Trifluoromethylation using Copper-based Reagents and Catalysts

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Recent advances in copper catalysed cross-couplings have led to significant and growing academic / commercial interest in these systems. Although this field was originally driven by the much-improved Green and economic credentials of copper compared to palladium and other late transition metals, recent studies have also highlighted the versatility of copper catalysts and their often-complimentary nature to existing systems. Nevertheless, understanding of the mechanism of operation of copper catalysts is still lacking for most systems, often leading to poor reproducibility and unpredictable results. This has inhibited a more widespread uptake in the use of these reagents. We have sought to address this using a Quality-by-Design approach based on improved understanding of the mechanism including the role of the ancillary ligand, synergic / antagonistic interactions between the base, catalyst and substrates, and the role of off-cycle events including catalyst deactivation. This has been achieved using a range of spectroscopic, kinetic, and analytical methods, including in situ reaction monitoring. Using this approach, we have been able to develop improved reaction protocols including, for example, the first room temperature reactions using sub mol% copper loadings. In this work we will now extend this approach to look at the development of copper-based reagents and catalysts for trifluoromethylation reactions.