Palladium(II)-Catalyzed Enantioselective Arylation of Unbiased Methylene C(sp(3))-H Bonds Enabled by a 2-Pyridinylisopropyl Auxiliary and Chiral Phosphoric Acids

摘要

Enantioselective functionalizations of unbiased methylene C(sp(3))-H bonds of linear systems by metal insertion are intrinsically challenging and remain a largely unsolved problem. Herein, we report a palladium(II)-catalyzed enantioselective arylation of unbiased methylene -C(sp(3))-H bonds enabled by the combination of a strongly coordinating bidentate PIP auxiliary with a monodentate chiral phosphoric acid (CPA). The synergistic effect between the PIP auxiliary and the non-C-2-symmetric CPA is crucial for effective stereocontrol. A broad range of aliphatic carboxylic acids and aryl bromides can be used, providing -arylated aliphatic carboxylic acid derivatives in high yields (up to 96%) with good enantioselectivities (up to 95:5 e.r.). Notably, this reaction also represents the first palladium(II)-catalyzed enantioselective C-H activation with less reactive and cost-effective aryl bromides as the arylating reagents. Mechanistic studies suggest that a single CPA is involved in the stereodetermining C-H palladation step.