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: 9321445
• 负责人: Nilay Hazari
• 金额: $ 29.01万
• 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/9321445
• 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.

项目概要/摘要 过渡金属催化交叉偶联是最强大的合成方法之一， 主要用于制备活性药物成分 这项工作的目标是。 利用基础机理研究开发改进的镍和钯催化剂，用于新型和 最近，我们小组开发了商业化的交叉偶联反应。 预催化剂支架 (3-1-tBu-茚基)Pd(L)(Cl) (IndPdL, L = N-杂环卡宾 (NHC) 或 PR3)，它可以产生用于一系列重要交叉偶联反应的高活性催化剂。 设计更好的催化剂，促进新反应并在更温和的条件下运行 在条件允许的情况下，我们将使用 IndPdL 派生系统进行详细的机理研究，包括 我们的研究将涵盖催化过程的各个方面。 包括阐明预催化剂活化的途径，了解基本步骤 催化循环和确定催化剂分解途径首先，我们将研究。 IndPdL在多种条件下对单连接Pd0活性物质的激活机制 用于交叉耦合的条件这将是第一个对激活的全面研究。 在一系列常用反应条件下的任何交叉偶联预催化剂。 信息将与催化基本步骤的知识结合使用， 这将通过化学计量研究和动力学实验获得，以合理地 开发与芳基氯、氨基甲酸酯和等进行无氟桧山反应的系统 氨基磺酸盐以及与 2-芳基和 2-烷基氮丙啶的 Suzuki-Miyaura 偶联。 与 Pd 体系活性相当的 Ni 催化剂的发现是优选的，因为 Ni 更便宜、更丰富且毒性更低。因此，我们还将使用一种。 基于合理设计的方法开发用于交叉偶联的镍基催化剂。 初步结果表明，铃木宫浦的几种高活性镍预催化剂 反应在催化条件下快速形成 NiI 络合物在这里，我们将确定 的作用。 单齿和双齿膦支持的体系中的 NiI 物质催化 配体，以及 NHC 配体，这些信息将用于开发改进的系统。 与芳基氨基甲酸酯和氨基磺酸酯 A 的 Suzuki-Miyaura 和 Buchwald-Hartwig 反应。 我们的机械方法的主要额外好处是我们阐明的总体趋势 关于 Ni 和 Pd 催化交叉偶联的催化剂设计和反应条件将 可推广到与合成相关的大量其他反应 药品，但本提案中不会具体研究。