Chemistry of thienopyridines. XXXII. Direct introduction of C-substituents gamma to the heteronitrogen atom in the thieno[2,3-b]pyridine system

Treatment of the N-oxide 1a of thieno[2,3-b]pyridine ( 1 ) with either (a) acetic anhydride and ethyl cyanoacetate or (b) benzoyl chloride and an enamine of cyclohexanone (Hamana reactions) serves to introduce a C-substituent at the 4-position of 1 . In case (a) one obtains a yellow, isolable vinylogous N-ylide 5 (23% yield), which undergoes facile transformation into ethyl 2-(4-thieno[2,3-b]pyridyl)cyanoacetate ( 1e ) (88–93 %). Acetic anhydride reconverts 1e to 5 (95%). Case (b) produces 2-(4-thieno[2,3-b]pyridyl)cyclohexanone (39%), hydrolyzable to 6-(4-thieno[2,3-b]pyridyl)hexanoic acid (45%). The hydrochloride of 1a is also reported. Structural formulations are based on spectral studies (including ¹³C nmr data for 1 and 1e ) and chemical transformations. Major contrasts (plus some similarities) between the systems 1 and quinoline in the Hamana reactions are discussed.     

Chemistry of thienopyridines. XII. Selective formation of N-oxides,sulfoxides, and sulfones in some tricyclic systems

Direct conversion of [1]benzothieno[3,2-b]pyridine (IVa), thieno[3,2-b:4,5-b']dipyridine (Va), and thieno[2,3-b:4,5-b']dipyridine (VIa) into their sulfoxides was effected by means of an equimolar quantity of iodobenzene dichloride in aqueous acetonitrile. Treatment of IVa-VIa with excess chlorine gas in carbon tetrachloride and then with water gave the corresponding sulfones, IVc-VIc. Hydrogen peroxide in glacial acetic acid converted Va and VIa into di-N-oxides, thieno[3,2-b]pyridine into its N-oxide, and sulfone VIc into an N-oxide sulfone (X). Spectral and chemical means of distinguishing amongst the oxide functions are noted, and rationalizations for selectivity in the oxidations are discussed.     

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.     

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.     

Chemistry of benzo[b]furan. V.. Synthesis of substituted thia-analogs and oxa-analogs of dihydrorutecarpine and evodiamine

Cycloaddition of 3,4-dihydrobenzo[b]thieno[2,3-c]pyridine ( 6 ) with the sulfinamide anhydride 9 (R = H) afforded the thia-analog of dihydrorutecarpine ( 2a ). Condensation of the imine 6 with the sulfinamide anhydride 9 (R = CH₃) gave the thia-analog of evodiamine ( 2b ). Starting from 1-methyl-3,4-dihydrobenzo[b]thieno[2,3-c]pyridine ( 12 ) and 1-methyl-3,4-dihydrobenzo[b]furo[2,3-c]pyridine ( 14 ), a series of 3-methyl derivatives of thia-analogs of dihydrorutecarpine and evodiamine ( 2c-2i ) and oxa-analogs of dihydrorutecarpine and evodiamine ( 1a-1g ) were similarly prepared.     

Chemistry of thienopyridines. XXXVI. Further studies on nitration in the thieno[2,3-b]- and thieno[3,2-b]pyridine systems

Three compounds, thieno[3,2-b]pyridine 4-oxide, 7-nitrothieno[3,2-b]pyridine 4-oxide ( 1 c), and 6-cyano-thieno[2,3-b]pyridine, undergo nitration by means of a mixture of nitric and sulfuric acids to yield 3,7-dinitro-thieno[3,2-b]pyridine (3%), 3,7-dinitrothieno[3,2-b]pyridine 4-oxide ( 1d ) (26%), and 6-carbamoyl-5-nitrothieno[2,3-b]pyridine ( 6b ) (11%), respectively. Structures of the products were ascertained by spectral means, notably infrared, ¹H nmr, and ¹³C nmr. It is proposed that 1d exists (at least in part) as a tricyclic structure and that 6b may result from an intramolecular mechanism of nitration. An attempt to de-N-oxygenate 1c with excess triphenylphosphine removes more than one oxygen atom per molecule (as triphenylphosphine oxide) without producing an identified thienopyridine product.     

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.     

Chemistry of thienopyridines. XXXIII. Synthetic routes to 5- and 7-substituted thieno[3,2-b]pyridines from the N-oxide

Thieno[3,2-b]pyridine ( 1 ) is oxidized to N-oxide 1a by means of m-chloroperoxybenzoic acid (83%). Compound 1a forms adducts with hydrogen chloride and picric acid and gives ring substitution alpha or gamma to the heteronitrogen atom. Thus, 1a plus nitric and sulfuric acids produces the 7-nitro-N-oxide 1m (63%), or plus phosphorus oxychloride gives a mixture of 5-chloro and 7-chloro ( 1j ) derivatives of 1 . Compound 1m is convertible into a variety of other derivatives of 1 , viz. 7-chloro-N-oxide, 1j , 7-bromo-N-oxide, 7-nitro and 7-amino. 5-Cyano- 1 , formed from 1a , is, in turn, transformed into a methyl imidate (93%), cyclic amidines, and a 5-tetrazolyl- 1 (91%). These results confirm the prediction that 1a , thieno[2,3-b]pyridine-4-oxide and quinoline 1-oxide should exhibit closely similar (i.e. analogous) chemical reactions.     

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.     

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.     

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).     

Furopyridines. XIX. Reaction of furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine with acetic anhydride

Acetoxylation of N-oxide of furo[2,3-b]- 2a , -[3,2-b]- 2b , -[2,3-c]- 2c and -[3,2-c]pyridine 2d with acetic anhydride afforded compounds substituted normally at the α- or γ-position to the ring nitrogen, 3a, 4a, 4b, 3d, 4d, 8 and 9 , and in addition compounds substituted on the furan ring, 5a, 6a, 5b, 6b, 7b, 5c and 7c which were unexpected compounds. The structures of these compounds were established from the ir, nmr and mass spectra, and x-ray crystal analysis of 5b .     

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.     

Chemistry of thienopyridines. VIII. Substitution products derived from thieno[2,3-b] pyridine 7-oxide

Thieno[2,3-b]pyridine (I) was concerted to the N-oxide (II, 53%) by means of hydrogen peroxide and acetic acid. Nitration of II in sulfuric acid gave 4-nitrothieno[2,3-b]pyridine 7-oxide (III, 50%), while nitration in acetic acid formed the isomeric 5-nitrothieno[2,3-b]pyridine 7-oxide (IV, 54%). Compounds III and IV were reduced to the corresponding 4- and 5-aminothieno[2,3-b]pyridines, respectively. Treatment of III with acetyl chloride gave 4-chlorothieno-[2,3-b]pyridine 7-oxide (XI, 81%), convertible in two steps to 4-(N-substituted amino)thieno-[2,3-b]pyridines (especially of the 4-dialkylaminoalkylamino type) for screening as potential antimalarial drugs. 4-Aminothieno[2,3-b]pyridine reacted with aromatic aldehydes to give Schiff's bases and other products. Mechanisms for some of the reactions are suggested. NMR spectral data are reported for various 4-substituted thieno[2,3-b]pyridine compounds.     

Intramolecular cyclization of amido acids into pyrrolidinothieno(or [1]benzothieno)[3]azepinediones

The synthesis of pyrrolidino[2,1-b]thieno[3,2(2,3)-f][3]azepinediones 7a,b and pyrrolidino[2,1-b]-[1]benzothieno[3,2(2,3)-f][3]azepinediones 7c,d are described starting from thiophenes or [1]benzothio-phenes acetic acids. Their selective reduction using triethylsilane led to the corresponding azepinones 17a-d.     

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.     

Heteroaromatic boron compounds. XV. Deuteriodeprotonation in some borazarothienopyridines and thienopyridines

Deuteriodeprotonation of some substituted 4,5-borazarothieno[2,3-c]pyridines (I) and 7,6-borazarothieno[3,2-c]pyridines (II) has been studied by the nmr technique. Exchange occurred predominantly in the 3-position, and the effect of methyl substitution on rate is discussed. The rates of exchange in some derivatives of I and II were compared with those of the isoelectronic thieno[2,3-c]pyridines (III) and thieno[3,2-c]pyridines (IV). Similar rates were obtained, confirming the aromatic nature of I and II. The deuteriodeprotonation of 4-methyl-4,5-borazaro-thieno[2,3-c]pyridine (Ie), 7-methyl-7,6-borazarothieno[3,2-c]pyridine (IIe), 4-methylthieno-[2,3-c]pyridine (IIIe), and 7-methylthieno[3,2-c]pyridine (IVe) were measured at different concentrations of deuteriosulfuric acid and different temperatures, showing that the protonated heterocycles are substrates in the deuteriodeprotonation reaction. Standard rates at p0 H and 100° were calculated for these systems.     

Angular polycyclic thiophenes containing two thiophene rings. I

We describe the synthesis of thieno[2,3-c]dibenzothiophene ( 6 ), thieno[3,2-c]dibenzothiophene ( 10 ), thieno-[3,2-a]dibenzothiophene ( 14 ), thieno[2,3-a]dibenzothiophene ( 16 ), benzo[1,2-b:4,3-b]bisbenzo[b]thiophene ( 18 ), benzo[1,2--6:3,4-b]bisbenzo[b]thiophene ( 20 ), benzo[2,1--6:3,4-b]bisbenzo[b]thiophene ( 22 ), benzo[1,2-b:3,4-g]bisbenzo[b]thiophene ( 27 ), benzo[1,2-b:4,3-e]bisbenzo[b]thiophene ( 29 ), benzo[2,1--6:3,4-g]bisbenzo[b]thiophene ( 36 ), benzo[2,1--6:4,3-e]bisbenzo[b]thiophene ( 38 ), benzo[1,2--6:4,3-g]bisbenzo[b]thiophene ( 41 ), benzo[1,2-b:4,5-g]bisbenzo[b]thiophene ( 42 ), benzo[1,2-b:3,4-e]bisbenzo[b]thiophene ( 44 ) and benzo-[1,2-b:5,4-e]bisbenzo[b]thiophene ( 45 ).     

Utility of Pyridine‐2(1H)‐thiones in the Synthesis of Novel Bis‐Thieno[2,3‐b]pyridines and Their Fused Azines

The starting materials pyridine‐2(1H)‐thiones are prepared and reacted with halogen‐containing reagents in ethanolic sodium acetate solution to give the corresponding 2‐S‐alkylpyridines, which cyclized upon their boiling in methanolic sodium methoxide solution at reflux to give the corresponding thieno[2,3‐b]pyridines in excellent yields. Bis (thieno[2,3‐b]pyridine‐2‐carboxamides), incorporating 2,6‐dibromophenoxy moiety, are prepared by the bis‐O‐alkylation of thieno[2,3‐b]pyridine‐2‐carboxamide derivatives. Two synthetic routes are designed to prepare the target molecules pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4(3H)‐ones, pyrido[3′,2′:4,5]thieno[3,2‐d][1,2,3]triazin‐4(3H)‐ones, and their bis‐analogues using thieno[2,3‐b]pyridine‐2‐carboxamides and their bis‐analogues. The structure of the target molecules is elucidated using elemental analyses as well as spectral data.     

Synthesis of some pyrimido[4′,5′:4,5]thieno[2,3-b]quinolines and related heterocycles

Several thieno[2,3-b]quinolines 6a-i have been synthesized. These compounds were used as key intermediates in the synthesis of oxazino[4′,5′:4,5]thieno[2,3-b]quinoline 8 , pyrimido[4′,5′:4,5]-thieno[2,3-b]quinolines 9–12 , triazino[4′,5′:4,5]thieno[2,3-b] quinolines 14 and imidazo[4′,5′:4,5]-thieno[2,3-b]quinolines 17 .