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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...

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Detalles Bibliográficos
Autores principales: Dalidovich, Tatsiana, Nallaparaju, Jagadeesh Varma, Shalima, Tatsiana, Aav, Riina, Kananovich, Dzmitry G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303792/
https://www.ncbi.nlm.nih.gov/pubmed/34932893
http://dx.doi.org/10.1002/cssc.202102286
Descripción
Sumario: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.