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

Authors

Xiushan Liu, Cai Zhai, Yong Jiang, Jianru Xie, Baihui Liang, Chen Zhu, And Huifeng Yue

Published in

Journal of the American Chemical Society. Jul 07, 2026. Epub Jul 07, 2026.

Abstract

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.

PMID:
42411298
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

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