Palladium-Catalyzed Aerobic Oxidative Indole Arylation: Mechanistic Studies

钯催化有氧氧化吲哚芳基化：机理研究

基本信息

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
项目类别：
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

项目摘要

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.

该提案旨在研究简化合成三种物质的新化学工艺生物活性小分子中常见的结构基序：酚/芳基醚（例如 DetrolTM、 Nexium®）、叔酰胺（例如 Januvia®、Diovan®）和带有两个芳基的叔碳（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结构单元，钯催化将芳烃 C(sp2)−H 键转化为芳烃 C(sp2)−O 键的有氧氧化策略是大多数钯催化的芳烃 C−H 氧化反应都使用昂贵且昂贵的方法。产生废物的氧化剂，例如 PhI(OAc)2 和过硫酸盐，以及理想的先例有氧替代品的缺点是周转次数低 (<15) 和/或氧气含量过高所提议的研究需要使用氧化还原介体策略以按顺序进行。动力学上促进有氧钯催化芳烃 C−H 氧化，特别是 NOx-。基于助氧化剂（例如 HNO3、亚硝酸叔丁酯），很容易被 O2 再氧化，目的是为了实现钯金的高成交量。为了合成叔酰胺，一种新的铜/硝酰基催化的有氧反应是正在探索能够在存在下将伯醇氧化成叔酰胺伯醇氧化成叔酰胺是通过以下方法实现的。钌或金纳米粒子催化的过程，但局限性包括窄基板范围广，并且催化剂昂贵且/或合成具有挑战性。铜催化策略利用廉价的、市售的催化剂并建立在先前用于铜/硝酰基催化的醇氧化为醛的方法。对于带有两个芳基的叔碳的合成，此类基序通常是通过与预官能化苄基底物的交叉偶联反应获得据我们所知，非定向的苄基 C−H 芳基化具有从未实现过铜催化的苄基 C−H 芳基化策略（使用芳基硼）。酯）目前正在探索该方法的灵感来自Kharasch-Sosnovsky C(sp3)−H。到 C(sp3)−O 或 C(sp3)−N 氧化转化；然而，Kharasch-Sosnovsky 反应迄今为止，C(sp3)−C 键的构建尚未实现。