Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates

Abstract

An expansion of the solvent-free synthetic toolbox is essential for advances in the sustainable chemical industry. Mechanochemical reactions offer a superior safety profile and reduced amount of waste compared to conventional solvent-based synthesis. Herein we report a new mechanochemical method for nucleophilic substitution of alcohols using fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TFFH) and K2HPO4 as an alcohol-activating reagent and a base, respectively. Alcohol activation and reaction with a nucleophile were performed in one milling jar via reactive isouronium intermediates. Nucleophilic substitution with amines afforded alkylated amines in 40–91% yields. The complete stereoinversion occurred for the SN2 reaction of (R)- and (S)-ethyl lactates. Substitution with halide anions (F−, Br−, I−) and oxygen-centered (CH3OH, PhO−) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients (APIs) has been demonstrated.