亲核试剂的烷基化是化学中最基本和最完善的转化之一。然而,实现复杂底物的选择性烷基化仍然是一项艰巨的任务。我们在此报告了一种不使用强酸的一般和选择性烷基化方法,基地,或金属。在这种方法中,容易获得的亚磷酸盐/亚磷酸盐,与丙烯酸乙酯结合使用,作为有效的烷化剂。各种亲核基团,包括酒精,酚类物质,羧酸,酰亚胺,和硫醇可以烷基化。该方法可应用于天然产物和药剂的后期烷基化,实现复杂底物的化学和位点选择性修饰。实验研究表明,亲核试剂的相对反应性取决于其酸度和空间环境。机理研究表明,反应途径类似于Arbuzov-Michalis反应。
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.