Metal-free cross-coupling reactions of radiofluorinated tosylhydrazones with different nucleophiles.

1083 Objectives Numerous metal-free cross-coupling reactions of tosylhydrazones with different reaction partners have been recently reported. These building blocks are easily available from carbonyl compounds by reaction with tosylhydrazide. The aim of this work was the preparation of 18F-labeled tosylhydrazone and its utilization as an 18F-labeled building block for the preparation of radiofluorinated compounds via cross-coupling reactions with different model reaction partners like boronic acids, alkenes, thiols and alkynes. Methods 4-[18F]Fluorobenzylidene tosylhydrazone ([18F]1) was synthesized by the reaction of [18F]FBA with tosylhydrazide. [18F]1 was allowed to react with aromatic boronic acids with different reactivity; internal and terminal alkene; aromatic and aliphatic thiols; terminal alkyne; to afford the corresponding radiofluorinated diarylmethanes [18F]2a-c, cyclopropanes [18F]3a,b, thioethers [18F]4a,b and pyrazole [18F]5a respectively. The cross-coupling step for the preparation of [18F]2-5 was optimized with respect to base, solvent, reaction temperature and reaction time. Additionally, the feasibility of a one-pot preparation of [18F]1 and [18F]2a were studied. Results [18F]2 was obtained from [18F]FBA under optimized reaction conditions (MeOH, 70 °C, 10 min) in 91±2% RCY and in 97±1% RCP. Using acetyl chloride to neutralize excess of base after the [18F]FBA synthesis [18F]2 was prepared via a one-pot two-step reaction sequence in DMSO in 62±10% RCY. Highest RCCs of [18F]3a-c (28-75%) were achieved in 1,4-dioxane at 105°C for 10 min using K2CO3 as a base. Disubstituted cyclopropanes in ca. 50% RCC were obtained by the reaction between [18F]2 and alkenes in toluene at 140°C for 10 min in the presence of K2CO3 and TEACl. Thioethers [18F]5a,b were prepared in 67±2% and 20±2% RCC, respectively (K2CO3/TBAB, pyridine, 100 °C, 10 min). Finally, 3,5-disubstituted pyrazoles were prepared in MeCN at 95 °C for 25 min using LiOtBu as base to deliver [18F]5a,b in RCC of 62% and 34% respectively. Conclusions 18F-labeled tosylhydrazone is an easily accessible building block for metal-free cross-coupling reactions with different reaction partners to provide a broad spectrum of radiofluorinated compounds. The newly developed method could be used for the radiosynthesis of clinically applicable PET imaging agents.