Electrophilic fluorination reagents perchloryl fluoride

Although the majority of radiopharmaceuticals labeled with fluorine-18 have been prepared using nucleophilic fluorination reactions, in a few instances the application of electrophilic fluorination reactions has proved quite suitable. The most significant limitation of electrophilic 18F-fluorinations is the relatively low specific activities (less than lOCi/mmol) commonly obtained for final products. This is a result of the fact that electrophilic 18F-fluorination reagents (perchloryl fluoride, acetyl hypofluorite, xenon difluoride, A-fluoro-zV-alkylsulfonamides, diethylaminosulfur trifluoride) are prepared in low specific activity from 18F-labeled fluorine gas, which in itself produced in a carrier-added fashion. A second drawback of electrophilic fluorination is that the maximum radiochemical yield obtainable is 50%, as only one of the two fluorine atoms in fluorine gas can end up in the product (or, for preparation of electrophilic reagents such as acetyl [18F]hypofluorite, the maximum yield of preparing the reagent from [18F]F2 is 50%). 

A considerable effort is still devoted to the preparation of halogeno-steroids. A new family of electrophilic fluorinating reagents (hypofluorites) can now replace the less powerful and explosive perchloryl fluoride (C103F). A review of the fluorination of cholestane derivatives with CF3OF has appeared. ... 

The first electrophilic fluorination reagent with industrial relevance was perchloryl fluoride FCIO3 [172] (Scheme 2.77) a gas (m. p. —147.8 °C, b. p. —46.7 °C) which is thermally stable up to 500 °C [173], It was used commercially from the beginning of the 1960s for production of fluoropharmaceuticals, in particular fluorosteroids. 

In 1999, both enantiomers of the fluorinated analog were obtained using LiHMDS and perchloryl fluoride as an electrophilic source of fluorine in 71% yield. After several steps, the enantiomers were separated using chiral high-performance liquid chromatography (HPLC) and biologically evaluated. More recently, the first enantioselective synthesis of both enantiomers of thalidomide was described with the aid of a chiral [N-F]+ reagent obtained by combination of a cinchona alkaloid, dihydroquinine (DHQ), and... 

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