Syntheses of meta-[F]Fluorobenzaldehyde and meta-[F]Fluorobenzylbromide from Phenyl(3-Formylphenyl) Iodonium Salt Precursors

¹⁸F‐labeled fluorobenzaldehydes and fluorobenzylbromides are useful synthons for the preparation of positron emission tomography radiopharmaceuticals. Although ortho‐ and para‐¹⁸F]fluorobenzaldehydes can easily be prepared with high yields, the corresponding meta‐derivatives are more problematic. In order to improve the yield of meta‐¹⁸F]fluorobenzaldehyde, we used the corresponding diaryliodonium salt precursors, since diaryliodonium salts had already been used as precursors in the preparations of ¹⁸F‐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. ¹⁸F 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‐¹⁸F]fluorobenzaldehyde was obtained using CsHCO₃ base at a reaction temperature of 110°C. To study iodonium salt counter ion effects on radiofluorination, each precursor was separately treated with Cs¹⁸F]F/CsHCO₃ in DMF at 110°C for 5 min in the presence of TEMPO. Our observed reactivity order was OTsMeta‐¹⁸F]fluorobenzaldehyde thus obtained was reduced to the corresponding alcohol with aqueous NaBH₄ at room temperature and then converted to meta‐¹⁸F]fluorobenzylbromide using triphenylphosphine dibromide. Formation of meta‐¹⁸F]fluorobenzylbromide was confirmed using high‐performance liquid chromatography and the desired product was purified on a silica Sep ‐ Pak^® plus cartridge. Published in 2011 by John Wiley & Sons, Ltd.