Modular silver catalysts to elucidate the role of non-covalent interactions in asymmetric C‒H amidation reactions

Abstract

Chiral, non-racemic amines and aminoalcohols are common structural motifs in bioactive molecules. Asymmetric nitrene transfer offers a powerful approach to prepare enantioenriched amines directly from abundant C–H bonds; however, the development of general, cost-effective catalysts supported by easily tunable ligands remains a significant challenge. Herein, we report that Ag salts coordinated with unique bis(oxazoline) ligands catalyze site- and enantioselective nitrene transfer into benzylic, allylic, and unactivated C–H bonds of carbamate esters. This method provides 1,3-aminoalcohols in high yields with enantiomeric excess (ee) of up to 98%. Computations were used to rationalize key features influencing the observed stereochemical outcomes. Analysis of the enantiodetermining transition states revealed that high ee arises from a preferred square-planar geometry at the silver nitrene and stabilizing C–H/π interactions between the ligand and substrate. These features enable broad substrate scope and high chemo-, site-, and enantioselectivity in Ag-catalyzed C–H bond amidations via nitrene transfer.