Preparation of 4-Hydroxy-2-trifluoromethylthiophene: A Novel Bioisostere of α,α,α-Trifluoro-m-cresol

A simple and convenient four-step synthesis of 4-hydroxy-2-trifluoromethylthiophene (1) a novel bioisostere of α,α,α-trifluoro-m-cresol is reported. The key step is the condensation between ethyl 3-methoxy-4,4,4-trifluorocrotonate and methyl thioglycolate to form methyl 3-hydroxy-5-trifluoromethylthiophene-2-carboxylate (6). Hydrolysis of the ester followed by decarboxylation furnishes 1. Multi-hundred gram quantities of 1 have been obtained utilizing the present procedure.