A Flow Process For Aminomethylations Using Catalysts Supported On Magnetic Nanoparticles

与多相催化剂相比，均相催化剂有几个优点，包括更好的选择性和可控性，因为它们的分子性质确保了只有一种类型的活性中心存在。此外，据估计，85%的化工过程是催化运行的，多相催化与均相催化的应用比例约为75：25。然而，涉及均相催化的连续流动过程存在困难，间歇过程中的许多有效系统无法转化为流动。一个主要问题是将产品从催化剂中分离出来。巴斯的研究小组最近制备了两种类型的催化剂，要么是有机金属物种，要么是围绕着超顺磁性氧化铁核心的金属外壳。初步结果表明，固定化的磺化膦或醋酸酯配体可以配位高效地催化(高达100%转化率)硼酸共轭加成、Suzuki和Heck偶联以及氢化和二羟化反应的Rh或Pd络合物。在磁分离后，催化剂保持了活性，在某些情况下，甚至在连续运行10次后也保持了活性。在这项建议中，我们希望使用新型磁性可移动和可回收的半均相催化剂来开发钯催化的氨基烷基硼试剂偶联的流动化学方案。它们的大小意味着它们的工作方式与均相催化剂相同，但它们很容易在磁场中回收。我们的重点是开发在药物合成中广泛应用的方法学，重点是芳基/乙烯基卤化物的催化氨甲基化，作为还原胺化的战略替代。通常，纳米颗粒的磁性被用来促进与反应产物的分离(S)。我们希望通过进一步利用磁性来扩展这一点，以(I)将纳米颗粒催化剂捕获在流动反应器的特定区域内，以及(Ii)施加交变磁场来操纵和移动纳米颗粒在反应器周围，从而增强传质。这项新技术将提供许多优点，主要是将均相催化剂固定在反应器中，而不需要与产品分离。

Homogeneous catalysts offer several advantages over their heterogeneous counterparts; including the greater selectivity and controllability because their molecular nature ensures that only one type of active site is present. Furthermore, it is estimated that 85% of all chemical processes are run catalytically, with the ratio of applications of heterogeneous to homogeneous catalysis of ca. 75:25.However, continuous flow processes involving homogeneous catalysis present difficulties and many efficient systems in batch processes cannot be transferred to flow. A major problem is associated with separating the products from the catalyst. The group at Bath has recently prepared two types of catalyst consisting of either organometallic species or a metallic shell around superparamagnetic iron oxide cores. Preliminary results indicate that immobilized sulfonated phosphines or acetate ligands allow the coordination of rhodium or palladium complexes that efficiently catalyse (up to 100% conversion) the conjugate addition of boronic acids, and Suzuki and Heck coupling, as well as hydrogenation and dihydroxylation reactions. The catalysts retained activity after magnetic separation, in some cases even after 10 consecutive runs. In this proposal we wish to develop flow chemistry protocols for the palladium-catalysed coupling of aminoalkylboron reagents using new types of magnetically moveable and recoverable semi-homogeneous catalysts. Their size means that they operate in the same manner as homogeneous catalysts but they are easily recovered in a magnetic field. With a clear emphasis on developing methodology of broad application to the synthesis of medicinal compounds, we will focus on the catalytic aminomethylation of aryl/vinyl halides as a strategic alternative to reductive amination. Normally the magnetic properties of the nanoparticles have been used to facilitate separation from the reaction product(s). We wish to extend this by further exploitation of the magnetism to (i) entrap the nanoparticle catalyst within certain regions of a flow reactor and (ii) to apply alternating magnetic fields to manipulate and move the nanoparticles around the reactor, enhancing mass transfer. This new technology will offer a number of advantages, chiefly entrapment of the homogeneous catalyst in the reactor without necessity of separation from products.