Ligand-Enabled Palladium(II)-Catalyzed Enantioselective β-C(sp3)-H Arylation of Aliphatic Tertiary Amides

Amide is one of the most widespread functional groups in organic and bioorganic chemistry, and it would be valuable to achieve stereoselective C(sp(3))-H functionalization in amide molecules. Palladium(II) catalysis has been prevalently used in the C-H activation chemistry in the past decades, however, due to the weakly-coordinating feature of simple amides, it is challenging to achieve their direct C(sp(3))-H functionalization with enantiocontrol by Pd-II catalysis. Our group has developed sulfoxide-2-hydroxypridine (SOHP) ligands, which exhibited remarkable activity in Pd-catalyzed C(sp(2))-H activation. In this work, we demonstrate that chiral SOHP ligands served as an ideal solution to enantioselective C(sp(3))-H activation in simple amides. Herein, we report an efficient asymmetric Pd-II/SOHP-catalyzed beta-C(sp(3))-H arylation of aliphatic tertiary amides, in which the SOHP ligand plays a key role in the stereoselective C-H deprotonation-metalation step.

Automated summary

We developed sulfoxide-2-hydroxypridine (SOHP) ligands that showed great efficiency in the Pd-catalyzed C(sp(2))-H activation. In this study, we presented an efficient asymmetric Pd-II/SOHP-catalyzed beta-C(sp(3))-H arylation of aliphatic tertiary amides, where the SOHP ligand played a crucial role in the stereoselective C-H deprotonation-metalation step.