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%), and anhyd. Cu(OAc)₂ (10 mol%) in DCE (3.0 mL) at 110 °C delivered 36 novel amide derivatives in 62–86% yields. The protocol exhibits a broad substrate scope and excels in late-stage functionalization of pharmacologically active quinoxalinones and the naturally occurring substrate 2-phenylpyridine, accommodating diverse electronic, steric, and functional groups. 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 the practicality of the reaction. The structures of the compounds were verified by NMR, HETCOR, HRMS, and X-ray crystallography. Mechanistic studies indicate that the reaction involves reversible C–H activation, nitrene insertion, and proto-demetalation, as confirmed by several control experiments. This atom-economical C–N bond-forming strategy provides a versatile platform for synthesizing pharmacologically privileged amide-quinoxalinone analogues for medicinal chemistry.