Electrophilic Fluorination Reactions

Although fluorine mostly reacts as a radical species, under certain conditions it can also act as an electrophile. Some cases of a direct fluorination of electron-rich C—H bonds have been described (80NJC239 84TL449 87JOC2769 88JOC2803). 

In recent years a second generation of reagents for electrophilic fluori-nation has been developed. These reagents contain N—F bonds. They are more stable, easier to handle, and often more selective. These reagents could be useful in the synthesis of bioactive molecules where selectivity and mild reaction conditions are essential. 

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Scheme 6. First enantioselective electrophilic fluorination reaction catalysed by enantiopure Ti-TADDOLates 33a,b. The absolute configuration of the product is unknown.

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%). 

Scheme 7.73 Tandem oxa-Michael/electrophilic fluorination reaction for the as5rm-metric synthesis of fluorinated flavanones.

A novel scandium complex bearing perfluorinated binaphthyl phosphate ligand, Sc[(R)-F8BNP]3, has been synthesized and used as a catalyst for asymmetric electrophilic fluorination reactions of P-keto esters [156]. In combination with 1-fluoro-pyridinium triflate (NFPY-OTf) as a fluorinating agent, the desired a-fluoro-P-keto esters were obtained in moderate to high yields (16-94%) and enantiomeric excesses (47-88%) under mild conditions. 

The above three reactions employed ortAo-directing groups for assisted C—H activation in the presence of palladium(II) catalysts. The electrophilic fluorination reaction involved cyclopalladation and two electrophilic fluorination processes. Subtly, differential nitrogen atoms (pyridine, substituted amines, and amides) in the molecules were proposed to act as the electron donor, which is required for intramolecular Pd participation in the process. In this case, formation of a flve-membered palladium (II) complex (Schemes 9.12 and 9.13) has been proposed. ... 

Rozen, S., "Electrophilic Fluorination Reactions with Fluorine and Some Reagents Directly Derived From It," In Synthetic Fluorine Chemistry Olah, G. A. Chambers, R. D. Prakash, G. K. S., Eds. Wiley New York, 1992 p 143. 

Wang H-F, Cui H-F, Chai Z, Li P, Zheng C-W, Yang Y-Q, Zhao G. Asymmetric synthesis of fluorinated flavanone derivatives by an organocatalytic tandem intramolecular oxa-Michael addition/electrophilic fluorination reaction by using bifunctional cinchona alkaloids. Chem. Eur. J. 2009 13299 13303. 

Numerous reagents have been reported to be capable of effecting electrophilic fluorination reactions. Representative structures of the most prevalent are presented in Figure 15.3. 

Fluorinated esters may also act as electrophiles in reactions with nonfluori-nated ketones [28] (equation 23) or malononitrile [29] (equation 24). Unfortunately, the yields of -diketones may be modest, but those of p-keto nitnles are excellent (Table 9)... 

Chlorine and iodine can be introduced into aromatic rings by electrophilic substitution reactions, but fluorine is too reactive and only poor yields of monofluoro-aromatic products are obtained by direct fluorinafion. Aromatic rings react with CI2 in the presence of FeCl3 catalyst to yield chlorobenzenes, just as they react with Bi 2 and FeBr3. This kind of reaction is used in the synthesis of numerous pharmaceutical agents, including the antianxiety agent diazepam, marketed as Valium. 

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. 

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>. 

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

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]. 

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

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

Difluoroaspartic acid has been prepared by electrophilic fluorination of Ai-tert-butyl 2-ketosuccinate. The amino group is further introduced via an oximation reaction, followed by a reduction. Difluoroaspartic acid may be converted further into difluoroasparagine (Figure 5.19). 

Pyridine is converted into perfluoropiperidine (82) in low yield by reaction with fluorine in the presence of cobalt trifluoride (50JCS1966) quinoline affords (83) under similar conditions (56JCS783). Perfluoropiperidine can be obtained electrochemically. This is useful, as it may be readily aromatized to perfluoropyridine by passing it over iron or nickel at ca. 600 °C (74HC(14-S2)407). Recently, pyridine has been treated with xenon difluoride to yield 2-fluoropyridine (35%), 3-fluoropyridine (20%) and 2,6-difluoropyridine (11%), but it is not likely that this is simply an electrophilic substitution reaction (76MI20500). 

Two routes to the electrophilic fluorination of pyrrolo[2,3-3]pyridine A -oxide lead to the 4-fluoro derivative. The Balz-Schiemann reaction route, via a diazonium tetrafluoroborate salt, or a lithium/halogen-exchange reaction followed by quenching with an electrophilic fluorine source, generates the 4-fluoro product in moderate yields <20030L5023>. 

Due to the highly exothermic nature of the process, the replacement of primary, secondary and tertiary hydrogens upon reaction with electrophilic fluorine atoms is not as selective as for other radicals. For example, early work by Tedder [30,34], showed that the order of selectivity follows the usual pattern, i. e. tert > sec > prim, but the relative selectivity of fluorine atoms is less than chlorine atoms (Table 2). 

In principle, two mechanisms involving either one or two-electron transfer from the aromatic substrate to fluorine may occur and, in practice, the mechanism of fluorination of any given aromatic molecule probably lies between these two extremes. The distinction between electron transfer (Path A, Fig. 55) and SN2-type processes (Path B, Fig. 55) in reactions between various electrophilic fluorinating agents and nucleophiles has been addressed by Differding [144, 145] but these principles can also be applied to reactions involving elemental fluorine. 

The nature of the solvent has a major effect on the rate (extent) of reaction. Recently, polar and acidic solvents have been used as reaction media to promote the electrophilic fluorination pathway (B) in which the interaction between fluorine and the acid is envisaged (Fig. 56) [146,147]. 

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