Department of Chemistry and Biotechnology, Tallinn University of Technology, Akadeemia tee 15, 12618, Tallinn, Estonia.
ChemSusChem. 2022 Feb 8;15(3):e202102286. doi: 10.1002/cssc.202102286. Epub 2022 Jan 20.
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 HPO 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 2 reaction of (R)- and (S)-ethyl lactates. Substitution with halide anions (F , Br , I ) and oxygen-centered (CH OH, PhO ) nucleophiles was also tested. Application of the method to the synthesis of active pharmaceutical ingredients has been demonstrated.
无溶剂合成工具的扩展对于可持续化学工业的发展至关重要。与传统的基于溶剂的合成相比，机械化学反应具有更高的安全性和更少的废物产生。本文开发了一种新的机械化学方法，使用氟代-N,N,N',N'-四甲基甲脒六氟磷酸盐（TFFH）和 KHPO 作为醇激活试剂和碱，用于醇的亲核取代。醇的激活和与亲核试剂的反应在一个研磨罐中通过反应性异噁唑啉中间体进行。与胺的亲核取代以 31-91%的收率得到烷基化胺。（R）-和（S）-乳酸乙酯的 S 2 反应完全发生了立体反转。还测试了卤化物阴离子（F、Br、I）和含氧（CH OH、PhO）亲核试剂的取代反应。该方法已应用于活性药物成分的合成。
