A Mild and General Method for Pd and Cu Catalyzed Trifluoromethylation

描述（由申请人提供）：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方法。三氟甲基基的催化安装是有机化学中一个尚未解决的问题。由于对氟化药物靶标的需求不断增加，开发这种方法是当前尚未满足的重要合成需求。除了使用原子经济型和无害环境的CF3基团来源外，安装三氟甲基的理想方法应该是温和和一般的。迄今为止，还没有普遍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似；因此，拟议的研究旨在揭示催化三氟甲基偶联的系统和控制这些反应的潜在基本化学。有三个具体的目的：1)开发一种铜催化的方法，用于芳香卤化物的三氟甲基化，其中三氟甲基阴离子是由铜催化的三氟乙酸脱羧产生的；2)开发芳基卤化物三氟甲基化的双催化剂方法，利用Pd中心还原消除芳基cf3；3)以氟仿为CF3基团源，开发催化芳香族三氟甲基化反应。为了实现这些目标，将合成并测试已知的铜催化剂，首先测试它们催化三氟乙酸脱羧的能力，然后测试它们催化芳基卤化物三氟甲基化的能力。这些信息可以应用于双催化剂系统，其中铜催化三氟乙酸脱羧，钯催化交叉偶联。一个成功的双催化系统将代表两个主要成就：一是发展了一种通用的芳基三氟甲基化方法，二是首次开发了在催化系统中从Pd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性消除的可行性将大大拓宽反应的范围，并将测试新的底物。在该项目的最后阶段，特氟龙工业的一种主要副产品氟仿将由钯催化剂活化，并应用于催化反应。为此，将尝试使用已知和表征的反应中间体进行氟仿的化学计量活化，然后在催化系统中进行尝试。

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.