Meta ‐Selective C─H Monofluoroalkylation of Pyridines With Difluoroalkyl Radicals

ABSTRACT C─H monofluoroalkylation of pyridines is a highly desirable transformation in medicinal chemistry because the monofluoroalkyl group is known to impart favorable properties to drug candidates, and pyridine rings are prevalent in drug molecules. However, only a few methods have been reported, and they are limited to ortho ‐selective reactions. Herein, we report an unprecedented method for meta ‐selective C─H monofluoroalkylation of pyridines via reactions between difluoroalkyl radicals and dihydropyridines generated in situ. During the reactions, a defluorination/olefin isomerization cascade converts initially formed difluoroalkylated dihydropyridines to monofluoroalkylated pyridines. The method accommodates a broad range of pyridine substrates, as well as other N ‐heteroarenes and fluoroalkylating reagents, and shows promise for late‐stage functionalization of pyridine‐containing drugs.