Base-Free C-N Cross-Electrophile Coupling via a Nitrogen-First Mechanism

Metal-catalyzed carbon-nitrogen (C-N) cross-coupling-a philicity-matched reaction of carbon electrophiles with nitrogen nucleophiles under basic conditions-is a foundational tool in modern medicinal chemistry. 1-4 Here we report a philicity-mismatched nickel-catalyzed C-N crosselectrophile coupling (XEC) that combines carbon and nitrogen electrophiles. This mild protocol exhibits broad functional group tolerance including base-sensitive substrates and is compatible with late-stage applications. The necessary nitrogen electrophiles can be accessed from diverse starting materials, including C-H bonds and olefins. Strategic implementation of C-N XEC enables synthesis of designer secondary and tertiary amines, unsymmetrical diamines, and native amine functionalization through a two-step, one-pot N-phenothiazination, C-N XEC sequence. Mechanistic investigations suggest a unique nitrogen-first pathway involving N-centered radical (NCR) intermediates, which enforces cross selectivity by avoiding metal aryl intermediates associated with homocoupling. These findings establish a paradigm for base-free C-N bond construction and introduce a mechanistic rationale for controlling C-X XEC selectivity.