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 synthesis¹. Over the past decade, several generations of bifunctional ligands developed have enabled C(sp³)-H activation reactions of free carboxylic acids², free aliphatic amines³, native amides^4,5 and alcohols⁶. 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(sp³)-H/C(sp²)-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 HBF₄ 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.