Fluorinated pyridines

The discovery of new broad spectmm antibiotics has been accompanied by the development of processes for fluorinated feedstocks ring-fluorinated aromatics for those quinolones containing a fluorobenzopyridone group, and fluorinated pyridine precursors for those antibiotics containing a naphthyridine nucleus (enoxacin, tosufloxacin) (see Table 14). 

We have also noted some strange behaviour with fluorinated pyridines, for example, 3-fluoro nicotinic acid (Structure 6.19 and Spectrum 6.12). The signal for H= (approx. 8.1 ppm) clearly shows couplings of 9.1, 2.9 and 1.7 Hz. The 9.1 Hz coupling must be from the fluorine as it does not appear anywhere else in the spectrum and its chemical shift distinguishes it from either of the other two protons. 

Blayo AL, Le Meur S, Gree D, Gree R (2008) New enantloselective synthesis of mono-fluorinated pyridines designed for the preparation of chemical libraries. Adv Synth Cat 350 471 76... 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

Xenon difluoride and xenon hexafluoride fluorinate pyridine to give a mixture of 2- and 3-fluoropyridines along with 2,6-difluoropyridine (76JFC(7)179). Cesium fluoroxysulfate at room... 

The preparation of fluorinated pyridine derivatives continues to be of considerable importance due to the effect that the fluorine atom can have on the physical, chemical, and biological properties of the heterocycle. Despite this, there are few reports on the direct electrophilic fluorination of pyridines. The treatment of various quinoline derivatives with elemental fluorine in acidic reaction media afforded mono- and difluorinated products where the halogenation occurred on the benzene ring of the heterocycles <2004JFC661>. 

We have found that several new fluorinated herbicide candidates currently under investigation at Monsanto are very efficient at electron capture and thus are ideally suited for negative ion LC/MS. One such candidate is the pre-emergence herbicide dithiopyr 1 which is illustrated in Figure 1. Dithiopyr is representative of a novel class of fluorinated pyridine herbicides whose metabolism has been studied extensively by negative ion LC/MS. 

Sensitivity of Electron Capture Ionization. We have found that negative ion LC/MS provides substantial increases in sensitivity as compared with positive ion LC/MS during analysis of fluorinated pyridines such as dithiopyr 1. An example of such sensitivity enhancement is shown in Figure 2. The top panel illustrates the total ion current trace obtained from injection of increasing amounts of dithiopyr in the positive ion mode with discharge ionization. 

The significant differences observed in the positive and negative ion mass spectra of fluorinated pyridines greatly assist metabolite identification in biological... 

Rate constants have been measured for the reaction of ammonia with various fluorinated pyridines in aqueous dioxane at 25°C (82MI1). The reactivity of some 3-substituted derivatives of 2,6-dihalopyridines toward potassium amide in liquid ammonia has been studied (85JHC985). The reaction of... 

In principle, this would be the preferred route, but in practice no generally successful procedure is available for the synthesis of highly fluorinated compounds directly by this approach. It has been reported that pentafluoro-pyridine may be obtained in approximately 15% yield by fluorinating pyridine over cesium tetrafluorocobaltate (Eq. 10).45 But it appears that... 

Various partly fluorinated pyridines can be synthesized by diazotization of the amino derivatives in aqueous hydrofluoric acid,50 or by using anhydrous hydrogen fluoride followed by thermal decomposition of the diazo-nium fluoride.51,52 There are also many examples of the application of the classical Balz Schiemann reaction to heteroaromatic systems,53,54 and the interesting photolysis of diazonium tetrafluoroborates has given fluoro-imidazole derivatives55,56 and fluorazoles.57... 

Radical-anions are generated by electrochemical reduction of fluorinated pyridines (Scheme 31348) and other heterocycles.349 Radical-anions have also been produced from polyfluoropyridines by X-ray irradiation and studied by ESR using matrix isolation techniques. It was concluded that crossover of [Pg.64]

Isomers 120 and 121 appear to be the only valence isomers of aromatic diazines described, and they are surprisingly stable. Even more spectacular, however, are the stabilities of valence isomers of fluorinated pyridines corresponding to structures 122-124. So far however, an azabenzvalene derivative (e.g., 125) has not been described. Pyridine itself forms a valence isomer that... 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

Trifluorothymidine is a fluorinated pyridine nucleoside structurally related to idoxuridine (55). It has been approved by the U.S. FDA and is a potent, specific inhibitor of replication of HSV-1 in vitro. Its mechanism of action is similar to that of idoxuridine. Like other antiherpes drugs, it is first phos-phorylated by thymidine kinase to mono-, di-, and triphosphate forms, which are then incorporated into viral DNA in place of thymidine to stop the formation of late virus mRNA and subsequent synthesis of the virion proteins. 

Compound 13 can be obtained in one-pot process by reacting the corresponding pyridines with F2/N2 mixture followed by the subsequent treatment with EtaN. However, the yields of the fluorinated pyridines obtained by this protocol are significantly lower (22-35%). 

SYNTHESIS OF RING-FLUORINATED PYRIDINES HForHF-Py, NaNOg... 

Several variations of the Baltz-Schiemann reaction allow synthesis of fluorinated pyridines in almost quantitative yields. For example, 2-fluoropyridines 28 were prepared in 91-94% yields by diazotation of 2-aminopyridines 27 with sodium nitrite in anhydrous HF or HF-pyridine complex (Scheme 6.11). " ... 

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