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Updated: Oct 9, 2025

A Two-Step Protocol for Umpolung Functionalization of Ketones Via Enolonium Species
Published on: August 16, 2018
Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates
Tatsiana Dalidovich1, Jagadeesh Varma Nallaparaju1, Tatsiana Shalima1
1Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, 12618, Tallinn, Estonia.
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 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.
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