β-C-H bond functionalization of ketones and esters by cationic Pd complexes.

C-H activation is the most direct way of functionalizing organic molecules. Many advances in this field still require specific directing groups to achieve the necessary activity and selectivity. Developing C-H activation reactions directed by native functional groups is essential for their broad application in synthesis. Over the past decade, several generations of bifunctional ligands developed have enabled C(sp)-H activation reactions of free carboxylic acids, free aliphatic amines, native amides and alcohols. However, an effective catalyst for ketones and carboxylic esters remains to be realized. Here we report diverse methyl β-C-H functionalizations, including intermolecular arylation, hydroxylation and intramolecular C(sp)-H/C(sp)-H coupling of ketones and carboxylic esters with a monoprotected amino neutral amide (MPANA) ligand. The in situ generation of cationic Pd(II) complexes by the combination MPANA ligand and HBF is crucial for achieving the reactivity. The compatibility of these reactions with cyclic ketones and lactams provides a method to access spirocyclic and fused ring systems. Mechanistic experiments and density functional theory studies support the role of cationic Pd complexes with MPANA ligands in enhancing catalyst-substrate affinity and facilitating the C-H cleavage step.