Enantioconvergent Negishi Cross-Coupling of Racemic sec-Alkylzinc Reagent with Aryl Halides Enabled by Bulky N-Heterocyclic CarbenePd Catalyst

Transition-metal-catalyzed cross-coupling reactions have revolutionized synthetic approaches for forging C-C bonds. However, catalytic enantioconvergent couplings of racemic secondary organometallics with aryl electrophiles remain a significant challenge. We herein describe a rare Pd-catalyzed enantioconvergent coupling of sec-alkylzinc reagents with aryl halides, providing a range of enantioenriched 1,1-diarylalkane products in excellent yield (up to 99%) and high enantioselectivity (up to 95.5:4.5 er). The reaction showed broad substrate scope, and excellent functional group tolerance and was efficiently applied to modification of pharmaceutically relevant molecules. The use of a bulky C2-symmetric chiral N-heterocyclic carbene (NHC) ligand for palladium catalyst was key to attaining high reactivity and enantioselectivity. Mechanistic studies and DFT calculations elucidated the enantioselectivity-determining transmetalation step and the origins of enantiocontrol by the NHC ligand.