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: 8815124
• 负责人: Susan Zultanski
• 金额: $ 5.27万
• 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/8815124
• 关键词: Acetates; Aerobic; Alcohols; Aldehydes; Amides; Amines; Area; Benzene; Carbon; Chemicals; Copper; Coupling; Development; Disease; Equilibrium; Esters; Ethers; Gases; Goals; Gold; Health; Hydrogen Bonding; Indoles; Kinetics; Lactams; Marketing; Mediator of activation protein; Metals; Methodology; Methods; Molecular; Nature; Nexium; Nitric Acid; Nitrites; Outcome; Oxidants; Oxidation-Reduction; Palladium; Pharmaceutical Preparations; Phenols; Play; Process; Production; Reaction; Reagent; Research; Role; Route; Ruthenium; Side; Societies; Titrations; Update; Zoloft; base; catalyst; design; diphenyl; insight; nanoparticle; nitrobenzene; nitroxyl; oxidation; pressure; prevent; research study; small molecule; sound; spectroscopic survey; uptake; wasting

This proposal aims to study new chemical processes for the streamlined syntheses of three common structural motifs in bioactive small molecules: phenols/aryl ethers (e.g., DetrolTM, Nexium®), tertiary amides (e.g., Januvia®, Diovan®) and tertiary carbons bearing two aryl groups (e.g., Zoloft®, Condylox®). Contingent upon the successful design of these new methodologies, kinetic and spectroscopic studies will aid in the elucidation of their catalytic mechanisms. Toward the production of phenolic and aryl ether building blocks, a palladium-catalyzed aerobic oxidation strategy that converts arene C(sp2)−H bonds into arene C(sp2)−O bonds is being pursued. Most palladium-catalyzed arene C−H oxygenation reactions use expensive and waste-generating oxidants such as PhI(OAc)2 and persulfates, and precedents for desirable aerobic alternatives suffer from low turnover numbers (<15) and or hazardously high O2 pressures (e.g. 60 atm). The proposed research entails using a redox mediator strategy in order to kinetically facilitate aerobic palladium-catalyzed arene C−H oxygenation. In particular, NOx- based co-oxidants (e.g., HNO3, tert-butyl nitrite), which can readily be reoxidized by O2, are being employed in order to achieve high turnover numbers for palladium. Toward the synthesis of tertiary amides, a new copper/nitroxyl-catalyzed aerobic reaction is being explored that enables oxidation of primary alcohols to tertiary amides in the presence of secondary amines. Oxidation of primary alcohols to tertiary amides has been achieved via ruthenium- or gold nanoparticle-catalyzed processes, yet limitations include narrow substrate scope, and the catalysts are expensive and/or challenging to synthesize. The proposed aerobic copper-catalyzed strategy utilizes inexpensive, commercially available catalysts and builds upon previous methodology for copper/nitroxyl-catalyzed alcohol oxidation of alcohols to aldehydes. Toward the synthesis of tertiary carbons bearing two aryl groups, such motifs are often accessed via cross-coupling reactions with prefunctionalized benzylic substrates and prefunctionalized aryl substrates. To our knowledge, non-directed benzylic C−H arylation has never been achieved. A copper-catalyzed strategy for benzylic C−H arylation (using arylboronic esters) is currently being explored. This method was inspired by Kharasch-Sosnovsky C(sp3)−H to C(sp3)−O or C(sp3)−N oxidative transformations; however, the Kharasch-Sosnovsky reaction has thus far not been achieved for the construction of C(sp3)−C bonds.

该建议旨在研究三个简化合成的新化学过程 生物活性小分子中的常见结构基序：苯酚/芳基醚（例如，Detroltm， nexium®），第三纪（例如Januvia®，Diovan®）和三级碳 （例如，Zoloft®，Condylox®）。取决于这些新方法的成功设计， 动力学和光谱研究将有助于阐明其催化机制。 为了生产酚类和芳基醚构建块，钯催化 有氧氧化策略将Arene C（SP2）-H键转换为Arene C（SP2）-O键为 被追捕。大多数钯催化的Arene C-H氧合反应都使用昂贵，并且 废物生成的氧化剂，例如phi（OAC）2和过硫酸盐，以及理想的先例 有氧替代方案的营业额数量低（<15）和或危险高的O2 压力（例如60 atm）。拟议的研究实体使用氧化还原调解人策略按顺序 动力学促进有氧钯催化的芳烃C-H氧化。特别是，nox- 基于基于o2的基于基于的共氧化剂（例如，HNO3，丁基亚硝酸盐），可以很容易地被O2重新氧化 用于实现钯的高周转数量。 为了合成第三纪酰胺，新的铜/硝氧培养氧反应是 正在探讨在存在的情况下，可以使初级醇氧化成为三级酰胺 中酰胺。通过 唯一或金纳米颗粒催化过程，但局限性包括狭窄的基板 范围，催化剂是昂贵的和/或挑战合成的。提出的有氧运动 铜催化的策略利用便宜的，可商购的催化剂，并基于 先前的铜/硝氧培合酒精氧化为醛的方法。 朝着携带两个芳基的三级碳合成，这种基序通常是 通过与预官能化的二苯基底物和 预官能化的芳基底物。据我们所知，非指导的苯基C-H芳基化具有 从未实现。一种铜催化的苄基C-H芳基化策略（使用芳基硼酸盐 酯）目前正在探索。此方法的灵感来自Kharasch-Sosnovsky C（SP3）-H 到C（SP3）-O或C（SP3）-n氧化转化；但是，Kharasch-Sosnovsky反应 到目前为止，尚未实现C（SP3）-C键的构建。