Imine-Directed Ru(II)-Catalyzed ortho-C(sp²)–H Amidation of 3-Arylquinoxalin-2(1H)-ones via Nitrene Transfer from Acyl/Heteroacyl Azides

Abstract

Imine-directed Ru(II)-catalyzed C(sp²)-H amidation enables regioselective ortho C-N bond formation in 3-arylquinoxalin-2(1H)-ones using aromatic acyl azides and heteroaryl acyl azides as nitrene precursors, with N₂ as the sole byproduct of the reaction. Optimized reaction conditions ([Ru(p-cymene)Cl₂]₂ (10 mol%), AgSbF₆ (20 mol%), anhyd. Cu(OAc)₂ (10 mol%) in DCE (3.0 mL) at 110 °C delivered 36 novel amide derivatives in 62–86% yield. The protocol exhibits broad substrate scope and excels in late-stage functionalization of pharmacologically active quinoxalinones and naturally occurring substrate 2-phenylpyridine, accommodating diverse electronics, steric, and functional groups. The aromatic acyl azides proved to be effective coupling partners with 3-arylquinoxalin-2(1H)-ones and aliphatic acyl azides showed no reactivity under the optimized conditions. Gram-scale synthesis confirms practicality of the reaction. The structures of the compounds were verified by NMR, HETCOR, HRMS, and X-ray crystallography. Mechanistic studies support reversible C-H activation, nitrene insertion, and proto-demetalation, which was supported by several controlled experiments. This atom-economical C-N bond-forming strategy provides a versatile platform for synthesizing pharmacologically privileged amide-quinoxalinone analogues for medicinal chemistry.