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

A user-friendly reagent for mild and general activation of alcohols towards bimolecular nucleophilic substitution (S_N2) 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.