Selective meta-C-H trifluoromethylation of pyridines via 1,4-dihydropyridinephosphonate

Abstract

The meta-selective trifluoromethylation of pyridines has remained a significant challenge due to the inherent electronic constraints of the aromatic system. This study developed a novel dearomatization-rearomatization strategy based on 1,4-dihydropyridinephosphonate intermediates, which underwent copper-catalyzed regioselective C–CF₃ bond formation with Togni II reagent followed by DABCO-promoted rearomatization, achieving highly regioselective meta-C-H trifluoromethylation of pyridine derivatives. This approach accommodated mostly meta-substituted pyridine substrates and enabled late-stage meta-C-H trifluoromethylation of pharmaceutical molecules containing pyridine motifs.