Synthesis of ¹⁸F-labeled aromatic and heteroaromatic compounds using 1,3-dipolar-cycloaddition reactions with o-benzyne

Objectives (3+2) Dipolar cycloadditions of arynes with different dipoles (CAAs) are widely used in the syntheses of (hetero-)aromatic compounds and pharmaceuticals. Despite of their fast reaction kinetics and versatility CAAs have not yet been applied for radiolabeling. The goal was to evaluate the feasibility of CAAs for the preparation of radiofluorinated compounds. The reaction between o-benzyne and various ¹⁸F-labeled 1,3-dipoles was studied.

Methods o-Benzyne was generated in situ by thermal decomposition of benzediazonium-2-carboxylate (thermal route) or by fluoride-promoted ortho-elimination of o-(trimethylsilyl)phenyl triflate (fluoride-promoted route) and allowed to react with the appropriate ¹⁸F-labeled 1,3-dipole. The following compounds were prepared: 3-(4-[¹⁸F]fluorophenyl)-benzisoxazole ([¹⁸F]1), 2-tert-butyl-3-(4-[¹⁸F]fluorophenyl)-1,2-benzisoxa-zoline ([¹⁸F]2), (4-[¹⁸F]fluorophenyl)-2-hydroxybenzophenone methylimine ([¹⁸F]3), 3-(4-[¹⁸F]fluorophenyl)indazole ([¹⁸F]4), 3-(4-[¹⁸F]fluorophenyl)-1-phenyl-indazole ([¹⁸F]5) and 1-(2-[¹⁸F]fluoroethyl)-benzotriazole ([¹⁸F]6).

Results [¹⁸F]1-3 were prepared by the thermal route in RCY of 60-70% (MeCN, 10 min, 50-80 °C) from 4-[¹⁸F]fluorobenzonitriloxide, C-4-[¹⁸F]fluorophenyl-N-tert-butylnitrone and C-4-fluorophenyl-N-methylnitrone respectively. The fluoride-promoted route yielded [¹⁸F]1, [¹⁸F]4 and [¹⁸F]5 in 20-90% RCY (TBAF, THF, 10 min, 50 °C). [¹⁸F]4 and [¹⁸F]5 were prepared from the newly generated 1,3-dipoles, 4-[¹⁸F]fluorophenyl-diazomethane and 4-[¹⁸F]fluorobenzonitrile-N-phenylimine, respectively. [¹⁸F]6 was prepared from 2-[¹⁸F]fluoroethylazide in RCYs of 65% and 90% (fluoride-promoted and thermal route, respectively).

Conclusions The CAA reactions with radiofluorinated 1,3-dipoles provide a new, efficient tool for an easy preparation of ¹⁸F-labeled homo/heterocyclic compounds hardly accessible via alternative radiolabeling methods.

Research Support Supported by the EFRE-Ziel2 program (North-Rhine-Westphalia, Germany).