A Mild and General Method for Pd and Cu Catalyzed Trifluoromethylation

描述(申请人提供)：该项目的长期目标是发现将三氟甲基引入复杂分子的新的、实用的方法。三氟甲基的催化安装在有机化学中是一个很大程度上尚未解决的问题。由于对氟化药物靶标的需求不断上升，这种方法的开发是当前尚未满足的重要合成需求。理想的安装三氟甲基的方法应该是温和的和一般的，除了使用CF3基团的原子经济和环境友好的来源之外。到目前为止，还没有一般或广泛使用的涉及安装三氟甲基的催化交叉偶联反应。催化三氟甲基化方法的缺乏与我们对含CF3配体的过渡金属配合物的反应性缺乏了解相平行；因此，拟议的研究旨在揭示催化三氟甲基偶联的体系和控制这些反应的基础化学。有三个具体的目标：1)开发一种铜催化的芳香族卤化物的三氟甲基化方法，其中三氟甲基阴离子是由铜催化的三氟乙酸酯的脱羧基生成的；2)开发一种利用Pd中心的芳基-CF3的还原消除的双催化剂方法来进行芳香族卤化物的三氟甲基化；3)开发一种以氟仿为CF3基团的来源的催化芳香族三氟甲基化反应。为了实现这些目标，将合成和测试已知的铜催化剂，首先是它们催化三氟乙酸酯脱羧基的能力，然后是它们催化芳基卤化物的三氟甲基化的能力。然后，这些信息可以应用于双催化剂系统，其中铜催化三氟乙酸酯的脱羧基，钯催化交叉偶联。成功的双催化体系将代表两大成就：一是开发了通用的芳基-三氟甲基化方法，二是首次开发了催化体系中从钯中心还原消除芳基-CF3的方法。此外，在催化环境中建立这种还原消除的可行性将极大地扩大反应的范围，并将测试新的底物。在该项目的最后阶段，特氟龙工业的主要副产品氟仿将被钯催化剂活化，并应用于催化反应。为此，将尝试使用已知的和表征的反应中间体进行氟仿的化学计量活化，然后尝试催化系统。 与公共健康相关：将氟添加到药物靶标中通常会赋予分子有价值的特性，如生物利用度和稳定性。合成新药物分子的能力受到科学家可以使用的合成方法的限制。因此，发展将氟引入复杂分子的方法是很重要的，这样就可以快速合成和评价新的潜在药物。

DESCRIPTION (provided by applicant): The long-term objective of this project is to discover new, practical methods for introducing trifluoromethyl groups to complex molecules. The catalytic installation of trifluoromethyl moieties is a largely unsolved problem in organic chemistry. Due to the rising demand for fluorinated pharmaceutical targets, the development of such a method is an important, current, unmet synthetic need. An ideal method for installing a trifluoromethyl group should be both mild and general, in addition to using atom-economical and environmentally benign sources of the CF3 group. To date, there are no catalytic cross-coupling reactions involving the installation of trifluoromethyl groups that are general or widely employed. The absence of catalytic trifluoromethylation methods parallels our lack of knowledge about the reactivity of transition metal complexes containing CF3 ligands; consequently the proposed studies are aimed to unearth systems that catalyze coupling of trifluoromethyl groups and the underlying fundamental chemistry that controls these reactions. There are three specific aims: 1) to develop a copper-catalyzed method for the trifluoromethylation of aromatic halides in which the trifluoromethyl anion is generated from the copper-catalyzed decarboxylation of trifluoroacetate; 2) to develop a dual catalyst method for trifluoromethylation of aryl halides that capitalizes on the reductive elimination of aryl-CF3 from a Pd center; 3) to develop a catalytic aromatic trifluoromethylation using fluoroform as the source of the CF3 group. To realize these goals, known copper catalysts will be synthesized and tested, first for their ability to catalyze the decarboxylation of trifluoroacetate, and then for their ability to catalyze the trifluoromethylation of aryl halides. This information can then be applied to a dual-catalyst system, where copper catalyzes the decarboxylation of trifluoroacetate and palladium catalyzes the cross-coupling. A successful dual-catalytic system would represent two major achievements: the development of a general aryl-trifluoromethylation method and the first exploitation of a reductive elimination of an aryl-CF3 from a Pd center in a catalytic system. Furthermore, establishing the viability of this reductive elimination in a catalytic setting will vastly broaden the scope of the reaction and new substrates will be tested. In the final stage of this project, fluoroform, a major by-product of the Teflon industry, will be activated by a palladium catalyst and applied to a catalytic reaction. To do so, the stoichiometric activation of fluoroform will be attempted using known and characterized reaction intermediates followed by attempts at the catalytic system. PUBLIC HEALTH RELEVANCE: The addition of fluorine to drug targets often imparts valuable qualities to the molecule, such as bioavailability and stability. The ability to synthesize new pharmaceutical molecules is limited by the synthetic methods that scientists can employ. As such, it is important to develop methods for introducing fluorine to complex molecules such that new potential drugs can be quickly synthesized and evaluated.