Late-Stage Defluorinative Functionalization: Synthesis of Thioamides and Heterocycles from Trifluoromethylarenes

Abstract

We report the first general strategy for converting trifluoromethylarenes into thioamides and heterocycles through a telescoped two-step, one-pot process. The transformation proceeds via a methyl-dithioester intermediate formed by defluorination and thiolation using the commercially available reagent BF₃·SMe₂, followed by rapid substitution with amines. This operationally simple method enables the synthesis of both primary and secondary thioamides in high yields and is readily extended to heterocycle formation using bifunctional nucleophiles. The approach demonstrates broad substrate scope, including late-stage functionalization of pharmaceuticals (flufenamic acid, cinacalcet, leflunomide, celecoxib) and amino acids/peptides, highlighting its potential in medicinal chemistry. Beyond introducing a new retrosynthetic disconnection, this work unlocks unprecedented CF₃-to-heterocycle transformations, offering a powerful tool for structural diversification and drug design.