Chemistry Research Laboratory, Department of Chemistry, Oxford University, OX1 3TA Oxford, UK.
Chem Soc Rev. 2021 Jul 21;50(14):8214-8247. doi: 10.1039/d1cs00360g. Epub 2021 Jun 2.
This review describes the recent advances made in difluoromethylation processes based on X-CFH bond formation where X is C(sp), C(sp), C(sp), O, N or S, a field of research that has benefited from the invention of multiple difluoromethylation reagents. The last decade has witnessed an upsurge of metal-based methods that can transfer CFH to C(sp) sites both in stoichiometric and catalytic mode. Difluoromethylation of C(sp)-H bond has also been accomplished through Minisci-type radical chemistry, a strategy best applied to heteroaromatics. Examples of electrophilic, nucleophilic, radical and cross-coupling methods have appeared to construct C(sp)-CFH bonds, but cases of stereoselective difluoromethylation are still limited. In this sub-field, an exciting departure is the precise site-selective installation of CFH onto large biomolecules such as proteins. The formation of X-CFH bond where X is oxygen, nitrogen or sulfur is conventionally achieved upon reaction with ClCFH; more recently, numerous protocols have achieved X-H insertion with novel non-ozone depleting difluorocarbene reagents. All together, these advances have streamlined access to molecules of pharmaceutical relevance, and generated interest for process chemistry.
这篇综述描述了基于 X-CFH 键形成的二氟甲基化反应的最新进展，其中 X 是 C(sp)、C(sp)、C(sp)、O、N 或 S，这个研究领域受益于多种二氟甲基化试剂的发明。在过去的十年中，出现了许多基于金属的方法，可以通过计量和催化模式将 CFH 转移到 C(sp)位点。通过 Minisci 型自由基化学，也实现了 C(sp)-H 键的二氟甲基化，这是一种最适用于杂芳烃的策略。亲电、亲核、自由基和交叉偶联方法的例子已经出现，用于构建 C(sp)-CFH 键，但立体选择性二氟甲基化的情况仍然有限。在这个子领域中，一个令人兴奋的发展是精确的位点选择性地将 CFH 安装到大分子如蛋白质上。通常通过与 ClCFH 反应形成 X-CFH 键，其中 X 是氧、氮或硫；最近，许多新的非消耗臭氧层的二氟卡宾试剂的 X-H 插入反应已经实现。所有这些进展都简化了获得具有药物相关性的分子的途径，并为过程化学带来了兴趣。
