Late-stage defluorinative functionalization: synthesis of thio-amides and heterocycles from trifluoromethylarenes

Abstract

A novel transformation of trifluoromethyl arenes into thioamides has been developed. The reaction proceeds in a two-step, one-pot fashion via a methyl–dithioester intermediate formed in a defluorination/thiolation using BF₃·SMe₂, followed by a mild and rapid substitution of the thiomethyl–moiety. The method was compatible with the synthesis of both secondary and tertiary thioamides, using a wide range of trifluoromethylarenes. In addition, the method was successfully extended to the synthesis of various heterocycles by utilizing amines with specific pendant functionalities. Finally, the method was demonstrated as a potent late-stage approach when applied to the installation of thioamides and heterocycles into flufenamic acid, cinacalcet, leflunomide and celecoxib as well as amino acid/peptide modifications.