Direct Synthesis of Cyclopropanes from <i>gem</i>-Dialkyl Groups through Double C–H Activation

Cyclopropanes are important structural motifs found in numerous bioactive molecules, and a number of methods are available for their synthesis. However, one of the simplest cyclopropanation reactions involving the intramolecular coupling of two C–H bonds on gem-dialkyl groups has remained an elusive transformation. We demonstrate herein that this reaction is accessible using aryl bromide or triflate precursors and the 1,4-Pd shift mechanism. The use of pivalate as the base was found to be crucial to divert the mechanistic pathway toward the cyclopropane instead of the previously obtained benzocyclobutene product. Stoichiometric mechanistic studies allowed the identification of aryl- and alkylpalladium pivalates, which are in equilibrium via a five-membered palladacycle. With pivalate, a second C­(sp3)–H activation leading to the four-membered palladacycle intermediate and the cyclopropane product is favored. A catalytic reaction was developed and showed a broad scope for the generation of diverse arylcyclopropanes, including valuable bicyclo[3.1.0] systems. This method was applied to a concise synthesis of lemborexant, a recently approved anti-insomnia drug.环丙烷（Cyclopropanes）是广泛存在于众多生物活性分子中的重要结构基元，目前已有多种合成方法可用于其制备。然而，涉及偕二烷基（gem-dialkyl）上两个C-H键分子内偶联的最简单环丙烷化反应之一，长期以来始终是难以实现的转化过程。 本研究证明，以芳基溴化物或三氟甲磺酸酯（triflate）为前体，借助1,4-钯迁移（1,4-Pd shift）机制，可实现该反应。研究发现，以新戊酸盐作为碱是关键，可将反应路径导向生成环丙烷产物，而非此前得到的苯并环丁烯（benzocyclobutene）产物。 通过化学计量比机理研究，我们成功鉴定出芳基钯新戊酸酯与烷基钯新戊酸酯两类中间体，二者可通过五元钯环中间体达成动态平衡。在新戊酸盐作用下，第二轮C(sp³)-H活化将生成四元钯环中间体，最终优先生成环丙烷产物。 我们开发了对应的催化反应体系，该体系底物适用范围广泛，可用于合成多种芳基环丙烷，包括具有较高应用价值的双环[3.1.0]（bicyclo[3.1.0]）体系。此外，该方法还被应用于近期获批的抗失眠药物莱博雷生（lemborexant）的简洁全合成。