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.

Figure 1

Syntheses of iodonium salts.

Figure 2

Fluorination reactions of Compounds 1–4.

Figure 3

HPLC analysis {Column: Agilent Eclipse C18 5 m, 9.4 × 250 mm; eluent: 40% B (A = 0.1% TFA in water, B = acetonitrile); flow rate = 4 mL/min} of an aliquot taken from the crude reaction mixture of iodonium salt 1 with Cs[¹⁸F]F after 5 min at 110 °C. Red line is for the radiodetector and the blue line is for the UV detector, meta-[¹⁸F] fluorobenzaldehyde rt at 9.45 min.

Figure 4

HPLC analysis {Column: Agilent Eclipse C18 5 μm, 9.4 × 250 mm; eluent: 40% B (A = 0.1% TFA in water, B = acetonitrile); flow rate = 4 mL/min} of 3-[¹⁸F]fluorobenzylbromide after Sep-Pak purification. Red line is for radiodetector and the blue line is for the UV detector, meta-[¹⁸F]fluorobenzylbromide at 11.68 min.