Enantioselective Synthesis of Aminals Via Nickel-Catalyzed Hydroamination of 2-Azadienes with Indoles and N-Heterocycles.

New methods for the enantioselective synthesis of N-alkylated indoles and their derivatives are of great interest because indoles are pivotal structural elements in biologically active molecules and natural products. They are also versatile intermediates in organic synthesis. Among well-established asymmetric hydroamination methods, the asymmetric hydroamination with indole-based substrates is a formidable challenge. This observation is likely due to the reduced nucleophilicity of the indole nitrogen. Herein, a unique nickel-catalyzed enantio- and branched-selective hydroamination of 2-azadienes with indoles and structurally related N-heterocycles is reported for the generation of enantioenriched ,-aminals. Salient features of this reaction include good yields, mild reaction conditions, high enantioselectivities, and broad substrate scope (60 examples, up to 96% yield and 99% ee). The significance of this approach with indoles and other N-heterocycles is demonstrated through structural modification of natural products and drug molecules and the preparation of enantioenriched N-alkylated indole core structures. Mechanistic studies reveal that olefin insertion into a Ni-H bond in the hydroamination is the enantio-determining step and oxidative addition of the N-H bond may be the turnover-limiting step.