Jia-Xi Wang, Mu-Qiu Chen, Yang Zhang, Bo Han, Ze-Dong Mou, Xitong Feng, Xia Zhang, Dawen Niu
{"title":"A Modified Arbuzov-Michalis Reaction for Selective Alkylation of Nucleophiles.","authors":"Jia-Xi Wang, Mu-Qiu Chen, Yang Zhang, Bo Han, Ze-Dong Mou, Xitong Feng, Xia Zhang, Dawen Niu","doi":"10.1002/anie.202409931","DOIUrl":null,"url":null,"abstract":"<p><p>The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov-Michalis reaction.</p>","PeriodicalId":125,"journal":{"name":"Angewandte Chemie International Edition","volume":null,"pages":null},"PeriodicalIF":16.1000,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Angewandte Chemie International Edition","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1002/anie.202409931","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/3 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a nontrivial task. We report herein a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates. Experimental studies indicate the relative reactivity of a nucleophile depends on its acidity and its steric environment. Mechanistic studies suggest the reaction pathway resembles that of the Arbuzov-Michalis reaction.
期刊介绍:
Angewandte Chemie, a journal of the German Chemical Society (GDCh), maintains a leading position among scholarly journals in general chemistry with an impressive Impact Factor of 16.6 (2022 Journal Citation Reports, Clarivate, 2023). Published weekly in a reader-friendly format, it features new articles almost every day. Established in 1887, Angewandte Chemie is a prominent chemistry journal, offering a dynamic blend of Review-type articles, Highlights, Communications, and Research Articles on a weekly basis, making it unique in the field.