2-Methyl-4-chloroquinoline, reaction

Illuminati et al. have also investigated the methoxydechlorination of 4-substituted-2- and 2-substituted-4-chloroquinolines. The relation between the reaction site, the 2- or 4-position, and the substituent in the 4- or 2-position, respectively, is always meta. The authors found the two reaction series well correlated with one another, but diverging quite seriously from the Hammett correlation. They concluded that mesomerically electron-donating substituents, because of the importance of resonance structures like 12 and 13, are more deactivating than expected, while electron-withdrawing substituents, and even the methyl group, seem to follow normal a correlation. 

The ortho indirect deactivating effect of the two methyl groups in 2,6-dimethyl-4-nitropyridine 1-oxide (163) necessitates a much higher temperature (about 195°, 24 hr) for nucleophilic displacement of the nitro group by chloride (12iV HCl) or bromide ions N HBr) than is required for the same reaction with 4-nitropyridine 1-oxide (110°). With 5-, 6-, or 8-methyl-4-chloroquinolines, Badey observed 2-7-fold decreases in the rate of piperidino-dechlorination relative to that of the des-methyl parent (cf. Tables VII and XI, pp. 276 and 338, respectively). 

The indirect deactivation in 2-amino-4-chloroquinoline (187) requires vigorous conditions (potassium hydroxide in hot ethylene glycol, or boiling propanolic propoxide for 16 hr) to displace the chloro group, which is stable to aqueous alkali and to hydriodic acid. The direct deactivation in 5-amino-2-chloro-3-cyano-6-methyl-pyridine (188) prevents reaction with alkoxide ion under conditions which produce smooth reaction of the des-amino analog. 

Deactivation in the anion formed under the reaction conditions prevents alkoxy-dechlorination of 4-chloro-2-quinolone (222) with boding alkoxide solution while 4-chloroquinoline and its 2-ethoxy and 2-anilino derivatives react. 4-Chloro-iV -methyl-2-quinolone reacts readily. 

Electronegative groups do not invariably prevent nuclear bromination, but reaction conditions must be much more severe, and the orientation of substitution may be affected by the substituent. Thus 6-nitroquinoline was brominated in sulfuric acid at 100°C to give the 8-bromo product (71) in 51% yield 8-methyl-5-nitroquinoline gave a 69% yield of the 7-bromo derivative (72) under similar conditions, whereas 7-chloroquinoline was transformed into the 5-bromo product (93%) (88CHE892) (Scheme 35). In a sealed tube reaction with bromine, 8-nitroquinoline gave a mixture... 

A somewhat different approach is used for the preparation of the analogue that contains a trifluoromethyl group. The scheme involves first the conversion of ort/zo-trifluoromethyl aniline (27-1) to a quinolol. The compound is thus condensed with EMME and cyclized thermally (27-2). That intermediate is then saponified the resulting acid is decarboxylated and finally converted to the 4-chloroquinoline (27-3) by reaction with phosphorus oxychloride. The displacement of chlorine with methyl anthranilate (27-4) then affords the coupled intermediate (27-5). An ester interchange of that product with glycerol leads to the glyceryl ester. There is thus obtained the NSAID flocatfenine (27-6) [31]. 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

Several examples have been reported of the preparation of 4,7-phenanthrolines from substituted 6-aminoquinolines by the Skraup and related reactions. In this way, 5-methoxy-, 5-chloro-, 3-methyl-6-methoxy-, l-methyl-, and l,2,3,4-tetrahydro-4-methyl-4,7-phenanthrolines have been synthesized while improvements have been made to the synthesis of the 3-methyl derivative. The Skraup reaction has also been applied to quaternary salts of 6-aminoquinolines. For example, 5-chloro-4-methyl-4,7-phenanthrolinium iodide (36) was obtained from the methiodide of 6-acetamido-8-chloroquinoline (35). Cyclizations starting from aminocarbostyrils have also been reported. Thus, 6-amino-1-methylcarbostyril (37) was condensed with paraldehyde in the presence of concentrated hydrochloric acid to afford 3,4-dihydro-4,8-dimethyl-3-oxo-4,7-phenanthroline (38), while under Skraup conditions, with glycerol as condensing agent, 6-amino-4-methylcarbostyril afforded 3,4-dihydro- l-methyl-3-oxo-4,7-phen-... 

Tin Reagents. The presence of a 3-methyl group in the 2-chloroquinoline 202 has a beneficial effect on reaction rates and efficiency in Stille-type alkenylations with terminal stannyl alkenes (Scheme 77). This was attributed to steric acceleration in the reductive elimination of Pd(0) from a Pd(II) complex. The purine 6-position is highly electrophilic. A chloro substituent is readily replaced under Stille conditions using tri(n-butyl)vinylstannane. The 6-vinylpurine product 203 from the coupling is reacted further in situ in Heck couphngs. These reactions proceed readily because of the electron-withdrawing effect from the ir-deficient pyrimidine moiety of the heterocycle.t ... 

The trifluoromethylation of 4-iodo-7-chloroquinoline by action of trifluoro-methylcopper(I)phenanthroline complex represents a modem way to 4-trifluoro-methyl-7-chloroquinoline 99a (Scheme 44) [66], 4-Trifluoromethyl substituted 3-aminoquinolines 99b have also been obtained by the reaction of 3-aminoquinoIine with trifluoroiodomethane-zinc-sulfur dioxide system (Scheme 44) [67],... 

The reaction of 3-iodo-5-fluoro-8-chloroqumoline with CFgSiHj, KF, and Cul proceeds rather smoothly in l-methyl-pyrroMm-2-one, leading to the formation of 3-trifluoromethyl-5-fluoro-8-chloroquinoline lOle in 41 % yield (Scheme 48) [43]. 

The enzymatic process was carried out with a slurry of (E)-methyl 2-(3-(3-(2-(7-chloroquinolin-2-yl)vinyl)phaiyl)-3-oxopropyl)benzoate 79 (230kg) in a mixture of isopropyl alcohol (5 vol), toluene (1 vol), and triethanolamine buffer of pH 8.0 (3 vol). KRED CDX-026 (92kg) and the cofactor NADP-Na (023kg) were added to the reaction mixture, and the reaction was carried out at 40-45°C under stirring for 40-45h. From the reaction mixture, the crude (S)-2-[3-2[7-chloro-2-quinolinyl]ethenyl]phenyl-3-hydrox5q)ropyl] benzoic acid methyl ester 80 was obtained, which was purified by recrystallization to obtain pme product 80 as monohydrate 3 (233 kg, 97.2% yield, >99.9% ee) [109,110]. 

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