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都非常重要，在制药和农业化学科学中很普遍。在这些化合物中，三氟甲基芳香族化合物尤为重要，它们在疾病治疗和农业化学品中都有广泛的用途。鉴于该基序的关键性质，将三氟甲基（CF3）残基直接安装到现有芳香化合物上是合成有机化学的一个重要目标，并为此进行了大量研究。虽然有几种有用的方法将CF3功能整合到芳香体系中，但它们仅限于含有预安装官能团的底物。例如，现有最强大的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，在这些边界之外还没有对底物进行三氟甲基化的方法，引入这种技术将大大简化含cf3芳香族化合物的合成。此外，杂芳香族化合物在药物中无处不在，杂环化合物（如-azine或-azole杂环家族）的直接三氟甲基化将是促进药物和农用化学品发现的技术的重大进步。提出的研究旨在通过应用交叉偶联和C-H功能化技术的基本原理来引入一种化学方法来实现杂芳烃化合物的C-H直接氧化三氟甲基化，从而解决这一问题。更具体地说，提议的工作将两个现有的钯催化过程的各个方面拼接在一起，分别单独完成CF3交叉偶联和C-H功能化。这些技术的成功合并将产生一种以选择性方式将有机碳氢键直接转化为碳碳（CF3）键的通用催化方法。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，用于快速构建非常重要的先导化合物或候选药物。此外，拟议的技术将能够在后期中间体中直接安装三氟甲基功能，否则这是极其困难的，如果不是不可能的话。这种能力将对鉴定和开发能够治疗疾病或生产食物的化学实体产生强有力的影响。

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. 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.