Reimagining Dearomatization: Arenophile-Mediated Single-Atom Insertions and π‑Extensions

• Published in: Accounts of chemical research Vol. 58; no. 7; pp. 1134 - 1150
• Main Authors: Siddiqi, Zohaib, Sarlah, David
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.04.2025
• DOI: 10.1021/acs.accounts.5c00035
• ISSN: 0001-4842; 1520-4898

Conspectus Dearomatization of simple aromatics serves as one of the most direct strategies for converting abundant chemical feedstocks into three-dimensional value-added products. Among such transformations, cycloadditions between arenes and alkenes have historically offered effective means to construct complex polycyclic architectures. However, traditionally harsh conditions, such as high-energy UV light irradiation, have greatly limited the scope of this transformation. Nevertheless, recent progress has led to the development of visible-light-promoted dearomative photocycloadditions with expanded scope capable of preparing complex bicyclic structures. A fundamentally distinct approach to dearomative photocycloadditions involves the visible-light activation of arenophiles, which undergo para-photocycloaddition with various aromatic compounds to produce arene-arenophile cycloadducts. While only transiently stable and subject to retro-cycloaddition, further functionalization of the photocycloadducts has allowed for the development of a wide collection of dearomatization methodologies that access products orthogonal to existing chemical and biological processes. Central to this strategy was the observation that arene-arenophile photocycloaddition reveals a π-system that can be functionalized through traditional olefin chemistry. Coupled with subsequent [4 + 2]-cycloreversion of the arenophile, this process acts to effectively isolate a single π-system from an aromatic ring. We have developed several transformations that bias this methodology to perform dearomative single-atom insertion and π-extension reactions to prepare unique products that cannot be prepared easily through traditional means. Through the application of a dearomative epoxidation, we were able to develop a method for the epoxidation of arenes and pyridines to arene-oxides and pyridine-oxides, respectively. Notably, when this arenophile chemistry is applied to polycyclic arenes, photocycloaddition reveals a π-system transposed from the site of native olefinic reactivity, enabling unique site-selectivity for dearomative functionalization. As a result, we were able to perform a single-atom insertion of oxygen into polycyclic (aza)­arenes to prepare 3-benzoxepines. When applying this strategy in the context of cyclopropanations, we were able to accomplish a dearomative cyclopropanation of polycyclic (aza)­arenes which yield benzocycloheptatrienes upon cycloreversion. Notably, while the Buchner ring expansion is a powerful method for the direct single-atom insertion of carbon into arenes, the corresponding cyclopropanation of polycyclic arenes does not yield ring-expanded products. Furthermore, this strategy could be utilized for the synthesis of novel nanographenes through the development of an M-region annulative π-extension (M-APEX) reaction. Traditionally, methods for π-extension rely on the native reactivity of polycyclic aromatics at the K- and bay-region. However, photocycloaddition of polycyclic aromatics with arenophiles acts as a strategy to activate the M-region for further reactivity. As a result, arenophile-mediated dearomative diarylation, followed by cycloreversion, could deliver π-extended nanographenes with exclusive M-region site selectivity.