Improving Iron Catalysed Kumada Couplings in Flow

点击翻译按钮获取中文摘要

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.