One-pot synthesis of functionalized benzo[b]thiophenes and their hetero-fused analogues via intramolecular copper-catalyzed S-arylation of in situ generated enethiolates.

An efficient one-pot synthesis of highly functionalized multisubstituted benzo[b]thiophenes and their hetero-fused analogues, such as thieno[2,3-b]thiophenes, indolo[2,3-b]thiophenes, and pyrazolo[3,2-c]thiophenes, has been reported. The overall strategy involves sequential base-mediated condensation of 2-bromohet(aryl)acetonitrile precursors with (het)aryl/alkyl dithioesters or other thiocarbonyl species such as dimethyl trithiocarbonate, S-methyl xanthates, methyl N-imidazolyl dithioate, N-alkyl dithiocarbamate, and phenyl isothiocyanate, followed by intramolecular copper-catalyzed arylthiolation of in situ generated enethiolates, furnishing a broad range of 2-functionalized 3-cyanobenzo[b]- and/hetero-fused thiophenes in high yields.

Sequential One-Pot Synthesis of Tri- and Tetrasubstituted Thiophenes and Fluorescent Push-Pull Thiophene Acrylates Involving (Het)aryl Dithioesters as Thiocarbonyl Precursors.

An efficient, one-pot three component synthesis of highly functionalized tri- and tetrasubstituted thiophenes has been reported involving (het)aryl dithioesters as thiocarbonyl precursors. Thus, sequential base mediated condensation of readily available (het)aryl active methylene ketones with (het)aryl dithioesters followed by S-alkylation of the resulting enethiolate salts with activated halomethylene compounds and concurrent intramolecular aldol-type condensation of S-alkylated compounds affords substituted thiophenes in excellent yields. The methodology has also been extended for the synthesis of highly fluorescent push-pull substituted thiophene-5-acrylates by using bromocrotonate as the activated methylene alkylating agent.

Synthesis of N-functionalized/NH-multisubstituted indoles, thienopyrroles, pyrroloindoles, and pyrazolopyrroles via sequential one-pot base-mediated and copper-catalyzed inter- and intramolecular amination of 2-[2-bromo(het)aryl]-3-(het)aryl-3-(methylthio)acrylonitriles.

A novel, efficient route to substituted 1-N-(het)aryl/NH-2-(het)aryl-3-cyanoindoles and related pyrrolo-fused heterocycles such as thienopyrroles, pyrroloindoles, and pyrazolopyrroles has been reported. The overall protocol involves sequential cycloamination of readily available 2-[2-bromo(het)aryl]-3-(het)aryl-3-(methylthio)acrylonitrile precursors with primary amines or amides via two key C-N bond-forming processes, one base-mediated intermolecular and the other Cu-catalyzed intramolecular arylamination leading to N(1)-C(2) and N(1)-C(7a) bond formation, respectively, in a two-step one-pot procedure.

Cyclocondensation of arylhydrazines with 1,3-bis(het)arylmonothio-1,3-diketones and 1,3-bis(het)aryl-3-(methylthio)-2-propenones: synthesis of 1-aryl-3,5-bis(het)arylpyrazoles with complementary regioselectivity.

Two efficient highly regioselective routes for the synthesis of unsymmetrically substituted 1-aryl-3,5-bis(het)arylpyrazoles with complementary regioselectivity starting from active methylene ketones have been reported. In the first protocol, the newly synthesized 1,3-bis(het)aryl-monothio-1,3-diketone precursors (prepared by condensation of active methylene ketones with het(aryl) dithioesters in the presence of sodium hydride) were reacted with arylhydrazines in refluxing ethanol under neutral conditions, furnishing 1-aryl-3,5-bis(het)arylpyrazoles 7, in which the het(aryl) moiety attached to the thiocarbonyl group of monothio-1,3-diketones is installed at the 3-position. In the second method, the corresponding 3-(methylthio)-1,3-bis(het)aryl-2-propenones (prepared in situ by base-induced alkylation of 1,3-monothiodiketones) were condensed with arylhydrazines in the presence of potassium tert-butoxide in refluxing tert-butyl alcohol, yielding 1-aryl-3,5-bis(het)arylpyrazoles 9 with complementary regioselectivity (method A). The efficiency of this protocol was further improved by developing a one-pot, three-component procedure for the synthesis of pyrazoles 9, directly from active methylene ketones, by reacting in situ generated 3-(methylthio)-1,3-bis(het)aryl-2-propenones with arylhydrazines in the presence of sodium hydride (instead of potassium tert-butoxide as base). The structures and regiochemistry of newly synthesized pyrazoles were confirmed from their spectral and analytical data along with X-ray crystallographic data of three pairs of regioisomers.

Synthesis of 2-phenyl-4,5-substituted oxazoles by copper-catalyzed intramolecular cyclization of functionalized enamides.

An efficient two-step synthesis of 2-phenyl-4,5-substituted oxazoles involving intramolecular copper-catalyzed cyclization of highly functionalized novel ß-(methylthio)enamides as the key step has been reported. These enamides are obtained by nucleophilic ring-opening of newly synthesized 4-[(methylthio)hetero(aryl)methylene]-2-phenyl-5-oxazolone precursors by alkoxides, amines, amino acid esters and aryl/alkyl Grignard reagents, thus leading to the introduction of an ester, N-substituted carboxamide or acyl functionalities at 4-position of the product oxazoles. Synthesis of two naturally occurring 2,5-diaryloxazoles, i.e., texamine and uguenenazole, via two-step hydrolysis-decarboxylation of the corresponding 2,5-diaryloxazole-4-carboxylates has also been described. Similarly, three of the serine-derived oxazole-4-carboxamides were elaborated to novel trisubstituted 4,2'-bisoxazoles through DAST/DBU-mediated cyclodehydration-dehydrohalogenation sequence. The present protocol is complementary and an improvement to our previously reported silver carbonate-induced cyclization of ß-bis(methylthio)enamides to 2-phenyl-5-(methylthio)-4-substituted oxazoles.