Regio-orthogonal single N-atom insertion into indoles via NO translocation

Abstract

The atom-by-atom manipulation of the core molecular framework has come into reality recently. In particular, the late-stage diversification of robust aza-arenes such as indole has been at the centre of research activity because of its importance in biological and pharmaceutical studies. The previous single-atom modifications of indoles were made possible through the insertion of a reactive nitrene species into the enamine-like C2-C3 bond, resulting in the incorporation of a new atom at the 3-position. Here we discovered an alternative reaction mode, in which the N-nitroso group underwent a sequential intramolecular translocation and deoxygenative rearrangement to afford regiochemically orthogonal 1,4-diazines that had been lacking in skeletal editing. This activation of the nearly inert aromatic C3-C9 bond was applicable to various indoles including bio-relevant molecules to furnish quinoxalines, a class of underexplored pharmacophores. The combined experimental and computational studies revealed the reaction mechanism for the unique selectivity pattern.