Trifluoromethylation using Copper-based Reagents and Catalysts

铜催化的交叉偶联反应的最新进展引起了学术界和商界对这些体系的浓厚兴趣。尽管这一领域最初是由铜与钯和其他后过渡金属相比大大改善的绿色和经济资质推动的，但最近的研究也强调了铜催化剂的多功能性及其对现有体系的往往互补性质。然而，对于大多数系统来说，对铜催化剂的操作机理仍然缺乏了解，往往导致重现性差和结果不可预测。这阻碍了这些试剂的更广泛的使用。我们试图用质量设计的方法来解决这个问题，这种方法基于对机制的更好的理解，包括辅助配体的作用，碱基、催化剂和底物之间的协同/拮抗作用，以及包括催化剂失活在内的非周期事件的作用。这是通过一系列光谱、动力学和分析方法实现的，包括原位反应监测。使用这种方法，我们已经能够开发改进的反应方案，包括，例如，第一个使用亚摩尔%铜负载的室温反应。在这项工作中，我们将扩展这一方法，以考察三氟甲基化反应的铜基试剂和催化剂的发展。

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.