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A para- to meta-isomerization of phenols

Nature Chemistry (2024)Cite this article

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Abstract

Phenols and their derivatives are ubiquitous in nature and critically important industrial chemicals. Their properties are intimately linked to the relative substitution pattern of the aromatic ring, reflecting well-known electronic effects of the OH group. Because of these ortho-, para-directing effects, meta-substituted phenols have historically been more difficult to synthesize. Here we describe a procedure to transpose phenols that hinges on a regioselective diazotization of the corresponding ortho-quinone. The procedure affords the meta-substituted phenol directly from its more common and accessible para-substituted isomer, and demonstrates good chemoselectivity that enables its application in late-stage settings. By changing the electronic effect of the OH group and its trajectory of hydrogen bonding, our transposition can be used to diversify natural products and existing chemical libraries, and potentially shorten the length and cost of producing underrepresented arene isomers.

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Fig. 1: Challenges and development of a 1,2-phenol transposition.
Fig. 2: Reaction development and optimization.
Fig. 3: Isomerization of complex substrates and complementarity with existing methodologies.

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Data availability

The data supporting the main findings of this study are available in the article, Supplementary Information and source data. Source data, including unprocessed free induction decays (FIDs) of all compounds, are available for download, free of charge, from the Open Science Framework (OSF) data repository at https://osf.io/e7q8n (ref. 50).

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Acknowledgements

We thank I. Mbaezue (McGill University) for help with high-performance liquid chromatography, and K. Levin (McGill University) for help with NMR. Financial support was provided by the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant to J.-P.L). S.E. acknowledges NSERC (CGS-M) and the Fonds de Recherche du Québec Nature et Technologies (FRQNT-B1X and FRQNT-B2X) for research fellowships, the Walter C. Sumner Foundation for a Memorial Fellowship and McGill University for financial support.

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  1. Department of Chemistry, McGill University, Montreal, Quebec, Canada

    Simon Edelmann & Jean-Philip Lumb

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  1. Simon Edelmann
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Contributions

S.E. designed and conducted experiments, and collected and analysed the data. J.-P.L. and S.E. conceptualized the project and wrote the manuscript. J.-P.L. supervised the research.

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Correspondence to Jean-Philip Lumb.

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Nature Chemistry thanks Junichiro Yamaguchi, Derrick Clive and Ning Jiao for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–3, discussion of procedures, and processed characterization data including tabulated infra-red and mass spectrometry, along with 1H- and 13C-NMR data, in both tabulated and graphical forms.

Supplementary Data

Unprocessed FIDs for all NMR characterization data, designated by compound numbers as they appear in the text of the paper or in Supplementary Information.

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Edelmann, S., Lumb, JP. A para- to meta-isomerization of phenols. Nat. Chem. (2024). https://doi.org/10.1038/s41557-024-01512-1

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