Microwave-induced nucleophilic [18F]fluorination on aromatic rings: synthesis and effect of halogen on [18F]fluoride substitution of meta-halo (F, Cl, Br, I)-benzonitrile derivatives

Abstract

The meta-halo-3-methylbenzonitrile derivatives (-F, -Cl, -Br, -I) were synthesized as model compounds to study reactivity towards aromatic nucleophilic substitution. A single-mode microwave system was incorporated into a commercial radiochemical synthetic module for (18)F labeling. Labeling yields of 64% for fluoro-, 13% for bromo- and 9% for chloro-precursors were achieved in DMSO in <3 min. The observed order of reactivity of the leaving groups toward aromatic nucleophilic substitution was F>>Br>Cl>>>I.

Fig. 1

Structure of meta-halo (F, Cl, Br, I)-benzonitrile model compounds

Fig. 2

A design for incorporation of the microwave reactor into the TRACERlab

Fig. 3

Radio-TLC of labeling product: 3-[¹⁸F]fluoro-5-methylbenzonitrile. TLC was developed in CHCl₃

Fig. 4

Effect of leaving group on the microwave labeling yield on 3^rd irradiation

Scheme I

Synthesis of 3-chloro-5-methylbenzonitrile and 3-bromo-5-methylbenzonitrile

Scheme II

Synthesis of 3-iodo-5-methylbenzonitrile

Scheme III

[¹⁸F]Fluorine labeling reaction