In 1999 Yoshida and co-workers developed the cation pool method which stabilized carbamate cationic intermediates generated during a two electron oxidation followed by deprotonation that takes place in the anodic compartment of a two compartment cell under low temperatures.¹ The method allows for rapid reactions with nucleophiles that may be unstable during electrolysis and can be added to the reaction mixture at the end of electrolysis to form the final product.

Here, we report on the extension of the cation pool method for the application of electrochemical fluorination and radio-fluorination of methyl (phenylthio)acetate. Electrochemical fluorination and no-carrier-added radio-fluorination were successfully achieved using the cation pool method . Figure 1 shows the schematic of no-carrier-added electrochemical radio-fluorination of methyl (phenylthio)acetate using cation pool method. The cation pool method has tremendous potential for radiofluorination experiments. The excess concentration of cations may provide an efficient reaction mechanism for late-stage fluorination under low fluoride concentrations encountered in radiochemistry. Furthermore, radiochemical yield, which is reduced by decay of the radioisotope, can benefit from a rapid late-stage fluorination reaction. The cation pool can be prepared prior to cyclotron production of ¹⁸F isotope, thereby, providing a rapid late-stage fluorination reaction, maximizing radiochemical yield by minimizing decay through a rapid reaction of the previously prepared cations with ¹⁸F-fluoride.

Synthesis parameters such as temperature, supporting electrolyte concentration and type, and precursor concentration were studied and optimized. The fluorination and radiofluorination yields of 12% and 6.7% were obtained, respectively, using the optimum conditions. The products were characterized using gas chromatography–mass spectrometry (GC-MS), nuclear magnetic resonance (NMR), radio-thin-layer chromatography (radio-TLC) and high-performance liquid chromatography (HPLC). This method can also be applied for a late-stage no-carrier-added radiofluorination to develop new positron emission tomography (PET) tracers.

Figure 1. Schematic of no-carrier-added electrochemical ¹⁸F-fluorination of methyl (phenylthio)acetate using cation pool method.

References

1. Yoshida, J. et al. Direct Oxidative Carbon−Carbon Bond Formation Using the “Cation Pool” Method. 1. Generation of Iminium Cation Pools and Their Reaction with Carbon Nucleophiles. J. Am. Chem. Soc. 121, 9546–9549 (1999).