Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics

Fluorine-18 ( t ½ =109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [ 18 F]fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general 18 F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of spirocyclic hypervalent iodine(III) complexes, which serve as precursors for rapid, one-step regioselective radiofluorination with [ 18 F]fluoride. This methodology proves to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta -substituted electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive 18 F-labelled building blocks, compounds and radiopharmaceuticals are synthesized. Fluorine-18 containing molecules are important for PET imaging, but due to the short half-life it is necessary to develop rapid methods for its introduction. Here, the authors use spirocyclic iodine(III) precursors, allowing direct 18F labelling of highly functionalized non-activated arenes and PET radiopharmaceuticals.