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）：双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)）。合成双芳基的新策略包括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；这种策略引起了人们的注意，因为芳烃的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生的领域，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，在开发高效工艺方面存在持续的挑战。提出的研究需要对最近报道的钯催化的有氧氧化吲哚芳基化进行系统的机制研究。这种方法证明了中性配体，其中