Introduction of the difluoromethyl group at the meta- or para-position of pyridines through regioselectivity switch

Difluoromethyl pyridines have gained significant attention in medicinal and agricultural chemistry. The direct C−H-difluoromethylation of pyridines represents a highly efficient economic way to access these azines. However, the direct meta-difluoromethylation of pyridines has remained elusive and methods for site-switchable regioselective meta- and para-difluoromethylation are unknown. Here, we demonstrate the meta-C−H-difluoromethylation of pyridines through a radical process by using oxazino pyridine intermediates, which are easily accessed from pyridines. The selectivity can be readily switched to para by in situ transformation of the oxazino pyridines to pyridinium salts upon acid treatment. The preparation of various meta- and para-difluoromethylated pyridines through this approach is presented. The mild conditions used also allow for the late-stage meta- or para-difluoromethylation of pyridine containing drugs. Sequential double functionalization of pyridines is presented, which further underlines the value of this work.