Palladium-Catalyzed Aerobic Oxidative Indole Arylation: Mechanistic Studies

钯催化有氧氧化吲哚芳基化：机理研究

• 批准号: 8647251
• 负责人: Susan Zultanski
• 金额: $ 4.99万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647251
• 关键词: Aerobic; Architecture; Attention; Benign; Benzene; Chemicals; Computing Methodologies; Coupled; Coupling; Crestor; Deuterium; Development; Disease; Drug Prescriptions; Due Process; Event; Gleevec; Health; Hydrogen Bonding; Indoles; Isotopes; Kinetics; Label; Laws; Ligands; Methods; Modeling; Modification; Molecular; Outcome; Oxidants; Palladium; Pharmaceutical Preparations; Prevalence; Process; Property; Reaction; Relative (related person); Reporting; Research; Rest; Role; Series; Societies; System; Testing; United States; atorvastatin; celecoxib; chemical kinetics; design; improved; insight; prevent; research study; scaffold; small molecule; sound; tool; wasting

DESCRIPTION (provided by applicant): Biaryls are one of the most pervasive structural motifs in biologically active molecules, and they can be found within the scaffolds of numerous highly prescribed drugs in the United States (e.g., Lipitor(r), Gleevec(r), Crestor(r), Celebrex(r)). An emerging strategy for the synthesis of biaryls involves palladium-catalyzed oxidative cross-coupling through two arene C-H activations to form an aryl-aryl bond; this strategy has attracted attention because arene prefunctionalization is unnecessary. Because palladium-catalyzed oxidative arene cross-coupling is a relatively nascent field, the mechanisms of these processes remain poorly understood; additionally, there exist ongoing challenges to the development of efficient processes, due to the relative inertness of C-H bonds. The proposed research entails systematic mechanistic studies of a recently reported palladium-catalyzed aerobic oxidative indole arylation. This method demonstrates that neutral ligands, which are uncommon in palladium-catalyzed oxidative arene couplings, have a positive influence on regiocontrol (selective C-H activation) and general reactivity; additionally, they enable the use of O2 as the sole, atom-economical, oxidant. Our mechanistic approach will include elucidation of the catalytic cycles for two regioselective (C2- ad C3-) indole arylations, via the synthesis and testing of potential key catalytic intermediates, coupled with kinetics and spectroscopic studies in order to determine the rate law, rae-determining step, and catalytic resting state. Additionally, the role of palladium and the neutral ligand in the event of each elementary step will be examined through a combination of experimental efforts and computational kinetic modeling. Insights gained will enable the logical design of more efficient palladium/neutral ligand systems for this process, and, more broadly, this study will prompt and direct efforts to develop new palladium-catalyzed aerobic oxidative arene coupling reactions that take advantage of neutral ligands as a tool for improving reactivity.

描述（由申请人提供）：联芳基是生物活性分子中最普遍的结构基序之一，在美国许多高度处方药物的支架中都可以找到它们（例如立普妥（R）、格列卫（R）） 、 Crestor(r)、Celebrex(r))。一种新兴的联芳基合成策略涉及钯催化的氧化交叉偶联，通过两个芳烃 C-H 活化形成芳基-芳基键；该策略引起了人们的关注，因为芳烃预功能化是不必要的。 由于钯催化的氧化芳烃交叉偶联是一个相对新兴的领域，因此这些过程的机制仍然知之甚少。此外，由于 C-H 键的相对惰性，高效工艺的开发持续存在挑战。 拟议的研究需要对最近报道的钯催化有氧氧化吲哚芳基化进行系统的机理研究。 该方法证明中性配体， 在钯催化的氧化芳烃偶联中并不常见，对区域控制（选择性 C-H 激活）和一般反应性有积极影响； 此外，它们还可以使用 O2 作为唯一的原子经济氧化剂。 我们的机制方法将包括通过合成和测试潜在的关键催化中间体，结合动力学和光谱研究来阐明两种区域选择性（C2-和C3-）吲哚芳基化的催化循环，以确定速率定律，rae-确定步骤和催化静止状态。此外，钯和中性金属的作用 配体在每个基本步骤的情况下将通过实验努力和计算动力学模型的结合进行检查。 获得的见解将使该过程更有效的钯/中性配体系统的逻辑设计成为可能，更广泛地说，这项研究将促进和指导开发新的钯催化有氧氧化芳烃偶联反应的努力，该反应利用中性配体作为提高反应性的工具。