Preparation of new nitrogen-bridged heterocycles. 53. Syntheses of 3-(benzylthio)thieno[3,4-b]indolizine derivatives and their intramolecular arene-arene interactions

Various ethyl 1-arylcarbonyl-3-[(un)substituted methylthio]thieno[3,4-b]indolizine-9-carboxylates were synthesized in good yields by a novel methodology in which the S-alkylation of 5-arylcarbonyl-4-ethoxycarbonylmethyl-3-(1-pyridinio)thiophene-2-thiolates with alkyl or benzyl halides, the 1,5-dipolar cyclization of the resulting pyridinium salts in the presence of a base, and the aromatization were performed. In the X-ray analyses of some 3-(benzylthio)thieno[3,4-b]indolizine-9-carboxylates, a gauche and two anti conformers in relation to the exocyclic sulfide linkage were found. Interestingly, all of the 3-(benzylthio)thieno[3,4-b]indolizine derivatives showed significant high-field shifts (delta up to 0.3 ppm) for the 5- and 6-proton signals compared with those of the 3-methylthio derivatives in the (1)H-NMR spectra and exhibited a definite absorption band near 425 nm in their UV spectra, indicating an intramolecular arene-arene interaction between the thieno[3,4-b]indolizine and the phenyl ring.     

Preparation of new nitrogen-bridged heterocycles. 49. A new access to thieno[3,4-b]indolizine derivatives

The title compounds, together with 3-vinylindolizine-1-carbonitriles (4-56%), were prepared in 1-18% yields from the S-alkylation of pyridinium 1-[3-ethoxycarbonyl-1-[cyanomethylthio(thiocarbonyl)]]all ylides with alkyl halides, followed by treatment of the resulting pyridinium salts with a base and then a dehydrogenating agent. In several reactions of pyridinium salts obtained from reaction of the allylides with benzylic halides, trace amounts of bis[1-cyano-9-(ethoxycarbonyl)thieno[3,4-b]indolizin-3-yl] disulfides with an interesting superimposed structure were also isolated. The structures of these compounds were confirmed by X-ray analyses.     

Preparation of new nitrogen-bridged heterocycles. 58. Syntheses and intramolecular arene-pi interactions of 3-(allylthio)- and 3-(propargylthio)thieno[3,4-b]indolizine derivatives

Various thieno indolizine derivatives having an allylthio or propargylthio group at the 3-position were prepared and their intramolecular arene-pi interactions were investigated. Their 1H-NMR spectra showed significant low-field shifts (delta 0.10-0.34 ppm) to the 5-proton on the thieno indolizine ring, and this effect was the reverse to that observed in 3-(arylmethylthio)thieno indolizines. However, their UV spectra exhibited a characteristic absorption band due to the arene-pi interaction near 430 nm and these values were almost similar to those for arene-arene interaction of 3-arylmethylthio derivatives though their molar extinction coefficients were largely varied by the 3-substituents. Furthermore, both types of gauche conformations in which the intramolecular arene-pi interactions are possible in one form and impossible in the other were confirmed by X-ray analyses of some compounds.     

Preparation of new nitrogen-bridged heterocycles. 59. Syntheses and intramolecular interactions of 3-(acylmethylthio)- and 3-[(3-ethoxycarbonyl-2-propenyl)thio]thieno[3,4-b]indolizine derivatives

Various thieno[3,4-b]indolizine derivatives having an acylmethylthio or (3-ethoxycarbonyl-2-propenyl)thio group at the 3-position which could not be obtained by a conventional method were prepared by a new procedure using cyanoethyl group as a protecting group and their intramolecular arene-pi interactions were investigated. In the (1)H-NMR spectra of these thieno[3,4-b]indolizines, the low-field shifts (delta 0.10-0.33 ppm) for the 5-protons were observed in comparison with those of 3-(methylthio)thieno[3,4-b]indolizines as a standard. The UV spectra also exhibited a characteristic absorption band at 425-445 nm attributable to the arene-pi interaction but their intensities were generally lower than those of 3-(arylmethylthio)thieno[3,4-b]indolizines. In their X-ray analyses, the anti conformation for 3-(acylmethylthio)thieno[3,4-b]indolizines and the gauche one for the 3-(3-ethoxycarbonyl-2-propenyl)thio derivatives were exhibited.     

Selenium heterocycles. XXXIII. Synthesis of thieno[3,4-b]furan,seleno[3,4-b]furan,thieno[3,4-b]indole and seleno[3,4-b]indole. four novel heterocycles

Starting from the readily available 2-methyl-3-benzoylfuran, 1-phenylthieno[3,4-b]furan and 1-phenyl-seleno[3,4-b]furan were prepared. Also, starting from phenyl 3-methylindol-2-yl ketone and aryl 2-methyl-indole-3-yl ketones a series of substituted thieno[3,4-b]indoles and substituted seleno[3,4-b]indoles were prepared.     

Synthesis of new heterocycles. 3,4-dihydropyrano[2,3,4-hi]indolizine and derivatives

Interaction of the lithium derivative of 2,3-dihydro-4H-pyrano[3,2-b]pyridine with the diethyl acetal of bromoacetaldehyde, followed by hydrolysis and subsequent ring closure afforded the novel heterocycle 3,4-dihydropyrano[2,3,4-hi]indolizine which was inacessible by the Tschitschibabin method. However, the 2-phenyl derivative was easily prepared by the Tschitschibabin method.     

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.     

Preparation of new nitrogen-bridged heterocycles 72. A new approach to 1-acyl-3-(substituted methylthio)thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives. [corrected

The alkaline treatment of the pyridinium salts, readily available from the S-alkylations of 3-amino-4-(1-pyridinio)thiophene-5-thiolates with various alkyl halides, in chloroform at room temperature afforded the corresponding thieno[3',4':4,5]imidazo[1,2-a]pyridine derivatives in low to moderate yields via the intramolecular cyclization of the resulting 1,5-dipoles followed by the aromatization of the primary cycloadducts. Interestingly, the reactions using unsymmetrical 3-amino-4-[1-(3-methylpyridinio)]thiophene-5-thiolates afforded only 8-methylthieno[3',4':4,5]imidazo[1,2-a]pyridines and the other 6-methyl derivatives were not formed at all. In addition the isolation of a byproduct in the condensation reaction of pyridinium salt with the solvent (CHCl?) is also discussed.     

Chemistry of thienopyridines. XV. Syntheses of thieno [3,4-b] - and thieno[3,4-c] pyridines

Thieno [3,4-b] pyridine (5) was synthesized by means of the successive steps of (a) photochlorination of 2,3-dimethylpyridine to the bis(chloromethyl) compound, (b) condensation with sodium sulfide, (c) oxidation to the sulfoxide, and (d) catalytic dehydration by means of alumina. Thieno[3,4-c]pyridine (6) was obtained in an analogous manner. Spectral properties indicate that 5 and 6 have aromatic character.     

Fluorine-containing heterocycles: Part III. Synthesis of some new furo[2,3-b]-, pyrazolo[3,4-b]- and thieno[2,3-b]pyridines with anticipated biological activities

3-Cyano-6-(2-thienyl)-4-trifluoromethylpyridine-2(1H)-one (1) and its thiono analog 2 were prepared by the reaction of (2-thenoyl)-ω,ω,ω-trifluoroacetone with cyanoacetamide or cyanothioacetamide, respectively. Interaction of compound 1 with ethyl chloroacetate or chloroacetamide led to the regioselective formation of O-alkylated pyridines 3 and 10. The latter compounds underwent some successive reactions to furnish the promising furopyridines (4 and 7–9) and pyrazolopyridines (12–15). The reaction of 2 with chloroacetamides or chloroacetonitrile furnished 2-functionalized 3-amino-6-(2-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridines (16a, b) which were used as key intermediates in the synthesis of the title thienopyridines. Structures of the newly synthesized compounds were established on the basis of their elemental and spectral (IR, ¹H NMR and mass) analyses.     

Preparation of new nitrogen-bridged heterocycles. 55. Reinvestigation of the bromination/dehydrobromination of ethyl 3-[2-(methylthio)indolizin-3-yl]acrylate derivatives

The bromination/dehydrobromination reactions of ethyl 3-[1-alkoxycarbonyl-2-(methylthio)indolizin-3-yl]acrylates were reinvestigated. Reactions of the title compounds with two equivalents of bromine, followed by heating of the resulting reaction mixture and then treatment with a base gave the unexpected dialkyl 7-bromothieno[2,3-b]indolizine-2,9-dicarboxylates, while similar reactions using benzyltrimethylammonium tribromide as a brominating agent afforded only non-brominated thieno[2,3-b]indolizine derivatives, which were converted to the corresponding 7-bromo derivatives upon further treatment with bromine.     

1H-pyrazolo[3,4-d]thieno[2,3-b]pyridine and its derivatives

The synthesis of the parent ring system and some of the derivatives of 1H-pyrazolo[3,4-d]thieno[2,3-b]pyridine are described.     

Selenium heterocycles XXVI. Synthesis of theino[3,4-b]benzofuran and selenolo[3,4-b] benzofuran. Two novel heterocycles

Starting from the readily available aryl 3-methyl-2-benzo[b] furyl ketones a series of 3-sub-stituted thieno[3,4-b] benzofurans and 3-substituted selenolo[3,4-b] benzofurans were prepared in high yield. The parent compound, thieno[3,4-b] benzofuran was prepared through the reaction of thioacetamide with 2-chloromethyl-3-formylbenzo[b] furan in moderate yield.     

Potential antitumor agents. III. Synthesis of pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine and 1H-pyrazolo[3,4-e]indolizine derivatives

The preparation of 5-dimethylaminoethyl-4,6-dioxo-1-phenyl-1,4,5,6-tetrahydropyrazolo[3,4-e]pyrrolo-[3,4-g]indolizine, a derivative of the still unknown tetracyclic parent ring pyrazolo[3,4-e]pyrrolo[3,4-g]indolizine, is reported starting from 1-phenyl-5-(1-pyrryl)pyrazole-4-acetonitrile by PPA catalyzed double cyclization of the related oxalylcyanomethyl derivative and subsequent alkylation. The synthesis of 4,5-bis(isopro-pylaminocarbonyloxymethyl) and 4,5-bis-(cyclohexylaminocarbonyloxymethyl) derivatives of 1-phenyl-1H-pyrazolo[3,4-e]indolizine is also described. The new tricyclic and tetracyclic derivatives were tested as potential antitumor agents.     

Preparation of new nitrogen-bridged heterocycles. 56. Syntheses and reactions of 1-[2,2-bis(alkylthio)-1-(ethoxycarbonylacetyl)vinyl]pyridinium salts

The title compounds, readily available from the S-alkylation of pyridinium 1-[alkylthio(thiocarbonyl)](ethoxycarbonylacetyl)methylides with alkyl halides or alkyl bromoacetates, were treated with a base and then a dehydrogenating agent to provide some unique products such as 3-[bis(alkylthio)methylene]-2(3H)-indolizinones and dialkyl 7-methyl-4-oxo-1,4,8,8a-tetrahydro-1,4-thiazino[3,4,5-cd]indolizine-1,5-dicarboxylates. On the other hand, similar reaction of these pyridinium salts in the absence of the dehydrogenating agent afforded alkyl 2-hydroxyindlizine-3-carboxythiolates, whose yields were increased by adding trifluoroacetic acid to the reaction mixture. The structures of some products were confirmed by the X-ray analyses.     

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).     

Mass spectra of isomeric thieno [2,3-b]- and thieno[3,2-b]pyridines

The mass spectra of six isomeric thieno- and thionaphthenopyridines were studied for the first time, and the pathways of fragmentation of the molecular ions, which made it possible to isolate the peaks of the fragment ions that characterize the destruction of the pyridine and thiophene rings, were traced. It is shown that the character and type of conjugation of the heterorings can be distinguished by analyzing the mass-spectral data. The relationship between the intensity of the peak of the doubly charged molecular ion and the number of electrons in the system and the -donor character of the heteroring was illustrated by means of the literature data on the mass spectrometry of heteroaromatic systems with one heteroatom.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 758–761, June, 1982.