A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides

Abstract

The catalytic union of amides, sulfonamides, anilines, imines or N-heterocycles with a broad spectrum of electronically and sterically diverse alkyl bromides has been achieved via a visible light-induced metallaphotoredox platform. The use of a halogen abstraction-radical capture (HARC) mechanism allows for room temperature coupling of C(sp3 )-bromides using simple Cu(II) salts, effectively bypassing the prohibitively high barriers typically associated with thermally-induced SN2 or SN1 N-alkylation. This regio- and chemoselective protocol is compatible with >10 classes of medicinally-relevant N-nucleophiles, including established pharmaceutical agents, in addition to structurally diverse primary, secondary and tertiary alkyl bromides. Furthermore, the capacity of HARC methodologies to engage conventionally inert coupling partners is highlighted via the union of N-nucleophiles with cyclopropyl bromides and unactivated alkyl chlorides, substrates that are incompatible with nucleophilic substitution pathways. Preliminary mechanistic experiments validate the dual catalytic, open-shell nature of this platform, which enables reactivity previously unattainable in traditional halide-based N-alkylation systems.