Difluorination of heterobenzylic C–H bonds with N-fluoro-N-(fluorosulfonyl)carbamate (NFC)

Abstract

N-Heterocycles constitute an important structural moiety of small molecules in pharmaceuticals and agrochemicals. Fluorination of heterobenzylic C–H bonds in these compounds has considerable practical value as it modulates the basicity of proximal heteroaromatics and enhances the metabolic stability of easily oxidizable heterobenzylic positions. In this work, difluorination at the heterobenzylic positions in N-heterocycles represented by pyridines was developed using a fluorinating reagent with a carbonyl group (NFC: N-fluoro-N-(fluorosulfonyl)carbamate). NFC efficiently facilitates the difluorination of heterobenzylic C–H bonds in various 4-alkylated pyridines and their analogs under mild reaction conditions. This is in contrast with the mixture of mono- and difluorinated products obtained using the common fluorinating reagent, NFSI (N-fluorobenzenesulfonimide).