Redox Controlled Reductive Elimination from Palladium II Complexes

描述(申请人提供)：含有碳氟键的分子在工业上很普遍，因为大约30%的农用化学品和20%的药物含有氟。在药物中掺入氟可以提高亲脂性、生物利用度、代谢稳定性，并可以改变化合物与药物相互作用的强度 靶蛋白。例如，非常成功的药物立普妥(高胆固醇血症)、西普罗韦(抗生素)和利培酮(抗精神病药物)都具有芳基氟键。此外， 放射性同位素18F被广泛用于肿瘤成像中的分子正电子发射断层扫描(PET)。虽然氟有广泛的用途，但将其结合到芳香族骨架中的传统方法通常需要苛刻的反应条件，不能容忍许多官能团。由于这些限制，具有战略优势的后期方法通常被放弃，所需的氟原子在早期合成阶段被引入芳烃中。然而，催化通过为反应物转化为产物提供较低的能量途径，使反应条件温和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 作为金属催化剂的碎片在现代合成中广泛存在。通过选择正确的配体，Pd已被证明催化Ar-F键的形成，尽管底物范围有限。该反应被认为是通过Pd(0)/Pd(II)催化循环进行的，机理研究表明还原消除是有问题的步骤。降低金属中心(或甲式氧化)的电子密度可以加速还原消除。这项建议旨在开发几个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的电子密度，允许MIL和特定的Ar-F键的形成。

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.