Selective sp 3 C-H alkylation via polarity-match-based cross-coupling

Chip Le, Yufan Liang, Ryan W. Evans, Ximing Li, David W.C. MacMillan

Research output: Contribution to journalArticlepeer-review

386 Scopus citations


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 3)-C(sp 2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp 3 C-H bonds are replaced with sp 3 C-alkyl groups. Here we describe a polarity-match-based selective sp 3 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 3 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.

Original languageEnglish (US)
Pages (from-to)79-83
Number of pages5
Issue number7661
StatePublished - Jul 6 2017

All Science Journal Classification (ASJC) codes

  • General


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