Fluorinating reagents
Electrophilic N-F fluorinating reagents incorporate electron-withdrawing groups attached to nitrogen to decrease the electron density on fluorine. Although N-fluorosulfonamides are fairly weak fluorinating reagents, N-fluorosulfonimides, such as N-fluorobenzenesulfonimide (NFSI), are very effective and in common use. N-fluoro-o-benzenedisulfonimide (NFOBS) is synthesized from the disulfonic acid.[2]
The use of salts of cationic nitrogen increases the rates and yields of electrophilic fluorination, because the cationic nitrogen removes electron density from fluorine. N-fluoropyridinium ions and iminium ions can also be used as electrophilic fluorinating reagents. The counteranions of these salts, although they are not directly involved in the transfer of fluorine to the substrate, influence reactivity in subtle ways and may be adjusted using a variety of methods.[8]
The most synthetically useful ammonium salts are the substituted DABCO bis(ammonium) ions, including Selectfluor.[9] These can be easily synthesized by alkylation followed by fluorination. The difluoro version, which might at first seem more useful, delivers only a single fluorine atom.
More specialized electrophilic fluorinating reagents, such as neutral heterocycles containing N–F bonds,[10] are useful for the fluorination of a limited range of substrates.
Nucleophilic substrates
Simple fluorinations of alkenes often produce complex mixtures of products. However, cofluorination in the presence of a nucleophile proceeds cleanly to give vicinal alkoxyfluorides.[11] Alkynes are not fluorinated with N-F reagents. An anionic surfactant was used to facilitate contact between aqueous Selectfluor and the alkene.
Fluorination of electron-rich aromatic compounds gives aryl fluorides. The two most common problems in this class of reactions are low ortho/para selectivities and dearomatization (the latter is a particularly significant problem for phenols).[12]
Enol ethers and glycals are nucleophilic enough to be fluorinated by Selectfluor.[13] Similar to other alkenes, cohalogenation can be accomplished either by isolation of the intermediate adduct and reaction with a nucleophile or direct displacement of DABCO in situ. Enols can be fluorinated enantioselectively (see above) in the presence of a chiral fluorinating agent.
Metal enolates are compatible with many fluorinating reagents, including NFSI, NFOBS, and sulfonamides. However, the specialized reagent 2-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide consistently affords better yields of monofluorinated carbonyl compounds in reactions with lithium enolates. Other metal enolates afforded large amounts of difluorinated products.[14]