Nickel-Catalyzed Regio-Controllable α- or β-Hydroalkylation of α,β-Unsaturated Amides

Abstract Novel transition-metal-catalyzed approaches to modulate chemo- and regioselectivity provide opportunities to tailor C–C bond formations from a common substrate, thereby diversifying accessible products and expanding chemists’ synthetic repertoire. Herein, a Ni-catalyzed chemo- and regioselective cross-electrophile coupling reaction of unsaturated amides with unactivated alkyl bromides has been developed. Most notably, the reactivity can be controlled to alkylate the unsaturated amide at the α- or β-carbon with excellent regioselectivity. The selectivity is attributed to subtle differences in the bidentate nitrogen-based ligand architectures and the additive (CaCl2). Mechanistic and DFT studies support two different reaction pathways. The reactivity patterns developed herein are distinct from previous reports and have potential applications in the synthesis of pharmaceuticals.