Improving Iron Catalysed Kumada Couplings in Flow

该项目致力于开发一种改进铁催化的烷基-烷基熊田交叉偶联的方法。这类反应是一种很有前途的可持续替代传统的钯催化反应，但提高效率、选择性和催化剂周转率是重要的，使该反应更可持续和工业可行。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。这种类型的反应以前在文献中报道过使用醋酸铁和杂环卡宾(NHC)配体；这些反应在15分钟后获得了高达%的产率，对于N-杂环卡宾(NHC)反应在总共27小时后获得了67%的产率。虽然催化剂和反应条件的进一步优化有望使该反应成为大规模化学生产的廉价、可持续和可行的选择；特别是对于制药、农用化学品和精细化工行业，这些行业通常依赖更昂贵和环境成本更高的钯催化剂。我们计划利用这样一个事实，即在连续流动反应器中进行的反应可以在稳定的状态下进行探索，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，以实现β功能化胺的合成，如功能化的哌拉定、氮杂环丁胺和人造氨基酸。它们是有价值的构建块，例如用于基于片段的药物发现和活性药物中间体(API)的合成。该项目将致力于开发一种模型反应和通用方法，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准备步骤。这将使该反应能够作为较长合成的一部分在连续设置中使用。此外，我们希望研究在该系统中加入一个循环以回收催化剂的可能性，作为概念的证明，以刺激这一领域的进一步发展。该项目的好处有三个方面，首先，熊田交叉偶联经常用于合成精细化学品和药物。用铁取代常用的钯催化剂将增加反应的可持续性，降低反应的总成本。其次，通过重点研究烷基-烷基交叉偶联，我们将提供方法，通过提供可扩展的方法来合成饱和结构，从而开拓探索的化学空间。特别是，我们对饱和的β-功能化胺的合成感兴趣，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，对于继续发现和生产这一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，并以一种可以控制其反应性的方式来最大限度地提高所需产品的产率，这一点至关重要。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地使用，并且具有高度的可控性，适合于现代可持续的化学制造。

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.