PdII-Catalyzed ?-C(sp3)-H (Hetero)arylation of Ketones Enabled by Transient Directing Groups

Pd(II)-catalyzed gamma-C(sp3)-H (hetero)arylation of aliphatic ketones is developed using alpha-amino acids as transient directing groups (TDG). A variety of aliphatic ketones were (hetero)arylated at the gamma-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 gamma-methylene C(sp3)-H arylation of ketones. Mechanistic investigation and comparison to the gamma-C-H arylation of aldehydes revealed a structural insight for designing site-selective TDG.

Automated summary

Pd(II)-catalyzed gamma-C(sp3)-H (hetero)arylation of aliphatic ketones using alpha-amino acids as transient directing groups (TDG) has been developed. By reducing the loading of acid additives, the crucial ligand effect of 2-pyridone is enhanced, leading to improved reactivity and the possibility of cyclic gamma-methylene C(sp3)-H arylation of ketones. Mechanistic investigation and comparison to the gamma-C-H arylation of aldehydes provide structural insights for designing site-selective TDGs.