School of Chemistry, University of Nottingham, Nottingham, UK.
Nat Chem. 2023 Mar;15(3):386-394. doi: 10.1038/s41557-022-01101-0. Epub 2022 Dec 12.
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.
亲电芳香取代反应是有机化学中应用最广泛的反应机理之一。然而，某些取代模式由于内在的、不可改变的取代基效应而被排除在外，这些效应最终限制了苯环化学空间的多样性。在这里，我们证明，通过将关键的 σ-络合物中间体引导至原本无法进入的取代产物，即可简单克服已确立的亲电芳香取代反应的区域选择性。这种“区域转换”策略是通过开发一种通用且简洁的方法来实现的，用于对空间位阻较大的苯酚进行间位选择性 C-H 芳基化。该方法由 Bi(V)介导的亲电芳基化和随后的芳基迁移/再芳构化组成，与传统的 C-H 活化和交叉偶联方法正交，并且不需要底物的预官能化。在合成中的应用表明，该方法在机制上是合理的，它是一种通用且有效的方法，可以获得高度官能化的、连续取代的芳香族构建块，这些构建块通过现有的方法难以合成。
