The Direct Oxidative Trifluoromethylation of Simple Heteroaromatic Systems

描述（由申请人提供）：有机氟化合物对化学科学的许多学科非常重要，并且在制药和农业化学科学中普遍存在。在这些化合物中，三氟甲基芳族化合物是特别重要的，并且它们在疾病治疗和农业化学品中都有广泛的用途。鉴于这一主题的关键性质，三氟甲基（CF3）残基直接安装到现有的芳香族化合物是合成有机化学的一个重要目标，许多研究已经致力于这一目标。虽然有几种有用的方法将CF3官能团引入芳族体系，但它们仅限于含有预安装官能团的底物。例如，最强大的现有芳烃三氟甲基化技术利用含有特定导向基团的芳基卤化物底物或联芳基底物。目前，不存在用于这些边界之外的底物的三氟甲基化的方法，并且引入这样的技术将极大地简化含CF 3的芳族化合物的合成。此外，杂芳族化合物在药物中是普遍存在的，并且杂环化合物（例如-吖嗪或-唑杂环家族）的直接三氟甲基化将代表能够发现药物和农用化学品的技术的显著进步。 拟议的研究旨在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个问题，以引入一种化学方法来实现杂芳族化合物的直接氧化C-H三氟甲基化。更具体地，所提出的工作将分别单独完成CF3交叉偶联和C-H官能化的两种现有钯催化方法的各个方面拼接在一起。这些技术的成功合并将导致以选择性方式将有机碳-氢键与碳-碳（CF3）键直接转化的通用催化方法。 这一理想的实现将为化学合成从业者提供一个强大的工具，用于快速构建高度重要的先导化合物或候选药物。此外，所提出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，否则这将是极其困难的，如果不是不可能实现的话。这种能力将对识别和开发能够治疗疾病或生产食品的化学实体产生重大影响。 公共卫生相关性：含有芳香族三氟甲基基团的有机分子对于治疗许多严重疾病（如HIV、II型糖尿病、抑郁症等）是重要的。以及使全球农业得以发展的技术。从容易获得的材料直接构建这种类型的分子是困难的（如果不是不可能的话），并且所提出的研究如果成功，将大大简化这一努力。

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. PUBLIC HEALTH RELEVANCE: Organic molecules that contain aromatic trifluoromethyl groups are important to the treatment of a number of critical diseases (such as HIV, type-II diabetes, depression etc.) and to the technologies that enable the global agricultural industry. The direct construction of this type of molecule from easily obtained materials is difficult (if not impossible) and the proposed research, if successful, would greatly simplify this endeavor.