There has been great interest in the development of convenient and efficient methods for the fluorination of aromatic rings that might be adapted to the preparation of fluorine-18 labeled radiopharmaceuticals for PET imaging. In particular, it has been challenging to fluorinate electron-rich arenes, especially those that produce o-fluorophenols. An ideal method would permit the use of [18F]fluoride ion as the fluoride precursor, rather than an electrophilic fluorine source, because this would enable the radiolabeled fluoroarenes to be prepared at very high specific activities and efficiency. Herein, we report novel methodology for the preparation of o-fluorophenols, which could be adapted to F-18 labeling. Treatment of an a-diazocyclohexenone in the presence of Selectfluor and Et3N.3HF affords an a,a-difluoroketone that readily converts to an ortho-fluorophenol after base promoted elimination of HF and tautomerization. All of the steps of this reaction proceeded rapidly, under very mild conditions, and resulted in the regioselective preparation of o-fluorophenols. To adapt this method to fluorine-18 labeling for PET tracer synthesis, bromine electrophiles such as 1,3-dibromo-5,5-dimethylhydantoin or N-bromoacetamide, were used in place of Selectfluor. These bromine electrophiles were found to be optimal for the incorporation of fluoride ion into the diazoketone precursor to form an a-bromo-a-fluoroketone intermediate, which could also be converted into the o-fluorophenol by hydrobromide elimination. Thus, this facile method for the preparation o-fluorophenols has potential as a method for the radiochemical synthesis of o-[18F]fluorophenols.

Facile preparation of <i>ortho</i>-fluorophenols from non-aromatic precursors and application to fluorine-18 labeling

248th National Meeting (2014)

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Facile preparation of ortho-fluorophenols from non-aromatic precursors and application to fluorine-18 labeling