Fluorination of quinolines

Fluorination. Direct fluorination of quinoline was accompanied by extensive fragmentation of the heteroring, but trifluoromethyl hypofluorite in trichlorofluoromethane at -70°C converted 5-fluoro-8-hydroxyquino-line into the 5,7-difluoro-8-hydroxy product (72JMC987). Quinoline, itself, was perfluorinated by fluorine and cobalt(III) fluoride (56JCS783), whereas cesium tetrafluorocobaltate at around 350°C converted it into a mixture of saturated polyfluoro compounds (82JFC413). It is much more satisfactory to introduce fluorine by nucleophilic methods. 

Early reports of the fluorination of quinoline over cobalt(III) fluoride are clearly incorrect to a large extent. More recent work98 shows that at 350°C, quinoline gives over 70% yield... 

Direct Fluorination of Heterocyclic Aromatics Selective fluorination of quinoline aromatics leads to various commercially important products such as 5-fluoroadl, 5-fluoroprimaquine and ciprofloxacin with the fluorine moiety being decisive of their chemical and biological properties. 

The fluorination of quinoline was performed in a microstructured reactor operated in the annular-flow regime, which contained one microchannel with two consecutive feeds for gas and liquid [311,312]. The role of the solvent was large. The reaction was totally unselective in acetonitrile and gave only tarlike products. With formic acid, a mixture of mono- and polyfluorinated products besides tar was formed. No tar formation was observed with concentrated sulfuric acid as solvent at 0-5 °C. In this way, a high selectivity of about 91% at medium conversion was achieved. Substitution was effective only in the electron-rich benzenoid core and not in the electron-poor pyridine-type core. The reactivity at the various positions in the quinoline molecule is 5 > 8 > 6 and thus driven by the vicinity to the heteroatom nitrogen that corresponds to the electrophilic reactivity known from proton/deuterium exchange studies in strong acid media. 

R.D. Chambers, D. Holling, G. Sandford, H. Puschmarm, J.A.K Howard, Selective direct fluorination of quinoline derivatives,/. Fluorine Chem. 2002, 117, 99-101. 

The direct fluorination of quinolines has a limited use since a low selectivity of the reaction, and also due to technological and ecological difficulties. However, there are several examples of selective syntheses of monofluorinated quinolines. For instance, 2-fluoroquinolines 72 were obtained by interacting quinoline 71 with elementary fluorine in the presence of I2 [46], yields proved to be in the range of 54-93 %, ratio la-quinoline 71 was 1 1, and ratio Fa-quinoline 71 was 2 1 (Scheme 28). To obtain 2-fluoro-4-chloroquinoline and 2-fluoro-4,7-dichloroquino-line the reaction was carried out in the presence of triethylamine. 

Also direct fluorination of quinoline 71a under acidic conditions has been reported [47,48]. Electrophilic substitution in the series of quinolines proceeds not selectively, therefore a mixture of 5-fluoroquinoline, 6-fluoroquinoline, 8-fluoroquinoline and 5,8-difluoroquinoline is formed. 6-Methoxyquinoline was shown to undergo direct fluorination at the position 5, and 5,5-difluoroquinolin-6-one was isolated in addition to the main 5-fluoro-6-methoxy compound [48]. 5-Fluoro-6-methoxy-8-nitroquinoline was obtained by the reaction of 6-methoxy-8-nitroquinoUne with N-fluorobenzolsulphonamide [9]. 

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]. 

The fluorinated 4-quinoline antibiotic ciprofloxacin (295) is known to interact with iron-containing drugs and mineral supplements. Stability constants have been determined for complex formation of iron(III) with ciprofloxacin, presumably acting as a bidentate 0,(9-donor, in aque-ous " and in micellar media. 

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. 

Quinoline undergoes phase I metabolism to form an enamine oxide, a rapid transitional epoxide, which can then form DNA adducts. This epoxide is formed on the pyridine moiety of quinoline. Fluorination at position 3 completely prevents the mutagenicity of quinoline. The major metabolic enzyme is the CYP2E1 isoform with the primary end-product from this reaction being 3-hydroxyquinoline. 

Direct lithiation, i.e. C-deprotonation of quinolines requires an adjacent substituent, such as chlorine, fluorine or alkoxy. Historically, what is probably the first ever strong base C-lithiation of a six-membered heterocycle was the 3-lithiation of 2-ethoxyquinoline. Both 4- and 2-dimethylaminocarbonyloxyquinolines lithiate at C-3 4-pivaloylaminoquinoline lithiates at the peri position, C-5. Quinolines with an ortfto-directing... 

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

Perfluoroalkylfuran Derivatives Fluorination of 2,4-furandicarboxylic acid by sulfur tetrafluoride results in the mixture of products 45-47." The carboxylic group in position 4 is more reactive than in position 2 and the yield of the compound 46 higher than that of the compound 47. Decarboxylation of the acid 46 in the presence of copper powder in quinoline gives 3-trifluoromethylfuran. 

Various trifluoromethylated quinolines also can be prepared in good yield by the liquid-phase fluorination of the corresponding trichloromethyl- derivatives using anhydrous HF and antimony pentafluoride (chloride) as a catalyst. 

Syntheses of quinolines from the products of the nucleophilic substitution of hydrogen proved to be also valuable. For instance, orf/io-nitrobenzyl sulfones react with dialkyl maleates and fumarates to produce directly quinoline 2,3-dicarboxylate N-oxides [211]. The reaction proceeds via the Michael addition of the nitrobenzyl carbanion followed by elimination of benzenesulfinic acid and subsequent intramolecular addition of the allylic carbanion to the nitro group. This approach has recently been used for the synthesis of fluorine-substituted quinoline N-oxides (Scheme 89) [212]. 

In another example of pyridine activation of C—H bonds, 8-amino-quinoline and picolinic acids promote Cu-catalyzed fluorination of y-sp C-H bonds (Scheme 43) (13JA9342).The arenes can be mono- or difluo-rinated. The reaction proceeds well for both electron-rich and electron-poor arenes it also works for heterocycles such as indoles and pyridines.The reaction does not affect key functional groups such as nitro, nitriles, and carboxylates. 

Electrochemical fluorination of various aromatic compounds such as benzene, substituted benzenes toluene, and quinolines is achieved at high current densities using these molten fluoride salts in the absence of organic solvent with good to high current efficiencies (66-90 %)... 

Halogenation. Direct halogenation of quinoline proceeds at the 2-position. Fluorination and bromination are known, but they proceed using forcing conditions (eqs 24 and 25). lodination proceeds under milder conditions, but requires an additional titanium-based reagent (eq 26). Chlorination of quinoline without prior activation has not been reported. 

A number of fluorinated quinolines have found application in agriculture, and also as components for liquid crystals. Cyanine dyes on the basis of quinolines also make a considerable share in commercial production. 

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