title: Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics.
abstract: Fluorine-18 (t½=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.
authors.affiliation: 1] Division of Nuclear Medicine and Molecular Imaging, Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA [2].
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Rotstein
authors.affiliation: 1] Division of Nuclear Medicine and Molecular Imaging, Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA [2].
authors.forename: Nickeisha A
authors.initials: NA
authors.lastname: Stephenson
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Vasdev
authors.affiliation: Division of Nuclear Medicine and Molecular Imaging, Center for Advanced Medical Imaging Sciences, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
authors.forename: Steven H
authors.initials: SH
authors.lastname: Liang
mesh_terms: D003500:Cyclization; D005462:Fluorine Radioisotopes; D054879:Halogenation; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D006847:Hydrocarbons, Iodinated / Q000737:chemistry; D017613:Iodine Compounds / Q000737:chemistry*; D007553:Isotope Labeling; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D013141:Spiro Compounds / Q000737:chemistry
chemical_list: D005462:Fluorine Radioisotopes; D006841:Hydrocarbons, Aromatic; D006847:Hydrocarbons, Iodinated; D017613:Iodine Compounds; D019275:Radiopharmaceuticals; D013141:Spiro Compounds