Syntheses of meta‐[¹⁸F]fluorobenzaldehyde and meta‐[¹⁸F]fluorobenzylbromide from phenyl(3‐Formylphenyl) iodonium salt precursors

Abstract

Abstract18 F-labeled fluorobenzaldehydes and fluorobenzylbromides are useful synthons for the preparation of PET radiopharmaceuticals. Whereas ortho-and para-[ 18 F]fluorobenzaldehydes can easily be prepared with high yields, the corresponding meta-derivatives are more problematic. In order to improve the yield of meta-[ 18 F]fluorobenzaldehyde we used the corresponding diaryliodonium salt precursors, since diaryliodonium salts had already been used as precursors in preparations of 18 F-labeled electron rich, as well as electron deficient, aromatic rings. Diaryliodonium salts with different counter ions [PhIPhCHO]X (X = Cl, Br, OTs, OTf) were synthesized. 18 F radiolabeling was performed using different bases at different temperatures in the presence of a radical scavenger, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO). The best conversion (~80%) to meta-[ 18 F] fluorobenzaldehyde was obtained using CsHCO 3 base at a reaction temperature of 110°C. To study iodonium salt counter ion effects on radiofluorination, each precursor was separately treated with CsF[ 18 F]/CsHCO 3 in DMF at 110 °C for 5 min in the presence of TEMPO. Our observed reactivity order was OTs<Cl<OTf<Br. Meta-[ 18 F]fluorobenzaldehyde thus obtained was reduced to the corresponding alcohol with aqueous NaBH 4 at room temperature and then converted to meta-[ 18 F]fluorobenzylbromide using triphenylphosphine dibromide. Formation of meta-[ 18 F]fluorobenzylbromide was confirmed by HPLC and the desired product was purified on a silica Sep-Pak ® plus cartridge.

Automated radiosynthesis of no‐carrier‐added 4‐[18F]fluoroiodobenzene: a versatile building block in 18F radiochemistry

“…Methods include hot atom recoil chemistry and direct electrophilic and nucleophilic aromatic radiofluorination chemistry . Significant improvements were achieved by using iodonium and sulfonium salts as labelling precursors. Moreover, novel technologies like microwave activation and microfluidic devices have also been applied to prepare 4‐[ 18 F]fluorohalobenzenes.…”

Single-step syntheses of no-carrier-added functionalized [18F]fluoroarenes as labeling synthons from diaryliodonium salts

“…23 Recently, microwave-promoted radiofluorinations of (3-formylphenyl)(phenyl)iodonium salts in DMF have been shown to provide [ 18 F] 17 in useful yields (up to 62%), but only in the presence of a relatively large amount of the free-radical scavenger, 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), and with co-production of a low proportion of [ 18 F]-fluorobenzene. 24 We were interested in whether the radio-synthesis of [ 18 F] 17 would be viable in the microfluidic apparatus in the absence of TEMPO. Also we considered that the use of 4-methoxyphenyl or 2-thienyl as the partner aryl ring in the diaryliodonium salt precursor might increase the selectivity for producing the desired [ 18 F] 17 .…”

“…Recently, [ 18 F] 22 was prepared, from a diaryliodonium salt but in two steps. 24 The rapid single-step process described here should greatly expand the utility of [ 18 F]fluorobenzyl halides as labeling synthons.…”

Rapid synthesis of maleimide functionalized fluorine‐18 labeled prosthetic group using “radio‐fluorination on the Sep‐Pak” method

“…The same research group has demonstrated high radiochemical conversion using the pyridine derivative by halogen (Cl) exchange . More challenging fluorine‐18 labelings at the meta‐position to prepare 3‐[ 18 F]fluorobenzaldehydes have also been reported by our and other groups from a variety of precursors . Recently, Richarz et al reported fluorine‐18 labeled benzaldehydes according to the “minimalist” radiolabeling protocol, without base and azeotropic drying of [ 18 F]fluoride .…”