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Abstract Dearomative cycloadditions offer rapid access to complex 3D molecular architectures, commonly via a sp2‐to‐sp3rehybridization of two atoms of an aromatic ring. Here we report that the 6e π‐system of a benzenoid aromatic pendant could be exhaustively depleted within a single photochemical cascade. An implementation of this approach involves the initial dearomative [4+2] cycloaddition of the Excited State Intramolecular Proton Transfer (ESIPT)‐generated azaxylylene, followed by two consecutive [2+2] cycloadditions of auxiliary π moieties strategically positioned in the photoprecursor. Such photochemical cascade fully dearomatizes the benzenoid aromatic ring, saturating all six sp2atoms to yield a complex sp3‐rich scaffold with high control of its 3D molecular shape, rendering it a robust platform for rapid systematic mapping of underexplored chemical space. Significant growth of molecular complexity—starting with a modular synthesis of photoprecursors from readily available building blocks—is quantified by Böttcher score calculations.
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Facile access to fused 2D/3D rings via intermolecular cascade dearomative [2 + 2] cycloaddition/rearrangement reactions of quinolines with alkenes
Abstract Hybrid fused two-dimensional/three-dimensional (2D/3D) rings are important pharmacophores in drugs owing to their unique structural and physicochemical properties. Preparation of these strained ring systems often requires elaborate synthetic effort and exhibits low efficiency, thus representing a limiting factor in drug discovery. Here, we report two types of energy-transfer-mediated cascade dearomative [2 + 2] cycloaddition/rearrangement reactions of quinoline derivatives with alkenes, which provide a straightforward avenue to 2D/3D pyridine-fused 6−5−4−3- and 6−4−6-membered ring systems. Notably, this energy-transfer-mediated strategy features excellent diastereoselectivity that bypasses the general reactivity and selectivity issues of photochemical [2 + 2] cycloaddition of various other aromatics. Tuning the aza-arene substitutions enabled selective diversion of the iridium photocatalysed energy transfer manifold towards either cyclopropanation or cyclobutane-rearrangement products. Density functional theory calculations revealed a cascade energy transfer scenario to be operative.
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- PAR ID:
- 10354887
- Date Published:
- Journal Name:
- Nature Catalysis
- Volume:
- 5
- Issue:
- 5
- ISSN:
- 2520-1158
- Page Range / eLocation ID:
- 405 to 413
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41929-022-00784-5
