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

Senior, Aaron; Ruffell, Katie; Ball, Liam T.

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.

Citation

Senior, A., Ruffell, K., & Ball, L. T. (2022). meta-Selective C–H arylation of phenols via regiodiversion of electrophilic aromatic substitution. Nature Chemistry, https://doi.org/10.1038/s41557-022-01101-0

• Journal Article Type: Article
• Acceptance Date: Oct 27, 2022
• Online Publication Date: Dec 12, 2022
• Publication Date: Dec 12, 2022
• Deposit Date: Dec 13, 2022
• Publicly Available Date: Jun 13, 2023
• Journal: Nature Chemistry
• Print ISSN: 1755-4330
• Electronic ISSN: 1755-4349
• Publisher: Springer Science and Business Media LLC
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1038/s41557-022-01101-0
• Keywords: General Chemical Engineering; General Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/14885006
• Publisher URL: https://www.nature.com/articles/s41557-022-01101-0
• Additional Information: This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1038/s41557-022-01101-0