Trifluoromethyl quinoline oxides

Kobayashi et al. reported the synthesis of 2-, 3- and 4- trifluoromethyl- quinoline oxides, having quite different chemical properties. While in the reaction 2-CF3-quinoline with P(0)Cl3 gave 4-chloro-2-CF3-quinoline, 3- and 4-CF3 isomers selectively produce the corresponding 2-chloro- derivatives. ... 

Reduction. Quinoline may be reduced rather selectively, depending on the reaction conditions. Raney nickel at 70—100°C and 6—7 MPa (60—70 atm) results in a 70% yield of 1,2,3,4-tetrahydroquinoline (32). Temperatures of 210—270°C produce only a slightly lower yield of decahydroquinoline [2051-28-7]. Catalytic reduction with platinum oxide in strongly acidic solution at ambient temperature and moderate pressure also gives a 70% yield of 5,6,7,8-tetrahydroquinoline [10500-57-9] (33). Further reduction of this material with sodium—ethanol produces 90% of /ra/ j -decahydroquinoline [767-92-0] (34). Reductions of the quinoline heterocycHc ring accompanied by alkylation have been reported (35). Yields vary widely sodium borohydride—acetic acid gives 17% of l,2,3,4-tetrahydro-l-(trifluoromethyl)quinoline [57928-03-7] and 79% of 1,2,3,4-tetrahydro-l-isopropylquinoline [21863-25-2]. This latter compound is obtained in the presence of acetone the use of cyanoborohydride reduces the pyridine ring without alkylation. 

Kobayashi, Y. Kumadaki, I Taguchi, S. Organic fluorine compounds. VI. Preparations and reactions of (trifluoromethyl)quinoline 7V-oxide. Chem. Pharm. Bull. 1969, 77(11), 2335-2339. 

Cyclizations of alkynyl derivatives proved to be a synthetically convenient way to 2-(trifluoromethyl)quinolines. Indeed, the intramolecular cyclization of N-(a-trifluoromethyl)propargyl anilines 89 takes place with the gold(I) catalyst under extremely mild conditions to afford 2-trifluoromethylquinolines 90 (Scheme 36). The reaction mechanism has been suggested to involve cyclization and oxidation steps [57],... 

Kaneko, C., Hayashi, S., and Kobayashi, Y., Photolysis of 2-(trifluoromethyl)quinoline 1-oxides and isoquinoline 2-oxides, Chem. Pharm. Bull, 22, 2147, 1974. 

Heterocycles containing limited amount of fluorinated substituents (usually 1-3) can be named using trivial names or conventional nomenclature in combination with indication of the position of fluorinated substituents, for example, 2-fluoro-4-tri-fluoromethylpyridine. The situation becomes more complicated in case of poly-fluorinated and completely fluorinated heterocycles. In case of heterocycles with relatively small number of fluorinated substituents and well-defined stmctures, Greek or Latin numeral roots can be used. Names such as hexafluoropropene oxide, 2,2-bis (trifluoromethyl)oxirane, 2,2,3,3-tetrafluorooxetane, tetrakis(trifluoromethyl)furane, pentafluoropyridine, tetrafluoropyridazine, tetrafluoropyrimidine, and heptafluoro-quinoline are unambiguous and commonly accepted (see Fig. 0.1). 

The importance of the carboxylic acid moiety for activity is clearly illustrated by the next group of compounds. Removal of the carbethoxy substituent provided 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one (LIN) which is inactive at 3 mg/kg i.v. in the PCA procedure. Interestingly, the 2-methyl analog (LIV) exhibits excellent oral activity while displaying only weak intravenous activity. This may be rationalized on the basis of metabolic oxidation of this compound to the carboxylic acid (LX, Figure 10). The fact that the 2-ethyl (LV), 2-trifluoromethyl (LVI), and 2-acetyI (LVIl) analogs are considerably less active, and the 2-phenyl (LVI II) and 2-hydroxy (LIX) analogs are inactive, supports this explanation. 

Rousseaux, Liegault, and Fagnou reported the elegant formation of quinoline and tetrahydroquinoline derivatives via a Pd(0)-catalyzed C-H activation of cyclopropane methylene bond [26]. Both bromophenyl and chlorophenyl cyclopropyl carbamates 31 and 32 were found to be suitable substrates for the transformation into dihydroquinoline 33, albeit under slightly different conditions (Scheme 5). It was found that the resulting dihydroquinolines 33 were prone to decomposition thus protocols for either oxidation or reduction of the unstable intermediates were developed. A variety of substituents (nitro, cyano, trifluoromethyl, methoxy, ester)... 

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