,5-dimethyl-4,5-dihydro-7H-thieno[2,3-c]pyran.     

Palladium-catalyzed reductive N-heterocyclization of alkenyl-substituted nitroarenes as a viable method for the preparation of bicyclic pyrrolo-fused heteroaromatic compounds

Palladium-catalyzed, carbon monoxide-mediated reductive N-heterocyclization of nitro-heteroaromatic compounds having an alkene adjacent to the nitro-group affords bicyclic pyrrolo-fused heteroaromatic molecules. This type of reaction was used to prepare the fused bicyclo[3.3.0] ring-system: thieno[3,2-b]pyrrole, thieno[2,3-b]pyrrole, furo[2,3-b]pyrrole, pyrrolo[3,2-d]thiazole, and pyrrolo[2,3-d]imidazole and the bicyclo[4.3.0] ring-systems: pyrrolo[3,2-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridazine, and pyrrolo[3,2-d]pyrimidine in 32-94% yield.     

Derivatives of Condensed Thieno[2,3-d]pyrimidines. 15. Synthesis of 2-Substituted 3-Amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4'3':4,5]thieno[2,3-d]pyrimidin-4-ones

A method has been developed for the preparation of 2-R-substituted 3-amino-6,6-dimethyl-5,6-dihydro-8H-pyrano[4'3':4,5]thieno[2,3-d]pyrimidin-4-ones based on 2-R-amino-3-ethoxycarbonylpyrano[2,3-c]thiophenes. It has been established that their cyclization with hydrazine hydrate requires vigorous conditions.     

Chemistry of thienopyridines. XXXVIII. Diels-Alder reactions of thienopyridine sulfones. Part 2

Thieno[3,2-b]pyridine 1,1-dioxide ( 2 ) undergoes Diels-Alder condensation with the dienophiles cyclopentadiene, anthracene, and naphthacene in a manner analogous to its isomer thieno[2,3-b]pyridine 1,1-dioxide ( 1 ). Compound 2 dimerizes in refluxing xylene with the loss of sulfur dioxide plus either the loss or transfer of hydrogen to give a small yield (ca. 2%) of pyrido[2′,3′:4,5]thieno[3,2-f]quinoline 7,7-dioxide ( 7 ) and its 5,6-dihydro derivative 12 . Formation of 7 and 12 are compared and contrasted with products reported from dimerization of 1 and of benzo[b]thiophene 1,1-dioxide and its derivatives.     

Construction of new heteroacenes based on benzo[b]thieno[2,3-d]thiophene / quinoline or 1,8-naphthyridine systems using the Friedländer reaction

Two new classes of heteroacenes, namely benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]quinolines and benzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b][1,8]naphthyridines, have been formed using the Friedländer reaction to annulate the benzo[b]thieno[2,3-d]thiophene scaffold to quinoline or 1,8-naphthyridine fragments. In accordance with this synthetic strategy, benzo[b]thieno[2,3-d]thiophen-3(2H)-ones were treated with 2-aminobenzaldehydes or 2-aminonicotinaldehyde in the presence of pyrrolidine in glacial acetic acid at reflux to give the desired quinoline- or 1,8-naphthyridine-fused compounds, respectively. The optical and electrochemical properties of selected heteroacenes were determined.     

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 of 5,8-Diamino-Substituted Pyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]pyrimidines and Pyrimido[4′,5′:4,5]thieno[2,3-<Emphasis Type="Italic">c</Emphasis>]isoquinolines

Ethyl 1-amino-8,8-dimethyl-5-(piperidin-1-yl)-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carboxylate and ethyl 1-amino-5-(piperidin-1-yl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline-2-carboxylate reacted with benzoyl isothiocyanate to give the corresponding 1-thioureido derivatives which underwent cyclization to 2,2-dimethyl-5-(piperidin-1-yl)-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 and 5-(piperidin-1-yl)-10-thioxo-1,2,3,4,10,11-hexahydropyrimido-[4′,5′:4,5]thieno[2,3-c]isoquinolin-8(9H)-one. The cyclization products were converted into 8-chloro derivatives, and the chlorine atom therein was replaced by various amines.     

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.     

Chemistry of thienopyridines. XLII. Three novel compounds derived from thienopyridine N-oxides

Extension of the Reissert-Henze reaction to treatment of thieno[2,3-b]pyridine 7-oxide with potassium thiocyanate and benzoyl chloride in water-methylene chloride gives a 2% yield of bis(6-thieno[2,3-b]pyridyl) disulfide. Peroxidation of 5-ethylthieno[2,3-b]pyridine ( 4 ) forms the 7-oxide 5 (53%), converted to a monopicrate 5a . Picrate 5a undergoes N-deoxygenation to 4 -picrate on drying at 78° in vacuo, but shows the expected additive mass spectrum of 5 (thermally stable) and picric acid. Nucleophilic displacement of chloride ion from 7-chlorothieno[3,2-b]pyridine (derived, in turn, from thieno[3,2-b]pyridine 4 -oxide) by the anion from ethyl cyanoacetate gives 7-(1-cyano-1-ethoxycarbonyl)methylene-4,7-dihydrothieno[3,2-b]pyridine (82%), stable in this iminodienic tautomeric form.     

Building libraries of skeletally diverse scaffolds from novel heterocyclic active methylene compound through multi-component reactions

Libraries of skeletally diverse potential bioactive polycyclic/spirocyclic heterocyclic compounds; 2-amino-7,9-dimethyl-5-oxo-4-aryl-4,5,6,7-tetrahydropyrano[2,3-d]pyrazolo[3,4-b]pyridine-3-carbonitrile, 2′-amino-7′,9′-dimethyl-2,5′-dioxo-6′,7′-dihydro-5′H-spiro[indoline-3,4′-pyrano[2,3-d]pyrazolo[3,4-b]pyridine]-3′-carbonitrile, and 5,5′-(arylmethylene)bis(4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one) have been synthesized through a multi-component reaction using novel heterocyclic active methylene compound 4-hydroxy-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-6(7H)-one as one of the building blocks. This protocol can be considered to be an efficient and eco-friendly strategy for diversity oriented synthesis.     

A convenient synthesis of pyrrolo[2,3-b]pyridines and pyrido[2′,3′:5,4]pyrrolo[2,3-d]pyrimidines

2-Chloro-6-ethoxy-4-phenylpyridine-3,5-dicarbonitrile was taken as versatile building block that allows the synthesis of 1H-pyrrolo[2,3-b]pyridine, thieno[2,3-b]pyridine and pyrido[2′,3′:5,4]pyrrolo[2,3-b]pyrimidine systems. Some of the synthesized compounds were screened as antibacterial agents.     

Synthesis of condensed tricyclic pyrazolo[3,4-b]thieno[2,3-d]pyridine and related isostere derivatives

In this paper we report the synthesis of an isosteric series of new heterotricyclic derivatives, corresponding to pyrazolo[3,4-b]thieno[2,3-d]pyridine ( 1 ), pyrazolo[3,4-b]furano[2,3-d]pyridine ( 2 ) and pyrazolo[3,4-b]pyrrolo[2,3-d]pyridine ( 3 ). These functionalized compounds were obtained, in high overall yield, by an ‘one-pot’ reaction of the chloroester intermediate 4 , possessing the pyrazolo[3,4-b]pyridine system, with an adequate α-hetero-acetyl ester derivative, in SNAr/Dieckman cyclization type consecutive reactions.     

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.