Oxygen-substituted arenes not only commonly exist in biologically important molecules, but also serve as a versatile handle to install other functional groups. However, to date it remains challenging to install oxygen groups directly and site-selectively to common aromatic compounds, especially when additional arene functionalization is simultaneously required. Current arene C−H oxidation strategies generally require directing groups to control site-selectivity and/or use strong oxidants, whereas other approaches need precisely pre-functionalized substrates. While the palladium/norbornene (Pd/NBE) cooperative catalysis is promising for site-specific arene vicinal difunctionalization through simultaneous reactions with an electrophile and a nucleophile, respectively, at the ortho and ipso positions, the electrophile scope has been limited to species based on relatively “soft” elements, such as carbon, nitrogen, and sulfur. To shift the Pd/NBE-catalysis paradigm, here we report the development of an ortho oxygenation reaction with readily available aryl halides to rapidly deliver diverse methyl aryl ethers. The coupling of the “hard” oxygen-electrophile is enabled by a stable, polarity reversed, conformationally pre-distorted N−O reagent and facilitated by a C7-bromo-substituted NBE mediator. Mechanistic studies reveal a unique SN2-type pathway between the N−O reagent as the oxygen electrophile and an electron-rich Pd(II) nucleophile. This new C−H oxygenation reaction allows streamlined synthesis of complex bioactive compounds containing methyl aryl ethers and provides an efficient modular approach to access underrepresented benzenoid substitution patterns that are challenging to prepare otherwise.

中文翻译：

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通过极性反转 N-O 试剂实现芳基卤化物的邻-C-H 甲氧基化

氧取代的芳烃不仅普遍存在于生物学上重要的分子中，而且还可以作为安装其他官能团的多功能手柄。然而，迄今为止，将氧基直接和位点选择性地安装到常见的芳香族化合物上仍然具有挑战性，特别是当同时需要额外的芳烃官能化时。目前的芳烃 C−H 氧化策略通常需要定向基团来控制位点选择性和/或使用强氧化剂，而其他方法需要精确的预功能化底物。虽然钯/降冰片烯 (Pd/NBE) 协同催化有望通过分别在邻位和 ipso 位置与亲电试剂和亲核试剂同时反应，实现位点特异性芳烃邻位双官能化，亲电试剂的范围仅限于基于相对“软”元素的物种，例如碳、氮和硫。为了改变 Pd/NBE 催化范式，我们在这里报告了邻位氧化反应的发展，该反应与现成的芳基卤化物快速产生多种甲基芳基醚。“硬”氧-亲电子试剂的偶联是由稳定的、极性反转的、构象预扭曲的 N-O 试剂实现的，并由 C7-溴取代的 NBE 介体促进。机理研究揭示了作为氧亲电子试剂的 NO 试剂和富电子 Pd(II) 亲核试剂之间独特的 SN2 型途径。