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meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution

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Abstract

Electrophilic aromatic substitution is among the most widely used mechanistic manifolds in organic chemistry. Access to certain substitution patterns is, however, precluded by intrinsic and immutable substituent effects that ultimately restrict the diversity of the benzenoid chemical space. Here we demonstrate that the established regioselectivity of electrophilic aromatic substitution can be overcome simply by diverting the key σ-complex intermediate towards otherwise inaccessible substitution products. This ‘regiodiversion’ strategy is realized through the development of a general and concise method for the meta-selective C–H arylation of sterically congested phenols. Consisting of a Bi(V)-mediated electrophilic arylation and a subsequent aryl migration/rearomatization, our process is orthogonal to conventional C–H activation and cross-coupling approaches, and does not require prefunctionalization of the substrate. Mechanistically informed applications in synthesis showcase its utility as a versatile and enabling route to highly functionalized, contiguously substituted aromatic building blocks that defy synthesis via existing methods.

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Fig. 1: Origins, consequences and diversion of EAS regioselectivity.
Fig. 2: Proof of principle and reaction development.
Fig. 3: Mechanistic analysis of σ-complex regiodiversion.
Fig. 4: Synthetic applications of meta-selective C–H arylation.

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Data availability

The authors declare that all data supporting the findings of this study are available within the paper and its Supplementary Information files.

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Acknowledgements

We acknowledge support from K. Butler, S. Aslam and B. Pointer-Gleadhill from the University of Nottingham Analytical Services. This work was supported by the EPSRC Centre for Doctoral Training in Sustainable Chemistry (grant no. EP/S022236/1, studentship to A.S.), Syngenta (studentship to K.R.), UKRI (grant no. MR/V022067/1, Future Leaders Fellowship to L.T.B.) and the University of Nottingham.

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  1. School of Chemistry, University of Nottingham, Nottingham, UK

    Aaron Senior, Katie Ruffell & Liam T. Ball

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L.T.B. conceived and directed the project. L.T.B., A.S. and K.R. designed the experiments. A.S. and K.R. carried out the experiments. All the authors analysed the data. L.T.B. wrote the manuscript.

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Correspondence to Liam T. Ball.

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Supplementary Figs. 1–3, Tables 1–4, discussion, experimental procedures, characterization data and NMR spectra.

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Senior, A., Ruffell, K. & Ball, L.T. meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution. Nat. Chem. 15, 386–394 (2023). https://doi.org/10.1038/s41557-022-01101-0

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