Carbon-Hydrogen Bond Functionalization By Transition Metal Complexes

描述（由申请人提供）：拟议研究的主要目标是使用过渡金属络合物介导的亲电碳-氢键活化反应开发新的有用转化。基于C-X键（X=卤素、杂原子）的氧化加成反应，已经开发了广泛的合成方法。由C-H键活化引起的催化C-C键形成反应不太常见，尽管与官能化化合物相比，起始烃具有更广泛的可用性、价格和环境优势。由C-H键活化引起的反应将补充目前的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，从而产生新的和通用的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，可用于合成药物和生物化合物的兴趣。我们已经在未活化的sp3中心实现了第一个一般的钯催化的C-H活化/C-C偶联序列。具体研究目的如下：A.扩展了C-H活化/C-C键形成方法的通用性和方便性。将开发含导向基团芳烃的烷基化/芳基化/烯基化的通用方法。这些反应中的邻位和Meta、帕拉选择性都应是可获得的，这取决于初步结果部分中所述的反应条件。本文将发展一种非官能化芳烃的芳基化方法。研究了sp3 C-H键芳基化的新助剂。B。非对映选择性反应的发展。通过使用手性助剂，将实现非对映选择性的C-H键芳基化和烷基化。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。机械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工艺。在这项研究中开发的新方法将导致更有效的路线药物及其前体。提出了大幅缩短药物相关化合物的报道途径。

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.