Harnessing O-Vinylhydroxylamines for Ring-Annulation: A Scalable Approach to Azaindolines and Azaindoles

We report a convenient and scalable strategy for the synthesis of 7-azaindolines and 7-azaindoles using O-vinylhydroxylamines as ring-annulation reagents. These fused nitrogen-containing heterocycles are prominent in numerous biologically active molecules, including FDA-approved pharmaceuticals. Traditional synthetic approaches to these motifs often rely on costly transition metal catalysts and/or high-temperature conditions, such as those employed in the Larock and Fischer indole syntheses. In our approach, O-vinylhydroxylamines undergo N-arylation with aza-arene N-oxides, triggering a rapid [3,3]-sigmatropic rearrangement. This is followed by re-aromatization and cyclization to deliver 7-azaindolines, which can be readily dehydrated to afford the corresponding 7-azaindoles. The method offers a broad substrate scope, enabling access to a diverse array of highly functionalized derivatives. Moreover, the mild reaction conditions facilitate late-stage functionalization of complex molecules, demonstrating their value in both synthetic and medicinal chemistry.