Molecular Imaging Branch National Institute of Mental Health, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1003, USA.
Published: April 2023
AI Article Synopsis
Article Abstract
Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t =20.4 min) or fluorine-18 (t =109.8 min) from readily accessible aryl(mesityl)iodonium salts. In this method, the aryl(mesityl)iodonium salt is treated rapidly with no-carrier-added [ C]CuCF or [ F]CuCF . The mesityl group acts as a spectator allowing radiolabeled trifluoromethylarenes to be obtained with very high chemoselectivity. Radiochemical yields from aryl(mesityl)iodonium salts bearing either electron-donating or electron-withdrawing groups at meta- or para- position are good to excellent (67-96 %). Ortho-substituted and otherwise sterically hindered trifluoromethylarenes still give good yields (15-34 %). Substituted heteroaryl(mesityl)iodonium salts are also viable substrates. The broad scope of this method was further exemplified by labeling a previously inaccessible target, [ C]p-trifluoromethylphenyl boronic acid, as a potentially useful labeling synthon. In addition, fluoxetine, leflunomide, and 3-trifluoromethyl-4-aminopyridine, as examples of small drug-like molecules and candidate PET radioligands, were successfully labeled in high yields (69-81 %).
Efficient methods for labeling aryl trifluoromethyl groups to provide novel radiotracers for use in biomedical research with positron emission tomography (PET) are keenly sought. We report a broad-scope method for labeling trifluoromethylarenes with either carbon-11 (t =20.4 min) or fluorine-18 (t =109.
A regiodivergent C-H arylation of triphenylene derivatives with diaryliodonium salts was developed. The regiodivergence was controlled by electronic effects of diaryliodonium salts. When the aryl(mesityl)iodonium salts bearing strong electron-donating groups at the -position of aryl groups were used, the arylation reactions occurred to amide groups.
In the era of personalized precision medicine, positron emission tomography (PET) and related hybrid methods like PET/CT and PET/MRI gain recognition as indispensable tools of clinical diagnostics. A broader implementation of these imaging modalities in clinical routine is closely dependent on the increased availability of established and emerging PET-tracers, which in turn could be accessible by the development of simple, reliable, and efficient radiolabeling procedures. A further requirement is a GMP production of imaging probes in automated synthesis modules.
The visible-light-induced arylation of tertiary phosphines with aryl(mesityl)iodonium triflates to produce the quaternary phosphonium salts occurs under mild, metal, and catalyst-free conditions. Photo-excited EDA complexes between diaryliodonium salts and phosphines supposedly enable this transformation, which is difficult to achieve through the traditional ground-state reactions. Demonstrating high functional group tolerance, broad scope, and complete selectivity of the aryl group transfer, the method is particularly compatible with sterically congested phosphines, which are challenging under metal-based catalytic methods.
Employing DABCO as a substrate, aryl(mesityl)iodonium triflates are introduced as arylating agents for a tertiary sp-nitrogen. Mild conditions and exceptional selectivity of the aryl group transfer allow unprecedented N-aryl-DABCO salts to be obtained, bearing substituents of different electronic natures. This metal-free methodology has no analogy among known transition-metal-based reactions.
