Synthesis of New 2-[(Substituted-pyrazolin-1-yl)carbonyl]-thieno[2,3-b]pyridine Derivatives

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate chalcones 2a-2d in the presence of acid catalyst produced the corresponding 3-amino-2-[(3,5-disubstituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d . 3-Amino-2-[(3-substituted-pyrazolin-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 7a, 7b were also obtained by the cyclization reaction of carbohydrazide 1 with Mannich base derivatives 6a, 6b under basic condition.     

Synthesis of New 2-[(Substituted-pyrazol-1-yl)carbonyl]-thieno[2,3b]pyridine Derivatives Using 1,3-Diketones,Alkylethoxymethylenes and Ketene Dithioacetals

The reaction of 3-amino-4,6-dimethyl-2-thieno[2,3-b]pyridine carbohydrazide ( 1 ) with appropriate 1,3-diketones 2a-2d in glacial acetic acid afforded 3-amino-2-[(3,5-disubstituted-pyrazo)-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 3a-3d. 3-Amino-2-[(5-amino-3,4-disubstituted-pyrazol-1-yl)carbonyl]-4,6-dimethylthieno[2,3-b]pyridines 5a-5h were also prepared by treatment of carbohydrazide 1 with appropriate alkylethoxymethylenes and ketene dithioacetals 4a-4h , respectively.     

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.     

Functionalized sulfur-containing compounds. 13. Synthesis of substituted 3-amino-2-(organylsulfinyl)-and-(organylsulfonyl)thieno[2,3-b]pyridines

A method for the synthesis of substituted 3-amino-2-(organylsulfinyl)thieno[2,3-b]pyridines by the Thorpe—Ziegler intramolecular cyclization of substituted 3-cyano-2-[(organyl-sulfinyl)methylthio]pyridines was proposed. 3-Amino-2-(organylsulfonyl)thieno[2,3-b]pyridines were obtained by reactions of substituted 3-cyanopyridine-2-thiones with chloromethyl organyl sulfones. The reaction intermediates 3-cyano-2-[(organylsulfonyl)methylthio]pyridines were transformed into 3-amino-2-(organylsulfonyl)thieno[2,3-b]pyridines. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 510–515, March, 2006.     

Synthesis of substituted 2-amino-3-cyano-7,9-dimethyl-4H-pyrano[2",3":4,5]thieno[2,3-b]pyridines

4,6-Dimethyl-2H-thieno[2,3-b]pyridin-3-one reacts with 2-aryl-1,1-dicyanoethylenes or an aromatic aldehyde/ketone (cyclohexanone and piperidone derivatives) and malononitrile to give substituted 2-amino-3-cyano-7,9-dimethyl-4H-pyrano[2",3":4,5]thieno[2,3-b]pyridines.     

Synthesis and Properties of Substituted Isoxazolo[3',4':4,5]thieno[2,3-b]pyridines

We synthesized derivatives of a novel heterocyclic system, isoxazolo[3',4':4,5]thieno[2,3-b]pyridine by sequential conversions in three steps: isomerization of 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides obtained by alkylation from substituted 3-cyano-2(1H)-pyridinethiones by -halomethyl ketones in alkaline medium, to form 3-aminothieno[2,3-b]pyridines; diazotization of the amino group followed by nucleophilic substitution of the diazonium group by an azido group, bypassing the step of isolating the diazonium salts; and thermolysis of the azides formed.     

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).     

Preparation of 5-substituted- and 3,5-disubstituted-s-triazolo[4,3-a]pyridines

Cyclization of N-acyl-N′-(6-chloropyrid-2-yl)hydrazines ( 2a-2e ) with phosphorus oxychloride has produced several 5-chloro-s-triazolo[4,3-a]pyridines ( 3a-3e ). Nucleophilic displacement of the chlorosubstituent of 5-chloro-s-triazolo[4,3-a]pyridine ( 3a ) availed the 5-ethoxy ( 4a ) and 5-thioethoxy ( 4b ) derivatives and di(s-triazolo[4,3-a]pyrid-5-yl)sulfide ( 8 ) while reaction of 5-ethylsulfonyl-s-triazolo[4,3-a]pyridine ( 4d ) with potassium hydroxide yielded the 5-hydroxy/5-one system ( 4c or 6 ). Further reaction of 3a with bromine to give 3-bromo-5-chloro-s-triazolo-[4,3-a]pyridine ( 3g ) has provided the corresponding 3-cyano- and 3-carboxamido-5-chloro-s-triazolo[4,3-a]pyridine derivatives ( 3h and 3i ). Treatment of 6-chloro-2-hydrazinopyridine ( 1 ) with cyanogen bromide has provided 3-amino-5-chloro-s-triazolo[4,3-a]pyridine ( 3f ) which, with bromoacetaldehyde dimethyl acetal, transformed into 7-chloroimidazo[1,2-b]-s-triazolo[4,3-a]-pyridine ( 7 ). Finally, attempts at cyclizing N-oxalyl-N′-(6-chloropyrid-2-yl)hydrazine derivatives ( 2g-2i ) with intentions of preparing various 3-acyl-5-chloro-s-triazolo[4,3-a]pyridines for entry into other 3,5-disubstituted systems were unsuccessful.     

Synthesis of 5-Phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridines

Syntheses are reported for a series of 2-alkylamino-6-phenyl-4-trifluoromethylpyridines. The reaction of 3-cyano-2-(hydroxyalkylamino)-6-phenyl-4-trifluoromethylpyridines with thionyl chloride gave the corresponding 2-(chloroalkylamino)pyridines, 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydro-imidazo[1,2-a]pyridines, and 9-cyano-6-phenyl-8-trifluoromethyl-2,3,4-trihydropyrido[1,2-a]-pyrimidines. X-ray diffraction structural analysis was used to study 8-cyano-5-phenyl-7-trifluoromethyl-2,3-dihydroimidazo[1,2-a]pyridine.     

Interaction of 3-amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-methyl-thieno[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridine with Raney nickel

3-Amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-methylthieno[2,3-b]pyridine was synthesized by the reaction of 2(1H)-thioxopyridine-3-carbonitrile with 3-chloromethylisoxazole in the presence of two equivalents of KOH. Boiling of 3-amino-2-(isoxazol-3-yl)-4-methoxymethyl-6-meth-ylthieno[2,3-b]pyridine with Raney nickel results in 4-aminothieno[2,3-b;4,5-b′]dipyridine or 5-(4-amino-2-pyridyl)pyridine depending on the reaction conditions. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 669–670, March, 2008.     

Synthesis of new condensed thieno[2,3-b]pyridines containing pyrimidine and imidazole rings

Two different convenient methods have been developed for the synthesis of condensed thieno[2,3-b]pyridines. The intramolecular cyclization of 3-amino-2-hydrazinocarbonyl-7,7-dimethyl-7,8-dihydo-5H-pyrano[3,4-e]-thieno[2,3-b]pyridine was carried out to give 7,7-dimethyl-2-oxo-1,2,6,7-tetrahydro-9H-pyrano[3′,4′-e]-imidazo[4″,5″∶2,3]thieno[5,4-b]pyridine, which is the first representative of a new heterocyclic system.     

Synthesis of some fused heterocycles based on thieno[2,3-<Emphasis Type="Italic">b</Emphasis>]pyridine and their antimicrobial activity

The reaction of 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile with ethylenediamine in the presence of a catalytic amount of carbon disulfide afforded 2-(4,5-dihydro-1H-imidazol-2-yl)-4,6-dimethylthieno-[2,3-b]pyridine-3-amine while its reaction with triethyl orthoformate followed by the reaction with hydrazine hydrate gave 4-imino-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-3(4H)-amine. These two derivatives underwent cyclocondensation reactions with commercially available reactants to afford new heterocycles containing the thieno[2,3-b]pyridine moiety. Some of the synthesized derivatives were tested for antimicrobial and antifungal activity.     

Synthesis of Substituted 1,3-Cyclohexadienes,Pyridine-2(1H)-thiones,and Thieno[2,3-d]pyrimidine- 4(3H)-thiones by the Michael Reaction

Cyclopentylidene- and cyclohexylidene(cyano)acetamides reacted with malononitrile and cyano-(thioacetamide) according to the Michael pattern with exchange of the methylene components to give substituted 1-amino-2,6,6-tricyano-1,3-cyclohexadienes and thieno[2,3-d]pyrimidine-4(3H)-thiones. Condensation of cyclopentylidene- and cyclohexylidene(cyano)acetamide with 1,3-dicarbonyl compounds afforded 4,6-di-methyl-3-cyanopyridine-2(1H)-thione and morpholinium 4-methyl-6-oxo-3-cyano-1,6-dihydropyridine-2-thiolate which were converted into substituted 2-alkylsulfanylpyridines, thieno[2,3-b]pyridines, thiazolo[3,2-a]pyridine, and 2H-[1,3]thiazino[3,2-a]pyridine.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

Thieno [2,3 -b] pyridines and thieno [ 3,2 -b] pyridines by the method of gould-jacobs

Bis(2-, and 3-thienylammonium) hexachlorostannates were condensed with ethoxymethylene derivatives of active methylene compounds in pyridine. The resulting condensation products IVa-IVc and Va-Vc on heating under reflux in Dowtherm or diphenyl ether provided various 4-hydroxythieno[2,3-b] pyridines (Ia-Ic) and 7-hydroxythieno[3,2-b]pyridines (IIa-IIc). The compound Ic on further transformations gave yet other derivatives If-Ik.     

Synthesis of 6-amino-4-aryl-5-cyano-3-(3-cyanopyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles and their hydrogenated analogs. Molecular structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole

Substituted 3-hydroxypyrazoles, which were prepared based on ethyl esters of substituted 4-(pyridin-2-ylthio)- or 4-(1,4-dihydropyridin-2-ylthio)acetoacetic acids and hydrazine hydrate, were used in the synthesis of 6-amino-4-aryl-5-cyano-3-(pyridin-2-ylthiomethyl)-2,4-dihydropyrano[2,3-c]pyrazoles. The molecular and crystal structure of 6-amino-5-cyano-3-(3-cyano-4,6-dimethylpyridin-2-ylthiomethyl)-4-(2-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole was established by X-ray diffraction analysis.     

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.     

Pseudo-four-component synthesis and in silico studies of 5-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-substituted 5H-chromeno[2,3-b]pyridines

Multicomponent reactions (MCRs) are important processes, in which more than three different reactants directly get converted into one new structure bearing most of the atoms of these reactants. It is a very powerful tool in drug discovery and combinational chemistry. A new pseudo-four-component synthetic approach to 5-(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-substituted 5H-chromeno[2,3-b]pyridines with 68%–95% yields is reported. This MCR opens an efficient and convenient way to substituted 5H-chromeno[2,3-b]pyridines, which are promising compounds in medicinal chemistry and for the treatment of lung cancer through inhibition of aldo-keto reductase 1B10. A new consensus approach of molecular docking and molecular dynamics was applied for the investigation of interaction of synthesized 5H-chromeno[2,3-b]pyridines and aldo-keto reductase 1B10.     

A Convenient Synthetic Approach to Newly Condensed Pyrazoloazines Based on Pyrazolo[3,4-b]pyridine

The reaction of 6-amino-5-cyano-3-methyl-1H-1-phenylpyrazolo[3,4-b]pyridine ( 2 ) and 6,7-dihydro-3-methyl-6-oxo-1H-1-phenylpyrazolo[3,4-b)]pyridine-5-carbonitrile ( 3 ) and 5-amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]-1H-pyrazolo[4′,3′-e]pyridine ( 12 ) with different reagents have been conducted to give newly condensed pyrazoloazines.