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Electrochemically driven desaturation of carbonyl compounds

Nature Chemistry volume 13, pages 367–372 (2021)Cite this article

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Abstract

Electrochemical techniques have long been heralded for their innate sustainability as efficient methods to achieve redox reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent reactivity through the formal removal of two hydrogen atoms. To date, the most reliable methods to achieve this seemingly trivial reaction rely on transition metals (Pd or Cu) or stoichiometric reagents based on I, Br, Se or S. Here we report an operationally simple pathway to access such structures from enol silanes and phosphates using electrons as the primary reagent. This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable (1–100 g) and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR shifts. Systematic comparisons to state-of-the-art techniques reveal that this method can uniquely desaturate a wide array of carbonyl groups. Mechanistic interrogation suggests a radical-based reaction pathway.

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Fig. 1: α,β-desaturation of carbonyl and enol compounds, state-of-the-art and design of this work.
Fig. 2: Scale-up and mechanistic study of EDD reaction.
Fig. 3: Gaussian computational experiment to assess the feasibility of the EDD reaction; case study of TMS- enolates.

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Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information.

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Acknowledgements

Financial support for this work was provided by the NIH (Grant GM-118176), the NSF (no. 1740656) and AGC Inc. (to Y.T.). S.G. thanks the Council for Higher Education, Fulbright Israel and Yad Hanadiv for the generous fellowships. Authors are grateful to D.-H. Huang and L. Pasternack (Scripps Research) for assistance with the NMR spectroscopy, to J. Chen, B. Sanchez and E. Sturgell (Scripps Automated Synthesis Facility) for assistance with HPLC, high-resolution mass spectroscopy and LCMS.

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Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Samer Gnaim, Yusuke Takahira, Henrik R. Wilke, Julien C. Vantourout & Phil S. Baran

  2. Asymchem Life Science (Tianjin) Co., Ltd, Tianjin, P.R. China

    Zhen Yao & Jinjun Li

  3. Minakem Recherche, Beuvry-la-Forêt, France

    Dominique Delbrayelle & Pierre-Georges Echeverria

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Contributions

S.G., Y.T. and H.R.W. performed and analysed the experiments. P.S.B., S.G. Y.T. and J.C.V. designed the experiments. S.G. and H.R.W. performed the computational analysis. Z.Y. and J.L. designed the flow apparatus and ran the reaction on a 100 g scale in flow. P.-G.E. and D.D. aided in the substrate preparation, control studies and mechanistic analysis. P.S.B., J.C.V. and S.G. prepared the manuscript.

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Correspondence to Phil S. Baran.

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Supplementary Information

Supplementary Tables 1–4 and Figs. 1–13.

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Gnaim, S., Takahira, Y., Wilke, H.R. et al. Electrochemically driven desaturation of carbonyl compounds. Nat. Chem. 13, 367–372 (2021). https://doi.org/10.1038/s41557-021-00640-2

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