Pd II -Catalyzed γ -C(sp 3 )-H (Hetero)Arylation of Ketones Enabled by Transient Directing Groups.

Pd(II)-catalyzed γ -C(sp 3 )-H (hetero)arylation of aliphatic ketones is developed using α -amino acid as transient directing groups (TDG). A variety of aliphatic ketones were (hetero)arylated at the γ -position via a 5,6-membered fused cyclopalladation intermediate to afford the remotely arylated products in up to 88% yield. The crucial ligand effect of 2-pyridone is further enhanced by reducing the loading of acid additives. Consequentially, the improved reactivity of this catalytic system has also made possible the cyclic γ -methylene C(sp 3 )-H arylation of ketones. Mechanistic investigtigation and comparison to the γ -C-H arylation of aldehydes revealed a structural insight for designing site selective TDG.