Regioselective synthesis of 2,4-disubstituted thiophenes

A highly regioselective route was established to 2-aryl-, 2-cyclohexyl-, and 2-(2-arylethyl)-4-alkylthiophenes, which are potential candidates as liquid crystalline compounds of low viscosity. The key synthetic intermediates, 2- substituted-4-(chloromethyl)thiophenes 6, 14, and 20 were prepared respectively from the reactions of beta,gamma -epoxycarbonyl compounds 5, 13, and 19 with Lawesson's reagent in the presence of a catalytic amount of p-toluenesulfonic acid. The epoxycarbonyl compounds were obtained from the TiCl4-mediated reactions of 2-(chloromethyl)-3-(trimethylsliyl)propene (10) with acid chlorides followed by epoxidation with m-chloroperoxybenzoic acid, or from prior epoxidation followed by oxidation with pyridinium dichromate of homoallylic alcohols 3. The homoallylic alcohols 3 were synthesized from the reactions of 2-(chloromethyl)-3-(trichlorosilyl)propene (2) with aldehydes in N,N-dimethylformamide. Copper(I) catalysed cross-coupling reactions of 2-substituted4-(bromomethyl)thiophenes (which were prepared by transhalogenation of 2-substituted-4(chloromethyl)thiophenes with NaBr in acetone) with Grignard reagents afforded 2,4-disubstituted thiophenes. Using this method, eleven 2,4-disubstituted thiophenes were synthesized and their potentials as liquid crystalline compound of low viscosity were examined. The synthesized 2-(4-cyanophenyl)-4-pentylthiophene was observed to have a lower melting point than the corresponding 2,5-disubstituted thiophene. This observation is consistent with the expectation from the basis of molecular linearity which can affect the viscosity and/or melting point of crystalline compounds.