美国康奈尔大学Lin, Song团队报道了卤代烷的电化学驱动交叉亲电偶联。相关研究成果发表在2022年2月21日出版的《自然》。
最近的药物化学研究表明，候选药物中sp3碳（与其他四个原子结合的碳）分数的增加与临床试验成功率的提高之间存在相关性。因此，在现代有机化学中，开发稳健和选择性的方法来构建C（sp3）-C（sp3）键仍然是一个关键问题。由于烷基卤化物的广泛可用性，它们的直接交叉偶联（通常称为交叉亲电偶联（XEC））为实现这一目标提供了一条有希望的途径。这种转化绕过了传统交叉偶联反应中使用的碳亲核试剂的制备，以及通常与这些试剂相关的稳定性和官能团耐受性问题。然而，在C（sp3）-C（sp3）XEC中实现高选择性仍然是一个很大程度上尚未解决的挑战。
该文中，研究人员使用电化学，利用不同的电子和空间特性来实现卤代烷的差异活化。具体而言，取代度较高的卤代烷选择性阴极还原产生碳负离子，碳负离子通过双分子亲核取代（SN2）与取代较少的卤代烷优先偶联，形成新的C–C键。与现有方法相比，这种无过渡金属的方法能够实现多种功能化和未激活的烷基亲电试剂的高效XEC，并表现出更好的化学选择性。
附：英文原文
Title: Electrochemically driven cross-electrophile coupling of alkyl halides
Author: Zhang, Wen, Lu, Lingxiang, Zhang, Wendy, Wang, Yi, Ware, Skyler D., Mondragon, Jose, Rein, Jonas, Strotman, Neil, Lehnherr, Dan, See, Kimberly A., Lin, Song
Issue&Volume: 2022-02-21
Abstract: Recent research in medicinal chemistry suggests a correlation between an increase in the fraction of sp3 carbons, those bonded to four other atoms, in drug candidates with their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of C(sp3)-C(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross coupling—commonly known as cross-electrophile-coupling (XEC)—provides a promising route toward this objective3–5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions as well as stability and functional group tolerance issues that commonly associate with these reagents. However, achieving high selectivity in C(sp3)-C(sp3) XEC remains a largely unmet challenge. Here, we employ electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution (SN2) to forge a new C–C bond. This transition-metal-free protocol enables efficient XEC of a variety of functionalized and unactivated alkyl electrophiles and exhibits improved chemoselectivity versus existing methods.
DOI: 10.1038/s41586-022-04540-4
Source: https://www.nature.com/articles/s41586-022-04540-4