Heterocyclic compounds fluorination

Fluorinated Heterocyclic Compounds. HeterocycHc compounds containing the CF group are prepared by methods similar to those used in the fluorination of aHphatic compounds. The direct action of fluorine on uracil yields the cancer chemotherapy agent, 5-fluorouracil [51-21-8] as one special example of a selective fluorination on a commercial scale (25). 

Table 13. Properties of Miscellaneous Fluorinated Heterocyclic Compounds...

Yagupol skii, L M Aromatic and Heterocyclic Compounds with Fluorine Containing Suhsniuenis (Russ ) Naukova Dumka Kiev USSR 320... 

Preparation and Reactions of Polyfluorinated Aromatic Heterocyclic Compounds Yakobson G G, Petrova, T D, Kobnna, L S Fluorine Chem Rev 7, 115-223 285... 

Reactions of heterocycles with fluorinated organometallic compounds 97MI31. 

This discussion is separated into three sections depending on whether fluorine, or polyfluoroalkyl group, is introduced into a heterocycle or whether the heterocycle is formed from fluorinated synthons. Methods of introduction of fluorine into N-containing heterocyclic compounds have been reviewed (90CLY959). 

As well as phenyl derivatives, other products have been prepared by hydrolysis of alkoxysilanes such as cyclohexenyl or naphthyl derivatives as well as heterocyclic compounds based on thienyl rings (Table 31, entries 28-33). Few practical applications have been reported for this type of compound, except for the styryl compound T81C6H4-A-CFI = CH2]s, and the fluorinated TslCeFsJs which have been used in polymer blending (Table 31, entries 13 and 28). ... 

The synthesis of biologically significant fluorinated heterocyclic compounds has been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles [51], This reaction was noticeably improved under solvent-free conditions and using microwave irradiation (Eq. (8) and Tab. 3.5). 

Halides in heterocyclic compounds can also be reduced selectively by tin hydrides. For example, the more reactive chlorine in a fluorinated aziridine can be reduced readily using very mild conditions and without a catalyst75. Again, the more reactive chlorine is reduced preferentially (equation 67). 

Fluorinated ethylene propylene materials, acid resistance of, 23 785 Fluorinated heterocyclic compounds, 77 867... 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

In a recent review, Tao etal. [34] describe the partial fluorination and the perfluorination of organics with particular emphasis on medically important compounds and pharmaceuticals. The selective electrofluorination (SEF) of olefins and active methylene groups is reviewed by Noel et al. [35] In the case of heterocycles, nuclear fluorination is known to be the predominant process. However, in aromatic compounds, nuclear substitution as well as addition proceeds simultaneously, leading to the formation of a mixture of products. The influence of solvents, supporting electrolytes, and adsorption on product yield and selectivity is summarized and evaluated. Dimethoxyethane is found to be a superior solvent for SEF processes. Redox mediators have been employed to minimize anode passivation and to achieve better current efficiencies. 

The fluorination of heterocyclic compounds with xenon difluoride has received much less attention. Pyridine reacts readily with xenon difluoridc in dichloromethane without a catalyst to form 2-fluoropyridine (35 %), 3-fluoropyridine (20 %) and 2,6-difluoropyridine (11 %).80 8-Hydroxyquinoline treated with xenon difluoride forms 5-fluoro-8-hydroxyquinoline at room temperature in 35% yield.80 Uracil reacts with xenon difluoride to give 5-fluorouracil in 10% yield.81 Only one example exists of a highly substituted pyrrole fluorinated with xenon difluoride in acetonitrile in 35% yield.82... 

The reagent F-Teda BF4 (6) is effective for the fluorination of nitrogen-containing heterocyclic compounds.107 Thus, 1-fluoroquinuclidinium (cf. preparation of compounds 3, vide supra), 1-fluoropyridinium (cf. Section 9.4.) and l-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate have been prepared in excellent yield by fluorination of quinuclidine, pyridine and 2,4,6-trimethylpyridine with F-Teda BF4 (6).107... 

Sodium fluoride does not effect any replacement of aromatic chlorine atoms with fluorine, unless they are activated by substitution of electron-withdrawing groups in the ring. Several examples are reported for heterocyclic compounds. 

Analogous to aromatic halides, heterocyclic halides can be transformed to the corresponding fluorides by nucleophilic displacement with fluoride ions. Fluorinated heterocyclic compounds are also biologically interesting and several technical applications are also known.116... 

In spite of the fact that cesium fluoride is very expensive and needs care in handling (very hygroscopic ), it is the reagent of choice for several reactions where halogens and fluorosulfonate groups have to be replaced by fluorine in aromatic and heterocyclic compounds. Cesium fluoride is more reactive than potassium fluoride and also possesses greater solubility. Often a phase-transfer catalyst is added to aid and enhance the reaction rate and yield of the products. 

Table 13. Formation of Fluorinated Unsaturated Heterocyclic Compounds by Dehalogenation...

Further examples of dehydrofluorinations of heterocyclic compounds can be found in refs 113 (formation of fluorinated dihydrofuran derivatives), 114 [formation of 3-fluoro-2,2-bis(tri-fluoromethyl)-2//-oxete], and 115 (formation of fluorinated 2,3-dihydro-l, 4-dioxin derivatives). 

In organo-fluorine compounds fluorine atoms can be eliminated by nucleophilic sulfur species to form C —S bonds. In principle, the fluorine to be eliminated can be bonded to aliphatic or araliphatic compounds, as well as to aromatic or heterocyclic compounds however, the replacement proceeds more efficiently the more the fluorine is activated. Therefore, the synthetic usefulness of these reactions is the broadest with fluoroaromatic compounds, including heteroaromatics, with which the reactions often proceed smoothly under mild conditions. The nucleophilic sulfur compound to be reacted is. in most cases, an aliphatic or aromatic thiol or a metal sulfide, but reactions with, for example, thiourea or ammonium thiocyanate have also been described. The sulfur introduced this way can be either oxidized or removed by reduction, opening additional possibilities for modifications of the original fluoro compounds. 

Methods of Introduction of Fluorine into Aromatic and Nitrogen-Containing Heterocyclic Compounds (Czech) Hradil, P, Radi, S Chem Listy M, 952-969 m... 

Intramolecular cyclization in perfluoroaromatic systems proves useful for the synthesis of heterocyclic compounds [72] For example, the Fischer indole synthesis, which normally requires the presence of an ortho proton, occurs satisfactorily with an ortho fluorine in theperfluoronaphthalene senes [73] (equation 37)... 

Examples of modem fluorine-containing herbicides, insecticides, and fungicides are shown below Most of these compounds are prepared starting from fluorinated bulk chemicals, such as fluorinated carbocyclic and heterocyclic compounds, benzotnfluonde, fluorinated acetic acid derivatives, and Freons Direct fluonnation is used only occasionally by producers of fine chemicals and will, at least in the near future, remain the domain of producers of bulk chemicals who have the necessary technical expertise... 

Buscemi, S., Pace, A., Pibiri, I., Vivona, N. and Caronna, T. (2004) Fluorinated heterocyclic compounds. An assay on the photochemistry of some fluorinated l-oxa-2-azoles an expedient route to... 

Fluorine-containing heterocyclic compounds play an important role in drug and pesticide design. The key methods of synthesis of these compounds are based on condensation and intramolecular cyclization processes induced by heteronucleophiles. They may affect the fluorine atoms of a benzene ring and the multiple bond of perfluoroolefins. Intramolecular cyclizations are characteristic of unsaturated polyfluorinated compounds. Therefore,... 

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