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.     

Synthesis of thiabenzene oxides and azathiabenzene oxides

Fused thiabenzene oxide, 2-methyl-4-methylthiobenzo[b]thieno[3,2-c]thiapyran 2,5,5-trioxide (2) was synthesized by the reaction of 2,3-dihydro-2-bis(methylthio)methylene-3-oxobenzo[b]thiophene 1,1-dioxide (1) with trimethyl sulfoxonium iodide in the presence of sodium hydride in tetahydrofuran. Similarly, fused azathiabenzene oxide, 2-methyl-4-methylthiobenzo[b]thieno[2,3-c][1,2]thiazine 2,5,5-trioxide (3) was prepared from 1 and sulfoximine in good yield.     

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.     

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).     

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 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.

     

Benzo[b]thiophen-3(2H)-one 1,1-dioxide—a versatile reagent in the synthesis of spiroheterocycles

New applications of benzo[b]thiophen-3(2H)-one 1,1-dioxide have been investigated. The synthesis of a new heterocyclic system 3H,2′H-spiro[benzo[b]thieno[3,2-b]pyridine-3,2′-benzo[b]thiophene] is described and a mechanism for the cyclisation is proposed.     

Chemistry of thienopyridines. XIX. Further studies on chlorination and S-oxidation in the thieno[2,3-b] pyridine system

Treatment of thieno [2,3-b] pyridine (1a) with chlorine gas in chloroform (plus water) gave a mixture of two 2,3-dichloro-2,3-dihydrothieno[2,3-b] pyridine 1-oxides [trans-syn (IIa), and cis-anti (IIb)) [and 2,3,3-trichloro-2,3-dihydrothieno[2,3-b]pyridine syn-1-oxide (IVa), as well as a non-isolated fourth product (prohably the anti isomer of IVa) and sometimes a small amount of thieno[2,3-b]pyridine 1,1-dioxide (III). Treatment of Ia in a solvent (water, chloroform-water, or THF-water) with sulfuric acid and sodium hypochlorite gave a mixture of IIb and III. Effects of variations of reaction conditions on the composition of the product mixture were ascertained through chemical isolation and/or pmr analysis. Products formed were rationalized in terms of the chlorine-water-hypochlorous acid equilibrium, plus attack of chlorine variously at positions 1 (S-atom), 2, and 3 of 1a, but of hypochlorous acid only at position 1. Thermal and chromatographic limitations on isolation procedures for some of the products were established. Stereochemistries of IIa, IIb, and IVa were assigned by means of pmr spectrometry with the aid of the shift reagent Eu(fod)₃. Spin-spin couplings between the proton at position 2 and those at positions 4 and 6 were observed at high resolution. In exploratory runs, 5-ethyl-la was converted into isolable 2,3-dichloro-5-ethyl-2,3-dihydrothieno[2,3-b]pyridine 1-oxide, and 5-acetyl-Ia yielded 3-chloro-5-acetylthieno] 2,3-b]pyridine. Mass spectral fragmentation patterns for the various products are presented.     

Chemistry of thienopyridines. XXXV. Synthesis,tautomerism, and reactions of quinoline and thienopyridine systems which bear a 1-carboethoxy-1-cyanomethyl substituent in the pyridine ring,part 2

A comparison is made amongst the isosteric Systems quinoline, thieno[2,3,-b]pyridine, and thieno[3,2-b]-pyridine which bear the 1-carboethoxy-1-cyanomethyl substituent (R) alpha or gamma to the heterocyclic nitrogen atom. Treatment of thieno[3,2-b]pyridine 4-oxide with ethyl cyanoacetate and acetic anhydride at room temperature (Hamana reaction) gives the alpha R-derivative 6 (27%), formulated as an intramolecular H-bonded structure. Neither 6 nor its quinoline alpha analog reacts with refluxing acetic anhydride, while the quinoline gamma isomer 8 , existing as NH and CH tautomers, yields an N-acetyl derivative 10 (70%) under similar conditions. For each of 6 and 8 one can isolate two crystalline forms which differ considerably in color. Compound 10 and its gamma analog in the thieno[2,3-6]pyridine series (previously obtained directly from a Hamana reaction) serve as acetylating agents for aniline, 1-aminobutane, morpholine, and cholesterol. Correlations and contrasts in the three Systems are presented.     

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 of 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine

4-Methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 3 ) was synthetized from 2-acetylfuro[3,2-f]benzo[b]furan ( 4 ) or from 2-acetyl-5,6-dihydrofuro[3,2-f]benzo[b]furan ( 10 ). The key step involves a rearrangement-cyclization of azides 6 and 12 to form 4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridin-1(2H) one ( 7 ) and 8,9-dihydro-4-methylfuro[3′,2′:5,6]benzofuro[3,2c]pyridin-1(2H)-one ( 13 ). Introduction of an aminoalkyl chain on carbon 1 was effected by substitution of 1-chloro-4-methylfuro[3′,2′:5,6]benzofuro[3,2-c]pyridine ( 8 ).     

Furopyridines. XVII . Cyanation,chlorination and nitration of furo[3,2-b]pyridine N-oxide

The N-oxide 2 of furo[3,2-b]pyridine ( 1 ) was cyanated by the Reissert-Henze reaction with potassium cyanide and benzoyl chloride to give 5-cyano derivative 3 , which was converted to the carboxamide 4 , carboxylic acid 5 , ethyl ester 6 and ethyl imidate 8 . Chlorination of 2 with phosphorus oxychloride yielded 2-9a , 3- 9b , 5- 9c and 7-chloro derivative 9d . Reaction of 9d with sodium methoxide, pyrrolidine, N,N-dimethylformamide and ethyl cyanoacetate afforded 7-methoxy- 10 , 7-(1-pyrrolidyl)- 11 and 7-dimethylaminofuro[3,2-b]pyridine ( 14 ) and 7-(1-cyano-1-ethoxy-carbonyl)methylene-4,7-dihydrofuro[3,2-b]pyridine ( 12 ). Nitration of 2 with a mixture of fuming nitric acid and sulfuric acid gave 2-nitrofuro[3,2-b]pyridine N-oxide ( 15 ).     

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.     

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.     

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.     

Furopyridines. III. A new synthesis of furo[3,2-b]pyridine

A convenient synthesis of furo[3,2-b]pyridine and its 2- and 3-methyl derivatives from ethyl 3-hydroxypiconate ( 1 ) is described. The hydroxy ester 1 was O-alkylated with ethyl bromoacetate or ethyl 2-bromopropionate to give the diester 2a or 2b . Cyclization of compound 2a afforded ethyl 3-hydroxyfuro[3,2-b]pyridine-2-carboxylate ( 3 ) which in turn was hydrolyzed and decarboxylated to give furo[3,2-b]pyridin-3-(2H)-one ( 4a ). Cyclization of 2b gave the 2-methyl derivative 4b . Reduction of 4a and 4b with sodium borohydride yielded the corresponding hydroxy derivative 5a and 5b respectively, which were dehydrated with phosphoric acid to give furo[3,2-b]pyridine ( 6a ) and its 2-methyl derivative ( 6b ). 2-Acetylpyridin-3-ol ( 8 ) was converted to the ethoxycarbonylmethyl ether ( 9 ) by O-alkylation with ethyl bromoacetate, which was cyclized to give 3-methylfuro[3,2-b]pyridine-2-carboxylic acid ( 10 ). Decarboxylation of 10 afforded 3-methylfuro[3,2-b]pyridine ( 11 ).     

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.     

Synthesis and identification of new thieno[3,2-b] benzothiophenes

The reaction of 2-lithiobenzo[b]thiophenes with ketones produced 2-hydroxyalkylbenzo[b]thiophenes which were cyclized in thionyl chloride to give novel thieno[3,2-b][1]benzothiophenes. Oxidation with peroxyacetic acid gave the S,S-dioxides whose regiochemistry was identified from ¹H nmr model studies using substituted benzo[b]thiophenes and their corresponding-1,1-dioxides [1].     

Synthesis of new hetero[1,2,4]thiadiazin‐3‐one S,S‐dioxides and oxazolo[3,2‐b]hetero[1,2,4]thiadiazine S,S‐dioxides as potential psychotropic drugs

A series of 2‐substituted 2H‐thieno[3,4‐e][1,2,4]thiadiazin‐3(4H)‐one 1,1‐dioxides ( 2 ), 2‐substituted 2H‐thieno[2,3‐e][1,2,4]thiadiazin‐3(4H)‐one 1,1‐dioxides ( 3 ), 2‐substituted 4,6‐dihydropyrazolo[4,3‐e]‐[1,2,4]thiadiazin‐3(2H)‐one 1,1‐dioxides ( 4 ), 2‐substituted 2,3‐dihydrooxazolo[3,2‐b]thieno[3,4‐e]‐[1,2,4]thiadiazine 5,5‐dioxides, ( 5 ), 6‐substituted 6,7‐dihydro‐2H‐oxazolo[3,2‐b]pyrazolo[4,3‐e][1,2,4]thia‐diazine 9,9‐dioxides ( 6 ) and 7‐substituted 6,7‐dihydro‐2H‐oxazolo[3,2‐b]pyrazolo[4,3‐e][1,2,4]thiadiazine 9,9‐dioxides ( 7 ) were synthesized as potential psychotropic agents.     

Reactions of 2-benzylidene-3-methyl-4-nitro-2,5-dihydrothiophene 1,1-dioxide with CH acids

2-Benzylidene-3-methyl-4-nitro-2,5-dihydrothiophene 1,1-dioxide reacted with acyclic CH acids (acetylacetone, diethyl malonate, and its derivatives) according to the 1,4-addition pattern, whereas reactions of the title compound with cyclohexane-1,3-dione and 5,5-dimethylcyclohexane-1,3-dione (dimedone) were complicated by subsequent intramolecular heterocyclization leading to thieno[3,2-b]chromene derivatives.