Mechanistic Studies to Rationally Design Ni and Pd Catalysts for Cross-Coupling

合理设计交叉偶联镍和钯催化剂的机理研究

• 批准号: 9892110
• 负责人: Nilay Hazari
• 金额: $ 6.51万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892110
• 关键词: Address; Aziridines; Carbamates; Catalysis; Chlorides; Complex; Coupling; Development; Disease; Electrons; Fluorides; Goals; Investigation; Kinetics; Knowledge; Ligands; Methods; Mission; Outcome; PRTN3 gene; Pathway interactions; Pharmacologic Substance; Phosphines; Preparation; Process; Protocols documentation; Reaction; Research; Role; Route; Support System; Synthesis Chemistry; System; Toxic effect; Transition Elements; United States National Institutes of Health; Work; base; carbene; catalyst; cost effective; design; experimental study; improved; scaffold; sulfamate; theories; trend

Project Summary/Abstract Transition metal catalyzed cross-coupling is one of the most powerful synthetic methods and is used extensively in the preparation of active pharmaceutical ingredients. The goal of this work is to use fundamental mechanistic studies to develop improved Ni and Pd catalysts for new and existing cross-coupling reactions. Recently, our group developed the commercially available precatalyst scaffold (3-1-tBu-indenyl)Pd(L)(Cl) (IndPdL, L = N-Heterocyclic carbene (NHC) or PR3), which generates highly active catalysts for a range of important cross-coupling reactions. To design even better catalysts, which can facilitate new reactions and operate at milder conditions, we will perform detailed mechanistic studies using IndPdL derived systems, involving both experiment and theory. Our studies will encompass all aspects of the catalytic process including elucidating the pathway for precatalyst activation, understanding the elementary steps in catalytic cycles and determining the catalyst decomposition pathway. Initially, we will study the mechanism of activation of IndPdL to the monoligated Pd0 active species under a variety of conditions used for cross-coupling. This will be the first comprehensive study of the activation of any cross-coupling precatalyst under a range of commonly used reaction conditions. This information will be used in combination with knowledge of the fundamental steps in catalysis, which will be gained through stoichiometric studies and kinetics experiments, to rationally develop systems for fluoride free Hiyama reactions with aryl chlorides, carbamates and sulfamates and Suzuki-Miyaura couplings with 2-aryl and 2-alkylaziridines. The discovery of Ni catalysts with comparable activity to Pd systems is preferred because Ni is cheaper, more abundant and has lower levels of toxicity. Accordingly, we will also use an approach based on rational design to develop Ni based catalysts for cross-coupling. In preliminary results we showed that several highly active Ni precatalysts for the Suzuki-Miyaura reaction rapidly form a NiI complex under catalytic conditions. Here, we will establish the role of NiI species in catalysis with systems supported by monodentate and bidentate phosphine ligands, as well as NHC ligands. This information will be used to develop improved systems for the Suzuki-Miyaura and Buchwald-Hartwig reactions with aryl carbamates and sulfamates. A major additional benefit of our mechanistic approach is that the general trends we elucidate in regard to catalyst design and reaction conditions for Ni and Pd catalyzed cross-coupling will be generalizable to a plethora of other reactions, which are relevant to the synthesis of pharmaceuticals, but will not specifically be studied in this proposal.

项目摘要/摘要 过渡金属催化的交叉偶联是最强大的合成方法之一，是 广泛用于活性药物成分的制备。这项工作的目的是 使用基本的机械研究来开发改进的NI和PD催化剂，以进行新的和 现有的跨耦合反应。最近，我们的小组开发了市售的 前催化脚手架（3-1-TBU-吲哚基）PD（L）（Cl）（INDPDL，L = N-杂环卡宾（NHC）或 PR3），它为一系列重要的交叉偶联反应产生高度活性的催化剂。 设计更好的催化剂，这可以促进新反应并在Miller运行 条件，我们将使用INDPDL派生系统进行详细的机械研究，涉及 实验和理论。我们的研究将涵盖催化过程的所有方面 包括阐明预催化剂激活的途径，了解基本步骤 在催化周期并确定催化剂分解途径中。最初，我们将学习 在各种 用于交叉耦合的条件。这将是对激活的首次全面研究 在一系列常用的反应条件下的任何交叉偶联预催化剂。这 信息将结合了解催化的基本步骤， 这将通过化学计量研究和动力学实验获得，以合理地进行 开发用于氟化物无芳基氯化物，氨基甲酸酯和碳酸盐和 硫酸盐和铃木 - 米约拉尔夫妇与2-芳基和2-烷基二嘧啶。 首选具有与PD系统相当活性的NI催化剂的发现，因为Ni是 更便宜，更丰富，毒性水平较低。根据，我们还将使用 基于合理设计的方法开发基于NI的催化剂以进行交叉耦合。在 初步结果我们表明，铃木 - 米约拉拉的几个高度活性的NI预催化剂 反应在催化条件下迅速形成NII复合物。在这里，我们将确定 nii物种在催化中与单次元素和鸟类磷酸支持的系统的催化物种 配体以及NHC配体。此信息将用于开发改进的系统 Suzuki-Miyaura和Buchwald-Hartwig与芳基氨基甲酸酯和硫酸盐的反应。一个 我们机械方法的主要额外好处是我们阐明的一般趋势 关于Ni和PD催化的交叉偶联的催化剂设计和反应条件将是 与其他反应有关的概括，这些反应与合成有关 药品，但不会在此提案中具体研究。