Palladium-Catalyzed Aerobic Oxidative C-H Carbonylations: Synthesis and Mechanistic Studies

 描述（由申请人提供）：杂环在药物化合物、天然产物和其他生物活性化合物中普遍存在。因此，研究人员正在寻求新的制备方法。一个值得注意的催化反应， 是钯催化的羰基化。该反应使用一氧化碳作为杂环的C1源。许多钯催化的羰基化反应具有（假）卤化物官能度，其被构建到底物中以改善反应的区域选择性。然而，这种卤化物官能团通常使用产生废物和耗时的操作安装到基底中。这种所谓的“经典”羰基化反应的有吸引力的替代方案是钯催化的有氧氧化C-H羰基化反应。在这些条件下，底物中的（假）卤化物被C-H键取代，并使用氧化剂来实现催化转化。定向好氧氧化C-H羰基化反应是一种非常有吸引力的反应，因为该反应的唯一副产物是水，O2可以作为末端氧化剂，并且可以以良好的区域控制合成杂环产物。然而，许多公开的定向氧化羰基化反应使用化学计量的助氧化剂如铜（II）、银（I）和1，4-苯醌（BQ）以实现有效的催化转化，并且高负载量的钯（10摩尔%）是典型的。这些条件阻止了氧化性C-H羰基化反应在工业工艺规模上应用。理想地，助氧化剂的负载量可以降低到助催化水平，并且钯的负载量可以降低到个位数或更少的摩尔%。本文提出的化学组成了一个公开的氧化C-H羰基化反应的反应机理的详细研究，使用创新的技术，如操作高压NMR光谱和操作X-射线吸收光谱（XAS）。高压NMR光谱仪器的开发也将是该项目的一部分。此外，通过将钯负载量以及BQ负载量降低至助催化水平，进一步开发了一种已发表的反应，该反应规定使用2当量BQ进行有氧氧化羰基化，以提供生物活性3，4-二氢-β-咔啉-1-酮。该反应的底物范围也针对包括生物活性靶标在内的扩展。此外，提出了一种新的反应：钯催化的2-酯取代的E-乙烯基苯胺的有氧氧化C-H羰基化为4-喹诺酮-3-羧酸酯，其是FDA批准的抗生素如环丙沙星和左氧氟沙星（a.k.a.左旋喹（r））。该反应的拟定底物范围包括生物活性靶标，如批准的抗生素。

 DESCRIPTION (provided by applicant): Heterocycles are ubiquitous in pharmaceutical compounds, natural products, and other bioactive compounds. For this reason, new methods for their preparation are sought after by researchers. A notable catalytic reaction for the preparation of heterocycles is palladium-catalyzed carbonylation. This reaction uses carbon monoxide as a C1 source for the heterocycle. Many palladium-catalyzed carbonylation reactions have (pseudo)halide functionality built into the substrate to improve the regioselectivity of the reaction. However, this halide functionality is often installed into the substrate using waste-generating and time-consuming manipulations. An attractive alternative to this so-called "classical" carbonylation reaction is the palladium-catalyzed aerobic oxidative C-H carbonylation reaction. Under these conditions, a (pseudo)halide in the substrate is replaced with a C-H bond, and an oxidant is used to attain catalytic turnover. Directed aerobic oxidative C-H carbonylation is attractive because the only byproduct of the reaction is water, O2 can be used as the terminal oxidant, and heterocycle products can be synthesized with excellent regiocontrol. However, many published directed oxidative carbonylation reactions use stoichiometric amounts of cooxidants such as copper(II), silver(I), and 1,4-benzoquinone (BQ) to achieve efficient catalytic turnover, and high loadings of palladium (10 mol%) are typical. These conditions prevent oxidative C-H carbonylation reactions from being applied on an industrial process scale. Ideally, the loading of cooxidants could be reduced to a cocatalytic level, and the loading of palladium could be reduced to the single digits or less mol%. The chemistry proposed herein constitutes a detailed study of the reaction mechanism of a published oxidative C-H carbonylation reaction using innovative techniques such as operando high-pressure NMR spectroscopy and operando X-ray absorption spectroscopy (XAS). The development of high-pressure NMR spectroscopic instrumentation will also be a portion of this project. Additionally, a published reaction that prescribes two equivalents of BQ for aerobic oxidative carbonylation to afford bioactive 3,4-dihydro-β-carbolin-1-ones is targeted for further development by lowering the palladium loading as well as the BQ loading to a cocatalytic level. The substrate scope for this reaction is also targeted for expansion including bioactive targets. Moreover, a new reaction is proposed: The palladium-catalyzed aerobic oxidative C-H carbonylation of 2-ester substituted E-ethenylanilines to 4-quinolone-3-carboxylate esters, which are privileged scaffolds in FDA-approved antibiotics like ciprofloxacin and levofloxacin (a.k.a. Levaquin(r)). The proposed substrate scope of this reaction includes bioactive targets such as approved antibiotics.