Fluorinated heterocycles, synthesis

Attanasi OA, FUippone P, Guidi B, Mantellini F, Santeusanio S (2001) Regioselective synthesis of stable 2-(trifluoromethyl)-2,3-dihydro-lH-pyrrol-2-ols and derived fluorinated heterocycles. Synthesis 1837-1845... 

Pubhcations have described the use of HFPO to prepare acyl fluorides (53), fluoroketones (54), fluorinated heterocycles (55), as well as serving as a source of difluorocarbene for the synthesis of numerous cycHc and acycHc compounds (56). The isomerization of HFPO to hexafluoroacetone by hydrogen fluoride has been used as part of a one-pot synthesis of bisphenol AF (57). HFPO has been used as the starting material for the preparation of optically active perfluorinated acids (58). The nmr spectmm of HFPO is given in Reference 59. The molecular stmcture of HFPO has been deterrnined by gas-phase electron diffraction (13). 

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). 

The Kyoto group has developed some interesting chemistry based upon this readily available alcohol. / -Fluoro vinamidinium salts with potential for the synthesis of fluorinated heterocycles were prepared according to Eq. (89) [265]. Treatment of the tosylate of tetrafluoropropanol with n-butyllithium achieves regioselective dehydrofluorination a short reaction time appears to be critical [266]. 

Fluorodediazoniation in anhydrous hydrogen fluoride has been also applied to the synthesis of fluorinated heterocycles, especially pyridines 2. In this case, the reaction is more sensitive to the reaction conditions. For example, diazotization must be performed at lower temperatures than usual and the dediazoniation temperature must be raised slowly in order to obtain good yields. Workup is also important addition of dichloromethane prior to neutralization with ammonia32 as well as treatment of the organic phase with calcium hydride before distillation33 has been recommended, particularly for 4-fluoropyridines (4-fluoropyridine itself forms 4-fluoro-l-(4-pyridyl)pyridinium fluoride if not stored in a sealed tube with cooling33 or stabilized as the hydrochloride32). 

Perfluoro-2-methyl-2-penten-3-yl isothiocyanate, which was prepared from perfluoro-2-methyl-2-pentene and KSCN in benzonitrile in high yield by direct substitution of fluorine, is a stable and versatile educt for heterocyclic synthesis. This a,p-unsaturated isothiocyanate reacted with enamines, such as 1-methylindole and 2-methyl-1-morpholino-l-propene, to yield 2-(l-methylindol-3-yl)-perfluro-4,5-dihydro-5,5-dimethyl-4-ethylidene-l,3-thiazole and its analogue in fair yield. [95H1015]... 

Pace, A., Pibiri, I., Buscemi, S., Vivona, N. and Malpezzi, L. (2004) The photochemistry of fluorinated heterocyclic compounds. An expedient route for the synthesis of fluorinated... 

Synthesis of chiral and bioactive fluorinated heterocycles 93T9385. 

By utilizing a 5-endo-trig cyclization process, several p, 3-difluorostyrenes (71) were transformed to the 2-fluoroindoles 72. Modifications of this method also proved to be useful for the synthesis of numerous other fluorinated heterocycles <02S1917>. A series of 3-arylamino-2-chloroindoles have been prepared by thermal cyclization of l,2-diarylamino-l,2-dichloroethenes, an event which takes place via intermediate arylaminochlorocarbenes <02S2426>. 

Synthesis of Fluorinated Heterocyclic Compounds through Halogen Exchange... 

Chiral heterocycles in asymmetric synthesis of heterocycles 84MI15. Fluorinated heterocycles 89YGK619 90YGK16. 

Within a potential range where radicals (like CF ) are not readily reduced or/and using indirect formation in solution by means of electron carrier, a chemistry—rather similar to that already developed by the Kolbe method by oxidation of CF3COO at a platninum anode—can be developed. Thus, Medebielle [193] showed that radical additional onto electron-rich olefins was possible and applied this for convenient synthesis of fluorinated heterocyclic compounds. Let us stress that the electrochemical process is in this case stoichiometric in electrons. 

Reaction of trifluoromethyl vinyl ketones with magnesium/MesSiCl leads to a di-fluoro analog of Danishefsky s diene (24) [34] (Scheme 2.200) which is a useful building block for synthesis of fluorinated heterocycles [35],... 

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). 

Fluorinated Heterocyclic Compounds Synthesis, Chemistry, and Applications, Edited by Viacheslav A. Petrov Copyright 2009 John Wiley Sons, Inc., Publishers... 

Banks and coworkers published a series of papers describing the reaction of pyridinium methylides with prefluoroalkenes, perfluoroazaolehns, and trifloroace-tonitrile to produce fluorinated heterocycles, exemplihed by the synthesis of indolizine 74 (Fig. 3.33). Modest yields isolated from complex mixtures were reported. 

From these examples, the versatility of 1,3-cycloaddition reactions in the synthesis of 1,2,3-triazoles is apparent. Other strategies, however, are available. Greif and coworkers developed perfluoroalkyl-substituted p-chlorovinylaldehydes as new building blocks for a number of fluorinated heterocyclic systems such as thiazoles, pyridines, pyrazoles, and benzimidazoles. Reaction of the chlorovinylaldehydes with sodium azide leads to the formation of moderate to good yields of 4-perfluor-... 

Molines, H. Wakselman, C. Fluoromalonaldehyde bis(dialkyl acetals) synthesis by carbene condensation and transformation to dialkyl fiuoromalonates and fluorinated heterocyclic compounds. J. Org. Chem. 1989, 54, 5618-5620. 

Burger, K. Hennig, L. Fuchs, A. Greif, D. Spengler, J. Albericio, F. Domino reactions with fluorinated five-memhered heterocycles synthesis of trifluoromethyl substituted hutenohdes and y-ketoacids. Monatsh. Chem. 2005,136, 1763-1779. 

It should be pointed out that perfluorinated aromatic heterocyclic compounds is another valuable feedstock for the synthesis of unsaturated fluorinated heterocycles. For example, fluorination of F-pyridine over C0F3 at 120°C results in saturation of both C=C, leading to 81 as principal product, along with smaller amount of F-l-azacyclohexadiene-1,3." Fluorination of substituted pyridine 115 over C0F3 gives diene 116 in a high yield. 

FIGURE 10.38 Synthesis of fluorinated heterocycles using F-propene oligomers 16 and 24. 

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