化学
羟基化
区域选择性
催化作用
亲核芳香族取代
芳基
亲电芳香族取代
脱质子化
组合化学
化学选择性
亲核细胞
有机化学
亲核取代
烷基
酶
离子
作者
Kendelyn I. Bone,Thomas R. Puleo,Jeffrey S. Bandar
摘要
Hydroxylated (hetero)arenes are valued in many industries as both key constituents of end products and diversifiable synthetic building blocks. Accordingly, the development of reactions that complement and address the limitations of existing methods for the introduction of aromatic hydroxyl groups is an important goal. To this end, we apply base-catalyzed halogen transfer (X-transfer) to enable the direct C–H hydroxylation of mildly acidic N-heteroarenes and benzenes. This protocol employs an alkoxide base to catalyze X-transfer from sacrificial 2-halothiophene oxidants to aryl substrates, forming SNAr-active intermediates that undergo nucleophilic hydroxylation. Key to this process is the use of 2-phenylethanol as an inexpensive hydroxide surrogate that, after aromatic substitution and rapid elimination, provides the hydroxylated arene and styrene byproduct. Use of simple 2-halothiophenes allows for C–H hydroxylation of 6-membered N-heteroarenes and 1,3-azole derivatives, while a rationally designed 2-halobenzothiophene oxidant extends the scope to electron-deficient benzene substrates. Mechanistic studies indicate that aromatic X-transfer is reversible, suggesting that the deprotonation, halogenation, and substitution steps operate in synergy, manifesting in unique selectivity trends that are not necessarily dependent on the most acidic aryl position. The utility of this method is further demonstrated through streamlined target molecule syntheses, examples of regioselectivity that contrast alternative C–H hydroxylation methods, and the scalable recycling of the thiophene oxidants.
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