Scalable route to N-trifluoromethyl amides via radical trifluoromethylamination

N -CF ₃ amides are promising targets for medicinal and agrochemistry. However, they have not yet been practically applied because of the limitations of their synthetic method. Traditional amidation can not be utilized to prepare N -CF ₃ amides due to the unavailability of corresponding N -CF ₃ amines. The development of effective alternative route has become a research focus in this field. We describe here a conceptually novel trifluoromethylamination method, in which the reactivity of trifluoromethylamidyl radicals derived from N -( N -CF ₃ imidoyloxy) pyridinium salts can be harnessed for the rapid construction of diverse N -CF ₃ amides. Such stable imidoyloxy pyridinium salts are conveniently prepared by the imidoylation of pyridine- N -oxide with the in situ formed N -CF ₃ nitrilium ions. The ensuing pyridinium fragmentation under photoredox catalysis liberates trifluoromethylimidoyloxy radical, which can efficiently participate in the trifluoromethylaminations of (hetero)arenes, alkenes and functionalized alkenes, alkynes, silylenol ethers, and isocyanides in the form of trifluoromethylamidyl radical through imidoyloxy-amidyl resonance. Density functional theory calculations indicate that although initial charge distribution and spin density of key radical intermediates in the optimized structure are not conducive to the reaction at the N-site, the trifluoromethylamidyl radical can be dynamically activated when approaching the reactant, thereby selectively serves as an effective radical aminating reagent for subsequent C-N coupling reactions. The tolerance of the reaction to steric and electronic factors has allowed for the synthesis of the most diverse set of N -CF ₃ amides and their cyclic derivatives.