Redox Controlled Reductive Elimination from Palladium II Complexes

钯 II 配合物中的氧化还原控制还原消除

• 批准号: 9038383
• 负责人: Aaron Christopher Sather
• 金额: $ 5.61万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2017-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038383
• 关键词: Agrochemicals; Alkanesulfonates; Antibiotics; Antipsychotic Agents; Biological Availability; Carbon; Catalysis; Chemicals; Complex; Coupling; Development; Electron Transport; Electronics; Electrons; Environment; Equilibrium; Event; Excision; Exhibits; Fluorides; Fluorine; Foundations; Health; Image; Ligand Binding; Ligands; Metabolic; Metals; Methods; Mind; Mission; Molecular; Nature; Oxidants; Oxidation-Reduction; Palladium; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phosphines; Positioning Attribute; Positron-Emission Tomography; Process; Proteins; Radioisotopes; Reaction; Research Training; Series; Solvents; Source; Staging; Stimulus; System; Testing; Transition Elements; United States National Institutes of Health; Work; aryl halide; atorvastatin; base; catalyst; chemical bond; design; electron density; ferrocene; forging; functional group; hypercholesterolemia; lipophilicity; oncology; oxidation

DESCRIPTION (provided by applicant): Molecules containing carbon fluorine bonds are industrially prevalent as approximately 30% of all agrochemicals and 20% of all pharmaceuticals contain fluorine. The incorporation of fluorine into pharmaceuticals can enhance lipophilicity, bioavailability, metabolic stability, and can alter the strength of a compound's interaction with a target protein. For example, the highly successful drugs Lipitor (hypercholesterolemia), Ciprobay (antibiotic), and Risperdal (antipsychotic) boast an aryl fluorine bond. Additionally, the radioactive isotope 18F is widely used for molecular positron emission tomography (PET) in oncology imaging. While fluorine has widespread use, the traditional methods to incorporate it into an aromatic framework generally require harsh reaction conditions that do not tolerate many functional groups. Because of these restrictions, strategically advantageous late-stage approaches are generally abandoned, and the desired fluorine atoms are introduced into aromatics at an early synthetic stage. Catalysis, however, enables mild reaction conditions and selective transformations by providing lower energy pathways for the conversion of reactants into products. Specifically, transition metal-catalyzed cross-coupling reactions-the joining of two fragments by way of a metal catalyst-are widespread in modern synthesis. By selection of the correct ligand, Pd has been shown to catalyze Ar-F bond formation, albeit with limited substrate scope. The reaction is believed to proceed though a Pd(0)/Pd(II) catalytic cycle and mechanistic studies revealed that reductive elimination is the problematic step. Decreasing the electron density of the metal center (or formal oxidation) is known to accelerate reductive elimination. This proposal aims at developing several bulky monophosphine ligands that contain a ferrocene unit to reversibly control the electron density on the catalytically metal center, allowing for mil and specific Ar-F bond formation.

描述（由申请人提供）：含有碳氟键的分子在工业上是普遍的，因为大约30%的所有农用化学品和20%的所有药物含有氟。将氟掺入药物中可以增强亲脂性、生物利用度、代谢稳定性，并且可以改变化合物与药物相互作用的强度。 目的蛋白例如，非常成功的药物立普妥（高胆固醇血症），Ciprobay（抗生素）和Risperdal（抗精神病药）都拥有芳基氟键。另夕h 放射性同位素18F广泛用于肿瘤成像中的分子正电子发射断层摄影（PET）。虽然氟具有广泛的用途，但将其并入芳族骨架中的传统方法通常需要苛刻的反应条件，其不容许许多官能团。由于这些限制，战略上有利的后期方法通常被放弃，并且在早期合成阶段将所需的氟原子引入芳烃中。然而，催化通过为反应物转化为产物提供较低能量的途径，使温和的反应条件和选择性转化成为可能。具体地说，过渡金属催化的交叉偶联反应-两个 通过金属催化剂的碎片-在现代合成中是广泛的。通过选择正确的配体，Pd已被证明可以催化Ar-F键的形成，尽管底物范围有限。据信该反应通过Pd（0）/Pd（II）催化循环进行，并且机理研究表明还原消除是有问题的步骤。降低金属中心的电子密度（或形式氧化）已知可加速还原消除。该提议旨在开发几种含有二茂铁单元的大体积单膦配体，以可逆地控制催化金属中心上的电子密度，从而允许形成mil和特定的Ar-F键。