Quinoline fluorination

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. 

This coupling works best when the halogen at the 7-position is bromine rather than chlorine or fluorine. This represents the first appUcation of this coupling reaction to the intact quinoline nucleus and thus represents an important advance in quinolone chemistry. 

In quinoline and isoquinoline, the benzene ring is more receptive to fluorma-tion, its double bonds being saturated and the hydrogen atoms replaced in preference to those in the pyridine ring As with pyridine and its homologues, ring contraction takes place during fluorination with cesium tetrafluorocobaltate at... 

Using Cohn s conditions fluorinated quinoline 16 was synthesized from the... 

Acetylated aniline 21 was reacted under Skraup/Doebner-von Miller conditions in the presence of an arsenic salt to yield quinoline 22 with concurrent displacement of fluorine. ... 

Spectroscopic evidence indicates that protonation of 2-fluoro-and 2-chloro-quinoline is not appreciable in O.OlJf aqueous hydrochloric acid. Protonation becomes evident in more strongly acidic solution in the case of the chloro compound without any accompanying decomposition, but the fluoro compound hydrolyzes to carbostyril under the latter conditions. The hydrolysis is acid-catalyzed, but it is doubtful whether protonation on the heterocyclic nitrogen is responsible, owing to its low basicity (presumably below that for the chloro compound). An alternative explanation in this case would be hydrogen bond formation with fluorine, Ar—F. .. H-O+H2. 

The usual order found with halogenonitrobenzenes is F > Cl Br I, the order of Cl and Br being variable, just as in heteroaromatic reactivity. The position of fluorine is of interest the available data indicate that it is usually the same as for nitrobenzene derivatives. Thus, in acid hydrolysis the order F > Cl for 2-halogeno-quinolines can be deduced beyond doubt since the fluoro derivative appears to react in the non-protonated form and the chloro derivative to resist hydrolytic attack even in the protonated form under appropriate conditions (Section II,D, l,d). Furthermore, in the benzo-thiazole ring, fluorine is displaced by the CHgO reagent at a rate 10 times that for chlorine. ... 

Irradiation of lomefloxacin 271 in dilute neutral aqueous solution (in which it exists as a zwitter ion) in Pyrex-filtered 500 W medium pressure mercury (Helios Italquartz) at 17°C gave pyrrolo[3,2,l-(/ ]quinoline 272 (99JOC5388). Under this condition, reductive defluorination via a radical anion took place. This study is important because of the phototoxicity of the fluorinated compounds which could be used as antibacterials (Scheme 49). 

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]. 

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. 

In the case of pyridine, large differences in chemical shift are observed for fluorines at the 2-, 3-, and 4-positions, with fluorines at the 2-position of pyridines and quinolines being the most deshielded, and those at the 3-position being the most shielded. (Scheme 3.60). 

Further new competitive AMPA antagonists include the imidazo-fused 23-benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson k disease <00BMC2127>. An efficient synthesis of fluorine-containing H-1,4-diazepino[6,5-/t]quinolines has been described based on iV,/V-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>. 

The quinoline antibiotics are relatively late arrivals on the antibiotic scene. The parent compound of this class of drugs is nalidixic acid. The downside of this molecule is the rapid development of resistance by pathogenic bacteria. A major step forward was the introduction of a single fluorine atom at a key position, to yield new molecules such as ciprofloxacin, ofloxacin, levofloxacin, andmoxifloxacin. Of these, levofloxacin and moxifloxacin have the best combinations of spectrum of action, potency, and pharmacokinetic properties. In time, they are likely to largely replace the current quinoline antibiotic of choice, ciprofloxacin. Since these molecules work by a different mechanism than do the p-lactams, organisms that become resistant to the latter are generally susceptible to the former. 

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. 

Pyridine is converted into perfluoropiperidine (82) in low yield by reaction with fluorine in the presence of cobalt trifluoride (50JCS1966) quinoline affords (83) under similar conditions (56JCS783). Perfluoropiperidine can be obtained electrochemically. This is useful, as it may be readily aromatized to perfluoropyridine by passing it over iron or nickel at ca. 600 °C (74HC(14-S2)407). Recently, pyridine has been treated with xenon difluoride to yield 2-fluoropyridine (35%), 3-fluoropyridine (20%) and 2,6-difluoropyridine (11%), but it is not likely that this is simply an electrophilic substitution reaction (76MI20500). 

The trichloromethyl group in 4-chIoro-8-methyl-2-(trichloromethyl)quinoline is completely fluorinated with antimony(V) fluoride/antimony(V) chloride when the reaction is carried out in dichloromethane at — 5 to 0 C and then at room temperature for 48 hours to give 4-chloro-8-methyI-2-(trifluoromethyI)quinoIine in 68% yield.4,3... 

Cesium tetrafluorocobaltate(III) and quinoline react at 335-350°C to give98 over 60% of a mixture of 11 identified compounds two products 13 and 14 dominate the rest (each was about one-third of the product mixture). The rearranged structure of 14 is quite remarkable at first sight, but its formation resembles that of the polyfluoropyrrolidines from pyridines. Aromatic compounds are not so prominent as products as with other fluorinations over cesium tetrafluorocobaltate(III), but six are formed all have structures analogous to 15, with up to three fluorines on the pyridine ring. 

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... 

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... 

Fluoropyridines have been prepared by direct reaction of fluorine diluted in an inert gas and dissolved in a polyhalogenated solvent (91BCJ1081). Presumably these reactions involve attack by free halogen atoms as distinct from the ionic halogenation at lower temperatures which gives p-orientation (cf. Section 3.2.1.4.7). Under similar conditions (Br2,450°C) quinoline gives 2-bromoquinoline. 

Fischer indole synthesis, 157 fluorinated phosphine, 136 fuostifoline, 276 furo[2,3- ]pyridine, 281 furopyrimidine, 281, 393 furo[2,3-c]quinoline, 274 furylaniline, 272 furylboronic acid, 274 furylpyridine, 274 furylstannane, 277-9 2-furylzinc chloride, 271-4... 

Intramolecular replacement of fluorine by nitrogen has been used for the formation of fused heterocycles, i.e. derivatives of indole,187 - 189 2,3-dihydroindole.190 benzopyrazole.191 benzo-pyridazine,192 benzoxazine,193194 bcnzothiadiazole,193 quinoline,196-198 and benzothiazinc (e.g., 9).194 1"-200... 

Aryl fluoroalkyl ethers have been prepared from the reaction, at room temperature in HMPA, of fluo-ro-substituted alkoxides with activated fluoro-,149 nitro-,149 and, at 150 °C, also chloro-arenes150,151 and some chloro-substituted pyrazines (equation 15), pyrimidines, quinolines,150,152 and pyridines.152 Disubstitution was observed in die presence of comparably activated leaving groups such as in 2,4- and 2,6-di-chloronitro- or cyano-benzenes, whereas regiospecific substitution took place at position 4 in 3,4-dichloronitro- or cyano-benzene and at position 2 in 2-fluoro-6-chlorocyanobenzene.151 Steric hindrance and the number of fluorine substituents in the alkoxide pose limits to the reactivity. Thus, tertiary alkoxides, or alkoxides containing more than four fluorine substituents, displace activated nitro and fluoro, but not chloro substituents.149,150 The secondary hexafluoro-2-propoxide anion does not react even with the more reactive nitro and fluoro derivatives.149... 

The fluorine chemical shifts of a few 2- and 4-fluoromethyl pyridines and quinolines are available. The 4-substituted isomers appear to exhibit the shielding (relative to the phenyl and naphthyl analogs) that would be expected based on pyridine s electron-withdrawing hyperconjugative n-ocp impact (Scheme 3.84) (see Section 2.2.1.1). 

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