Ligand-Enabled γ‑C(sp3)–H Activation of Ketones

We report the first example of Pd­(II)-catalyzed γ-C­(sp3)–H activation of ketones directed by a practical 2,2-dimethyl aminooxyacetic acid auxiliary. 2-Pyridone ligands are identified to enable C­(sp3)–H activation for the first time. A rare six-membered palladacycle intermediate is isolated and characterized to elucidate the reaction mechanism. Both (hetero)­arylation and vinylation of γ-C­(sp3)–H bonds are demonstrated. Sequential β- and γ-C­(sp3)–H (hetero)­arylation of muscone showcases the utility of this method for late-stage diversification. A convenient Mn­(II)-catalyzed auxiliary removal is also developed to further underscore the practicality of this transformation.