A Mild and General Method for Pd and Cu Catalyzed Trifluoromethylation

一种温和通用的 Pd 和 Cu 催化三氟甲基化方法

• 批准号: 8073970
• 负责人: Nichole Danielle Litvinas
• 金额: $ 4.66万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-16 至 2012-07-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8073970
• 关键词: Achievement; Acidity; Address; Anions; Benign; Biological Availability; Carbon; Chemistry; Complex; Copper; Coupling; Decarboxylation; Development; Drug Delivery Systems; Esters; Fluorine; Goals; Health; Industry; Ketones; Knowledge; Ligands; Methods; Organic Chemistry; Palladium; Pharmaceutical Preparations; Pharmacologic Substance; Process; Reaction; Reagent; Reporting; Scientist; Source; Staging; System; Teflon; Testing; Transition Elements; Trifluoroacetate; Work; aryl halide; catalyst; deprotonation; fluoroform; functional group; metal complex; novel; pollutant; public health relevance; trifluoromethyl group

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.

描述（由申请人提供）：本项目的长期目标是发现新的，实用的方法，将三氟甲基基团引入复杂的分子。三氟甲基部分的催化安装是有机化学中一个很大程度上未解决的问题。由于对氟化药物靶标的需求不断增长，开发这种方法是重要的、当前的、未满足的合成需求。安装三氟甲基基团的理想方法应该是温和和通用的，除了使用CF 3基团的原子经济和环境友好的来源。迄今为止，还没有涉及安装三氟甲基的催化交叉偶联反应是普遍或广泛使用的。催化三氟甲基化方法的缺乏与我们缺乏关于含有CF 3配体的过渡金属络合物的反应性的知识平行;因此，所提出的研究旨在发掘催化三氟甲基基团偶联的系统和控制这些反应的基础化学。有三个具体目标：1）开发用于芳族卤化物的三氟甲基化的铜催化方法，其中三氟甲基阴离子由三氟乙酸盐的铜催化脱羧产生; 2）开发用于芳基卤化物的三氟甲基化的双催化剂方法，其利用芳基-CF 3从Pd中心的还原消除; 3）开发使用氟仿作为CF 3基团的来源的催化芳族三氟甲基化。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酯脱羧的能力，然后测试它们催化芳基卤化物的三氟甲基化的能力。然后，该信息可以应用于双催化剂系统，其中铜催化三氟乙酸盐的脱羧，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：一个通用的芳基-三氟甲基化方法的发展和第一次开发的还原消除的芳基-CF 3从Pd中心的催化系统。此外，在催化环境中建立这种还原消除的可行性将大大拓宽反应的范围，并将测试新的底物。在这个项目的最后阶段，氟仿，一个主要的副产品的聚四氟乙烯工业，将被激活的钯催化剂和应用于催化反应。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，然后尝试催化体系。 公共卫生相关性：将氟添加到药物靶点通常赋予分子有价值的品质，例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采用的合成方法的限制。因此，重要的是开发用于将氟引入复杂分子的方法，使得可以快速合成和评估新的潜在药物。