Quinoline 3-fluoro

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. ... 

In an extensive investigation of the behavior of halogeno-pyridines and -quinolines towards potassium amide in liquid ammonia, tendencies to react according to the hetaryne type and other mechanisms were compared. The following results may be mentioned. 3-Fluoropyridine does not react via 3,4-pyridyne, but yields fluoro derivatives of 4,4 - and 2,4 -bipyridine. 3,6-Dibromopyridine is converted first into 6-bromo-3,4-pyridyne and not into 6-amino-3-bromopyridine. 2-Bromoquinoline yields 2-methylquinazoline together with 2-aminoquinohne. ... 

Treatment of 8-fluoro-l,2-dihydro-4 7,67/-[l,4]oxazino[4,3-a]quinoline-4,6-dione with 6N aqueous NaOH and PhCH2Br under reflux overnight and with NaOMe in DMF at ambient temperature yielded l-(2-benzyloxyethyl)- and l-vinyl-6-fluoro-l, 4-dihydroquinoline-2-carboxylic acids, respectively (01SL833). 

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. 

Treatment of 8-fluoro-4-hydroxy-l/7-[l,2,4]triazino[4,5- ]quinoline-l,6(2/7)-dione 72 with POCl3 readily and selectively gave compound 103 which was subsequently hydrodechlorinated affording 104 (Scheme 6) <2003JHC789>. 

The thermal cyclization of 4-fluoro-3-(l-pyrrolyl)phenylaminomethy-lenemalonate (757, R = l-pyrrolyl, R1 = F) in diphenyl ether at 250°C for 5 min gave 6-fluoro-7-(l-pyrrolyl)quinoline-3-carboxylate (759, R = 1-pyrrolyl, R1 = F) in 55% yield (86FRP2574404). 

Flumequine was prepared when 6-fluoro-2-methyl-1,2,3,4-tertrahydro-quinoline was first reacted with alkylidene malonates and trimethyl orthoformate in THF in the presence of p-toluenesulfonic acid, and then the products, alkylidene (6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1 -yl) methylenemalonates, were cyclized in xylene on the action of polyphos-phoric acid or ethyl polyphosphate at 110-115°C for 1 hr (89EUP310849). 

Ethyl 4,5-difluoro-7-oxo-2,3-dihydro-7//-pyrido[3,2,l-i)][2,l]benzox-azinone-6-carboxylate (98) was formed when ethyl 6,7-fluoro-4-hydroxy-8-(2-hydroxyethyl)quinoline-3-carboxylate (97) was treated with m-chloro-peroxybenzoic acid in chloroform [92JAP(K)92/208287, 92JAP(K)92/ 210656],... 

S,S)- and (S,R -1-(2-p8F]Fluoro-1-methyl-ethyl-amino)-3-(quinolin-5-yloxy)-propan-2-ol 7 [104] ... 

The propensity of nucleophilic attack of fluoro and chloro quinolines by RLi reagents dictates the use of LDA for DoM processes that normally occur at the most acidic sites. Thus, LDA metalation of 3-chloro and 3-fluoro quinolines leads, after TMSC1 quench, to 4-substituted products [79JOM(171)273]. Furthermore, 4-chloro [89JHC1589] and 5-fluoro [79JOM(171)273] quinolines, under similar conditions, lead to 3- and... 

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