Le Chip, Liang Yufan, Evans Ryan W, Li Ximing, MacMillan David W C
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.
Nature. 2017 Jul 6;547(7661):79-83. doi: 10.1038/nature22813. Epub 2017 Jun 21.
The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp)-C(sp) coupling, there is a growing demand for C-H alkylation reactions, wherein sp C-H bonds are replaced with sp C-alkyl groups. Here we describe a polarity-match-based selective sp C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.
碳氢键（C-H）官能团化是有机化学中分子构建最具吸引力的策略之一。氢原子被认为是一种理想的偶联基团，这是由于其在有机分子中相对丰富，并且在合成序列的几乎任何阶段都可用于官能团化。尽管许多C-H官能团化反应涉及C(sp)-C(sp)偶联，但对C-H烷基化反应的需求日益增长，其中sp C-H键被sp C-烷基取代。在此，我们描述了一种基于极性匹配的选择性sp C-H烷基化反应，该反应通过光氧化还原、镍和氢原子转移催化的组合实现。这种方法同时使用三个催化循环来实现氢化C-H键的夺取（通过极性匹配实现）、卤代烷的氧化加成以及还原消除以实现烷基-烷基片段偶联。sp C-H烷基化对胺、醚和硫化物的α-C-H具有高度选择性，这些结构常见于药物相关体系中。这种交叉偶联方法应能在从头合成和后期官能团化化学中实现广泛的合成应用。
