4-Chloro-7-methoxyquinoline

yellow powder

6i (3.60 g, 20.40 mmol) was refluxed in phosphorus oxychloride at 140 °C for 20 minutes. The mixture was then cooled to room temperature and excess phosphorus oxychloride evaporated leaving a slurry mixture. Ice cold sodium hydroxide was added and the precipitated solid was filtered, washed with water and dried. 7i (2.20 g, 56percent) was obtained as a brown solid, mp. 84 - 85 °C (lit. Lauer et al 1946, 82 - 83 °C).3-Methoxyaniline (1.23 g) and 5-methoxymethylene-2, 2-dimethyl-[1, 3]dioxan-4, 6-dione (1.90 g) were dissolved in 2-propanol (40 ml), and the mixture was stirred at 70°C for one hr. The solvent was removed by distillation under the reduced pressure, and the residue was washed with ether to give 5-[(3-methoxy-phenylamino)-methylene]-2, 2-dimethyl-[1, 3]dio xan-4, 6-dione (1.22 g, yield 44percent). 5-[(3-Methoxy-phenylamino)-methylene]-2, 2-dimethyl-[1, 3]dioxan-4, 6-dione (1.22 g) and biphenyl (5.1 g) were suspended in diphenyl ether (15 ml), and the mixture was stirred at 220°C for 1.5 hr. The reaction mixture as such was purified by column chromatography with a methanol-chloroform system to give 7-methoxy-1H-quinolin-4-one (394 mg, yield 51percent). 7-Methoxy-1H-quinolin-4-one (394 mg) was suspended in diisopropylethylamine (3 ml), phosphorus oxychloride (1 ml) was added to the suspension, and the mixture was stirred at 100°C for one hr. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give 4-chloro-7-methoxyquinoline (312 mg, yield 72percent).General procedure: 4-chloroquin(az)olinederivative (1.0 eq.), aniline derivative (1.1 eq.), and iPr2NEt (2.5 eq.) were suspended inethanol (10 mL) and refluxed for 18 h. The crude mixture was purified by flash chromatographyusing EtOAc:hexane followed by 1-5 % methanol in EtOAc; After solventremoval under reduced pressure, the product was obtained as a free following solid orrecrystallized from ethanol/water.General procedure: A mixture of 7-substituted 4-chloroquinoline 7a-d (2 mmol), acetone (20 mL), the corresponding aromatic amine (10 mmol) andhydrochloric acid (0.75 mL) was refluxed for 4-8 h. After completionof the reaction as indicated by TLC, the solution was pouredinto H2O (100 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phasewas washed with water and brine andthen dried over anhydrous sodium sulfate, filtered and evaporated.The resulting oil was purified by column chromatography using a mixture of petroleum ether and ethyl acetate 3:1 as the eluent tosuccessfully afford the target products 8a-s in good yield.General procedure: A mixture of 7-substituted 4-chloroquinoline 7a-d (2 mmol), acetone (20 mL), the corresponding aromatic amine (10 mmol) andhydrochloric acid (0.75 mL) was refluxed for 4-8 h. After completionof the reaction as indicated by TLC, the solution was pouredinto H2O (100 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phasewas washed with water and brine andthen dried over anhydrous sodium sulfate, filtered and evaporated.The resulting oil was purified by column chromatography using a mixture of petroleum ether and ethyl acetate 3:1 as the eluent tosuccessfully afford the target products 8a-s in good yield.General procedure: A mixture of 7-substituted 4-chloroquinoline 7a-d (2 mmol), acetone (20 mL), the corresponding aromatic amine (10 mmol) andhydrochloric acid (0.75 mL) was refluxed for 4-8 h. After completionof the reaction as indicated by TLC, the solution was pouredinto H2O (100 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phasewas washed with water and brine andthen dried over anhydrous sodium sulfate, filtered and evaporated.The resulting oil was purified by column chromatography using a mixture of petroleum ether and ethyl acetate 3:1 as the eluent tosuccessfully afford the target products 8a-s in good yield.General procedure: A mixture of 7-substituted 4-chloroquinoline 7a-d (2 mmol), acetone (20 mL), the corresponding aromatic amine (10 mmol) andhydrochloric acid (0.75 mL) was refluxed for 4-8 h. After completionof the reaction as indicated by TLC, the solution was pouredinto H2O (100 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phasewas washed with water and brine andthen dried over anhydrous sodium sulfate, filtered and evaporated.The resulting oil was purified by column chromatography using a mixture of petroleum ether and ethyl acetate 3:1 as the eluent tosuccessfully afford the target products 8a-s in good yield.General procedure: A mixture of 7-substituted 4-chloroquinoline 7a-d (2 mmol), acetone (20 mL), the corresponding aromatic amine (10 mmol) andhydrochloric acid (0.75 mL) was refluxed for 4-8 h. After completionof the reaction as indicated by TLC, the solution was pouredinto H2O (100 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phasewas washed with water and brine andthen dried over anhydrous sodium sulfate, filtered and evaporated.The resulting oil was purified by column chromatography using a mixture of petroleum ether and ethyl acetate 3:1 as the eluent tosuccessfully afford the target products 8a-s in good yield.General procedure: A mixture of 7-substituted 4-chloroquinoline 7a-d (2 mmol), acetone (20 mL), the corresponding aromatic amine (10 mmol) andhydrochloric acid (0.75 mL) was refluxed for 4-8 h. After completionof the reaction as indicated by TLC, the solution was pouredinto H2O (100 mL), and extracted with ethyl acetate (50 mL x 3).The combined organic phasewas washed with water and brine andthen dried over anhydrous sodium sulfate, filtered and evaporated.The resulting oil was purified by column chromatography using a mixture of petroleum ether and ethyl acetate 3:1 as the eluent tosuccessfully afford the target products 8a-s in good yield.

Molecular Weight:193.63
XLogP3:2.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:193.0294416
Monoisotopic Mass:193.0294416
Topological Polar Surface Area:22.1
Heavy Atom Count:13
Complexity:176
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes