Chemoselective cross-coupling via control of anion metathesis at Pd(II)

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Palladium-catalysed cross-coupling has revolutionised the way molecules are made and are essential to the continued production of myriad products from small bioactive molecules to materials and from small scale to manufacture. A number of these processes have become privileged, with their impact demonstrated from tonne-scale application to the Nobel Prize. Increased mechanistic understanding of catalytic reactions underpins improvements of existing processes while driving development of new methods. By interrogating reactivity and selectivity as a function of the palladium species formed from a key anion exchange (metathesis) event, this proposal aims to bring new understanding to the most important classes of cross-coupling reaction while providing methods for the preparation of novel and synthetically powerful architectures.Our preliminary proof-of-concept experiments in support of this proposal have shown that the anion metathesis event is influenced by different variables specific to catalytic reactions (for example, the substrate, the reaction medium). We have also shown that stoichiometrically prepared palladium complexes with different anions have profoundly different reactivities when assessed using a bifunctional chemical probe. Lastly, we have tentatively shown that this differential reactivity can allow the preparation of highly useful molecules. This proposal will comprehensively investigate this anion metathesis event to allow predictability and the rational application of this unappreciated event as a method for catalytic control of multi-reactive systems and, in this proposal, allow access useful synthetic scaffolds tailored towards application in Medicinal Chemistry.