Synthesis of heterocyclic compounds from 4-formylpyrazoles

Formylation of pyrazole and 2,5-dimethylpyrazole gave a number of pyrazole-containing aldehydes, which can be used to obtain chromenes, tetrahydrochromenes, 1,4-dihydropyrano[2,3-c]pyrazoles, pyrano[3,2-c]chromenes, thiochromeno[4,3-b]pyrans, pyrano[3,2-c]-quinolines, and thiazolo[3,2-a]pyridines.     

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).     

New thieno[3,2-b]indole conjugates with 5-(methylene)rhodanine-3-acetic acid in dye-sensitized solar cells

Five new dyes with D–π–A structure bearing 5-(methylene)-rhodanine-3-acetic acid as an acceptor-anchoring part and thieno[3,2-b]indole or benzo[g]thieno[3,2-b]indole as an electron-donating part were synthesized and applied as photosensitizers for dye-sensitized solar cells (DSSCs). In addition, thermal stability, optical and electrochemical properties of these dyes were investigated. The highest PCE value of 1.09% (J_sc = 3.01 mA cm^–2, V_oc = 0.53 V, FF = 0.69) was achieved for DSSC based on benzo[g]thieno[3,2-b]indole dye under AM 1.5G irradiation.     

Cyclization of 2- and 3-indolylthiobenzoic,phenylacetic and nicotinic acids and esters to novel indole-containing tetracyclic ring systems

A series of 2- and 3-indolylthio benzoic, phenylacetic and nicotinic acids or esters were cyclized under dehydrative conditions affording several tetracyclic indole-containing ketones, several of which constitute the first reported examples of novel ring systems, such as the [1]benzothiepino[2,3-b] and [3,2-b]indole and the pyrido[3′2′:5,6] and [3′4′:5,6]thiopyrano[2,3-b] and [3,2-b]indole as well as the [3′2′:5,6] and [3′4′:5,6][1,3]thiazino[3,2-a]indole ring systems.     

Synthesis of 4H-furo[3,2-b]indole derivatives A new heterocyclic ring system

4H-Furo[3,2-b]indole (III) was prepared from deoxygenation of 2-(2-nitrophenyl)furan (II) with triethyl phosphite and thermolysis of 2-(2-azidophenyl)furan (VI). 4H- or 4-alkylfuro [3,2-b]indole-2-carboxaldehydes (VIII, IXa-c) were obtained by Vilsmeier formylation of the corresponding furo[3,2-b]indoles (III, VIIa-c). 4H-Furo[3,2-b]indole-2-carboxaldehyde (VIII) was submitted to the Cannizzaro, Wittig and reduction reactions. The Shiff's bases were obtained by the reaction of 4-ethylfuro[3,2-b]indole-2-carboxaldehyde (IXb) with amines. J. Heterocyclic Chem., 14, 975 (1977)     

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.

     

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.     

Cyclization of 2- and 3-indolythioalkanoic acids to novel indole-containing tricyclic ring systems

A series of 2- and 3-indolylthioalkanoic acids of various chain lengths were cyclized under dehydrative conditions affording tricyclic indole-containing ring systems wherein the third ring contains a sulfur atom attached to the 2- or 3-position of the indole ring. This methodology affords entry into the novel thiepino[3,2-b]indole, thiocino[2,3-b]indole and thiocino[3,2-b]indole ring systems.     

Gold-catalyzed heteroannulation and allyl migration: synthesis of highly functionalized indole derivatives

Highly substituted indole derivatives have been prepared in good to excellent yields by a novel gold-catalyzed cyclization accompanied by [3,3]-migration of the allyl strategy. We have been able to introduce an allyl group at the C1 position of pyrano[3,2-e]indol-6(7H)-one and pyrrolo[3,2-f]quinolin-7(6H)-one moieties that provide a scope for further transformation.     

A synthesis of 5-carboxamidopyrrolo[3,2-b]pyridine

A four-step synthesis of 5-carboxamidopyrrolo[3,2-b]pyridine ( 3 ) from pyrrolo[3,2-b]pyridine ( 4 ) is described (45% overall yield). The one-step conversion of the N-oxide 6 of the pyrrolo[3,2-b]pyridine 5 leads to the 5-cyanopyrrolo[3,2-b]pyridine 7. The cyano group is hydrolyzed to afford the title compound 3 , which is the 4-aza analog of the indole backbone in 5-carboxamidotryptamine, a potent agonist of the neurotransmitter, serotonin.     

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.     

Synthesis of novel pyrano fused quinolones,coumarins, and pyridones

Dedicated to Professor Dr. Hans Junek, Graz, on the occasion of his 70th birthday A novel efficient synthesis of pyrano fused heterocycles namely, pyrano[3,2-c]quinoline-2,5(6H)-diones 3a-e, 7b-d , pyrano[3,2-c]benzopyran-2,5(6H)-dione ( 7f ), and pyrano[3,2-c]pyridine-2,5(6H)-diones 10, 11 was achieved by the condensation of 4-hydroxy-2-(1H)-quinolones 1a-e , 4-hydroxycoumarin ( 1f ), or 4-hydroxy-2(1H)-pyridone ( 9 ) with α-acetyl-γ-butyrolactone ( 2 ) or the sodium salt of α-formyl-γ-butyrol-actone ( 6 ), respectively, in the presence of ammonium acetate.     

The synthesis of thienocycloheptenoindoles

A synthesis of the methylthieno[3,2-c]cyclohepteno[b]indole 7 from 2-methylthieno[3,2-b]cycloheptanone 3 is described. Unsuccessful attempts to prepare the isomeric thienocycloheptenoindole system present in formula 2 , from the dihydrobenzothiophenone 8 , and from derivatives of 5-(2-thienyl)-4-oxopentanoic acid, 17 and 18 , and from N-benzylcycloheptindol-1-one 22 were unsuccessful. The preparation of 4,5-dihydro-2-phenyl-1-thienylmethyl-3H-pyridazin-3-one 20 and of the 5-aminopyrazole 21 are reported.     

Fused pyrimidine systems: XIII. Synthesis and some transformations of 1,3-thiazolo(thiazino)-fused pyrido[3,4-d]pyrimidines

2-[Allyl(propargyl)sulfanyl]pyrido[3,4-d]pyrimidin-4-ones at heating in polyphosphoric acid undergo an intramolecular cyclization with the formation of pyrido[4,3-e]thiazolo-[3,2-a]pyrimidin-5-ones of angular structure. Under similar conditions the cyclization of 2-(cinnamylsulfanyl)pyrido[3,4-d]-pyrimidin-4-one results in a linear pyrido[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazin-6-one. The iodocyclization of the same substrates affords the corresponding 9-(iodomethyl)(iodomethylidene)pyrido[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-5-ones and 3-iodopyrido[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-6-one of angular structure. 9-(Iodomethyl)-8,9-dihydro-5H-pyrido[4,3-e][1,3]thiazolo[3,2-a]pyrimidin-5-one treated with sodium azide gave 9-(azidomethyl) derivative whose cyclization with substituted alkynes in the presence of copper compounds provided pyrido [4,3-e][1,3]thiazolo[3,2-a]pyrimidinylmethyltriazoles.     

2-Benzyliden-2H-thieto[3,2-b]quinoline: a new heterocycle and its rearrangement to 2-phenylthieno[3,2-b]quinoline

Synthesis of the strained 2H-thieto[3,2-b]quinoline ring system is reported for the first time. Treatment of (Z)-2-benzyliden-2H-thieto[3,2-b]quinoline derivatives of this heterocycle with base, at reflux in ethanol, causes a novel rearrangement to 2-phenylthieno[3,2-b]quinolines. Indeed, the one-pot reaction of 2-aminobenzaldehydes and (Z)-2-benzylidenethietan-3-one in refluxing basic ethanol leads directly to 2-phenylthieno[3,2-b]quinolines in good yields.     

Synthesis and Structure of 4-Indolyl-5-(thieno[3,2-<Emphasis Type="Italic">b</Emphasis>]pyrrol-6-yl)imidazoles

A procedure was proposed for regioselective acylation of methyl 2-methyl-4H-thieno[3,2-b]-pyrrole-5-carboxylate with 2-(3-indolyl)-2-oxoacetyl chloride. Reactions of the resulting methyl 6-[2-(3-indolyl)-1,2-dioxoethyl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate with aromatic aldehydes and ammonium acetate in acetic acid afforded the corresponding methyl 6-[2-aryl-4-(3-indolyl)imidazol-5-yl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylates. The structure of methyl 6-[2-(4-chlorophenyl)-4-(3-indolyl)imidazol-5-yl]-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate was studied by X-ray analysis.     

New approach to the functionalization of δ-carboline derivatives

The possibility of transformation of 3-cyano-1-p-nitrophenyl--carbolin-2-one into 2-amino-3-cyano-1-p-nitrophenyl-1H-pyrido[3,2-b]indole derivatives and 2-imino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indole derivatives (-carbolines) is demonstrated. Methylation of 1-p-nitrophenyl-2-piperidino-1H--carboline followed by treatment with acetone in an alkaline medium yields 4-acetonyl-5-methyl-1,4-dihydro-5H-pyrido[3,2-b]indole derivative. The rearrangement of 2-arylimino-3-cyano-1-p-nitrophenyl-5H-pyrido[3,2-b]indoles into 2-(aryl)nitrophenylamino-3-cyano-5H-pyrido[3,2-b]indoles was accomplished on heating above the melting point or on treatment with potassium tert-butoxide. The structures of the resulting compounds were proved by ¹H and ¹³C NMR spectroscopy and X-ray diffraction analysis.     

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.     

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.     

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.