Department of Chemistry, Southern Methodist University , Dallas, Texas 75275, United States.
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
J Org Chem. 2017 Aug 4;82(15):7887-7904. doi: 10.1021/acs.joc.7b01069. Epub 2017 Jul 14.
The use of copper in directed C-H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of CuO intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCu(OOR) intermediate undergoes homolytic O-O cleavage to generate reactive RO species, which are responsible for key C-H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.
铜在定向 C-H 氧化中的应用相对较少被探索。在一个重要的例子中，Schönecker 表明铜和 O 促进了含甾体配体的羟化。最近，Baran（J. Am. Chem. Soc. 2015, 137, 13776）改进了反应条件，以优异的收率氧化类似的底物。在这两个报告中，都提出了 CuO 中间体的参与。在这篇合作文章中，我们详细研究了羟化机制，导致了之前被接受的机制的全面检修和改进反应条件的开发。大量的实验证据（光谱表征、动力学分析、分子间反应性和自由基捕获实验）提供了支持所提出的每个基本步骤的证据，以及假设一个关键的单核 LCu（OOR）中间体经历均裂 O-O 裂解，生成活性 RO 物种，这是溶剂笼内关键 C-H 羟化的原因。这些关键发现使得氧化方案得以重新制定，提高了反应成本、实用性和分离收率。
