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

项目概要/摘要 过渡金属催化的交叉偶联是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Ni和Pd催化剂， 存在交叉偶联反应。最近，我们的团队开发了商业上可用的 预催化剂支架（NH3 -1-tBu-茚基）Pd（L）（Cl）（IndPdL，L = N-杂环卡宾（NHC）或 PR 3），其产生用于一系列重要的交叉偶联反应的高活性催化剂。 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操作， 条件下，我们将使用IndPdL衍生系统进行详细的机理研究，包括 实验和理论。我们的研究将包括催化过程的各个方面 包括阐明预催化剂活化的途径，理解基本步骤， 在催化循环和确定催化剂分解途径。首先，我们将研究 研究了IndPdL在多种条件下活化为单配体Pd 0活性物种的机理。 用于交叉耦合的条件。这将是第一次全面研究激活 任何交叉偶联预催化剂在一系列常用的反应条件下。这 信息将与催化的基本步骤的知识结合使用， 通过化学计量研究和动力学实验， 开发用于与芳基氯化物、氨基甲酸酯和氨基甲酸酯进行无氟Hiyama反应的系统， 氨基磺酸酯和Suzuki-Miyaura偶联与2-芳基和2-烷基氮杂环丙烷。 具有与Pd体系相当的活性的Ni催化剂的发现是优选的，因为Ni是 更便宜，更丰富，毒性更低。因此，我们还将使用 基于合理设计的方法开发用于交叉偶联的Ni基催化剂。在 初步结果表明，几种高活性Ni预催化剂的铃木-宫浦 反应在催化条件下迅速形成NiI络合物。在这里，我们将确定 单齿和双齿膦催化体系中的NiI物种 配体，以及NHC配体。这些信息将用于开发更好的系统， 与芳基氨基甲酸酯和氨基磺酸酯的Suzuki-Miyaura和Buchwald-Hartwig反应。一 我们的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， 可推广到过多的其他反应，这是有关的合成 药物，但不会在本提案中具体研究。

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.