Copper-catalyzed transformations of carboradicals generated by electrochemical and photochemical methods: oxidative amination and polyfluoroarylation

Organic radicals are highly active species that can undergo various transformations. Electrochemistry and photochemistry are efficient methods for the generation of these species of high energy, through single electron transfer processes under mild conditions. These methods have been frequently used to form various carboradical intermediates, for example, via the addition of N-centered radicals to alkenes (Section 1.4). Copper is a versatile transition metal that can transform carboradicals for the formation of various chemical bonds (Section 1.6). Combining electrochemistry or photochemistry for the generation of carboradicals with the copper-catalyzed carboradical functionalization will potentially lead to a large chemical space of useful organic reactions. So far, this intersection of electrochemistry or photochemistry with copper chemistry is still highly underdeveloped. In this thesis, we have developed three useful reactions, testifying the practicability of this concept.In Chapter 2, we describe an intramolecular oxidative amination reaction by integrating electrochemical oxidation with Cu catalysis. Electrochemical oxidation facilely generates N-radical from N-H for the intramolecular cyclization to double bonds, and then the resultant carboradicals are transformed into a new double bond via copper-catalyzed oxidative elimination (Section 1.6.1). A wide range of 5-membered N-containing heterocycles bearing a pendant, functionalizable alkene moiety can be synthesized under mild conditions. Mechanistic studies revealed that direct oxidation on the electrode couldn't efficiently convert primary and secondary alkyl radical intermediates into alkenes, and that the assistance of copper was indispensable.In Chapter 3, an intermolecular oxidative amination reaction of unactivated alkenes by integrating photoredox with Cu catalysis is described. This method relied on photochemical reduction of a hydroxyamine derivative to generate amidyl radical which then adds to unactivated alkenes. The obained carboradicals are trapped by the copper catalyst to form allylic amines. The reaction exhibited a broad scope and excellent tolerance for functional groups including highly polar groups. In Chapter 4, we report a decarboxylative coupling reaction of aliphatic acids with polyfluoroaryl nucleophiles by integrating photoredox with copper catalysis. A set of polyfluoroaryl zinc reagents were prepared and applied to the coupling. The aliphatic esters of N-hydroxyphthalimide (NHPI esters) were transformed into alkyl radicals by photoreduction. Then, the trapping of the radical by the copper catalyst and subsequent reductive elimination render the alkyl polyfluoroarenes as products. This method allows the installation of polyfluoroaryls with variable F-content (2F -5F) and F-substitution patterns on primary or secondary alkyl groups, with good compatibility of functional groups. In summary, this thesis demonstrates the combination of electrochemistry and photochemistry with copper catalysis to construct useful synthetic methods. Considering the diversity of radicals that could be generated by electrochemical and photochemical methods, and the versatility of copper catalyzed functionalization of carboradicals, we believe that this combination has far more potential than these three reactions.