Fluorine‐18 Labeling of Difluoromethyl and Trifluoromethyl Groups via Monoselective C−F Bond Activation

Abstract

We report a general method for the labeling of both CF 3 and CF 2 H groups in a broad range of chemical settings (aryl, oxide, sulfide). The method utilizes frustrated Lewis pair mediated selective CÀ F activation to formally substitute fluorine-19 with fluorine-18 in a two-step defluorination/radiofluorination process, and as such can utilize the target compounds as starting materials. The radiotracer precursors can be isolated as stable salts prior to radiofluorination. The method delivers good radiochemical yields and molar activities (up to 35.2 � 6.5 % non-decay corrected isolated activity yields and 12.0 � 1.7 GBq μmol À 1 molar activities) and is shown to be applicable to biologically relevant compounds. The ability to utilize the target compound as the starting material and the synthetic simplicity of the method coupled with the ever-increasing use of CF 3 and CF 2 H groups in pharmaceuticals makes this method attractive for drug and radiotracer development.In molecular imaging, fluorine-18 (t 1/2 � 110 min) finds use as the most suitable radionuclide for positron-emission tomography (PET). [1] PET utilizes radiotracers that contain (most commonly) the positron-emitting fluorine-18 to noninvasively image biological tissue and organs in real-time. Most notably, PET is utilized in diagnostic medicine but has also found application in pharmacokinetic studies. [2] Recent attention has turned to the incorporation of fluorine-18 into difluoromethyl and trifluoromethyl groups due to their increasing presence in bioactive molecules as bioisosteres. [3] The ability to readily label CF 3 and CF 2 H groups with fluorine-18 in biologically relevant molecules for use in PET would directly benefit drug development, pharmacokinetic studies and biological imaging. [4] A number of reports have demonstrated incorporation of fluorine-18 into CF 2 H and CF 3 (Figure 1, A). [5] For example, halogen exchange (Halex) has been utilized to generate fluorine-18 labeled CF 2 H and CF 3 groups, most successfully with bromide leaving groups. [5a-k] The harsh reaction conditions required for exchange of CÀ X bonds

A selective and mild electrochemical defluorinative carboxylation for late-stage C(sp3)–F bond functionalization

“…17 Such platforms are highly valuable as they obviate the need for re-synthesis programs for 18 F radiotracer development. 18 Towards this goal, we effectively demonstrate that the α,α-difluorocarboxylic acids amino acid 32 generated from our procedure can be cleanly converted back to 54 through a decarboxylation fluorination protocol reported by Gouverneur. 19 Importantly, this proof-of-concept for a fluoride-exchange protocol may inspire new developments in 18 Fradiotracer synthesis for positron emission tomography (PET) imagining.…”

Synthetic Advantages of Defluorinative C−F Bond Functionalization

“…This approach also enables 18 F radiofluorination of di-and trifluoromethyl groups in bioactive polyfluoroalkylarenes for potential use in Positron Emission Tomography (PET) imaging (Scheme 28c). , [155,156] In 2019, our group discovered a fluoride-promoted defluoroallylation reaction of electron-deficient trifluoromethylarenes using allyltrimethylsilanes, which is proposed to proceed via single electron transfer (SET) from an anionic silicate intermediate to the ArCF 3 (Scheme 29a). [157] The utility of this method was demonstrated through gram-scale reactions and derivatization of the allyl group into diverse difluoroalkyl substituents.…”

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

“…However, this does not necessarily preclude the use of radiolabeled BAY1436032 analogs for glioma imaging, because the concentration of α-KG in IDH-mutated gliomas is expected to be low (<0.1 μmol/g) [ 5 ]. Radiolabeling could be achieved without structural modification by incorporating fluorine-18 into the trifluoromethoxy moiety of BAY1436032 (see, e.g., [ 99 , 100 ]). Potential drawbacks of this approach are the low molar activities often associated with CF 3 -labeling methods and a relatively high risk of in vivo defluorination due to the metabolic instability of the CF 3 group.…”