Improving Iron Catalysed Kumada Couplings in Flow

本项目的重点是开发一种改进铁催化烷基-烷基熊田交叉偶联的方法。这类反应是传统钯催化反应的一种有前途的可持续替代反应，但提高效率、选择性和催化剂周转率对于使反应更具可持续性和工业可行性至关重要。这将通过开发和使用流动装置来探索动力学和反应途径来实现。这种类型的反应在以前的文献中已经报道过，使用铁（II）醋酸酯和一个黄磷或n -杂环碳（NHC）配体；这些反应在15分钟后获得了高达64%的产率，NHC反应在27小时后获得了67%的产率。虽然这些产量很有希望，但进一步优化催化剂和反应条件将使该反应成为大规模化工生产的廉价、可持续和可行的选择；特别是对于制药、农化和精细化工行业，在这些行业中，通常依赖于更昂贵和环境成本更高的钯催化剂。我们计划利用在连续流动反应器中进行的反应可以在稳态下进行探测，以更好地了解反应并帮助优化过程。预计使用流动设备可以实现的对反应的额外控制也将有助于这一过程。此外，该项目将专注于扩大底物范围，以合成β功能化胺，如功能化哌替啶、氮杂啶和人造氨基酸。这些都是有价值的构建块，例如基于片段的药物发现和活性药物中间体（api）的合成。该项目将侧重于开发一种模型反应和一般方法，可供其他研究小组和行业使用和应用。最后，在整个项目中，我们将研究设计一个流动反应器系统，该系统将包括在线分析和反应后续步骤。这将使反应在连续装置中用作较长合成的一部分。此外，我们希望研究将循环催化剂纳入系统的可能性，作为概念验证，以促进该领域的进一步发展。这个项目的好处有三方面，首先熊田交叉偶联经常用于精细化学品和药品的合成。用铁代替常用的钯催化剂将增加反应的可持续性并降低反应的总成本。其次，通过关注烷基-烷基交叉偶联，我们将通过提供可扩展的方法来合成饱和结构，从而帮助开辟尚未开发的化学空间。我们特别感兴趣的是饱和β功能化胺的合成，这是原料药中常见的部分。扩大可用于药物开发的饱和结构的范围对于不断发现和制造在该领域通常被忽视的新药非常重要。最后，由于该反应中使用的一些成分的反应性，特别是格氏试剂，确保它们的合成和反应都是安全的，并且在某种程度上，它们的反应性可以被控制，以最大限度地提高所需产品的产量是至关重要的。通过开发该反应的流动方法，我们希望证明格氏试剂可以安全使用，并具有适合现代可持续化学制造的高度控制。

This project is focused on developing a methodology to improve iron catalysed alkyl-alkyl Kumada cross couplings. This type of reaction is a promising sustainable alternative to traditionally palladium catalysed reactions, but improving the efficiency, selectivity, and catalyst turnover is important to make the reaction more sustainable and viable for industry. This will be done by developing and using flow apparatus to explore kinetics and reaction pathway. This type of reaction has been previously reported in the literature using Fe(II) acetate, and a xantphos or N-heterocyclic carbene (NHC) ligand; these reactions have achieved yields up to 64% for the xantphos system after 15 mins, and 67% after a total of 27 hours for the NHC reaction. Whilst these yields are promising further optimisation of the catalyst and reaction conditions would make the reaction a cheap, sustainable, and viable option for large-scale chemical production; in particular for the pharmaceutical, agrochemical, and fine chemicals industries , where more expensive and environmentally costly palladium catalysts are commonly relied upon.We plan to exploit the fact that reactions carried out in continuous flow reactors can be probed at steady state to better insight into the reaction and aid the optimisation process. It is anticipated that the additional control over the reaction that can be achieved using flow equipment will also aid in this process. Additionally, this project will focus on expanding the substrate scope to enable the synthesis of beta-functionalised amines, such as functionalised piperadines, azetidines, and man-made amino acids. These are valuable building blocks e.g. for fragment based drug discovery and the synthesis of active pharmaceutical intermediates (APIs). The project will focus on developing a model reaction and general method that can used and applied by other research groups and industry. Finally, throughout this project we will investigate designing a flow reactor system that will include both in-line analysis and reaction workup steps. This will enable the reaction to be used in a continuous set up as part of a longer synthesis. Furthermore, we would like to investigate the possibility of incorporating into the system a loop to recycle the catalyst as a proof of concept to spur of further development in this area. The benefits of this project are three-fold, first of all the Kumada cross coupling is often used for the synthesis of fine chemicals and pharmaceuticals. Replacing commonly used palladium catalysts with iron will increase the sustainability and decrease the overall cost of the reaction.Second of all by focusing on alkyl-alkyl cross couplings we will help provide methods to open up under explored chemical space by providing scalable methods to synthesize saturated structures. In particular we are interested in the synthesis of saturated beta-functionalised amines, which are common moieties in APIs. Expanding the scope of saturated structures accessible for drug development is important to continuously enable the discovery and manufacture of new medicines typically neglected in this area. Finally, due to the reactivity of some of the components used in this reaction, in particular the Grignard reagent, it is critical to ensure that they are both synthesized and reacted safely and in a way where their reactivity can be controlled to maximise the yield of the desired product. By developing flow methodologies for this reaction we hope to demonstrate that the Grignard reagent can be used safely and with a high degree of control suitable for modern sustainable chemical manufacturing.