Enantioselective Synthesis\nof Aminals Via Nickel-Catalyzed\nHydroamination of 2‑Azadienes with Indoles and N‑Heterocycles

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