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Mechanochemical Nucleophilic Substitution of Alcohols via Isouronium Intermediates **
Author(s) -
Dalidovich Tatsiana,
Nallaparaju Jagadeesh Varma,
Shalima Tatsiana,
Aav Riina,
Kananovich Dzmitry G.
Publication year - 2022
Publication title -
chemsuschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.412
H-Index - 157
eISSN - 1864-564X
pISSN - 1864-5631
DOI - 10.1002/cssc.202102286
Subject(s) - chemistry , nucleophilic substitution , nucleophile , alcohol , substitution reaction , reagent , alkylation , nucleophilic aromatic substitution , solvent , organic chemistry , hexafluorophosphate , sn2 reaction , combinatorial chemistry , medicinal chemistry , catalysis , ionic liquid
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 K 2 HPO 4 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 S N 2 reaction of ( R )‐ and ( S )‐ethyl lactates. Substitution with halide anions (F − , Br − , I − ) and oxygen‐centered (CH 3 OH, PhO − ) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients has been demonstrated.