Reductive Amination of Carbonyl C–C Bonds Enables Formal Nitrogen Insertion

Given its relevance across numerous fields, reductive amination is one of the oldest and most widely used methods for amine synthesis. As a cornerstone of synthetic chemistry, it has largely remained unchanged since its discovery over a century ago. Herein, we report the mechanistically driven development of a complementary reaction, which reductively aminates the C-C σ-bond of carbonyls, not the carbonyl C-O π-bond, generating value-added linear and cyclic 3° amines in a modular fashion. Critical to our success 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. Experiments support the reaction occurring through a reductive amination/reductive Stieglitz cascade, via a ketonitrone, which can be interrupted under catalyst control to generate valuable <i>N</i>,<i>N</i>-disubstituted hydroxylamines. The method reported herein enables 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 valorization of hydrocarbon feedstocks, the 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.