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

钯催化有氧氧化 C-H 羰基化反应：合成与机理研究

• 批准号: 9273898
• 负责人: Stephen John Tereniak
• 金额: $ 4.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-03-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273898
• 关键词: Aerobic; Antibiotics; Antioxidants; Benzoquinones; Biological; Carbon Monoxide; Catalysis; Chemistry; Ciprofloxacin; Copper; Development; Digit structure; Disease; Drug Industry; Drug Prescriptions; Drug usage; Esters; FDA approved; Healthcare; Hydrogen Bonding; In Situ; Indoles; Industrialization; Kinetics; Laws; Levaquin; Methods; Molecular; NMR Spectroscopy; Natural Products; Nuclear Magnetic Resonance; Oxidants; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Publishing; Quinolones; Reaction; Reagent; Research; Research Personnel; Rest; Roentgen Rays; Role; Salts; Silver; Sodium Chloride; Source; Spectrum Analysis; Techniques; Time; Tryptamines; Water; Work; absorption; aryl halide; carboxylate; catalyst; design; drug development; improved; innovation; instrumentation; method development; para-benzoquinone; pressure; prevent; public health relevance; scaffold; scale up; screening; wasting

 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.

 描述（由应用程序提供）：杂环在药物化合物，天然产物和其他生物活性化合物中无处不在。因此，研究人员在感觉到他们准备的新方法。制备的显着催化反应 杂环是钯催化的羰基化。该反应使用一氧化碳作为杂环的C1来源。许多钯催化的羰基化反应具有内置在底物中的卤化物功能（伪），以改善反应的调节选择性。但是，这种卤化物功能通常使用废物生成和耗时的操作将其安装到底物中。这种所谓的“经典”羰基化反应的一种有吸引力的替代方法是钯催化的有氧氧化有氧氧化物C-H羰基化反应。在这些条件下，底物中的A（伪）卤化物被C-H键取代，并使用氧化物来实现催化性更新。定向有氧氧化物C-H羰基化是有吸引力的，因为该反应的唯一副产品是水，可以将O2用作末端氧化物，并且可以用出色的降压控制来合成杂环产物。然而，许多发表的定向氧化羰基反应使用化学计量量的二氧化剂，例如铜（II），银（I）和1,4-苯甲喹酮（BQ），以实现有效的催化性周转，以及钯（10 mol％）的高负载。这些条件可防止氧化C-H羰基反应在工业过程量表上应用。理想情况下，可以将二氧化剂的负载降低至肠系统水平，并且可以将钯的负载降低到单位数字或更少的摩尔％。本文提出的化学构成了使用创新技术（例如Operando High Pressure NMR光谱和操作X射线抽象光谱光谱（XAS））进行创新技术的氧化氧化物C-H羰基反应反应的详细研究。高压NMR光谱的发展也将是该项目的一部分。此外，发表的反应规定了有氧氧化羰基的两种等效物，用于提供生物活性3,4-二氢-β-核蛋白-1-酮，是通过降低钯负荷以及将BQ负载降低到cocatalytic水平的。该反应的底物范围也是针对包括生物活性靶标的扩展的。此外，提出了一种新的反应：钯催化的有氧氧化C-H羰基化的2-替代的e-乙基苯胺与4-夸诺酮-3-羧酸酯酯在FDA批准的ciproloxain和levofofofofofofofoffofoffofoffofoffloxacin（A.Ka）中是4-夸诺酮-3-羧酸酯，这些酯是特权的。 Levaquin（R））。该反应的拟议底物范围包括生物活性靶标，例如批准的抗生素。