Universal Reagent for Mild and Stereospecific Nucleophilic Substitution of Alcohols with Amines

Abstract

AbstractA user‐friendly reagent for mild and general activation of alcohols towards bimolecular nucleophilic substitution (SN2) leveraging diverse nucleophiles, including primary and secondary amines is reported herein. The new ion‐paired reagent discovery was based upon the putative zwitterionic betaine intermediate of the Mitsunobu reaction and enabled the one‐step conversion of enantioenriched alcohols to valuable chiral C−X bonds (where X=N, C, S, O or halide). The described activating reagent has also been applied to a one‐step methylation reaction using methanol and to an intermolecular amination/intramolecular cyclization sequence that generates heterocycles, such as tetrahydroisoquinolines. This work provides the first evidence by X‐ray crystallography of a protonated betaine as intermediate in the Mitsunobu reaction.