N-F fluorinating reagents

Table 3.4 Fluorinations using electrophilic N-F fluorinating reagents...

A variety of highly enantioselective chiral N-F fluorinating reagents derived from Cinchona alkaloids were developed for the direct enantioselective fluorination of C—H acidic substrates (for details, see Chapter 6). Simultaneously, metal-catalyzed... 

More pertinent to the interests of fluoro-organic chemists, a number of compounds bearing a single N—F bond have become useful electrophilic fluorination reagents, i.e., behaving as effective sources of F+. The structures of some of them are given below, along with the chemical shifts for the N—F fluorine substituent. 

Most reactions with electrophilic fluorinating agents involve transformation of a carbon-hydrogen bond to a carbon-fluorine bond at a carbon atom that is either sp hybridised or that bears a negative charge. Selective electrophilic fluorination at a tertiary sp carbon atom can be achieved with molecular fluorine but is very difficult with N-F type reagents. 

Over the last few years the number of heterocyclic N—F reagents has developed tremendously (Fig. 1). The driving force for this interest has been the need for easily accessible and safe reagents capable of the selective fluorination of bioactive molecules. Generated by reaction of F2 with the parent compound, products are obtained that are capable of fluorinat-ing species as diverse as carbanions and aromatics depending on their fluorinating power. 

Cyclic voltammetry and polarography have been used to study the mechanisms of fluorination and provide an indicator of their relative strengths [92JFC(59)157,92T1595], Two mechanisms have been proposed involving SN2 or electron transfer, although it is likely that which is followed depends on the N—F reagent used. 

N. Satyamurthy, G.T. Bida, M.E. Phelps, J.R. Barrio, Fluorine-18 labeled N-[ F] fluoro-N-alkylsulfonamides Novel reagents for mild and regioselective radiofluorina-tion, Appl. Radiat. Isot. 41 (1990) 733-738. 

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Catalytic enantioselective fluorination has recently emerged. Both organocatalysis and metal catalysis have been successfully developed. Chiral N-F reagents have been prepared or formed in situ starting form a chiral amine derivative and a classical N-F reagent vide supra)P These reagents allow the enantioselective fluorination of... 

Aromatic fluorination involves analogous methods to those used in the aliphatic series. The most utilized methods are electrophihc fluorination (F2, N— F reagents) and nucleophilic fluorination through the Balz-Schiemann reaction (diazotation in the presence of fluoride ion). This latter method is of prime importance in industry. When the aromatic ring is activated by one or several electron-withdrawing groups, the... 

Flurithromycin is an erythromycin fluorinated at C-8, which was launched several years ago (cf. Chapter 8). Its preparation involves an electrophilic fluorination with or with an N— F reagent (NFSI) of 8,9-anhydroerythromycin-6,9-hemiacetal or of erythronolide A. Glycosylations have also been performed by fermentation (Figure 4.57). ... 

One of the most active areas of research in fluorine chemistry over the last ten years has been the development of the N-F electrophilic fluorinating reagents. These compounds fall into two categories, namely, neutral molecules and salts, and the reader is referred to recent reviews and papers which describe in detail their preparation and chemistry [7,18,197,203-211]. 

Table 7. N-F Electrophilic Fluorinating Reagents Main Structural Types...

Although widely used in organic synthesis, reagents containing N-F bonds have remained poorly understood with respect to the mechanism of the fluorine-transfer step.8-10... 

A ranking of the relative fluorinating power of various N —F reagents in their reactions with steroids (Table 2) has also been possible. 

Oxathiazinone dioxides have been used for the synthesis of a new type of heterocyclic N — F reagent 4, which are obtained by direct fluorination of salts of the oxathiazinone dioxide derivatives 3 with a mixture of 5% fluorine in nitrogen at low temperatures.136 137 Isolation of the pure compound 4a or 4b is generally rather difficult and the material is not stable in air at room temperature. In contrast, 3-fluoro-l,2,3-benzoxathiazin-4(3//)-one 2,2-dioxide (4c) is a colorless, thermally stable solid with a melting point of 61 "C.137... 

Lal89a has discussed the application of a new family of N—F -type electrophilic-fluorination reagents consisting of l-alkyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane salts (37) whose preparation, patented by Banks89b, utilizes the reaction of elemental fluorine... 

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