Copper-catalyzed [¹⁸F]fluorination of unsymmetrical diaryliodonium salts

Objectives In an initial report we described the rapid and efficient fluorination of unsymmetrical diaryliodonium salts under mild conditions in the presence of a copper salt (Sanford et al. Org. Lett. 2013, 15, 5134). A key facet of this initial work was the ability of the copper catalyzed process to demonstrate exquisite selectivity for the more sterically accessible aryl group. The reaction was also readily amenable to fluorination of electron-rich aryl groups. The aim of this project is to translate the copper-catalyzed fluorination of diaryliodonium salts to radiofluorination reactions using nucleophilic [¹⁸F]fluoride.

Methods A wide range of reaction conditions have been evaluated to optimize the reaction for use with K[¹⁸F], including choice of copper catalyst and reaction temperature, time, solvent and stoichiometry. Additional experiments have been undertaken to determine substrate scope, the effect of different catalysts on the reaction outcome, and to demonstrate proof-of-concept through fluorination of clinically relevant targets.

Results A range of fluorine-18 labeled arenes have been synthesized from the corresponding diaryliodonium salts. The methodology was tolerant of electron rich arenes, demonstrated through the reproducible synthesis of [¹⁸F]4-fluoroanisole in >70% radiochemical yield.

Conclusions The copper-catalyzed fluorination of diaryliodonium salts has been adapted for radiofluorination reactions using nucleophilic [¹⁸F]fluoride. Radiochemical yields are excellent, and the methodology enables ready fluorination of electron rich arenes.

Research Support Financial support of this work by NIBIB (T32EB005172-02) and NIGMS (1RO1 GM073836) is gratefully acknowledged.