Fluorination electrophilic

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 

The asymmetric fluorination of enolates by means of chiral metal complexes has been reported with Selectfluor in the presence of a chiral Lewis acid derived from TADDOL (TiCl2/TADDOL), or with F-A-sulfonimide (NFSI) with palladium complexes and chiral phosphines. 

The fluorination of enolates of ketone, amide, or hydrazone bearing a chiral auxiliary (SAMP, Evans oxazolidine) with nonchiral fluorination reagent (A-fluoro sulfonimides, A-fluoropyridine) occurs with excellent diastereoselectivities.  

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 

CAUTION Both fluorine gas and some other electrophilic fluorinating agents are highly toxic and may react violently with organic materials. Hydrogen fluoride, a common by-product of electrophilic fluorinations, is highly corrosive. 

The reaction of organic materials with neat fluorine gas is very vigorous and can result in explosions. Fluorine diluted with an inert gas (nitrogen or helium) is much safer, although even this can, for example, ignite paper, even at very low concentrations. 

Other powerful fluorinating agents, such as trifluoromethyl hypofluorite, perchloryl fluoride and acetyl hypofluorite (CF3OF, FCIO3, AcOF) have been used successfully, but are not easy to obtain, are toxic and the last two are intrinsically explosive. Some newer, milder, but more limited, fluorinating agents are discussed later in this section. 

Direct reaction with fluorine, can be carried out successfully and selectively on robust electron-rich ring systems and has been used commercially for the synthesis of 5-fluorouracil, an important anti-cancer drug. This reaction proceeds via 5,6-addition of F and the solvent, elimination of the 6-substituent occurring on heating the reaction mixture.  

Heterocyclic Chemistry 5th Edition John Joule and Keith Mills 2010 Blackwell Publishing Ltd 

The discovery of Fried and coworkers [167] in the 1950s that incorporation of fluorine substituents into 9a-fluorocortisone acetate dramatically increased its therapeutic effect provided a strong stimulus for interest in fluorinated pharmaceuticals. One valuable component still missing from the toolbox of methods in organofluorine chemistry vas a generally applicable method for electrophilic fluorination of sensitive organic substrates under mild conditions. 

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Fluoroxytrifluoromethane, a source of electrophilic fluorine, has recently been employed by Barton et al. for the fluorination of unsaturated steroids. ... 

Table 3. Comparison of Electrophilic Fluorination of Aromatic Amino Acids with [ F]fluorine or [ F]acetyl Hypofluorite" [25]...

There are other reagents, such as CF3OF and CH3C02F, that transfer an electrophilic fluorine to double bonds. These reactions probably involve an ion pair that collapses to an addition product. 

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. 

Like nitrogen fluorides, compounds having an O—F bond are also very strong oxidants and, when utilized as such, are effective sources of electrophilic fluorine. Because the O—F bond is so weak, the chemistry of such compounds approaches that of F2 itself, and such chemistry can be free radical or electrophilic in nature, depending on the conditions and the reactants. 

There are several new methodologies based on the Julia olefination reaction. For example, 2-(benzo[t/Jthiazol-2-ylsulfonyl)-j -methoxy-i -methylacetamide 178, prepared in two steps from 2-chloro-iV-methoxy-jV-methylacetamide, reacts with a variety of aldehydes in the presence of sodium hydride to furnish the ajl-unsaturated Weinreb amides 179 <06EJOC2851>. An efficient synthesis of fluorinated olefins 182 features the Julia olefination of aldehydes or ketones with a-fluoro l,3-benzothiazol-2-yl sulfones 181, readily available from l,3-benzothiazol-2-yl sulfones 180 via electrophilic fluorination <06OL1553>. A similar strategy has been applied to the synthesis of a-fluoro acrylates 185 <06OL4457>. 

Additional publications from Sanford et al. describe the full exploration of palladium-catalyzed chelate-directed chlorination, bromination, and iodination of arenes using N-halosuccinimides as the terminal oxidant <06T11483>. Moreover, an electrophilic fluorination of dihalopyridine-4-carboxaldehydes was reported by Shin et al. <06JFC755>. This was accomplished via transmetalation of the bromo derivative, followed by treatment with A-fluorobenzenesulfinimide as the source of electrophilic fluorine. 

Electrophilic fluorinating agents, 77 847 Electrophilic quench, 72 828 Electrophilic reactions... 

Recently, it has been shown that the reactivity and selectivity of [ F]p2 in the electrophilic fluorination of l-DOPA can be modulated by using different acidic solvents (Scheme 7). These conditions have been exploited to produce clinically useful quantities of the regioisomer [5- F]fluoro-L-DOPA [69]. 

Fluoroxpergfluoroalkanes, 26 123-127 tert-butane, 26 125-126 electrophilic fluorination, 26 125 methane... 

One may conclude that the above-mentioned anhydrous [ F]fluorine compounds, except perhaps H[ F]F, have been abandoned, partly because of their limited potential and difficulty of preparation and also because of the success of the main three agents of today, [ F]fluoride (see Section 4), p F]fluorine gas (see Section 3.1.1) and acetyl [ F]hypofluorite (see Section 3.1.3). The advent of the first one, ([ F]fluoride), made less urgent the need for high-specific-activity electrophilic fluorine and the latter two, ([ F]fluorine gas and acetyl p F]hypo-fluorite), are able to perform practically all low-specific-activity electrophilic syntheses (see Section 3), putting a brake on the development of alternatives. 

Electrophilic fluorination is the process by which fluorine is delivered to an electron-donating reactant, such as an alkene, aromatic ring or carbanion, by a formal positive-fluorine reagent to form a carbon-fluorine covalent bond. These reactions are fast and have proven extremely valuable for some important fluorine-18-labelled radiopharmaceuticals. Over the years several reviews on electrophilic fluorination were written. The reader is encouraged to seek out these works for greater detail on the subject [7,68-70]. 

In this section the production of a number of radioactive electrophilic fluorination agents that have not already been dealt with in Section 2.6 will be discussed. 

Scheme 12. Mechanisms of electrophilic fluorination of a carbon-carbon double bond.

Scheme 25. The arenium ion mechanism of electrophilic fluorination of aromatic rings via fluorodehydrogenation or fluorodemetallation reactions.

Another example of a direct electrophilic fluorination of aromatic rings is the synthesis of the purine derivatives 8-[ F]fluoroganciclovir, 8-[ F]fluoropenciclo-vir and 8-[ F]fluoroacyclovir (Scheme 27). The radiochemical yields obtained for these compounds are low, about 1%, but no protecting group is required, allowing a one-step radiosynthesis [107]. 

The consistent poor regioselectivity in direct aromatic electrophilic fluorination has privileged the use of fluorodemetallation reactions. Tin clearly appears to... 

K. Adachi, Y. Ohira, G. Tomizawa, S. Ishihara, S. Oishi, Electrophilic fluorination with N,N -difluoro-2,2 -bipyridinium salt and elemental fluorine, J. Fluorine Chem. 120 (2003) 173-183. 

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). 

Several 2-fluoroerythromycin derivatives have also been prepared by means of electrophilic fluorination with Selectfluor of the enolate of the )S-ketoester fragment (Fig. 45) [121]. Fluorination is stereoselective and leads to the a-fluo-rine compound [122]. Two derivatives of 2-fluoroerythromycin are in clinical development HMR-3562 and HMR-3787). These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 45) [123]. 

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