A Radical Approach for Asymmetric α-C–H Addition of <i>N</i>-Sulfonyl Benzylamines to Aldehydes

Abstract

Efficient synthesis of enantioenriched amines is of great importance due to their significant synthetic and biological applications. Photoredox-mediated asymmetric <i>α</i>-amino C(sp³)-H functionalization offers an atom-economical and sustainable approach to access chiral amines. However, the development of analogous reactions is in its early stages, generally affording chiral amines with a single stereocenter. Herein, we present a novel synergistic triple-catalysis approach for the asymmetric <i>α</i>-C-H addition of readily available <i>N</i>-sulfonyl amines to aldehydes under mild conditions. This method allows for the efficient synthesis of a diverse array of valuable <i>β</i>-amino alcohols bearing vicinal stereocenters. Unlike previous reports, our protocol employs a radical approach using earth-abundant Cr catalysis. Quinuclidine plays a dual role by facilitating highly selective hydrogen-atom transfer to generate <i>α</i>-amino radicals and promoting the dissociation of the Cr-O bond, which is crucial for the overall catalytic cycle as evidenced by control, NMR, and DFT experiments. Preliminary mechanistic studies, including radical trapping, nonlinear effect, Stern-Volmer plot, kinetic isotope effect, and Hammett plot, offer valuable insights into the reaction pathway.