Surpassing the Limited Coordination Affinity of Native Amides by Introducing Pyridone-Pd-AgOAc Clusters to Promote Distal -C(sp³)-H Arylation

The utilization of weak coordination in promoting site-selective C(sp(3))-H functionalization is of immense importance. Herein, we report a Pd-catalyzed distal gamma-C(sp(3))-H arylation that harnesses the weak coordination affinity of keto groups with the native noncoordinating amide moiety. The current protocol overcomes one of the major challenges associated with the diversification of synthetic modular frameworks of quaternary centers: controlling the mono- vs difunctionalization of chemically equivalent C-H bonds. The developed condition overrides the interference of the acidic alpha-hydrogen for possible side reactions of amides and delivers the exclusive formation of the gamma-monoarylated product. The association of 2-hydroxy pyridine ligands bearing electron-withdrawing substituents demonstrated the best partnership with the Pd-Ag hetero-bimetallic complex to achieve this distal gamma-C(sp(3))-H activation of a range of noncoordinating aliphatic amides in the absence of any other exogenous ligand. Here, an array of mechanistic measurements helped us to realize the role of the ligand. A density functional theory (DFT) study was performed on four different computational models to elucidate the working principle of a single pyridone ligand in the absence of any externally installed strong chelating donor motifs. The reaction proceeds sequentially through three primary stages: initial C-H activation of the gamma-C(sp(3))-H bond of the amide, succeeded by the oxidative addition of the aryl halide, culminating in reductive elimination, which facilitates the C(sp(2))-C(sp(3)) coupling between the aryl and the aliphatic amide moieties. The role of the silver salt remained essential not only for successful C-H activation but also for turning over the catalytic cycle. [GRAPHICS]