Liu Tao, Li Talin, Tea Zhi Yuan, Wang Chu, Shen Tianruo, Lei Zhexuan, Chen Xuebo, Zhang Weigang, Wu Jie
Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore.
College of Chemistry, Beijing Normal University, Beijing, People's Republic of China.
Nat Chem. 2024 Oct;16(10):1705-1714. doi: 10.1038/s41557-024-01560-7. Epub 2024 Jun 27.
The 1,2-arylheteroaryl ethane motif stands as a privileged scaffold with promising implications in drug discovery. Conventional de novo syntheses of these molecules have relied heavily on pre-functionalized synthons, entailing harsh conditions and multi-step processes. Here, to address these limitations, we present a modular approach for the direct synthesis of 1,2-arylheteroaryl ethanes using feedstock chemicals, including ethylene, arenes and heteroarenes. We disclosed a photo triplet-energy-transfer-initiated radical cascade process, leveraging homolytic cleavage of C-S bonds in aryl sulfonium salts as the key step to access aryl radicals with excellent regioselectivity. This method allows for rapid structural diversification of bioactive molecules, showcasing excellent functional group tolerance and streamlining the synthesis of bioactive compounds and their derivatives. Furthermore, our approach can be extended to propylene, non-gaseous terminal alkenes and various other electrophilic radical precursors, including heteroaryl radicals, hydroxyl radicals, trifluoromethyl radicals and α-carbonyl alkyl radicals. This study highlights the significance of radical polarity matching in designing selective multi-component couplings.
1,2-芳基杂芳基乙烷基序是一种具有重要意义的骨架结构，在药物发现领域有着广阔的应用前景。传统的这些分子的从头合成方法严重依赖于预官能化的合成子，需要苛刻的条件和多步反应过程。在此，为了解决这些局限性，我们提出了一种模块化方法，用于使用包括乙烯、芳烃和杂芳烃在内的原料化学品直接合成1,2-芳基杂芳基乙烷。我们揭示了一种光三重态能量转移引发的自由基级联反应过程，利用芳基锍盐中C-S键的均裂作为关键步骤，以优异的区域选择性获得芳基自由基。该方法能够实现生物活性分子的快速结构多样化，展现出优异的官能团耐受性，并简化了生物活性化合物及其衍生物的合成。此外，我们的方法可以扩展到丙烯、非气态末端烯烃以及各种其他亲电自由基前体，包括杂芳基自由基、羟基自由基、三氟甲基自由基和α-羰基烷基自由基。这项研究突出了自由基极性匹配在设计选择性多组分偶联反应中的重要性。
