Palladium-Catalyzed Aerobic Oxidative Indole Arylation: Mechanistic Studies

这项建议旨在研究三个化合物的简化合成的新化学工艺。 生物活性小分子中常见的结构基序：酚/芳基醚(例如，DetroTM， Nexium®)、叔胺(例如Januvia®、Diovan®)和含有两个芳基的叔碳 (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它们的催化机理。 在生产酚醚和芳醚积木方面，钯催化的 将芳烃C(Sp2)−H键转化为芳烃C(Sp2)−O键的氧氧化策略为 被追捕。大多数钯催化的芳烃C−H氧化反应使用昂贵的 产生废物的氧化剂，如Phi(OAc)2和过硫酸盐，以及可取的先例 有氧替代品的周转次数低(&lt；15)，氧气含量高得危险 压力(例如60atm)。建议的研究需要按顺序使用氧化还原调节剂策略 为了从动力学上促进钯催化的芳烃C−H氧化反应。特别是，NOx- 容易被O2重新氧化的基础助氧化剂(例如，HNO3、亚硝酸叔丁酯)正在被 为了实现钯的高周转率而采用。 在叔胺的合成方面，一种新的铜/氮氧基催化的好氧反应是 正在探索的一种方法，能够使伯醇在存在的情况下氧化成叔胺 仲胺。伯醇氧化成叔胺的方法是通过 Ru-或金纳米颗粒催化的过程，但限制包括狭窄的衬底 范围大，催化剂合成昂贵和/或具有挑战性。建议的有氧运动 铜催化策略利用廉价的商业可用催化剂，并在 以前的铜/氮氧基催化醇氧化醇为醛的方法。 对于含有两个芳基的叔碳的合成，这样的基序通常是 通过与前官能化的苄基底物的交叉偶联反应获得 预官能化芳基底物。据我们所知，非定向的苄基C−H芳基化 从未实现过。铜催化下的苯基C-−-H芳基化反应(芳基硼酸) 酯)目前正在探索中。这种方法的灵感来自于Kharasch-Sosnovsky C(Sp3)−H 到C(Sp3)−O或C(Sp3)−N的氧化转化，但Kharasch-Sosnovsky反应 到目前为止，C(Sp3)−C键的构建还没有实现。

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.