Copper as a Photocatalyst: Applications in Decarboxylative Fluorination

项目总结 药物化合物的氟化已被证明通过以下方式提高其效力 它们的亲脂性、酸性和构象偏向的调节。光氧化还原脱羧剂 尤其是氟化已经被认为是获得氟化的一种有效策略 化合物。然而，这些方法通常仅限于与 昂贵的红外或有机光催化剂。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基。CuII羧酸盐的辐照 导致配体到金属的电荷转移，从而导致快速脱羧基生成烷基 激进的。他们将这一策略应用于苄基羧酸的脱羧胺化反应。 本提案详细介绍了这一策略在氧化脱酸氟化反应中的应用。 并对该方法的反应机理进行了探讨。在第一个目标中，光化学 将利用化学计量比开发烷基羧酸的氧化脱羧基氟化 铜既是终端氧化剂又是脱羧剂。激进的抽象和 亲核氟化机理将被探讨。第二个目标是开发一种 以选择性氟为氟源的铜催化光化学脱酸氟化反应 并作为氧化剂来反转催化剂。使用催化铜可以调节光吸收 通过配位选择进行铜的络合。紫外可见光谱将被用来识别形成铜的配体 在可见光区域吸收光并在过量的羧酸盐存在下稳定的络合物。 将通过量子产率研究来询问反应机理。最后，根据发展情况 在化学计量方法和催化方法中，活性铜物种的机理和特性 作为第三个目标的一部分，将通过UV-Vis、EPR和计算研究来研究解决方案。 这一战略的发展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，并提供了 洞察一种新的光化学氧化脱羧基方法。

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.