Carbon-Hydrogen Bond Functionalization By Transition Metal Complexes

描述（由申请人提供）：提出的研究的主要目标是利用过渡金属配合物介导的亲电碳氢键激活反应开发新的有用的转化。广泛的合成方法是基于C-X键（X=卤素，杂原子）的氧化加成反应。尽管与功能化化合物相比，起始碳氢化合物具有更广泛的可用性、价格和环境优势，但由C-H键活化引起的催化C-C键形成反应并不常见。由C-H键激活引起的反应将补充现有的C-C键形成方法，并对合成方法产生重大影响。在这个项目中，钯催化的C-H键与C-X键的偶联将被研究，从而导致新的和通用的C-C键形成方法。初步研究表明，所提出的化学是可行的，并将产生独特的反应，有助于合成具有药用和生物学意义的化合物。我们已经在未活化的sp3中心获得了第一个钯催化的C-H活化/C-C偶联序列。研究的具体目的如下：A.扩展C-H活化/C-C键形成方法的通用性和方便性。研究了含芳烃导向基团烷基化/芳基化/烯基化的一般方法。根据初步结果部分所述的反应条件，这些反应的邻位选择性和间位选择性、对选择性都应该是可获得的。将发展一种非功能化芳烃的芳基化方法。sp3碳-氢键芳化的新助剂将被研究。B.非对映选择性反应的发展。通过使用手性助剂，可以实现非对映选择性的碳氢键芳化和烷基化。该方法将在药学相关化合物的合成中进行测试。C.机械调查。对机制的理解应该使我们能够合理地改进在初步研究中开发的方法，并开发改进的第二代过程。在这项研究中开发的新方法将导致更有效的途径到药物及其前体。建议大幅度缩短已报道的获得药学上相关化合物的途径。

DESCRIPTION (provided by applicant): The primary goal of the proposed research is to develop new and useful transformations using electrophilic carbon-hydrogen bond activation reactions mediated by transition metal complexes. Extensive synthetic methodology has been developed based on oxidative addition reactions of C-X bonds (X=halogen, heteroatom). Catalytic C-C bond forming reactions arising from C-H bond activations are less common despite the wider availability, price, and environmental advantages of the starting hydrocarbons compared to functionalized compounds. The reactions arising from C-H bond activation will complement the current methods for C-C bond formation and have a substantial impact on synthetic methodology. In this project, palladium-catalyzed coupling of C-H bonds with C-X bonds will be investigated leading to new and general methods for C-C bond formation. Preliminary studies suggest that the proposed chemistry is viable and will yield unique reactions useful in the synthesis of compounds of medicinal and biological interest. We have already achieved the first general palladium-catalyzed C-H activation/C-C coupling sequences at unactivated sp3 centers. The specific aims of the research are as follows: A. Expansion of the C-H activation/C-C bond formation method generality and convenience. A general method for alkylation/arylation/alkenylation of directing group containing arenes will be developed. Both ortho- and meta, para selectivity in these reactions should be accessible depending on the reaction conditions as described in Preliminary results section. A method for the arylation of unfunctionalized arenes will be developed. New auxiliaries for the arylation of sp3 C-H bonds will be investigated. B. Development of diastereoselective reactions. By using chiral auxiliaries, diastereoselective C-H bond arylations and alkylations will be achieved. This methodology will be tested in the synthesis of pharmaceutically relevant compounds. C. Mechanistic investigations. Mechanistic understanding should allow us to rationally improve the methodology developed during the preliminary studies, and to develop improved second-generation processes. The new methodologies developed in this research will lead to more efficient routes to Pharmaceuticals and their precursors. Substantial shortening of the reported routes to pharmaceutically relevant compounds are proposed.