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Selective sp3 C–H alkylation via polarity-match-based cross-coupling

Nature volume 547, pages 79–83 (2017)Cite this article

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Abstract

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 sequence1. Although many C–H functionalization reactions involve C(sp3)–C(sp2) coupling, there is a growing demand for C–H alkylation reactions, wherein sp3 C–H bonds are replaced with sp3 C–alkyl groups. Here we describe a polarity-match-based selective sp3 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 sp3 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.

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Figure 1: Selective sp3 C–H alkylations via polarity-matched hydrogen-atom transfer (HAT).
Figure 2: Proposed mechanism for the triple catalytic selective sp3 C–H alkylation.
Figure 3: The scope of the alkyl bromide coupling partner in the light-enabled selective sp3 C–H alkylation.
Figure 4: Application of direct sp3 C–H alkylation in late-stage functionalization of pharmaceutical compounds.

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Acknowledgements

This research was supported by the NIH National Institute of General Medical Sciences (R01 GM078201-05) and gifts from Merck, Bristol-Myers Squibb, Eli Lilly and Johnson & Johnson. The authors thank T. Liu for assistance in preparing this manuscript.

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Author notes

  1. Chip Le, Yufan Liang and Ryan W. Evans: These authors contributed equally to this work.

Authors and Affiliations

  1. Merck Center for Catalysis at Princeton University, Princeton, 08544, New Jersey, USA

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

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Contributions

C.L., Y.L., R.W.E. and X.L. performed and analysed the experiments. C.L., Y.L., R.W.E., X. L. and D.W.C.M. designed the experiments. C.L., Y.L., R.W.E., X.L. and D.W.C.M. prepared the manuscript.

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Correspondence to David W. C. MacMillan.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks M. Greaney and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

This file contains supplementary information regarding HAT-Alkylation – see contents page for full details. (PDF 34045 kb)

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Le, C., Liang, Y., Evans, R. et al. Selective sp3 C–H alkylation via polarity-match-based cross-coupling. Nature 547, 79–83 (2017). https://doi.org/10.1038/nature22813

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