Electrophilic fluorination reagents acetyl hypofluorite

Fluoroaromatic compounds 8 are synthesized by reaction of aryltrialkyltin derivatives with electrophilic fluorinating reagents, such as cesium fluoroxysulfate,12,13 trifluoromethyl hypo-fluorite1314 and acetyl hypofluorite,1516 or with elemental fluorine.13 15 18 In Table 4 examples of these reactions arc summarized. 

Fluorinating reagents, including acetyl hypofluorite, have been reviewed by Rozen26. Rozen and coworkers discuss quite effectively electrophilic fluorine and electrophilic fluorination . They prepared acetyl hypofluorite from the reaction of sodium acetate with 10% fluorine in nitrogen in 10 1 CFC13/AcOH (equation 12), and it has been used in situ... 

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%). 

Acetyl hypofluorite (CH3CO2F) > has been used to fluorinate tetraisopropyl methylenediphosphonate in two steps. In the first step, the sodium salt of tetraisopropyl methylenediphosphonate is added to a solution of AcOF in CFCI3 at -78°C. After 5 min, the reaction is quenched, and tetraisopropyl fluoromethylenediphosphonate is isolated in 66% yield. This compound is metallated with NaH and submitted to a second electrophilic fluorination as above to obtain tetraisopropyl difluoromethylenediphosphonate in 40% yield. Even if acetyl hypofluorite seems to be a more selective reagent for electrophilic monofluorination than FCIO3, its relative instability and the special equipment required to manipulate moleculai fluorine greatly limit its use. 

Acetyl hypofluorite, prepared by reaction of fluorine gas with acetates, was introduced in 198111S. It reacts smoothly and quickly at -783C with many types of olefins to produce acetylatcd fluorohydrins. Electrophilic syn additions of this reagent across double bonds in unsaturated carbohydrates119,120, cytosine and uracil are described121. Other examples of stereoselective syn additions with this reagent include coumarin. stilbene and steroids118i l22. 

As has been exemplified in this chapter, fluorinations with fluorine-18 can be classified into two categories (1) the nucleophilic reactions, which usually involve no-carrier-added [ F]fluoride of high-specific radioactivity as its Kf FIF-K complex and include substitutions in the aliphatic and the /lomoaromatic series and (2) the electrophilic reactions, which mainly use moderately low-specific radioactivity molecular [ F]fluorine, or other reagents prepared from it, such as acetyl [ F] hypofluorite, and include addition across double bonds, reactions with carbanions and especially fluorodehydrogenation and fluorodemetallation reactions. 

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