Nucleophilic fluorination reagents

Examples of the utility of some nucleophilic fluorinating reagents are shown in Table 1. 

Fluoropyridines and substituted fluorodiazines were successfully prepared from the corresponding chlorazines using triethylamine tris(hydrogen fluoride) system as a selective nucleophilic fluorinating reagent." ... 

Table 15.1 Features of common nucleophilic fluorination reagents.

The enantioselective addition of a nucleophile to a carbonyl group is one of the most versatile methods for C C bond formation, and this reaction is discussed in Chapter 2. Trifluoromethylation of aldehyde or achiral ketone via addition of fluorinated reagents is another means of access to fluorinated compounds. Trifluoromethyl trimethylsilane [(CF SiCFs] has been used by Pra-kash et al.87 as an efficient reagent for the trifluoromethylation of carbonyl compounds. Reaction of aldehydes or ketones with trifluoromethyltrime-thylsilane can be facilitated by tetrabutyl ammonium fluoride (TBAF). In 1994, Iseki et al.88 found that chiral quaternary ammonium fluoride 117a or 117b facilitated the above reaction in an asymmetric manner (Scheme 8-42). 

The main reagents for nucleophilic fluorination are the metal and ammonium fluorides, the DAST reagent and its analogues, and the amine complexes of fluorhydric acid. 

HF—Amine Complexes Complexes of fluorhydric acid (HF) with pyridine or alkyl amines (Et3N, Et2NH) are often utilized as reagents in nucleophilic fluorination reactions such as the opening of oxiranes," the bromofluorination of double bonds in the presence of NBS, or the diazotation/fluorination of amines with sodium nitrite (the Balz-Schiemann-like reaction) (Figure 2.1). ... 

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... 

Tetrabutylphosphonium hydrogen difluoride [Bu4PF (HF)] and dihydrogen trifluoride [Bu4PF (HF)2] have been shown to be expedient reagents for nucleophilic fluorination of aromatic substrates containing a chlorine or bromine atom or a nitro group under mild conditions in non polar solvents. Thus, for example l-chloro-4-nitrobenzene (28) is converted to l-fluoro-4-nitrobenzene (29) in 90% yield.219... 

The nucleophilic fluorinations have to be performed with the exclusion of water and under an inert atmosphere in a non-protic organic solvent. Since under those circumstances 1SF is insoluble, a phase transfer reagent has to be used. Often used are Kryptofix 2.2.2 and tetra-A-butylammmoniumhydrogencarbonate, the first one giving the better yields [11],... 

The need for a variety of organofluorine molecules has encountered difficulties with oxygenated substitutes such as carboxylic esters due to their poor nucleophilicity towards electrophilic fluorinating reagents. This has led several groups to explore the conversion of the thiocarbonyl group into the CF2 moiety. It was successful with thioamides [174], dithioesters [175-177] and thionoesters [178, 179], providing new routes to difluoro-sulfides, amines, ethers and alkenes. 

The chemistry of fluorine-18 radiopharmaceuticals, the reagents employed in electrophilic and nucleophilic fluorination methods and in aliphatic and aromatic nucleophilic substitutions, for the period 1977-1986 have been reviewed by Berridge and Tewson1. The earlier 18F-chemistry has been reviewed by Palmer, Clark and Goulding2. 

The reagent triethylamine bishydrofluoride, which is prepared by mixing two equivalents of the known and stable reagent triethylamine trishydrolluoride with one equivalent of triethylamine, was recently introdueed as a new, efficient reagent for nucleophilic fluorine displacement reactions. Its nucleophilic power is even greater than that of triethylamine trishy-drofluoride, as can be seen from the reaction of 3. ... 

The synthesis of [18F]FDG has been very well developed and refined since its introduction by Ido and co-workers in 1978 [12]. Whereas the original synthesis of [18F]FDG was done using electrophilic fluorination of an alkene precursor, yields were limited by the maximum 50% possible from an electrophilic reagent (see later discussion on electrophilic 18F-fluorinations), and much higher-yield nucleophilic fluorination methods were subsequently developed [13] and have been adopted by virtually every investigator at present. 

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%). 

Because of the low nucleophilicity of the fluoride ion, nucleophilic fluorination is not very easy. The reaction conditions and the reagent are, however, sufficiently mild to produce unstable compounds. Perfluoroalkylnitrile can be fluorinated wifh bromine and cesium fluoride (Scheme 2.4). The N-haloimines obtained are potentially unstable compounds [7]. 

A more recent development of the same general type of reagent is 2,2-difluoro-1,3-dimethylimidazolidine (DPI), which is even more reactive, because of the stabilizing effects of two nitrogen atoms at the active center [124] (Scheme 2.55). By reaction with the inexpensive phosgene and subsequent nucleophilic fluorination the reagent can be recycled on an industrial scale. 

The actual chemical nature of the support material may be and often is of direct importance to its usefulness as a support material.15 Silicas can react with small nucleophiles such as F-, OH- and CN. Thus, silica-supported fluorides are inactive, both as nucleophilic fluorinating agents and as bases. Similarly, silicas are not effective support materials for cyanides due to the formation of strong Si-CN bonds. For different reasons, an acidic clay would not be a suitable support for cyanides, due to the possible formation of toxic HCN. Charcoal is the most effective support material for stabilising Cu(I), probably due to its aromatic character.16 For many chemisorbed supported reagent catalysts, silicas are preferred since they give relatively strong surface bonds. However, Si-O-C bonds are hydrolytically vunerable and direct Si-C bonds are preferred.17... 

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