Reductive Amination\nof Carbonyl C–C Bonds Enables\nFormal Nitrogen Insertion

Given its relevance across numerous\nfields, reductive\namination\nis one of the oldest and most widely used methods for amine synthesis.\nAs a cornerstone of synthetic chemistry, it has largely remained unchanged\nsince its discovery over a century ago. Herein, we report the mechanistically\ndriven development of a complementary reaction, which reductively\naminates the C–C σ-bond of carbonyls, not the carbonyl\nC–O π-bond, generating value-added linear and cyclic\n3° amines in a modular fashion. Critical to our success were\nmechanistic insights that enabled us to modulate the resting state\nof a borane catalyst, minimize deleterious disproportionation of a\nhydroxylamine nitrogen source, and control the migratory selectivity\nof a key nitrenoid reactive intermediate. Experiments support the\nreaction occurring through a reductive amination/reductive Stieglitz\ncascade, via a ketonitrone, which can be interrupted under catalyst\ncontrol to generate valuable <i>N</i>,<i>N</i>-disubstituted hydroxylamines. The method reported herein enables\nnet transformations that would otherwise require lengthy synthetic\nsequences using pre-existing technologies. This is highlighted by\nits application to a two-step protocol for the valorization of hydrocarbon\nfeedstocks, the late-stage C–C amination of complex molecules,\ndiversity-oriented synthesis of isomeric amines from a single precursor,\nand transposition of nitrogen to different positions within a heterocycle.