Seliger Jan, Fries Lydia R, Meinhardt Jonathan M, Knowles Robert R
Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States.
J Am Chem Soc. 2025 Mar 19;147(11):9931-9938. doi: 10.1021/jacs.5c01012. Epub 2025 Mar 6.
Nucleophilic aromatic substitution (SAr) reactions are widely employed in organic synthesis yet typically require the use of electron-deficient arenes for efficient reactivity. Herein, we report a photocatalytic protocol for formal SAr of electron-rich 4-halophenols with azole nucleophiles under mild, redox-neutral conditions. The transformation proceeds via a two-stage mechanism consisting of initial halophenol oligomerization to produce a key oligo(phenylene oxide) intermediate and its subsequent breakdown through SAr with the azole enabled by photoredox-catalyzed arene umpolung. Reaction monitoring, stoichiometric control experiments, and luminescence quenching data implicate phenoxyl radicals and Brønsted acid-activated oligo(phenylene oxide) radicals as the reactive species in the oligomerization and the SAr stages, respectively. The synthetic utility of this method is demonstrated across 17 (pseudo)halophenols bearing a variety of leaving groups (F, Cl, Br, OMs, and OTs) and 22 azole examples.
亲核芳香取代（SAr）反应在有机合成中被广泛应用，但通常需要使用缺电子芳烃才能实现高效反应。在此，我们报道了一种光催化方法，可在温和的氧化还原中性条件下，使富电子的4-卤代酚与唑类亲核试剂发生形式上的SAr反应。该转化过程通过两阶段机制进行，首先是卤代酚发生初始低聚反应生成关键的聚（亚苯基氧化物）中间体，随后通过光氧化还原催化的芳烃极性反转，使该中间体与唑类发生SAr反应而分解。反应监测、化学计量控制实验和发光猝灭数据表明，苯氧基自由基和布朗斯特酸活化的聚（亚苯基氧化物）自由基分别是低聚反应和SAr反应阶段的活性物种。该方法的合成实用性在17种带有各种离去基团（F、Cl、Br、OMs和OTs）的（伪）卤代酚以及22个唑类实例中得到了证明。
