Zhang Haiman, Lin Shuang, Gao Hui, Zhang Kaixin, Wang Yi, Zhou Zhi, Yi Wei
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
School of Chemical Engineering and Technology, Sun Yat-Sen University, Guangzhou, Guangdong, China.
Commun Chem. 2021 Jun 3;4(1):81. doi: 10.1038/s42004-021-00518-x.
Ortho-functionalized phenols and their derivatives represent prominent structural motifs and building blocks in medicinal and synthetic chemistry. While numerous synthetic approaches exist, the development of atom-/step-economic and practical methods for the chemodivergent assembly of diverse ortho-functionalized phenols based on fixed catalyst/substrates remains challenging. Here, by selectively controlling the reactivities of different sites in methylenecyclopropane core, Rh(III)-catalyzed redox-neutral and tunable C-H functionalizations of N-phenoxyacetamides are realized, providing access to both ortho-functionalized phenols bearing linear dienyl, cyclopropyl or allyl ether groups, and cyclic 3-ethylidene 2,3-dihydrobenzofuran frameworks under mild cross-coupling conditions. These divergent transformations feature broad substrate compatibility, synthetic applications and excellent site-/regio-/chemoselectivity. Experimental and computational mechanistic studies reveal that distinct catalytic modes involving selective β-C/β-H elimination, π-allylation, inter-/intramolecular nucleophilic substitution cascade and β-H' elimination processes enabled by different solvent-mediated and coupling partner-controlled reaction conditions are crucial for achieving chemodivergence, among which a structurally distinct Rh(V) species derived from a five-membered rhodacycle is proposed as the corresponding active intermediates.
邻位官能化苯酚及其衍生物是药物化学和合成化学中重要的结构基序和构建单元。虽然存在众多合成方法，但基于固定催化剂/底物，开发用于多种邻位官能化苯酚化学发散组装的原子/步骤经济且实用的方法仍然具有挑战性。在此，通过选择性控制亚甲基环丙烷核心中不同位点的反应性，实现了铑（III）催化的N-苯氧基乙酰胺的氧化还原中性且可调的C-H官能化反应，在温和的交叉偶联条件下，可得到带有线性二烯基、环丙基或烯丙基醚基团的邻位官能化苯酚，以及环状3-亚乙基-2,3-二氢苯并呋喃骨架。这些发散转化具有广泛的底物兼容性、合成应用以及出色的位点/区域/化学选择性。实验和计算机理研究表明，不同的溶剂介导和偶联伙伴控制的反应条件所实现的涉及选择性β-C/β-H消除、π-烯丙基化、分子间/分子内亲核取代级联和β-H'消除过程的独特催化模式对于实现化学发散至关重要，其中源自五元铑环的结构独特的铑（V）物种被提议为相应的活性中间体。
