Decarboxylative Trifluoromethylation and Trifluoromethoxylation via Iron-Mediated Photochemical Radical Generation and Copper Catalysis - Project Summary
Fluorinated compounds are privileged building blocks in pharmaceutical development due to the
beneficial properties of fluorine. Decarboxylative functionalization methods are useful tools for synthetic
chemists, as carboxylic acids are stable and readily available starting materials. However, the few
decarboxylative trifluoromethylation methods suffer from the necessity of expensive photocatalysts and
electrophilic trifluoromethyl sources, or preformed metal–CF3 sources. Furthermore, accessing
trifluoromethoxylated compounds through decarboxylative methods has not been realized. Recently, the Yoon
lab developed methodologies that utilize ligand-to-metal charge transfer (LMCT) to promote photochemical
decarboxylation of metal carboxylates using either copper or iron, both of which are inexpensive and minimally
toxic metals. This strategy was used for nucleophilic trapping of the carbocations formed from oxidation of the
radical; however, this method of radical generation has not been expanded to trap radicals in a Cu-catalyzed
cross-coupling or to access trifluoromethylated or trifluoromethoxylated compounds.
This proposal takes advantage of LMCT-generated radicals in combination with a copper-catalyzed C–
C or C–O cross-coupling. In Aim 1, the development of an enantioselective copper-catalyzed trifluoromethylation
between carboxylic acids and a nucleophilic source of trifluoromethyl is described. This reaction utilizes
inexpensive and non-toxic metals, both in the iron-mediated LMCT generation of benzylic radicals and in trapping
the radicals in a copper-catalyzed C–C or C–O bond forming cycle. Aim 1 will begin with the establishment of a
system using stoichiometric copper, followed by the development of a catalytic system. Lastly, the use of chiral
ligands will be explored to render the reaction enantioselective. Aim 2 will allow for development of an
enantioselective decarboxylative trifluoromethoxylation under similar reaction conditions. Multiple nucleophilic
sources of OCF3 will be investigated to access a copper trifluoromethoxy species that can form the desired C–
O bond. The substrate scope of the will be explored, including electronic and steric changes to the carboxylic
acid. Additionally, as many non-steroidal anti-inflammatory drugs (NSAIDs) contain carboxylic acid moieties, the
proposed methodologies will be tested on readily available biologically active starting materials, such as
ibuprofen. Finally, Aim 3 will focus on exploring the mechanism of the proposed reaction through radical trapping
experiments, computational studies, and kinetic experiments.
The proposed strategy allows for access to trifluoromethylated and trifluoromethoxylated compounds
from readily available carboxylic acids and nucleophilic CF3 or OCF3 sources to access pharmaceutically relevant
fluorinated compounds. This novel merging of LMCT benzylic radical generation and Cu-catalyzed cross-
coupling broadens the reactivity previously accessible using LMCT-generated radicals.
