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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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.
The authors declare no competing interests.
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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