A comparative study on the effect of solvent on nucleophilic fluorination with [18F]fluoride: protic solvents as co-solvents in SN2 and SNAr reactions

Abstract

AbstractThe effect of solvent on nucleophilic substitution with cyclotron-produced [18F]fluoride was studied in polar aprotic (CH3CN and DMF) and protic solvent (t-BuOH andt-amyl alcohol) mixtures (CH3CN/co-solvent, 2:8) in a series of model compounds, 4-(R1-methyl)benzyl R2-benzoates, using a K2.2.2/[18F]KF phase transfer system (R1=–Cl, –OMs or –OH; R2=–Cl, –I or –NO2).18F-fluorination of compounds 1–3, with chloride or mesylate as a leaving group in the benzylic position (R1), afforded the desired 4-([18F]fluoromethyl)benzyl analogues in all solvents during 15ߙmin reaction time. The highest radiochemical yields (RCY) in all the studied reaction temperatures (80, 120 and 160ºC) were achieved in CH3CN. Radiochemical yields in protic solvents were comparable to RCY in CH3CN only with the sulfonate ester 3 as a starting material.18F-Fluorination of the benzylic halides 1 and 2 was not promoted in the same extent; in addition, labelled side-products were detected at higher reaction temperatures. Radiofluorination intert-alcohols was also studied using [18F]CsF with and without added phase transfer catalyst, resulting in both conditions lower RCY when compared to K2.2.2/[18F]KF system. Protic solvents were not able to promote aromatic18F-fluorination.18F-Fluorination of compound 5, havingpara-activated nitro group in the aromatic position (R2), failed intert-alcohols even at the highest temperature, but it was labelled successfully in DMF and to some extent in CH3CN.