NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides

Abstract

[¹⁸F]-labeled aryl fluorides are widely used as radiotracers for positron emission tomography (PET) imaging. Aryl halides (ArX) are particularly attractive precursors to these radiotracers, as they are readily available, inexpensive, and stable. However, to date, the direct preparation of [¹⁸F]-aryl fluorides from aryl halides remains limited to S_NAr reactions between highly activated ArX substrates and K¹⁸F. This report describes an aryl halide radiofluorination reaction in which the C(<i>sp</i>^<i>2</i>)-¹⁸F bond is formed via a copper-mediated pathway. Copper <i>N</i>-heterocyclic carbene complexes serve as mediators for this transformation, using aryl halide substrates with directing groups at the <i>ortho</i> position. This reaction is applied to the radiofluorination of electronically diverse aryl halide derivatives, including the bioactive molecules vismodegib and PH089.