Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates**

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 a new mechanochemical method was developed for nucleophilic substitution of alcohols using fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH) and K2 HPO4 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 31-91 % yields. The complete stereoinversion occurred for the SN 2 reaction of (R)- and (S)-ethyl lactates. Substitution with halide anions (F- , Br- , I- ) and oxygen-centered (CH3 OH, PhO- ) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients has been demonstrated.