Allylic C-H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary aminesa 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).

Automated summary

In this study, a self-regulatory mechanism was developed for allylic carbon-hydrogen amination cross-coupling. By coupling the release of amine nucleophiles with catalyst turnover, excellent regio- and stereoselectivity were achieved. The method successfully produced a variety of drug compounds and complex drug derivatives.