Synthesis and oxidative transformations of 2-functionalized 2-trifluoromethyltetrahydrothiophenes

Abstract

2-Acetoxymethyl- and 2-hydroxymethyl-2-(trifluoromethyl)tetrahydrothiophenes have been prepared from readily obtainable 3-hydroxy-3-(trifluoromethyl)tetrahydropyran by its reactions of sulfur-assisted ring contraction. With the aim to explore the synthetic utility of new fluorinated tetrahydrothiophenes and to estimate the influence of trifluoromethyl group on their reactivity, various types of the oxidative transformations, involving oxidation and oxoimination of sulfur atom, oxidation of hydroxymethyl group and chlorination of free α-position to sulfur atom, were studied. Large sterical demand of CF3 group has been revealed from the stereochemical outcome of the oxidation and oxoimination of the sulfur atom. Electron withdrawing properties of CF3 group are evident from low susceptibility of 2-hydroxymethyl-(trifluoromethyl)tetrahydrothiophene to the oxidation of hydroxymethyl group and from low activity of 2-acetoxymethyl-5-chloro-2-(trifluoromethyl)tetrahydrothiophene in nucleophilic substitution and dehydrochlorination reactions. Convenient protocols for the preparation of trifluoromethylated tetrahydrothiophenes with sulfoxide, sulfone, sulfoximino, aldehyde and carboxy functionalities, acetoxy group in the position 5 of the heterocycle, and 2-(acetoxymethyl)-2-(trifluoromethyl)-2,3-dihydrothiophene have been developed. The results of these studies demonstrate that 2-acetoxymethyl- and 2-hydroxymethyl-2-(trifluoromethyl)tetrahydrothiophenes are useful precursors to a variety of new small fluorinated molecules.