Copper as a Photocatalyst: Applications in Decarboxylative Fluorination

项目摘要 药物化合物的氟化已显示通过以下方式增加其效力： 调节它们的亲脂性、酸性和构象偏差。光氧化还原脱羧 特别是，氟氯化碳被认为是获得氟化碳的有力战略。 化合物.然而，这些方法通常局限于协同催化， 昂贵的Ir或有机光催化剂。Yoon实验室最近展示了一种新的方法来促进 使用简单的CuII盐进行氧化光化学脱羧。CuII羧酸盐的辐照 导致配体到金属的电荷转移，这导致快速脱羧以产生烷基 激进他们将这种策略应用于苄型羧酸的脱羧胺化。 该提案详细介绍了这一战略对氧化脱羧酶的应用 并对该方法的反应机理进行了探讨。在第一个目标中， 烷基羧酸的氧化脱羧反应将采用化学计量比 铜作为终端氧化剂和脱羧剂。既有激进的抽象， 将探讨亲核的亲核反应机理。第二个目标侧重于发展一个 使用Selectfluor作为氟源的铜催化光化学脱羧法 并作为氧化剂来转化催化剂。使用催化铜允许调整光吸收 和通过配体选择的铜络合。紫外-可见光谱将用于识别形成铜的配体 在可见光区吸收光并在过量羧酸盐存在下稳定的络合物。 反应机理将通过量子产率的研究进行询问。最后，在发展 化学计量法和催化法中，活性铜物种的机理和身份， 作为第三个目标的一部分，将通过紫外-可见光谱、电子顺磁共振和计算研究来研究解决方案。 该战略的制定为现有方法提供了一种补充方法， 使用简单、廉价的试剂将氟掺入小分子中， 光化学氧化脱羧新方法。

PROJECT SUMMARY Fluorination of pharmaceutical compounds has been shown to increase their potency through modulation of their lipophilicity, acidity, and conformational bias. Photoredox decarboxylative fluorination in particular has been recognized as a powerful strategy for accessing fluorinated compounds. However, these methods have typically been limited to cooperative catalysis with expensive Ir or organic photocatalysts. The Yoon lab has recently demonstrated a novel way to promote oxidative photochemical decarboxylation using simple CuII salts. Irradiation of the CuII carboxylate results in ligand-to-metal charge transfer, which leads to rapid decarboxylation to generate the alkyl radical. They applied this strategy towards the decarboxylative amination of benzylic carboxylic acids. This proposal details the application of this strategy towards oxidative decarboxylative fluorination and investigation of the reaction mechanism of this approach. In the first Aim, the photochemical oxidative decarboxylative fluorination of alkyl carboxylic acids will be developed using stoichiometric copper as both the terminal oxidant and decarboxylating agent. Both radical abstraction and nucleophilic fluorination mechanisms will be probed. The second Aim focuses on the development of a copper-catalyzed photochemical decarboxylative fluorination using Selectfluor as a source of fluorine and as an oxidant to turn over the catalyst. Use of catalytic copper allows for tuning of light absorption and copper complexation through ligand choice. UV-Vis will be used to identify ligands that form copper complexes that absorb light in the visible region and are stable in the presence of excess carboxylate. The reaction mechanism will be interrogated through quantum yield studies. Finally, upon development of the stoichiometric and catalytic methods, the mechanism and identity of the active copper species in solution will be investigated through UV-Vis, EPR, and computational studies as part of the third Aim. Development of this strategy provides a complementary approach to existing methods for the incorporation of fluorine in small molecules using simple, inexpensive reagents and affords mechanistic insight into a novel method for photochemical oxidative decarboxylation.