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

 描述(申请人提供)：杂环广泛存在于药物化合物、天然产品和其他生物活性化合物中。因此，新的制备方法受到研究人员的追捧。一种值得注意的制备催化反应 杂环中的一种是钯催化的羰化反应。该反应使用一氧化碳作为杂环的碳源。许多钯催化的羰化反应都在底物中内置了(假)卤化物官能团，以提高反应的区域选择性。然而，这种卤化物功能通常是使用产生废物和耗时的操作安装到衬底中的。钯催化的有氧氧化C-H羰基化反应是这一所谓的“经典”羰基化反应的另一种有吸引力的替代反应。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循环。直接好氧氧化C-H羰基化反应的唯一副产物是水，O2可以作为末端氧化剂，而且杂环产物可以在很好的区域控制下合成，因此具有很大的吸引力。然而，许多已发表的直接氧化羰基化反应使用化学计量的辅氧化剂，如铜(II)、银(I)和1，4-苯二酚(BQ)来实现高效的催化循环，典型的是高负载量的钯(10mol%)。这些条件阻碍了氧化C-H羰基化反应在工业过程中的应用。理想情况下，助氧化剂的负载量可以减少到共催化水平，钯的负载量可以减少到个位数或更少的摩尔百分比。这里提出的化学构成了一个已发表的氧化C-H羰基化反应的详细研究，该反应使用了创新的技术，如操作手高压核磁共振光谱和操作手X射线吸收光谱(XAS)。高压核磁共振光谱仪器的开发也将是该项目的一部分。此外，一项已发表的反应通过将钯的负载量和BQ的负载量降低到共催化水平，为生物活性3，4-二氢-β-卡布林-1-酮提供了BQ的两个等价物，从而进行了进一步的开发。该反应的底物范围也是扩大的目标，包括生物活性靶标。此外，还提出了一种新的反应：钯催化的2-酯取代的E-乙基苯胺的有氧氧化C-H羰基化反应生成4-喹诺酮-3-羧酸酯，这是FDA批准的环丙沙星和左氧氟沙星等抗生素的优先骨架。左氧氟沙星(R))。该反应的拟议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.