Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay

Direct methods for stereoselective functionalization of sp³-hybridized carbon-hydrogen [C(sp³)-H] bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C-H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp³)-CN bond formation upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90 to 99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C-H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.