Site-specific allylic C–H bond functionalization with a copper-bound N-centred radical

Abstract

Methods for selective C–H bond functionalization have provided chemists with versatile and powerful toolboxes for synthesis, such as the late-stage modification of a lead compound without the need for lengthy de novo synthesis1,2,3,4,5. Cleavage of an sp3 C–H bond via hydrogen atom transfer (HAT) is particularly useful, given the large number of available HAT acceptors and the diversity of reaction pathways available to the resulting radical intermediate6,7,8,9,10,11,12,13,14,15,16,17. Site-selectivity, however, remains a formidable challenge, especially among sp3 C–H bonds with comparable properties. If the intermediate radical could be further trapped enantioselectively, this should enable highly site- and enantioselective functionalization of C–H bonds. Here we report a copper (Cu)-catalysed site- and enantioselective allylic C–H cyanation of complex alkenes, in which a Cu(ii)-bound nitrogen (N)-centred radical plays the key role in achieving precise site-specific HAT. This method is shown to be effective for a diverse collection of alkene-containing molecules, including sterically demanding structures and complex natural products and pharmaceuticals.

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Fig. 1: Site- and enantioselective oxidation of sp3 C–H bonds.
Fig. 2: Enantioselective allylic cyanation of alkenes.
Fig. 3: Mechanistic studies.
Fig. 4: Substrate scope and late-stage cyanation of drug derivatives.

Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. Metrical parameters for the structure of reagents 2c, 2d and products 10d, 17c and S8 (see Supplementary Information) are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference numbers CCDC 1945032, CCDC 1945034, CCDC 1945035, CCDC 1945033 and CCDC 1945036, respectively.

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Acknowledgements

Financial support was provided by the National Basic Research Program of China (grant number 973-2015CB856600), the National Natural Science Foundation of China (grant numbers 21532009, 21821002, 21790330 and 21761142010), the Science and Technology Commission of Shanghai Municipality (grant numbers 17XD1404500, 17QA1405200 and 17JC1401200), the Strategic Priority Research Program (grant number XDB20000000), the Key Research Program of Frontier Science (grant number QYZDJSSW-SLH055) and the Youth Innovation Promotion Association (grant number 2018292) of the Chinese Academy of Sciences, and the Research Grants Council of Hong Kong (grant numbers HKUST 16304416 and 16304017). J.L. thanks Y. Zhang for performing the electron paramagnetic resonance manipulation and analysis and X. Wan for HPLC analysis. G.L. thanks H. Guan (University of Cincinnati) and S. Stahl (University of Wisconsin-Madison) for discussions.

Author information

J.L., L.W., W.Z. and G.L. conceived the work and designed the experiments. J.L. performed most of the laboratory experiments (with help from L.W. and W.Z.). Z.Z. and Z.L. conducted density functional theory calculations. J.L., P.C., Z.L. and G.L. analysed the data and wrote the manuscript.

Correspondence to Zhenyang Lin or Guosheng Liu.

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Peer review information Nature thanks John Murphy, Peter Richard Schreiner and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Supplementary information

Supplementary Information

Supporting materials, including experimental procedure, mechanistic study, DFT calculation, and compound characterization.

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Li, J., Zhang, Z., Wu, L. et al. Site-specific allylic C–H bond functionalization with a copper-bound N-centred radical. Nature 574, 516–521 (2019) doi:10.1038/s41586-019-1655-8

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