Transition Metal-Free Transfer Hydrogenation of Aryl Azides with Alcohols: Direct Synthesis of Secondary Amines and N-Heterocycles

Abstract

Organic azides and alcohols were harnessed in a transition metal-free, base-mediated transfer hydrogenation system, which offers an efficient synthetic route to secondary amines. In the presence of KO t Bu, aryl azides underwent hydrogen transfer with alcohols to produce secondary amines in high yields. The method features a broad substrate scope, gram-scale applicability, and straightforward experimental setup. Furthermore, N-heterocycles such as quinoxalines and quinolines were synthesized under similar reaction conditions. Mechanistic studies demonstrated that both alcohols and KO t Bu were essential for facilitating hydrogen transfer to azides. The exclusion of a radical pathway, confirmation of alcohol as the reductant, and deuterium labeling experiments provided key insights into the reaction mechanism. DFT calculations revealed that the reduction of azides proceeded through a six-membered cyclic transition state, resembling the mechanism proposed for the Meerwein-Ponndorf-Verley (MPV) reduction. Notably, the potassium cation stabilized the transition state by interacting with both the aryl group and the nitrogen atom of the aryl azide.