Palladium-Catalyzed Aerobic Oxidative Indole Arylation: Mechanistic Studies

该提案旨在研究新的化学工艺，以简化合成三种 生物活性小分子中常见的结构基序：酚类/芳基醚（例如，DetrolTM， ）、叔酰胺（例如，和带有两个芳基的叔碳 (e.g., Zoloft®，Condylox®）。取决于这些新方法的成功设计， 动力学和光谱学研究将有助于阐明其催化机理。 为了生产酚和芳基醚结构单元，钯催化的 将芳烃C（sp2）−H键转化为芳烃C（sp2）−O键的有氧氧化策略是 被人追杀大多数钯催化的芳烃C-H氧化反应使用昂贵且 产生废物的氧化剂，如PhI（OAc）2和过硫酸盐，以及所需的 好氧替代品的周转率低（<15）和/或危险的高O2 压力（例如60 atm）。拟议的研究需要使用氧化还原介体策略， 动力学促进有氧钯催化芳烃C-H氧化。特别是NOx- 基于共氧化剂（例如，HNO 3，亚硝酸叔丁酯），它可以很容易地被O2再氧化， 使用该催化剂是为了获得钯的高周转数。 针对叔酰胺的合成，研究了一种新的铜/硝酰基催化的好氧反应， 正在探索的是能够在存在下将伯醇氧化成叔酰胺的方法， 仲胺伯醇氧化成叔酰胺已经通过以下方式实现： 钌或金纳米颗粒催化的工艺，但局限性包括窄的基底 范围，并且催化剂昂贵和/或合成具有挑战性。建议有氧 铜催化策略利用廉价的、可商购的催化剂， 铜/硝酰基催化的醇氧化成醛的先前方法。 为了合成带有两个芳基的叔碳，这样的基序通常是 通过与预官能化的苄基底物的交叉偶联反应获得， 预官能化的芳基底物。据我们所知，非定向苄基C−H芳基化具有 从未实现。铜催化的苄基C-H芳基化策略（使用芳基硼酸 目前正在研究中。这个方法的灵感来自于Kharasch-Sosnovsky C（sp3）−H 到C（sp3）−O或C（sp3）−N的氧化转化;然而，Kharasch-Sosnovsky反应 到目前为止，还没有实现C（sp3）−C键的构建。

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.