Pd(0)-Catalyzed Bidentate Auxiliary Directed Enantioselective Benzylic C-H Arylation of 3-Arylpropanamides Using the BINOL Phosphoramidite Ligand

Palladium-catalyzed enantioselective C(sp³)-H functionalization could provide valuable reactions for organic synthesis. While significant progress has been made on monodentate directing-group-mediated (DG-mediated) enantioselective C-H functionalization using amino acid or N-heterocycle-based chiral ligands, methods for enantioselective C(sp³)-H functionalization mediated by bidentate DGs have lagged far behind. For Pd-catalyzed C(sp³)-H functionalization reactions, 8-aminoquinoline (AQ) is a powerful N,N-bidentate auxiliary. The bidentate binding mode of AQ can stabilize high-valent Pd intermediates, enabling challenging transformations through a Pd^II/IV catalytic manifold. Recently, Duan reported an enantioselective Pd-catalyzed AQ-directed benzylic C-H arylation of 3-arylpropanamides using Pd^II catalyst and the BINOL phosphoramide (P^V) ligand. Herein, we report a protocol for Pd-catalyzed AQ-mediated enantioselective benzylic C-H arylation of 3-arylpropanamides using Pd⁰ catalyst and the BINOL-phosphoramidite (P^III) ligand. These reactions give good to high yield and improved enantioselectivity (up to 95% ee). Mechanistic studies indicate that the reactions proceed via a Pd^0/II catalytic cycle, unprecedented for AQ-directed reactions. DFT calculations suggest that both the phosphoramidite ligand and cesium carbonate base are involved in the enantiodetermining C-H palladation step, and that the AQ directing group converts between binding modes to accommodate the C-H palladation and reductive elimination steps.