Nickel-Catalyzed Enantioselective Addition of Aromatic, Heteroaryl, and Alkenyl Halides to Aliphatic Aldimines.

Nickel complexes of chiral bis(oxazoline)s of rigid conformation efficiently promoted highly enantioselective addition of aryl, heteroaryl halides, and alkenyl halides to alkyl aldimines, providing most chiral amines in 99% ee or above. The method features broad substrate scopes, mild conditions, good tolerance of sensitive groups, low loading of nickel catalysts and ready scalability to synthesis in grams. The method was applied in concise preparation of ten medicinally relevant chiral benzylamines and azacycles. Kinetic profiling revealed that efficient Mn reduction contributed significantly to overall rates, and Lewis-acidic titanium alkoxide assisted several reductive steps in the catalytic cycle. Density functional theory (DFT) calculations revealed a low-barrier 1,2-insertion of neutral complexes of aryl-nickel(I) to imines. The cyclic linker of chiral bis(oxazoline) not only rigidifies the chelate ring formed on nickel, but also induces 99% ee or above during aryl transfer via Thorpe-Ingold effect.