Development, Optimization, and Scope of the Radiosynthesis of 3/5-[¹⁸F]Fluoropyridines from Readily Prepared Aryl(pyridinyl) Iodonium Salts: The Importance of TEMPO and K₂CO₃

Abstract

A robust process for the radiosynthesis of 3/5-[ 18 F]fluoropyridines has been developed by radiofluorination of iodonium triflates using K 18 F/K 2 CO 3 /K 222 complex in the presence of TEMPO. Both electronically deficient and enriched iodonium salts were readily obtained from the corresponding 3/5-iodopyridines and afforded the corresponding 3/5-[ 18 F]fluoropyridines in 6−78% yields. The concentrations of K 2 CO 3 and TEMPO were found to be crucial for the radiofluorination efficiency. The process was validated using two automated systems for the 18 F-radiolabeling of 2-chloro and 2carboxamido-5-fluoropyridines carried out in 10−20% yields.

Diaryliodoniums Salts as Coupling Partners for Transition-Metal Catalyzed C- and N-Arylation of Heteroarenes

“…Diaryliodonium salts appear as fairly appealing electrophilic arylating reagents as well as precursors for positron emission tomography (PET) [39,40]. They are powerful intermediates for the synthesis of a broad range of radiofluorinated synthons and clinically relevant PET tracers [41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Since the pioneering works on the palladium-and copper-catalyzed arylation of sp2 C-H indoles reported respectively by Sanford [57] and Gaunt groups [58], Nand C-arylation involving diaryliodonium salts offer a highly complementary strategy for the synthesis and derivatization of heteroarenes (Scheme 1).…”

Fluorinated derivatives of pyridine-2,4-dicarboxylate are potent inhibitors of human 2-oxoglutarate dependent oxygenases

“…The F-substituted 2,4-PDCA derivatives may also be of use as 19 F NMR probes in fluorine chemical shift anisotropy and exchange high-throughput screening for protein binding [ 46 , 47 ]. Recent advances in fluorination reactions suitable for the rapid late-stage introduction of radioactive 18 F atoms into hetereoaromatic scaffolds [ 48 , 49 ], including in substituted pyridines such as fluorinated derivatives of the multiple sclerosis drug 4-aminopyridine [50] , [51] , [52] , suggest the F-substituted 2,4-PDCA derivatives might be useful scaffolds for positron emission tomography (PET) studies.…”

Oxidation-Cyclisation of Biphenyl Thioethers to Dibenzothiophenium Salts for Ultrarapid 18F-Labelling of PET Tracers

“…We have previously shown that coupling of aryl halides (bromide and iodide) with biaryl thiophenols tolerates a broad range of functional groups [ 19 ]. The subsequent oxidation-cyclisation reaction sequence is highly robust and enables facile synthesis of labelling precursors of complex ligands that otherwise are difficult to access, such as UCB-J [ 48 , 49 ] (We were unable to prepare the precursor using the method reported in reference [ 19 ]), electron-deficient substrates as exemplified by FNDP, and 3-pyridines which are challenging to label with alternative strategies [ 53 ]. While further studies are needed to determine the scope of the oxidation and cyclisation steps, it is worth noting that periodic acid typically requires a catalyst to mediate oxidation of other functional groups, with the exception of anilines, unprotected amino acids, and 1,2-diols [ 54 ].…”