Harnessing the Efficacy of 2-Pyridone Ligands for Pd-Catalyzed (β/γ)-C(sp³)-H Activations

Mechanisms of palladium-aminooxyacetic acid and 2-pyridone-enabled cooperative catalysis for the β- and γ-C(sp³)-H functionalizations of ketones are investigated with density functional theory. 2-Pyridone-assisted dissociation of the trimeric palladium acetate [Pd₃(OAc)₆] is found to be crucial for these catalytic pathways. The evolution of the [6,6]-membered palladacycles (Int-4) are elucidated and are active complexes in Pd(II/IV) catalytic cycles. Nevertheless, 2-pyridone acts as an external ligand, which accelerates β-C(sp³)-H activation. Computational investigations suggest that the C(sp³)-H bond activation is the rate-limiting step for both the catalytic processes. To overcome the kinetic inertness, an unsubstituted aminooxyacetic acid auxiliary is used for the β-C(sp³)-H activation pathway to favor the formation of the [5,6]-membered palladacycle intermediate, Int-IV. Among the several modeled ligands, 3-nitro-5-((trifluoromethyl)sulfonyl)pyridine-2(1H)-one (L8) is found to be highly valuable for both the (β/γ)-C(sp³)-H functionalization catalytic cycles. A favorable free energy pathway of late-stage functionalization of (R)-muscone paves the path to design other bioactive molecules.