Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives

Abstract

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug pK_a, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp³)–H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on transient sulfonylation by the electrophilic fluorinating agent N-fluorobenzenesulfonimide. We also report heterobenzylic trifluoromethylthiolation and ¹⁸F-fluorination, providing a suite of reactions for late-stage C(sp³)–H functionalization of drug leads and radiotracer discovery.