Reductive Coupling Reactions: Trading Organometallic Reagents for Organic Halides

还原偶联反应：用有机金属试剂换取有机卤化物

• 批准号: 8656364
• 负责人: Daniel John Weix
• 金额: $ 29.36万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656364
• 关键词: Academia; Address; Air; Alcohols; Alkanesulfonates; Alkenes; Alkynes; Biochemistry; Carbon Monoxide; Catalysis; Chemistry; Chloride Ion; Chlorides; Collection; Coupled; Coupling; Cross Reactions; Cyclization; Data; Development; Dimerization; Electron Transport; Electrons; Esters; Event; Exclusion; Goals; Grant; Health; Health Sciences; Human; Hydrocarbons; Industry; Investigation; Ketones; Laboratories; Ligands; Light; Lighting; Mediating; Metals; Methods; Mission; Molecular; Molecular Biology; Molecular Probes; Nickel; Nitrogen; Organic Synthesis; Outcome; Pharmaceutical Preparations; Pharmacology; Procedures; Process; Public Health; Reaction; Reagent; Reducing Agents; Reliance; Research; Solutions; System; Techniques; Time; Transition Elements; Translating; United States National Institutes of Health; Work; aryl halide; base; catalyst; cost; design; drug discovery; empowered; experience; functional group; improved; innovation; interest; prevent; programs; small molecule

DESCRIPTION (provided by applicant): Catalytic C-C bond forming reactions have revolutionized the discovery and synthesis of small molecules in academia and industry, but the full potential of transition-metal catalysis is now frequently limited by the need for pre-formed organometallic reagents. Few such reagents are commercially available because their synthesis is not trivial and many of the reagents have limited stability. These limitations have consequences for drug discovery and biochemistry because many potentially important molecules are not made when they are deemed too time consuming to access. One potential solution to this problem is the replacement of nucleophilic organometallic reagents with electrophiles, such as organic halides, which are bench stable and plentiful. This program's long-term goals are the development of new catalytic reactions that couple two or more electrophiles as well as the illumination of the factors which control selectivity and reactivity in these reductive coupling reactions. In the proposed grant, reductive alternatives will be developed for two of the most important types of C-C bond forming reactions: cross-coupling and conjugate addition. The guiding mechanistic hypothesis for this work is that the single-electron chemistry of first-row transition metals will enable the coupling of two electrophiles by allowing multiple oxidative additions to occur at a single metal center. Although radical intermediates are almost certainly involved, these transition-metal catalyzed reactions can be tuned through choice of metal and ligand. Thus, the reactions developed will provide a complementary reactivity to the better studied two-electron processes of other metals. Following up on strong preliminary data, the specific aims of the proposal are to: (1) develop direct reductive cross-coupling reactions that form Csp3- Csp2 bonds from simple organic halides or pseudohalides and better understand the mechanism of the transformation; (2) create direct reductive coupling methods that form Csp3-Csp3 bonds; and, (3) extend the concept of reductive coupling to include the coupling of organic halides with carbon monoxide, alkenes, and alkynes. Under each aim a promising catalyst system has been discovered in the applicant's laboratory that will become the basis for the development of several general methods. The approach is innovative because it focuses on the development of new reactions that completely avoid intermediate organometallic reagents. Strategies to overcome the challenges of cross-selectivity and reactivity have been identified that have previously prevented progress. By investigating reactions with different mechanisms, the proposed research presents the opportunity for dramatic improvements in critical C-C bond-forming reactions as well as new bond constructions that were not previously possible. The proposed research is significant because it is expected to expand the number of molecules that can be rapidly made from commercially available materials. In the long run, this expansion of readily accessible molecular diversity will enable discoveries in molecular biology and pharmacology that will directly impact human health.

描述（由申请人提供）：催化C-C键形成反应在学术界和工业界已经彻底改变了小分子的发现和合成，但是过渡金属催化的全部潜力现在经常受到对预成型有机金属试剂的需求的限制。很少有这样的试剂是市售的，因为它们的合成并不简单，而且许多试剂的稳定性有限。这些限制对药物发现和生物化学产生了影响，因为许多潜在的重要分子被认为太耗时而无法获得。这个问题的一个潜在解决方案是用亲电试剂代替亲核有机金属试剂，如有机卤化物，这是稳定和丰富的。该计划的长期目标是开发两种或两种以上亲电试剂偶联的新催化反应，以及阐明控制这些还原偶联反应的选择性和反应活性的因素。在提议的拨款中，将为两种最重要的C-C键形成反应开发还原性替代品：交叉偶联和共轭加成。这项工作的指导机制假设是，第一排过渡金属的单电子化学将通过允许在单个金属中心发生多个氧化添加来实现两个亲电试剂的耦合。虽然自由基中间体几乎肯定参与其中，但这些过渡金属催化反应可以通过选择金属和配体来调整。因此，所开发的反应将为其他金属的更好研究的双电子过程提供补充反应性。在强有力的初步数据基础上，本研究的具体目标是：(1)发展简单有机卤化物或假卤化物形成Csp3- Csp2键的直接还原交叉偶联反应，更好地了解转化机理；(2)创建形成Csp3-Csp3键的直接还原耦合方法；(3)将还原偶联的概念扩展到有机卤化物与一氧化碳、烯烃和炔的偶联。在每个目标下，申请人的实验室已经发现了一个有前途的催化剂体系，这将成为开发几种通用方法的基础。这种方法是创新的，因为它专注于开发完全避免中间有机金属试剂的新反应。已经确定了克服交叉选择性和反应性挑战的战略，这些挑战以前阻碍了进展。通过研究不同机制的反应，提出的研究为显著改进关键的C-C键形成反应以及以前不可能的新键构建提供了机会。这项提议的研究意义重大，因为它有望扩大从商业上可用的材料快速制造分子的数量。从长远来看，易于获得的分子多样性的扩大将使分子生物学和药理学的发现能够直接影响人类健康。