Reductive amination of carbonyl C–C bonds enables formal nitrogen insertion

Given its ubiquity in various biological and physical processes1–3, the reductive amination of ketones and aldehydes is one of the oldest and most widely used methods for amine synthesis4. As a cornerstone of synthetic chemistry, it has largely remained unchanged since its discovery over a century ago5. Herein, we report the mechanistically-driven development of a complementary reaction, which reductively aminates the C–C σ-bond attached to carbonyls, not the carbonyl C–O π-bond, generating value-added linear and cyclic 3° amines in a modular fashion. Critical to the success of this endeavor were mechanistic insights that enabled us to modulate the resting state of a borane catalyst, minimize deleterious disproportionation of a hydroxylamine nitrogen source, and control the migratory selectivity of a key nitrenoid reactive intermediate. Experimental evidence support the reaction occurring through a reductive amination/stepwise reductive Stieglitz cascade, via a ketonitrone, which can be interrupted under catalyst-control to generate valuable N,N-disubstituted hydroxylamines. The method reported herein enables various net transformations that would otherwise require lengthy synthetic sequences using pre-existing technologies. This is highlighted by its application to a two-step protocol for the formal insertion of a single nitrogen atom into the core framework of abundant hydrocarbon feedstocks, the site-selective late-stage C–C amination of complex molecules, diversity-oriented synthesis of isomeric amines from a single precursor, and transposition of nitrogen to different positions within a heterocycle.