Investigations of New Pd"/Pd"-catalyzed aryl C-F and C-CF3 Coupling Reactions

说明（由申请人提供）：在有机化合物中安装C-F键可以对分子的化学和生物学产生显著影响。有机氟化合物的独特性质导致了成功的药物开发，用于治疗从抑郁症到动脉粥样硬化等与健康相关的疾病，并用于临床应用，如[18] F正电子发射断层扫描（PET），这是一种非常有价值的多种癌症诊断工具。虽然有多种合成方法来产生脂肪族sp3和烯属sp2 C-F键，但几乎没有形成芳基C-F键的方法。该项目的长期目标是开发更实用的方法，通过钯催化转化合成这些键。该项目有三个具体目标：（i）开发使用芳基锡烷、硅烷或硼酸的Pd（II）/Pd（IV）钯催化的芳基C-F键形成方法（ii）开发使用Cu（I）-CF 3金属转移试剂和亲电子氧化剂的钯催化的芳基C-CF 3形成方法，和（iii）通过分离的Pd（IV）-氟化物和CF 3物质证明这些提议的催化循环的关键C-F和C-CF 3键形成步骤。Pd催化的芳基C-F键形成方法将利用在亲电氟化试剂存在下与芳基Pd（II）物质相比Pd（II）氟化物的相对反应性。所提出的催化循环涉及芳基锡烷到Pd（II）-F的金属转移以形成芳基Pd（II）物质。这种物质随后可以通过亲电氟化试剂氧化成Pd（IV），然后通过C-F键形成还原消除。这些转换的相对速率和衰减的不希望的C-C耦合产品提出控制的空间和电子调谐三齿“钳”配体。芳基C-CF 3键形成转化将利用现有的Pd（II）/Pd（IV）配体导向的C-H活化和官能化化学将芳基C-H键转化为C-CF 3键。这将通过使用Cu（I）-CF 3的原位形成作为芳基Pd（II）-物质的金属转移试剂以形成新的芳基Pd（II）CF 3物质来促进。然后，该物质可以通过强氧化剂氧化成Pd（IV），然后通过C-CF 3键还原消除形成。最后，为了给出催化C-F和C-CF3键形成转化通过Pd（IV）中间体进行的机理证据，将努力给出它们存在的化学计量证据。我们希望，这项工作将提供化学合成工具，在新的生物相关的有机氟化合物的发展。

DESCRIPTION (provided by applicant): The installation of C-F bonds in organic compounds can have a significant effect on the chemical and biological of the molecules. The unique properties of organofluorines have lead to the development of successful pharmaceutical drugs in treating health-related conditions from depression to atherosclerosis and for clinical applications such as [18]F positron emission tomography (PET), a highly valuable diagnostic tool for multiple cancers. Although there are a variety of synthetic approaches to create aliphatic sp3 and olefinic sp2 C-F bonds, there are few methods to form aryl C-F bonds. This project's long-term objective is to develop more practical methods to synthesize these bonds through palladium-catalyzed transformations. This project has three specific aims: (i) develop a Pd(ll)/Pd(IV) palladium-catalyzed aryl C-F bond forming methodology using aryl stannanes, silane or boronic acids (with no need for a directioning group) using electrophilic fluorinating reagents, (ii) develop a palladium-catalyzed aryl C-CF3 forming methodology using Cu(l)-CF3 transmetallating reagents and strong electrophilic oxidants, and (iii) demonstrate the key C-F and C-CF3 bond forming steps of these proposed catalytic cycles via isolated Pd(IV)-fluoride and CF3 species. The Pd-catalyzed aryl C-F bond forming methodology will exploit the relative reactivity of Pd(ll) fluorides compared to aryl Pd(ll) species in the presence of electophilic fluorinating reagents. The proposed catalytic cycle involve a transmetallation of an aryl stannane to a Pd(ll)- F to form an aryl Pd(ll) species. This species can be subsequently oxidized to Pd(IV) by the electrophilic fluorinating reagents followed by C-F bond forming reductive elimination. The relative rates of these transformations and the attenuation of the undesired C-C coupling products are proposed to be controlled by sterically and electronically tuning tridentate "pincer" ligands. The aryl C-CF3 bond forming transformation will utilize existing Pd(ll)/Pd(IV) llgand-dlrected C-H activation and functionalization chemistry to convert aryl C-H bonds to C-CF3 bonds. This will be facilitated by using in situ formation of Cu(l)-CF3 as a transmetallating reagent to an aryl Pdll - species to form a new aryl Pd(ll) CF3 species. This species can then be oxidized to Pd(IV) by a strong oxidant followed by C-CF3 bond reductive elimination formation. Finally, to give mechanistic evidence that both catalytic C-F and C-CF3 bond forming transformations proceed through a Pd(IV) intermediate, efforts will be taken to give stoichiometric evidence of their existence. We are hopeful that this work will provide practiical synthetic tools in the development of new biologically relevant organofluorine compounds.