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Scalable and sustainable electrochemical allylic C–H oxidation

Nature volume 533, pages 77–81 (2016)Cite this article

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Abstract

New methods and strategies for the direct functionalization of C–H bonds are beginning to reshape the field of retrosynthetic analysis, affecting the synthesis of natural products, medicines and materials1. The oxidation of allylic systems has played a prominent role in this context as possibly the most widely applied C–H functionalization, owing to the utility of enones and allylic alcohols as versatile intermediates, and their prevalence in natural and unnatural materials2. Allylic oxidations have featured in hundreds of syntheses, including some natural product syntheses regarded as “classics”3. Despite many attempts to improve the efficiency and practicality of this transformation, the majority of conditions still use highly toxic reagents (based around toxic elements such as chromium or selenium) or expensive catalysts (such as palladium or rhodium)2. These requirements are problematic in industrial settings; currently, no scalable and sustainable solution to allylic oxidation exists. This oxidation strategy is therefore rarely used for large-scale synthetic applications, limiting the adoption of this retrosynthetic strategy by industrial scientists. Here we describe an electrochemical C–H oxidation strategy that exhibits broad substrate scope, operational simplicity and high chemoselectivity. It uses inexpensive and readily available materials, and represents a scalable allylic C–H oxidation (demonstrated on 100 grams), enabling the adoption of this C–H oxidation strategy in large-scale industrial settings without substantial environmental impact.

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Figure 1: Widely applied allylic oxidation.
Figure 2: Optimization of a sustainable allylic C–H oxidation.
Figure 3: Scope of the electrochemical allylic oxidation.
Figure 4: Practicality of the electrochemical method.
Figure 5: Proposed mechanism for electrochemical allylic oxidation.

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Acknowledgements

This work was supported by an NSF predoctoral fellowship (B.R.R.), National Institute of General Medical Sciences grant GM-097444, Asymchem and Bristol–Myers Squibb. We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy; A. L. Rheingold, C. E. Moore and M. A. Galella for X-ray crystallographic analysis; and D. G. Blackmond, O. Luca, T. Paschkewitz, Y. Ishihara and T. Razler for discussions.

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Author notes

  1. Evan J. Horn and Brandon R. Rosen: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Chemistry, The Scripps Research Institute, La Jolla, 92037, California, USA

    Evan J. Horn, Brandon R. Rosen & Phil S. Baran

  2. Asymchem Life Science (Tianjin), Tianjin Economic-Technological Development Zone, Tianjin, 300457, China

    Yong Chen & Jiaze Tang

  3. Chemical Development, Bristol–Myers Squibb, New Brunswick, 08903, New Jersey, USA

    Ke Chen & Martin D. Eastgate

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Contributions

E.J.H., B.R.R. and P.S.B. conceived this work; E.J.H., B.R.R., K.C., M.D.E. and P.S.B. designed the experiments; E.J.H. and B.R.R. conducted the experiments and analysed the data; Y.C. and J.T. performed the large-scale experiments; E.J.H., B.R.R., K.C., M.D.E. and P.S.B. wrote the manuscript.

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Correspondence to Phil S. Baran.

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The authors declare no competing financial interests.

Additional information

Metrical parameters for the structure of 24 are available free of charge from the Cambridge Crystallographic Data Centre under reference number CCDC-1058554.

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This file contains Supplementary Text, Data and additional references (see Contents for more details). (PDF 17780 kb)

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Horn, E., Rosen, B., Chen, Y. et al. Scalable and sustainable electrochemical allylic C–H oxidation. Nature 533, 77–81 (2016). https://doi.org/10.1038/nature17431

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