Mitsunobu reactions using iminophosphorane reagents

Abstract The Mitsunobu reaction is one of the most celebrated reactions in organic synthesis, enabling stereospecific C–O, C–N and C–S bond formation from abundant alcohol feedstocks. However, its widespread use is constrained by the need for explosive reagents, laborious product purification and a pronucleophile p K a window that precludes C–C bond formation. Here we disclose iminophosphoranes as a class of reagents for the Mitsunobu reaction that readily overcome these limitations. The key iminophosphorane reagent is rapidly and quantitively formed in situ from commercially available 1-azido-4-methoxybenzene and a trialkylphosphine, allowing the construction of C–O, C–N, C–S and, notably, C–C bonds from primary and secondary alcohol substrates with vastly simplified product purification. Furthermore, we demonstrate that the direct use of a solution of preformed iminophosphorane eliminates end-user azide handling altogether. The utility of the reaction was demonstrated through reaction scale-up and late-stage functionalization of pharmaceutically relevant compounds.