Role of Lewis acid additives in a palladium catalyzed directed C–H functionalization reaction of benzohydroxamic acid to isoxazolone

Metallic salts as well as protic additives are widely employed in transition metal catalyzed C–H bond functionalization reactions to improve the efficiency of catalytic protocols. In one such example, ZnCl₂ and pivalic acid are used as additives in a palladium catalyzed synthesis of isoxazolone from a readily available benzohydroxamic acid under one pot conditions. In this article, we present some important mechanistic insights into the role of ZnCl₂ and pivalic acid, gained by using density functional theory (M06) computations. Two interesting modes of action of ZnCl₂ are identified in various catalytic steps involved in the formation of isoxazolone. The conventional Lewis acid coordination wherein zinc chloride (ZnCl₂ •(DMA)) binds to the carbonyl group is found to be more favored in the C–H activation step. However, the participation of a hetero-bimetallic Pd–Zn species is preferred in reductive elimination leading to C_aryl–N bond formation. Pivalic acid helps in relay proton transfer in C–H bond activation through a cyclometallation deprotonation (CMD) process. The explicit inclusion of ZnCl₂ and solvent N,N-dimethyl acetamide (DMA) stabilizes the transition state and also helps reduce the activation barrier for the C–H bond activation step. The electronic communication between the two metal species is playing a crucial role in stabilizing the C_aryl–N bond formation transition state through a Pd–Zn hetero-bimetallic interaction