Copper as a Photocatalyst: Applications in Decarboxylative Fluorination

点击翻译按钮获取中文摘要

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.