The Direct Oxidative Trifluoromethylation of Simple Heteroaromatic Systems

描述(申请人提供)：有机氟化合物对化学科学的许多学科非常重要，在制药和农用化学科学中很普遍。在这些化合物中，三氟甲基芳香化合物尤其重要，它们在疾病治疗和农用化学品中都有广泛的用途。鉴于这一基序的关键性质，将三氟甲基(CF3)残基直接安装到现有的芳香族化合物上是合成有机化学的一个重要目标，为此人们进行了大量的研究。虽然有几种将CF3官能团引入芳香族体系的有用方法，但它们仅限于含有预先安装的官能团的底物。例如，现有的最有效的芳烃三氟甲基化技术要么使用芳基卤化物底物，要么使用含有特定导向基团的联芳基底物。目前，在这些边界之外还没有底物的三氟甲基化方法，这种技术的引入将极大地简化含CF3的芳香族化合物的合成。此外，杂环化合物在药物中普遍存在，杂环化合物(如-氮杂环族或-氮杂环族)的直接三氟甲基化将代表着药物和农用化学品发现技术的重大进步。本研究试图通过应用交叉偶联和C-H官能化技术的基本原理来解决这一问题，引入一种化学方法来实现杂芳烃的直接氧化C-H三氟甲基化。更具体地说，拟议的工作将把现有的两个钯催化过程的各个方面拼接在一起，这两个过程分别实现CF3交叉偶联和C-H官能化。这些技术的成功融合将产生一种通用的催化方法，以选择性的方式直接转化有机碳氢键和碳碳(CF3)键。这一理想的实现将为化学合成从业者提供快速构建高度重要的先导化合物或候选药物的有力工具。此外，拟议的技术将能够将三氟甲基官能团直接安装到后期中间体中，否则将是极其困难的，如果不是不可能实现的话。这一能力将对识别和发展能够治疗疾病或生产食品的化学物质产生重大影响。

DESCRIPTION (provided by applicant): Organofluorine compounds are of great importance to many disciplines of the chemical sciences and are prevalent in the pharmaceutical and agrochemical sciences. Of these compounds, trifluoromethyl aromatic compounds are especially important and they have found broad use in both the treatment of disease and in agricultural chemicals. Given the critical nature of this motif, the direct installation of trifluoromethyl (CF3) residues onto existing aromatic compounds is an important goal for synthetic organic chemistry and much research has been devoted toward this end. While there are several useful methods for the incorporation of CF3 functionality into aromatic systems, they are limited to substrates that contain preinstaled functional groups. For example, the most powerful existing arene trifluoromethylation techniques utilize either aryl halide substrates or biaryl substrates that contain specific directing groups. Currently, no method exists for the trifluoromethylation of substrates outside of these boundaries and the introduction of such a technology would greatly streamline the synthesis of CF3-containing aromatic compounds. Furthermore, heteroaromatic compounds are ubiquitous in medicines and the direct trifluoromethylation of heterocyclic compounds (such as the -azine or -azole heterocyclic families) would represent a significant advance in the technologies that enable drug and agrochemical discovery. The proposed research seeks to address this problem by applying underlying principles from cross coupling and C-H functionalization technologies to introduce a chemical method to achieve the direct oxidative C-H trifluoromethylation of heteroaromatic compounds. More specifically, the proposed work would splice together individual aspects of two existing palladium catalyzed processes that individually accomplish CF3 cross coupling and C-H functionalization, respectively. The successful merger of these technologies would result in a general catalytic method for the direct transformation of an organic carbon-hydrogen bond with a carbon-carbon (CF3) bond in a selective fashion. The realization of this ideal would provide practitioners of chemical synthesis with a powerful tool for the rapid construction of highly important lead compounds or drug candidates. Moreover, the proposed technology would enable the direct installation of trifluoromethyl functionalities into late-stage intermediates that would otherwise be extremely difficult, if not impossible to accomplish. This ability would have a powerful impact on the identification and development of chemical entities that enable the treatment of disease or the production of food.