LAUSR

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines—a common motif in pharmaceuticals—remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal–catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z). Description Controlled release of amine reactants The formation of carbon–nitrogen bonds is a key step in the synthesis of numerous pharmaceuticals and related compounds. However, it is often not feasible to use the most direct nitrogen-bearing precursors because they inhibit metal catalysts at high concentration through strong coordination. Ali et al. report a creative way around this problem for allylic amination reactions. Most of the nitrogen reactants are protected as protonated salts, but the products can steadily deprotonate them a few at a time as the reaction progresses. —JSY Deprotonation of ammonium salts by a reaction product enables carbon–nitrogen bond formation without catalyst inhibition.