Fluorination of pyridines

Fluorination of pyridine (90TL775), uracil (90T3093), and octaethyl-porphyrin [88JCS(P1)1735] has been described using cesium fluorooxysulfate. The outcome of the former was strongly dependent on the solvent. For example, with pyridine in methanol no fluorination was observed and 2-methoxypyridine was obtained. 2-Fluoropyridine was isolated when cyclohexane was the solvent (90TL775). 

High-valency metal fluoride fluorination of pyridine [82JFC(21)171], quinoline [82JFC(21)413], and 2-methylfurans [91 JFC(51)179] has been reported. With 2-methylfuran a complex mixture of stereoisomers of partially fluorinated oxolans was obtained. These can be dehydrofluorinated to fluorooxolens and no furans have been observed. Conformation and structural group were found to influence the direction and readiness toward dehydrofluorination [91 JFC(52) 165]. 

Meinert demonstrated that fluorination of pyridine at low temperatures gives the ionic salt N-fluoropyridinium fluoride, a compound that was reported to be explosive at 0°C (Fig. 59) [154]. However, direct fluorination of variously substituted pyridines is possible and good yields of the corresponding 2-fluoro-pyridines (Figs. 60 and 61) [155] are obtained, offering an attractive alternative to the usual halogen-exchange and Balz-Schiemann routes to these products. These reactions probably proceed via N-fluoropyridinium salts (Fig. 62) which are activated towards nucleophilic attack. 

The fluorination of pyridine with cesium fluoroxysulfate in the presence of sodium tetrafluoro-borate in acetonitrile at 0-5 C gives 1-fluoropyridinium tetrafluoroborate (3).42... 

Ring fluorination of pyridine and its benzo derivatives is suggested to occur through nucleophilic attack of fluoride ion on an initial pyridine fluorine complex (87TL255, 91BCJ1081, 93AHC(58)29l). In electron-deficient pyridines and their benzo derivatives, fluorination on the pyridine ring is kinetically competitive with annular and side chain fluorination. 

Electrochemical fluorination of pyridine in the presence of a source of fluoride ion gave 2-fluoropyridine in 22% yield (85M11). With xenon difluoride, pyridine formed 2-fluoropyridine (35%), 3-fluoropyridine (20%), and 2,6-difluoropyridine (11%) in a reaction unlikely to be a conventional electrophilic substitution. Xenon hexafluoride has also been used (76JFC179). With cesium fluoroxysulfate at room temperature in ether or chloroform, the major product was 2-fluoropyridine (61 and 47%, respectively). Some 2-chloropyridine was also formed in chloroform solution. In methanol the entire product was 2-methoxypyridine (90TL775). Fluorine, diluted with argon in acetic acid, gave a 42% yield of the 5-fluoro derivative of l-methyl-2-pyridone [82H( 17)429],... 

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>. 

Fluorination of pyridine yields, inter alia, perfluoropiperidine.320 Iodine has been introduced in the 5- and 7-positions of 8-hydroxy-quinoline.321 Cathodic halogenation has been mentioned in Section IV, A, l,b. 

The fluorination of pyridine with cesium fluoroxysulfate in a variety of solvents yields a mixture of 2-fluoropyridine (7), 2-(fluorosuIfonyloxy)pyridine (8) and 2-substituted pyridincs 9. ... 

Fluorination of pyridine derivatives 880R(35)513 89YGK619 90-CLY952. 

Since 10 and pentafluoropyridine are the principal products in the small-scale fluorination of pyridine over cesium tetrafluorocobaltate (Eq. 10), this constitutes an overall direct synthesis of pentafluoropyridine via a very interesting rearrangement. 

Heteroaromatic fluorination. Fluorination of pyridine, quinoline, and quinoxaline systems occurs with fluorine-iodine mixtures. Pyridine is alkoxylated when an appropriate alcohol is present. 

Direct fluorination of pyridine or its derivatives with fluorine in the inert atmosphere (F2/N2 mixture) is not regioselective and usually gives 2-fluoropyridines in low yield. 

Direct fluorination of pyridine can also be carried out using CSSO4F as a source of fluorine. It was shown that pyridine readily reacts with CSSO4F at room temperature producing a mixture of different products (2-fluoro-, 2-fluorosulfonate- and 2-chloro- or 2-aLkoxypyridines). ... 

It was demonstrated that 4-fluoropyridine can be synthesized by electrochemical fluorination of pyridine on the platinum anode at constant voltage in acetonitrile solution containing Et3N-3HF as supporting electrolytes and fluorine sources. ... 

Mixtures of polyfluorinated pyridines can be obtained from the corresponding pyridines by fluorination with tefrafluorocobaltates(III) however, this reaction has a low selectivity. For example, the reaction mixture derived from the reaction of pyridine with KC0F4 at 220°C is reported to contain more than seven fluoropyridines, two fluoro-2-azahexenes, three azahexadienes, and two fluoro-Al-methylpyrrolidines. Four fluorinated products were isolated from a fluorination of pyridine by C0F3 at 150°C a 2-azahexene, two Al-methylpyrrolidines, and 4//-nona-fluoropiperidine. ... 

Chambers, R.D. Parsons, M. Sandford, G. Skinner, C.J. Atherton, M.J. Moilhet, J.S. Elemental fluorine. Part 10. Selective fluorination of pyridine, quinohne and quinoxaline derivatives with fluorine-iodine mixtures. J. Chem. Soc., Perkin. Trans. 1 1999, 803-810. 

Plevey, R.G. Rendell, R.W. Tatlow, J.C. Fluorinations with complex metal fluorides. Part 6. Fluorination of pyridine and related compounds with caesium tetrafluorocobaltate (111). J. Fluorine Chem. 1982, 21, 159-169. 

Anodic fluorination of pyridine in EtsN 3HF gives 2-fluoropyridine in 22% yield (85EA1075). Because the heterocyclic ring contains electron-accepting substituents. 

Fluorination of pyridine by complex AIF3 and CuF2 at 450-5(X) C forms a mixture of 2-fluoropyridine and 2,6-difluoropyridine in yields 32 and 11 % accordingly [47]. 3-Bromo-2-nitropyridine reacts with Bu4NT in DMF at 20 °C to form... 

Coe PL, Holton AG, Tatlow JC (1982) Fluorinations with potassium tetrafluorocobaltate (111). Part Vll. Further -investigations on the fluorination of pyridine. J Fluorine Chem 21 171-189... 

---