Wang Johnny Z, Mao Edna, Nguyen Jennifer A, Lyon William L, MacMillan David W C
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States.
J Am Chem Soc. 2024 Jun 12;146(23):15693-15700. doi: 10.1021/jacs.4c05744. Epub 2024 May 31.
The cross-coupling of aryl bromides with alkenes can provide access to diverse combinatorial chemical space. Two-component couplings between these partners are well-known, but three-component aryl-functionalizations of unactivated alkenes remain underdeveloped. In particular, the aryl-alkylation of unactivated alkenes would allow for rapid construction of molecular complexity and the expedient exploration of a pharmaceutically relevant and C(sp)-rich structural landscape. Herein, we report a general approach toward the aryl-alkylation of alkenes through a triple radical sorting mechanism. Over the course of the reaction, a high energy aryl radical, a primary radical, and a hindered alkyl radical are simultaneously formed. Through mediation by a nickel-based catalyst, the three radicals are sorted into productive bond-forming pathways toward the efficient aryl-alkylation of alkenes. A wide range of electronically and sterically differentiated alkenes and aryl radical precursors can be used to access complex scaffolds. This method was further applied to the synthesis of highly substituted semisaturated fused heterocycles.
芳基溴化物与烯烃的交叉偶联能够提供进入多样组合化学空间的途径。这些反应伙伴之间的双组分偶联是众所周知的，但未活化烯烃的三组分芳基官能化反应仍未得到充分发展。特别是，未活化烯烃的芳基烷基化反应将有助于快速构建分子复杂性，并方便地探索与药物相关且富含C(sp)的结构格局。在此，我们报道了一种通过三重自由基分选机制实现烯烃芳基烷基化的通用方法。在反应过程中，会同时形成一个高能芳基自由基、一个伯自由基和一个受阻烷基自由基。通过镍基催化剂的介导，这三个自由基被分选到形成有效键的途径中，以实现烯烃的高效芳基烷基化。多种电子和空间上有差异的烯烃和芳基自由基前体可用于构建复杂骨架。该方法进一步应用于高度取代的半饱和稠合杂环的合成。
