Fluorination heterocycles

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). 

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). 

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

Certain trifluoromethyl-substituted 1,2,4,5 tetrazines [260, 26i] and 1,2,4 triazines [i06] can be used as cyclic hetero-1,3-dienes and provide efficient preparative routes to partially fluorinated heterocycles (equations 55 and 56)... 

A new thermal preparation ot fluorinated species is copyrolysis Copyrolysis of fluorinated compounds like perfluorobenzene, fluorinated aromatic anhydndes, and fluorinated heteroaromatics with tetrafluoroethylene or other fluonnated olefins is a useful method of preparing fluorinated olefins [88 89], functionalized fluoroaromatics [90 91 92, 93, 94, 95], fluonnated benzocycloalkanes [80, 96, 97, 98, 99, 700], fluorinated heterocycles [80, 93, 101, 102, 103], and fluonnated polycyclic compounds [104] (equations 19 and 20)... 

Enzyme-controlled transformations of fluorinated heterocycles 97MI32. 

Fluorinated heterocycles have many uses and the following are some typical examples. Trifluoromethyl pyridines are useful building blocks for agrochemicals (91MI1). Fluorinated quinolones have evoked considerable interest in the last 10 years as antibacterial agents (90MI1, 90MI2). The... 

Having learnt the lessons from this simple little compound, it would seem reasonable to expect similarly surprising couplings in other fluorinated heterocycles. 

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). 

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

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]. 

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... 

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). 

Other well-known reactions are those offluorinated olefins with fluoride ion and negatively substituted aromatic compounds leading to the formation of per-fluoroalkylated aromatic compounds The reaction may be considered an anionic version ot a Friedel Crafts process and can result m introduction of one or several perfluoroalkyl substituents [HI] Aromatic substrates include substituted and unsubstituted perfluorobenzenes [131, 212, 213, 214], fluorinated heterocycles [131, 203, 215, 216, 217, 218, 219, 220, 221, 222, 223], perchlonnated heterocycles [224] (equation 44), and other activated aromatic compounds [225] (equation 45) The fluorinated olefins can be linear or cyclic [208] (equation 46)... 

The condensation-cyclization of fluoromethyl ketones with bifunctional aniline derivatives or anthranilic acid gives a range of fluorinated heterocycles (benzimida-zolines, benzothiazolines, benzoxazolines and dihydrobenzoxazinones) over Nafion-H and Nafion SAC-13 both exhibiting high catalytic activity.722 Products are formed under mild conditions in high yields with high selectivity and purity. Illustrative is the transformation shown in Eq. (5.271). 

Fluorine is a very important atom both for the biological applications of fluorinated heterocycles [175, 176] and for 19F chemical shifts and the large coupling constants with 19F [177], We have already discussed the case of fluoroindazoles, 44-46) [51] and we have published a paper reporting MP2/6-311G calculations of all C-fluoropyrazoles 191-197. The order of stability of monofluoropyrazoles is 3-F (191)... 

Hexafluoropropene reacts with tetrahydrothiopyran in the presence of di-/-butyl peroxide to give the 2-fluorinated heterocycle (Equation 51) <1996IC6676>. 

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... 

Synthesis of chiral and bioactive fluorinated heterocycles 93T9385. 

It seems that suitable reaction conditions leading to the formation of a specific compound may be found by using various nucleophiles. These reactions are potentially useful routes to fluorinated heterocyclic compounds. 

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>. 

Since partially fluorinated heterocyclic compounds are important in both academia and industry the synthetic state of the art has been reviewed regularly (74MI1 76MI2 77MI1 81AHC1 91MII). 

Synthesis of Fluorinated Heterocyclic Compounds through Halogen Exchange... 

Fluorinated heterocycles 88MI2 90UK149, 90YGK16. Heteroaromatic sulfoxides and sulfones 90AHC(48)1. 

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

Fluorinated heterocycles 87PHA73,87T3123 90FES1043, 90FES1137, 90YGK16. 

Hexafluoro-2-butyne readily undergoes anionic oligomeri2ation in the presence of fluoride ion [248], but the intermediate vinylic carbanion can be trapped by highly electrophilic fluorinated heterocycles [249] (equation 52)... 

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