Electrochemical Flow Processes for Ni-Catalysed Coupling Reactions

还原性交叉偶联/交叉亲电偶联反应是一种强大的合成工具，随着ni催化工艺的发展，这种反应得到了极大的关注（图1a）。其中许多是通过单电子转移（set）和自由基中间体发生的，这使得与传统pd催化的偶联反应具有不同的反应活性，例如与sp3偶联体偶联并保留立体化学。它们的主要缺点是需要化学计量还原剂，例如锌和锰，以及与成本和浪费相关的后续问题，这限制了放大工艺。有机还原剂，如PPh3，四（二甲氨基）乙烯（TDAE）和HNiPr2，已被证明在实验室规模上起作用，尽管它们的回收利用尚未在文献中进行探索。扩大使用锌或锌试剂的反应规模仍然很困难。电化学方法为解决这一问题提供了一种可能的方法。具有精细调整的氧化还原电位的还原剂可以在原位进行电化学回收，将其作用转变为氧化还原介质。或者，镍中间体可以直接在电极上进行SET，完全绕过还原剂。在相反的电极上仍然需要牺牲还原剂，但这些还原剂允许其氧化还原电位具有显著的灵活性。有机还原剂的一些早期成功已经被报道，但是这个领域的过程理解和发展还没有被更广泛的社区所接受。在这个项目中，我们的目标是开发电化学流动过程，以实现镍催化的还原偶联反应，并为其进一步发展产生必要的过程理解。这将通过以下目标实现：1 .发展无机和有机还原剂的电化学回收工艺，例如TDEA。O2：牺牲还原剂在阳极和流动反应器设计上的探索。电化学流动反应器（EFRs）镍催化还原脱羧交叉偶联的研究进展。O1和O2将直接解决镍催化还原性交叉偶联过程发展的各个方面，并使氧化还原介质的使用成为可能，这些介质已被Stahl和同事成功地应用于氧化电化学过程。O3旨在应用在O1和O2中获得的过程理解，通过用容易获得的羧酸偶联伙伴取代还原剂来完全避免对还原剂的需要。这是目前可行的光化学，但流动电化学过程将更容易控制和更节能。该项目将利用efr (Bao Nguyen - BN, Charlotte Willans - CEW, Nikil Kapur - NK)，催化（BN， CEW），锌的电化学活化（BN）， iPRD （NK）开发的交替极性（AP）以及利兹大学自优化的电化学流动平台（CEW， NK）的专业知识。它将提供以下内容：(i)深入了解用于还原性交叉偶联的各种还原剂的氧化还原化学和回收可能性；（ii）镍催化还原偶联反应的efr和工艺设计；（iii）电极动力学和对电极材料、溶剂、电压和电流密度影响的理解，以及（iv）与ni催化剂的电化学流动脱羧偶联反应。

Reductive cross-coupling/cross-electrophile coupling reactions are powerful synthetic tools which have gained significant attention with the development of Ni-catalysed processes (Fig. 1a). Many of these happens through single electron transfers (SETs) and radical intermediates, which enable access to different reactivity to those of traditional Pd-catalysed coupling reactions, e.g. coupling with sp3 partners with retention of stereochemistry. Their main drawback, which restricts scaled-up processes, is the need for stoichiometric reductant, e.g. Zn and Mn, and subsequent problems associated with cost and waste. Organic reductants, such as PPh3, tetra(dimethylamino)ethylene (TDAE) and HNiPr2, have been shown to work on lab-scale, although their recycling has not been explored in the literature. Scaling up reactions using Zn or zinc reagents remains difficult.Electrochemical methods present a possible solution to this problem. The reductant with finely tuned redox potential may be electrochemical recycled in situ, changing its role to a redox mediator. Alternatively, Ni-intermediates may undergo SET directly at the electrodes, bypassing the reductant altogether. A sacrificial reductant is still needed on the opposite electrode, but these allow significant flexibility in its redox potential. Some early successes with organic reductants have been reported, but process understanding and development in this area has yet to be taken up by the wider community.In this project, we aim to develop electrochemical flow processes to enable Ni-catalysed reductive coupling reactions and to generate the required process understanding for their further development. This will be achieved through the following objectives:O1: Development of electrochemical recycling processes for inorganic and organic reductants, e.g. TDEA.O2: Exploration of sacrificial reductant on anode and flow reactor designs.O3: Development of Ni-catalysed reductive decarboxylative cross coupling with electrochemical flow reactors (EFRs). O1 and O2 will directly address the various aspects of process development of Ni-catalysed reductive cross coupling and enable the use of redox mediators, which have been successfully employed in oxidative electrochemical processes by Stahl and co-workers. O3 is aimed at applying the process understanding gained in O1 and O2 to completely circumvent the need for a reductant by substituting it with the readily available carboxylate coupling partner. This is currently feasible with photochemistry, but a flow electrochemical process will be easier to control and more energy efficient.The project will take advantage of the expertise in EFRs (Bao Nguyen - BN, Charlotte Willans - CEW, Nikil Kapur - NK), catalysis (BN, CEW), electrochemical activation of zinc (BN), alternating polarity (AP) developed in the iPRD (NK), and the self-optimised electrochemical flow platform (CEW, NK) at Leeds. It will deliver the following: (i) in-depth understanding of the redox chemistry and recycling possibility of a wide range of reductants for reductive cross-coupling; (ii) EFRs and process designs for Ni-catalysed reductive coupling reactions; (iii) electrode kinetics and understanding of the influence of electrode material, solvent, voltage and current density, and (iv) electrochemical flow decarboxylative coupling reactions with Ni-catalysts.