Trifluoromethylation using Copper-based Reagents and Catalysts

铜催化交叉耦合的最新进展已经引起了对这些系统的重大和日益增长的学术/商业兴趣。虽然这一领域最初是由铜与钯和其他后期过渡金属相比的绿色和经济证书所推动的，但最近的研究也强调了铜催化剂的多功能性及其对现有系统的补充性质。然而，大多数系统对铜催化剂的操作机制仍然缺乏了解，这往往导致再现性差和结果不可预测。这抑制了这些试剂更广泛的使用。我们试图使用基于质量设计的方法来解决这个问题，该方法基于对机制的更好理解，包括辅助配体的作用，碱、催化剂和底物之间的协同/拮抗相互作用，以及包括催化剂失活在内的非循环事件的作用。这是通过一系列光谱、动力学和分析方法实现的，包括现场反应监测。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，我们现在将扩展这种方法，以研究用于三氟甲基化反应的铜基试剂和催化剂的开发。

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.