Palladium-Catalyzed Aerobic Oxidative Indole Arylation: Mechanistic Studies

描述(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，它们可以在美国许多高处方药物的支架中找到(例如，立普妥(R)、格列卫(R)、Crestor(R)、Celebrex(R))。一种合成联芳基的新策略是在钯的催化下，通过两次芳烃C-H活化形成芳基-芳基键的氧化交叉偶联反应；这一策略引起了人们的注意，因为芳烃的预官能化是不必要的。由于钯催化的氧化芳烃交叉偶联是一个相对较新的领域，这些过程的机理仍然知之甚少；此外，由于C-H键的相对惰性，高效过程的开发存在持续的挑战。这项拟议的研究需要对最近报道的钯催化的有氧氧化吲哚芳基化反应进行系统的机理研究。这种方法证明了中性配体，这是 在钯催化的氧化芳烃偶联反应中不常见，对区域控制(选择性C-H活化)和一般反应活性有积极影响；此外，它们使O2能够用作唯一的、原子经济的氧化剂。我们的机理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，阐明两个区域选择性(C2-ad C3-)吲哚芳基化的催化循环，以确定速率定律、RAE决定步骤和催化休止状态。此外，钯和中性金属的作用 将通过实验努力和计算动力学建模相结合的方法来检查每个基本步骤中的配体。所获得的见解将使为这一过程设计更有效的钯/中性配体体系成为可能，更广泛地说，这项研究将促进和指导开发新的钯催化的有氧氧化芳烃偶联反应，利用中性配体作为提高反应活性的工具。

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.