Nucleophilic fluorination on electron-rich aromatic rings from non-aromatic precursors: F-18 labeling study and interference from target water

Objectives Most conventional approaches to label phenols with F-18 involve nucleophilic substitution on electron-deficient precursors followed by conversion to phenols, a sequence often inefficient and time consuming. Our objective was to fill this methodological gap in F-18 radiochemisty by developing a series of unusual synthetic transformations to label phenols (and other electron-rich aromatic systems) with F-18 at high specific activity, rapidly, reliably, and conveniently.

Methods We conceived of a diazo compound as a precursor from which it should be possible to prepare F-18 labeled phenols through halofluorination of the diazo group followed by elimination. Diazoketone 1, derived from the corresponding cyclohexenone, was treated with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of an appropriate fluoride source to give α-fluoro-α-bromoketone 2. HBr elimination afforded the desired ortho-fluorophenol 3 in a moderate yield.

Results Despite the success of this unique ortho-fluorophenol synthesis using cold fluoride, adaptation to F-18 labeling has proved to be challenging, even beyond typical tracer-level reactivity problems. In fact, even the addition of decayed target water to an otherwise successful protocol for F-19 labeling, suppressed product formation. Current work is focused on two possible interferences, residual water and metal ions (possibly from target foil) which reduce fluoride nucleophilicity or form carbenoids from the diazo group, respectively. By removing water by additional drying with t-BuOH and adding a chelator to capture metal contaminants, we have observed formation of fluorophenol 3, even when target water is used.

Conclusions This halo-fluorination/elimination procedure enabled rapid preparation of o-fluorophenol rapidly and regioselectively. The interferences in target water were successfully removed by extensive drying and addition of chelator.

Research Support DOE (DE-SC0005434 and DE-FG02-08ER64671)