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

项目摘要/摘要 过渡金属催化的交叉偶联反应是目前最有效的合成方法之一。 广泛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的和 现有的交叉偶联反应。最近，我们团队开发了可商业化的 预催化剂骨架(3-1-Tbu-Indenyl)Pd(L)(氯)(IndPdL，L=N-杂环卡宾 Pr3)，它为一系列重要的交叉偶联反应产生高活性催化剂。 设计更好的催化剂，可以促进新的反应，并在更温和的条件下运行 条件，我们将使用IndPdL派生系统进行详细的机械研究，包括 无论是实验还是理论。我们的研究将涵盖催化过程的方方面面 包括阐明催化剂前活化的途径，了解基本步骤 在催化循环中，确定催化剂的分解途径。首先，我们将研究 不同条件下IndPdL对Pd0活性单体的活化机理 用于交叉耦合的条件。这将是第一次对激活的全面研究 在一系列常用反应条件下的任何交叉偶联预催化剂。这 信息将与催化基本步骤的知识结合使用， 它将通过化学计量研究和动力学实验获得，以合理地 开发无氟的Hiyama与芳基氯、氨基甲酸酯和 磺酸盐和铃木-宫浦与2-芳基和2-烷基氮杂环丙烷的偶联。 发现活性与Pd体系相当的镍催化剂是首选，因为镍是 更便宜，更丰富，毒性更低。因此，我们还将使用 基于合理设计开发交叉偶联镍基催化剂的途径。在……里面 初步结果表明，几种高活性的铃木-宫仓镍预催化剂 在催化条件下，反应迅速形成NiI络合物。在这里，我们将确立 单齿和双齿膦支撑体系催化中的NiI物种 配体，以及NHC配体。这些信息将用于开发改进的系统，以 Suzuki-Miyaura和Buchwald-Hartwig与芳基氨基甲酸酯和氨基磺酸的反应。一个 我们的机械论方法的主要额外好处是，我们在 关于镍和钯催化交叉偶联的催化剂设计和反应条件 可概括为与合成有关的大量其他反应 药品，但不会在这项提案中具体研究。

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.