Enantioselective Directed Nickel-Catalyzed Three-Component Reductive Arylalkylation of Alkenes via the Carbometalation/Radical Cross-Coupling Sequence

Asymmetric reductive three-component arylalkylation of alkenes via the radical relay method has been well established, while asymmetric arylalkylation via the migratory insertion strategy remains unexplored. We report enantioselective nickel-catalyzed cross-electrophile arylalkylation of alkenes with aryl- and alkyl halides via an integrated Heck carbometalation/radical cross-coupling sequence. This protocol employing a chiral Ni/PHOX catalytic system allows terminal and internal alkenes to successfully engage the arylalkylation with exquisite control of regio-, chemo-, and stereoselectivity. More importantly, this reductive arylalkylation undergoes regio- and enantioselective arylnickelation followed by radical cross-coupling via Csp3–Csp3 reductive elimination, thus exhibiting reverse regioselectivity to the radical relay method. Mild reaction conditions and exceptional functional group tolerance facilitate this method's compatibility with bioactive motifs and the modular synthesis of biologically active compounds. The control experiments and density functional theory calculations provide insights into the mechanism and origin of regio- and stereoselectivity, and the hemilabile nature of the PHOX ligand is critical for achieving this enantioselective arylalkylation.