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

Palladium-catalyzed enantioselective C(sp(3))-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-heterocyclebased chiral ligands, methods for enantioselective C(sp(3))-H functionalization mediated by bidentate DGs have lagged far behind. For Pd-catalyzed C(sp(3))-H functionalization reactions, 8-aminoquinoline (AQ) is a powerful N,N-bidentate auxiliary. The bidentate binding mode of AQcan 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 Pd 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 P-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 AQdirecting group converts between binding modes to accommodate the C-H palladation and reductive elimination steps.