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 PdII/IV catalytic manifold. Recently, Duan reported an enantioselective
Pd-catalyzed AQ-directed benzylic C–H arylation of 3-arylpropanamides
using PdII catalyst and the BINOL phosphoramide (PV) 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 (PIII) ligand. These reactions give good to high yield and improved
enantioselectivity (up to 95% ee). Mechanistic studies indicate that
the reactions proceed via a Pd0/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.