Ni-Catalyzed Regio- and Enantioselective Domino Reductive Cyclization: One-Pot Synthesis of 2,3-Fused Cyclopentannulated Indolines

Transition-metal-catalytic domino reactions represent important advances in synthetic organic chemistry. Their development benefits synthesis by providing highly efficient and step-economical methods to complex molecules with impressive selectivity. Herein, a Ni-catalyzed domino reductive cyclization of acrylamides with alkynyl bromides is reported, enabling rapid assembly of a range of substituted 2,3-fused cyclopentannulated indolines. Preliminary mechanistic studies revealed that tricyclic indolines are afforded through a highly regioselective migratory insertion of 1,3-diynes, which are formed from the homocoupling of alkynyl bromides, into the in situ generated sigma-alkyl-Ni(II) species, followed by nucleophilic addition of the resulting alkenyl nickel to unactivated amides. Most importantly, a highly regio- and enantioselective reductive cyclization of acrylamides and internal alkynes has also been developed. This transformation takes place under mild conditions with high efficiency, providing a rapid access to structurally diverse cyclopentannulated indolines in synthetically useful yields with high regioselectivity (>20/1) and enantioselectivity (27 examples, 82-96% ee).