Transition-Metal Hydride Catalysis Meets Nitrenoid Transfer: Design Principles for Precision C-N Bond Formation.

ConspectusTransition-metal hydride (TMH) catalysis has become a powerful strategy for hydroamination reactions, enabling direct C-N bond formation from simple alkenes and alkynes under mild conditions. In conventional TMH-catalyzed hydroamination, a metal hydride first engages a π system through hydrometalation or related hydrogen-atom-transfer processes to generate organometallic intermediates, wherein stabilization of the incipient carbon center dictates regioselectivity. As a consequence, subsequent coupling with a nitrogen electrophile intrinsically favors C-N bond formation at electronically activated positions. Accordingly, regioselectivity patterns such as α-amination adjacent to electronically polarizing substituents, directing-group-controlled sites, or sterically accessible terminal positions following migration are well-established, whereas complementary β-selective amination remains challenging to achieve.This Account summarizes our efforts to merge TMH catalysis with nitrenoid transfer chemistry and, in doing so, to uncover two distinct and mechanistically orthogonal hydroamidation regimes governed by the ordering of elementary steps. Using bench-stable dioxazolones as acyl nitrenoid precursors, we first established a canonical TMH manifold in which hydrometalation precedes inner-sphere nitrenoid transfer. In this regime, regioselectivity is programmed at the metal hydride insertion stage and can be predictably controlled across a wide range of TMH catalytic systems, enabling regioselective hydroamidation of alkynes and alkenes with broad scope and high functional-group compatibility.A conceptual turning point emerged from mechanistic studies of NiH catalysis, where an unexpected β-selective intramolecular hydroamidation exposed a fundamentally different reaction manifold. Rather than initiating with hydrometalation, NiH was found to activate the nitrenoid precursor first, generating a Ni-amido intermediate that subsequently engages the alkene through polarity-matched amidonickelation. This transposed hydroamidation regime inverts the selectivity-determining step, shifting control from alkene hydrometalation to C-N bond formation. As a result, regioselectivity patterns inaccessible under conventional TMH logic, including β-lactam formation, intermolecular β-amidation of conjugated carbonyls, and homobenzylic hydroamidation of vinylarenes, become attainable with high enantioselectivity.Together, these studies establish step order as a central design parameter in TMH-catalyzed hydroamidation. By deliberately choosing whether hydride delivery or nitrenoid generation occurs first, complementary regio- and stereochemical outcomes can be accessed from the same classes of unsaturated substrates. Beyond nitrenoid chemistry, extension of this transposed logic to carbene transfer processes further underscores its generality. We anticipate that continued mechanistic elucidation and expansion of this framework will transform TMH-nitrenoid synergy from a collection of reactions into a predictive platform for precision C-N bond construction.