Base-Free C-N Cross-Electrophile Coupling.

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. Here, we report a philicity-mismatched nickel-catalyzed C-N cross-electrophile coupling (XEC) that combines electrophilic carbon and nitrogen precursors. Because the method relies on electrophilic nitrogen precursors, basic additives are not required to activate the nitrogen coupling partner. This mild protocol exhibits broad functional group tolerance, including base-sensitive substrates, and is compatible with late-stage applications. The electrophilic nitrogen precursors can be accessed from diverse starting materials, including C-H bonds and olefins. We demonstrate a two-step, one-pot N-phenothiazination, C-N XEC sequence that provides the platform for application of C-N XEC to the functionalization of amine-containing bioactive small molecules. Strategic implementation of C-N XEC enables synthesis of designer secondary and tertiary amines as well as unsymmetrical diamines. Mechanistic investigations indicate the C-N XEC proceeds via a Ni(II)-aryl-amido intermediate and enforces cross-selectivity by avoiding Ni(II)-aryl-halide 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.