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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

基本信息

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
项目类别：
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

项目摘要

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.