Fluorination of heterocyclic compounds

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... 

Furin, G.G. Fluorine-containing heterocycles. Part. IV. Electrochemical fluorination of heterocyclic compounds. Adv. Heterocycl. Chem. 2006, 90, 239-310. 

Fluorine-containing Heterocycles. Part IV. Electrochemical Fluorination of Heterocyclic Compounds... 

III. Electrolytic Fluorination of Heterocyclic Compounds in Trialkylamine Complexes... 

A. Electrol5dic Fluorination of Heterocyclic Compounds whose Substituents... 

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. 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). 

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)... 

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,... 

Syntheses of heterocyclic compounds with perfluorinated side chains are mainly performed by substitutional fluorinations of the available fragments or by the introduction of a perfluoroalkyl group in the heterocycle. The development of convenient approaches and direct perfluoro-alkylation methods is a current challenge. 

In the syntheses of heterocyclic compounds with perfluoroalkyl groups, the key methods are based on two types of chemical transformations. The first type involves the introduction of the perfluoroalkyl group on the heterocyclic system, namely, substitutional fluorination of fragments already available in the system or direct introduction of the perfluoroalkyl group onto the heterocycle. 

Thus the synthesis of heterocyclic compounds with one or more heteroatoms along with perfluoroalkyl groups is possible if the fluorinated molecule has a multiple bond and if an anionic center may be generated at the heteroatom or carbon atom of the functional group in intramolecular nucleophilic cyclization reactions. These new approaches point to the specific effect of fluorine atoms and to the important role of the electronic effects in... 

Erian, A.W., Konno, A., and Euchigami, T., Electrolytic partial fluorination of organic compounds. Part 19. A novel synthesis of fluorothieno[2,3-h]pyridines using anodic fluorination of heterocyclic sulfides as a key step, J. Org. Chem., 60, 7654, 1995. 

Based on this approach, the synthesis of fluorine-containing heterocyclic compounds can use one of two possibilities. The first is the introduction of a perfluoroalkyl group together with a radical site into the substrate. The second is the use of a substrate with the above radical and generation of a new radical by addition at an unsaturated group. Some examples of such reactions are given below. 

Intramolecular cyclizations involving the fluorine atoms of the benzene ring and the multiple bonds of perfluoroolefins as induced by heteronucleophiles, as well as by condensations involving several molecules with suitable functional groups, are key methods for the synthesis of various heterocyclic compounds. While condensation as a method of synthesis of fluorinated heterocycles is well known and well characterized, intramolecular nucleophilic cyclization is a new technique, permitting one to obtain perfluoroalkyl derivatives of heterocyclic compounds. Due to the presence of fluorine atoms in the starting benzene molecules, cyclizations occur by elimination of ort/zo-fluorine atoms (74FCR115). 

Five-membered fluorine-containing heterocyclic compounds with two or three sulfur atoms are more extended. A ring expansion reaction of thietanes into 1,2-dithiolanes involving heating with sulfur was used. ... 

Written by a team of world-recognized experts In the area of organic and industrial chemistry of fluorine, Ftuorinated Heterocyclic Compounds Synthesis, Chemistry, and Applications will prove valuable to both students and researchers from academia and Industry seeking further knowledge of the synthetic methods, chemistry, and applications of msyor classes of fluorinated heterocycles. 

The material presented in this chapter indicates that the synthesis of fluorinated heterocyclic compounds has attracted considerable attention from the viewpoint of new methods and approaches the specific features of perfluorinated organic compounds are extensively used to create new fluorinated materials with wide applications. Recent growth of fluoroorganic chemistry has led to the discovery of new fluorine-containing heterocyclic compounds with unique structures many of these compounds exhibited specific biological activity and proved to be effective drugs and pesticides. It is hoped that more original methods for the synthesis of heterocyclic... 

---