Palladium-Catalyzed Enantioselective C(sp 3 )-H Arylation of 2-Propyl Azaaryls Enabled by an Amino Acid Ligand.

A palladium(II)-catalyzed enantioselective arylation of unbiased secondary C(sp 3 )-H bonds was developed. The enantioselectivity was controlled by the combination of a pyridyl or isoquinolinyl directing group and an amino acid, N -Boc-2-pentyl proline. A variety of 2-propyl azaaryls and biaryl iodides were employed to provide arylated products in moderate to good yields (up to 82%) with high enantioselectivities (up to 93:7 er). This reaction is a rare example of an amino-acid-enabled enantioselective acyclic methylene C(sp 3 )-H arylation. Furthermore, the reaction proceeded with high enantioselectivity even on a gram scale, and the product was transformed to a 5,6,7,8-tetrahydroisoquinoline bioactive molecule. Kinetic isotope effect (KIE) experiments indicated that C-H activation is the rate-determining step for the enantioselective C(sp 3 )-H arylation.