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Preparation of phenols by phthaloyl peroxide–mediated oxidation of arenes

Nature Protocols volume 9, pages 2624–2629 (2014)Cite this article

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Abstract

This protocol describes an approach to installing hydroxyls into arenes through the direct replacement of C–H bonds with C–O bonds. This direct oxidation avoids the need to prefunctionalize the substrate, use precious metals, introduce directing groups, or use strong Brønsted or Lewis acids. Phthaloyl peroxide, the sole reagent used for this transformation, can be prepared readily from the commodity chemicals phthaloyl chloride and sodium percarbonate. Phthaloyl peroxide oxidizes a diverse range of arenes, and the reactions that involve its use are characterized by high functional group compatibility, which enables the hydroxylation of simple arenes, advanced synthetic intermediates, natural products and other drug-like molecules forming the corresponding phenolic compounds. Notably, the reaction is operationally straightforward and has no special requirements for the exclusion of oxygen and water. The synthesis of phthaloyl peroxide takes 4 h and the subsequent hydroxylation of mesitylene takes 21 h.

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Figure 1: Hydroxylation of arenes via the reverse-rebound mechanism.
Figure 2
Figure 3: Hydroxylation of arenes by phthaloyl peroxide (2).
Figure 4

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Acknowledgements

Financial support from the Welch Foundation (F-1694) is gratefully acknowledged. The authors thank C. Bielawski and A. Teator for assistance with Karl Fischer titrations.

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Authors and Affiliations

  1. Department of Chemistry, The University of Texas at Austin, Austin, Texas, USA

    Changxia Yuan, Anders M Eliasen, Andrew M Camelio & Dionicio Siegel

  2. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.,

    Dionicio Siegel

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  1. Changxia Yuan
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  2. Anders M Eliasen
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Contributions

C.Y., A.E. and A.C. designed the experiments and carried out the experiments; C.Y., A.E., A.C. and D.S. analyzed the data and wrote the paper; and D.S. supervised the research.

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Correspondence to Dionicio Siegel.

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Yuan, C., Eliasen, A., Camelio, A. et al. Preparation of phenols by phthaloyl peroxide–mediated oxidation of arenes. Nat Protoc 9, 2624–2629 (2014). https://doi.org/10.1038/nprot.2014.175

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