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

Abstract

(18)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.