Direct α-Trifluoromethyl Amidation and Three-Component Alkene Trifluoroalkylamidation via Merging Halogen-Atom Transfer and Nickel-Mediated Nitrenoid Transfer.

Direct catalytic access to α-trifluoromethyl amides from simple fluorinated feedstocks has remained elusive despite the medicinal relevance of this motif. Here, we report the first catalytic platform for direct α-trifluoromethyl amidation through the merger of photochemical halogen-atom transfer (XAT) and nickel-mediated nitrenoid transfer. Under mild conditions, readily available α-bromo-trifluoromethyl alkanes couple with dioxazolones to forge challenging C(sp3)-N bonds at α-CF3 centers with broad functional-group tolerance. The same catalytic manifold further enables a three-component alkene trifluoroalkylamidation, providing modular access to densely functionalized γ-trifluoromethyl alkylamides. Mechanistic studies support a pathway involving photochemically generated α-CF3 alkyl radicals and nickel-nitrenoid intermediates. Gram-scale synthesis, late-stage functionalization of natural product- and drug-derived substrates, and concise conversion to pharmaceutically relevant analogues underscore the synthetic utility of the platform.