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

Nature volume 574, pages 516–521 (2019)Cite this article

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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.

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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.

References

  1. Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).

    Article  CAS  Google Scholar 

  2. Davies, H. M. L. & Morton, D. Guiding principles for site-selective and stereoselective intermolecular C–H functionalization by donor/acceptor rhodium carbenes. Chem. Soc. Rev. 40, 1857–1869 (2011).

    Article  CAS  Google Scholar 

  3. Zhang, F.-L., Hong, K., Li, T.-J., Park, H. & Yu, J.-Q. Functionalization of C(sp 3)-H bonds using a transient directing group. Science 351, 252–256 (2016).

    Article  ADS  CAS  Google Scholar 

  4. McNally, A., Haffemayer, B., Collins, B. S. L. & Gaunt, M. J. Palladium-catalysed C–H activation of aliphatic amines to give strained nitrogen heterocycles. Nature 510, 129–133 (2014).

    Article  ADS  CAS  Google Scholar 

  5. Prier, C. K., Zhang, R. K., Buller, A. R., Brinkmann-Chen, S. & Arnold, F. H. Enantioselective, intermolecular benzylic C–H amination catalyzed by an engineered iron-haem enzyme. Nat. Chem. 9, 629–634 (2017).

    Article  CAS  Google Scholar 

  6. Sharma, A. & Hartwig, J. F. Metal-catalyzed azidation of tertiary C–H bonds suitable for late-stage functionalization. Nature 517, 600–604 (2015).

    Article  ADS  CAS  Google Scholar 

  7. Le, C., Liang, Y., Evans, R. W., Li, X. & MacMillan, D. W. C. Selective sp 3 C–H alkylation via polarity-match-based cross-coupling. Nature 547, 79–83 (2017).

    Article  ADS  CAS  Google Scholar 

  8. Chen, M. S. & White, M. C. Combined effects on selectivity in Fe-catalyzed methylene oxidation. Science 327, 566–571 (2010).

    Article  ADS  CAS  Google Scholar 

  9. Horn, E. J. et al. Scalable and sustainable electrochemical allylic C–H oxidation. Nature 533, 77–81 (2016).

    Article  ADS  CAS  Google Scholar 

  10. Liu, W. & Groves, J. T. Manganese catalyzed C–H halogenation. Acc. Chem. Res. 48, 1727–1735 (2015).

    Article  CAS  Google Scholar 

  11. Che, C.-M., Lo, V. K.-Y., Zhou, C.-Y. & Huang, J.-S. Selective functionalisation of saturated C−H bonds with metalloporphyrin catalysts. Chem. Soc. Rev. 40, 1950–1975 (2011).

    Article  CAS  Google Scholar 

  12. Jeffrey, J. L., Terrett, J. A. & MacMillan, D. W. C. O–H hydrogen bonding promotes H-atom transfer from a C–H bonds for α-alkylation of alcohols. Science 349, 1532–1536 (2015).

    Article  ADS  CAS  Google Scholar 

  13. Schmidt, V. A., Quinn, R. K., Brusoe, A. T. & Alexanian, E. J. Site-selective aliphatic C–H bromination using N-bromoamides and visible light. J. Am. Chem. Soc. 136, 14389–14392 (2014).

    Article  CAS  Google Scholar 

  14. Milan, M., Salamone, M., Costas, M. & Bietti, M. The quest for selectivity in hydrogen atom transfer based aliphatic C–H bond oxygenation. Acc. Chem. Res. 51, 1984–1995 (2018).

    Article  CAS  Google Scholar 

  15. Carestia, A. M., Ravelli, D. & Alexanian, E. J. Reagent-dictated site selectivity in intermolecular aliphatic C–H functionalizations using nitrogen-centered radicals. Chem. Sci. 9, 5360–5365 (2018).

    Article  CAS  Google Scholar 

  16. Shields, B. J. & Doyle, A. G. Direct C(sp 3)–H cross coupling enabled by catalytic generation of chlorine radicals. J. Am. Chem. Soc. 138, 12719–12722 (2016).

    Article  CAS  Google Scholar 

  17. Milan, M., Bietti, M. & Costas, M. Highly enantioselective oxidation of nonactivated aliphatic C–H bonds with hydrogen peroxide catalyzed by manganese complexes. ACS Cent. Sci. 3, 196–204 (2017).

    Article  CAS  Google Scholar 

  18. Covell, D. J. & White, M. C. A chiral Lewis acid strategy for the enantioselective allylic C–H oxidation. Angew. Chem. Int. Ed. 47, 6448–6451 (2008).

    Article  CAS  Google Scholar 

  19. Bayeh, L., Le, P. Q. & Tambar, U. K. Catalytic allylic oxidation of internal alkenes to a multifunctional chiral building block. Nature 547, 196–200 (2017).

    Article  ADS  CAS  Google Scholar 

  20. Kharasch, M. S. & Sosnovsky, G. The reactions of t-butyl perbenzoate and olefins—a stereospecific reaction. J. Am. Chem. Soc. 80, 756 (1958).

    Article  CAS  Google Scholar 

  21. Eames, J. & Watkinson, M. Catalytic allylic oxidation of alkenes using an asymmetric Kharasch–Sosnovsky reaction. Angew. Chem. Int. Ed. 40, 3567–3571 (2001).

    Article  CAS  Google Scholar 

  22. Andrus, M. B. & Zhou, Z. Highly enantioselective copper-bisoxazoline-catalyzed allylic oxidation of cyclic olefins with tert-butyl p-nitroperbenzoate. J. Am. Chem. Soc. 124, 8806–8807 (2002).

    Article  CAS  Google Scholar 

  23. Wang, F. et al. Enantioselective copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes via radical process. J. Am. Chem. Soc. 138, 15547–15550 (2016).

    Article  CAS  Google Scholar 

  24. Zhang, W. et al. Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay. Science 353, 1014–1018 (2016).

    Article  ADS  CAS  Google Scholar 

  25. Czaplyski, W. L., Na, C. G. & Alexanian, E. J. C–H xanthylation: a synthetic platform for alkane functionalization. J. Am. Chem. Soc. 138, 13854–13857 (2016).

    Article  CAS  Google Scholar 

  26. Kärkäs, M. D. Photochemical generation of nitrogen-centered amidyl, hydrazonyl, and imidyl radicals: methodology development and catalytic applicants. ACS Catal. 7, 4999–5022 (2017).

    Article  Google Scholar 

  27. Artaryan, A. et al. Aliphatic C−H bond iodination by a N-iodoamide and isolation of an elusive N-amidyl radical. J. Org. Chem. 82, 7093–7100 (2017).

    Article  CAS  Google Scholar 

  28. Palucki, M. et al. The mechanistic basis for electronic effect on enantioselectivity in the (salen)Mn(ii)-catalyzed epoxidation reaction. J. Am. Chem. Soc. 120, 948–954 (1998).

    Article  CAS  Google Scholar 

  29. Barham, J. P., John, M. P. & Murphy, J. A. Contra-thermodynamic hydrogen atom abstraction in the selective C−H functionalization of trialkylamine N-CH3 groups. J. Am. Chem. Soc. 138, 15482–15487 (2016).

    Article  CAS  Google Scholar 

  30. Peters, J.-U. 11 years of cyanopyrrolidines as DPP-IV inhibitors. Curr. Top. Med. Chem. 7, 579–595 (2007).

    Article  CAS  Google Scholar 

  31. Liao, K. et al. Site-selective and stereoselective functionalization of non-activated tertiary C–H bonds. Nature 551, 609–613 (2017).

    Article  ADS  CAS  Google Scholar 

  32. Chen, M. S. & White, M. C. A predictably selective aliphatic C–H oxidation reaction for complex molecule synthesis. Science 318, 783–787 (2007).

    Article  ADS  CAS  Google Scholar 

  33. Fleming, F. F., Yao, L., Ravikumar, P. C., Funk, L. & Shook, B. C. Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore. J. Med. Chem. 53, 7902–7917 (2010).

    Article  CAS  Google Scholar 

Download references

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.

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Authors and Affiliations

  1. State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Jiayuan Li, Lianqian Wu, Wen Zhang, Pinhong Chen & Guosheng Liu

  2. Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China

    Zhihan Zhang & Zhenyang Lin

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Contributions

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.

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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). https://doi.org/10.1038/s41586-019-1655-8

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