Bone Kendelyn I, Puleo Thomas R, Bandar Jeffrey S
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States.
J Am Chem Soc. 2024 Apr 10;146(14):9755-9767. doi: 10.1021/jacs.3c14058. Epub 2024 Mar 26.
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 -heteroarenes and benzenes. This protocol employs an alkoxide base to catalyze X-transfer from sacrificial 2-halothiophene oxidants to aryl substrates, forming SAr-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 -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.
羟基化（杂）芳烃在许多行业中都很有价值，既是最终产品的关键成分，也是可多样化的合成构建块。因此，开发能够补充并解决现有引入芳族羟基方法局限性的反应是一个重要目标。为此，我们应用碱催化的卤素转移（X转移）来实现弱酸性杂芳烃和苯的直接C-H羟基化。该方案采用醇盐碱催化从牺牲性2-卤代噻吩氧化剂向芳基底物的X转移，形成经历亲核羟基化的SAr活性中间体。该过程的关键是使用2-苯乙醇作为廉价的氢氧化物替代物，其在芳族取代和快速消除后，提供羟基化芳烃和苯乙烯副产物。使用简单的2-卤代噻吩可实现六元杂芳烃和1,3-唑衍生物的C-H羟基化，而合理设计的2-卤代苯并噻吩氧化剂则将范围扩展到缺电子苯底物。机理研究表明芳族X转移是可逆的，这表明去质子化、卤化和取代步骤协同作用，表现出独特的选择性趋势，不一定取决于最酸性的芳基位置。通过简化目标分子合成、与其他C-H羟基化方法形成对比的区域选择性实例以及噻吩氧化剂的可扩展回收，进一步证明了该方法的实用性。
