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| Home > Publications database > Evaluation of tetramethylammonium salts in minimalist-like SNAr radiofluorinations |
| Conference Presentation (After Call) | FZJ-2024-03440 |
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2023
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Please use a persistent id in citations: doi:10.34734/FZJ-2024-03440
Abstract: Objective: Tetraalkylammonium salts like Et 4NX or Bu4NX repre-sent valuable alternatives to conventional K2 CO3 /K2.2.2., enablingpreprocessing of [ 18 F]fluoride without azeotropic drying. Additionally,the selection of appropriate counter ions like bicarbonate or triflateallow the adjustment of the basic strength in the reaction medium, e,g.,for radiolabeling of sensitive substrates or Cu-mediated 18 F-fluorin-ation. Recently, NMe4 HCO 3 was reported to improve the yield in SNArradiofluorination reactions if added to azeotropically dried [ 18F]KF·K2.2.2. The enhanced reactivity was attributed to in situ formationof strongly nucleophilic [ 18 F]Me4 NF [1]. Herein, we describe theazeotropic drying-free preparation of [ 18 F]Me4NF and evaluation of itsreactivity in SNAr 18 F-fluorinations compared to widely applied [18 F]Et 4NF.Methods: Aqueous [ 18 F]fluoride was loaded onto a QMA cartridgeand the resin was washed with anhydrous MeOH. [18 F]F– was elutedwith a solution of the respective salt (18 µmol) in MeOH. Evaporationof MeOH directly afforded anhydrous [ 18 F]R4 NF/X (R = Me, Et; X = OTf,HCO3 ) salts. The latter were comparatively evaluated using a series of(hetero)aromatic substrates containing various leaving groups (-F, -Cl,-Br, -I, Me3 N-+, -NO2 , -OTf, DABCO-onium, sulfonium and iodonium).Suboptimal reaction conditions (7 µmol of precursor, DMF, 100 °C,10 min) were intentionally used to obtain significant differences inradiochemical conversions (RCCs) even for highly reactive precursors.Results: Minimalist preprocessing of [ 18F]fluoride furnished therespective anhydrous [ 18F]NR4 F/X in radiochemical yields of >95%within only 5 min. With two exceptions concerning isotopic exchangeon heteroarenes (entries 5 and 6), the RCCs for labeling of the modelsubstrates were consistently higher for [ 18F]Me4NF/X in comparison tothe corresponding [ 18 F]Et4 NF/X salt. On average the absolute differenceamounted to 19% (or a 3.5 fold relative increase, respectively). The lessreactive DABCO precursors 16 and 17 furnished exclusively the SN2ring-opening products. With regard to the counter ion, less basicconditions appeared to be preferable, since 9 vs. 2 precursors gavehigher RCCs with triflate vs. bicarbonate counter ion. The counter ionhad no impact on radiofluorination of precursors bearing trimethy-lammonium and DABCO-ammonium leaving groups.Conclusions: [ 18 F]Me4NF/X can be rapidly prepared by minimalistpreprocessing and is considerably more reactive than commonly used[ 18 F]TEAF. In particular, [ 18 F]Me4NF/OTf is a promising radiofluorina-tion agent, which afforded high RCCs for a broad scope of radiolabelingprecursors.ReferenceLee et al., J. Org. Chem. 2021, 86, 14121–14130.
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