* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With boron tribromide In dichloromethane at 0 - 20℃; for 15 h;
General procedure: To a cooled solution of aryl methyl ether ( 1.0 equiv.) in DCM (10 mL) was added BBr3 (5.0 equiv.) slowly. The resulting mixture was stirred at 0 C and then warmed gradually to room temperature, and. stirred at room temperature for 15 hrs. After the reaction was completed, the reaction was quenched with NaHCO3 solution (50 mL) and extracted with DCM (4 × 10 mL). The combined organic layers were washed with H2O (3 × 10 mL), dried (Na2SO4) and concentrated in vacuo to afford the expected phenols. 2-chloroquinolin-6-ol: DHK-6-71 was prepared using general procedure G. Reaction was performed on a 2 g scale. DHK-6-71 was isolated as yellow solid. (1.72 g. 93percent).
70%
Stage #1: With boron tribromide In dichloromethane at 0 - 25℃; for 2 h; Stage #2: With ammonium chloride In dichloromethane; water
To a solution of 2-chloro-6-methoxyquinoline (Intermediate 1) (2.00 g, 10.4 mmol) in anhydrous DCM (100 mL) was added BBr3 (6 mL, 62.2 mmol) dropwise at 0°C. The reaction mixture was stirred at 25°C for 2 hours, then quenched with aqueous saturated NH4C1 (50 mL) and filtered. The filtrate was extracted with CH2C12 / MeOH (v / v =10 / 1, 30 mL x2) and the combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give 2-chloroquinolin-6-ol (1.30 g, yield 70percent) as yellow solid. 1H NMR (CDC13 300 MHz): δ 7.95 (t, J = 8.1 Hz, 2H), 7.35 (dd, J = 6.0, 3.3 Hz, 2H), 7.13 (d, J = 2.7 Hz, 1H).
70%
Stage #1: With boron tribromide In dichloromethane at 0 - 25℃; for 2 h; Stage #2: With ammonium chloride In dichloromethane; water at 25℃;
To a solution of 2-chloro-6-methoxyquinoline (Intermediate 1) (2.00 g, 10.4 mmol) in anhydrous DCM (100 mL) was added BBr3 (6 mL, 62.2 mmol) dropwise at 0°C. The reaction mixture was stirred at 25 °C for 2 hours, then quenched with aqueous saturated NH4C1 (50 mL) and filtered. The filtrate was extracted with CH2C12 / MeOH (v / v =10 / 1, 30 mL x2) and the combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give 2-chloroquinolin-6-ol (1.30 g, yield 70percent) as yellow solid. *H NMR (CDC13 300 MHz): δ 7.95 (t, / = 8.1 Hz, 2H), 7.35 (dd, / = 6.0, 3.3 Hz, 2H), 7.13 (d, / = 2.7 Hz, 1H).
Reference：
[1] Patent: CN102985411, 2016, B, . Location in patent: Paragraph 0906-0908
[2] Patent: WO2012/48181, 2012, A1, . Location in patent: Page/Page column 74
[3] Patent: WO2012/83165, 2012, A1, . Location in patent: Page/Page column 91
[4] ACS Chemical Neuroscience, 2016, vol. 7, # 7, p. 897 - 911
[5] Journal of the American Chemical Society, 1951, vol. 73, p. 4837
2
[ 5392-11-0 ]
[ 13676-02-3 ]
Yield
Reaction Conditions
Operation in experiment
57%
With trichloroisocyanuric acid; triphenylphosphine In neat (no solvent) at 160 - 170℃; for 15 h; Inert atmosphere
General procedure: Ina flask (50 mL) equipped with a magnetic stirrer bar and balloon, a mixture of triphenylphosphine (1191mg, 4.54 mmol) and trichloroisocyanuric acid (360 mg, 1.55 mmol) was heated under an argonatmosphere. During the heating process, triphenylphosphine melted, and trichloroisocyanuric acidvigorously reacted at 130-140 °C to form a dark brown oil, followed by further heating for 10 min.1-Methylquinolin-2(1H)-one (242 mg, 1.50 mmol) was added to the mixture followed by heating at130-140 °C for 3 h. Then, the reaction mixture was dissolved in CH2Cl2 and basified with triethylaminefollowed by silica gel column chromatography using hexane-EtOAc (6:1) as an eluate. The product2-chloroquinoline (204 mg, 82percent) was obtained.
Reference：
[1] Heterocycles, 2015, vol. 91, # 7, p. 1445 - 1454
[2] Pr. roy. Soc. <B>, 1931, vol. 108, p. 130,131
A solution of 6- methoxyquinolin-2-ol (400 mg, 2.29 mmol) in POCI3 (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), the organic layer was washed with saturated NaHC03 (30 mL x2), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column (PE / EtOAc=10 / 1) to give 2-chloro-6-methoxyquinoline (380 mg, yield 86percent) as a solid. 1H NMR (CDC13 400 MHz): δ 7.92 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H).
86%
for 2 h; Reflux
A solution of 6- methoxyquinolin-2-ol (400 mg, 2.29 mmol) in POCI3 (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), the organic layer was washed with saturated NaHCC>3 (30 mL x2), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column (PE / EtOAc=10 / 1) to give 2-chloro-6-methoxyquinoline (380 mg, yield 86percent) as a solid. *H NMR (CDC13 400 MHz): δ 7.92 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.00 (d, / = 2.4 Hz, 1H), 3.86 (s, 3H).
Reference：
[1] Patent: WO2012/48181, 2012, A1, . Location in patent: Page/Page column 74
[2] Patent: WO2012/83165, 2012, A1, . Location in patent: Page/Page column 91
[3] Ann. Inst. Pasteur, 1930, vol. 44, p. 719,736
Step 1a A solution of 6-methoxyquinoline N-oxide (5.0 g, 29 mmol) in CHCl3 (30 mL) was treated by slow addition of POCl3 (5.3 mL, 57 mmol) at 0° C. The mixture was heated at 80° C. for 14 hours. The mixture was cooled and poured onto ice. After stirring for 30 min., the aqueous layer was adjusted to pH 9 by Na2CO3 addition. The mixture was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 2.5 g (46percent) of 2-chloro-6-methoxyquinoline as a white solid, (M+) 193(100).
A solution of 6- methoxyquinolin-2-ol (400 mg, 2.29 mmol) in POCI3 (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), the organic layer was washed with saturated NaHC03 (30 mL x2), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column (PE / EtOAc=10 / 1) to give 2-chloro-6-methoxyquinoline (380 mg, yield 86%) as a solid. 1H NMR (CDC13 400 MHz): delta 7.92 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.00 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H).
86%
With trichlorophosphate; for 2h;Reflux;
A solution of 6- methoxyquinolin-2-ol (400 mg, 2.29 mmol) in POCI3 (5.0 mL) was refluxed for 2 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (50 mL), the organic layer was washed with saturated NaHCC>3 (30 mL x2), dried over Na2S04, filtered and concentrated to give the crude product, which was purified by silica gel column (PE / EtOAc=10 / 1) to give 2-chloro-6-methoxyquinoline (380 mg, yield 86%) as a solid. *H NMR (CDC13 400 MHz): delta 7.92 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.00 (d, / = 2.4 Hz, 1H), 3.86 (s, 3H).
With trichloroisocyanuric acid; triphenylphosphine; In neat (no solvent); at 160 - 170℃; for 15h;Inert atmosphere;
General procedure: Ina flask (50 mL) equipped with a magnetic stirrer bar and balloon, a mixture of triphenylphosphine (1191mg, 4.54 mmol) and trichloroisocyanuric acid (360 mg, 1.55 mmol) was heated under an argonatmosphere. During the heating process, triphenylphosphine melted, and trichloroisocyanuric acidvigorously reacted at 130-140 C to form a dark brown oil, followed by further heating for 10 min.1-Methylquinolin-2(1H)-one (242 mg, 1.50 mmol) was added to the mixture followed by heating at130-140 C for 3 h. Then, the reaction mixture was dissolved in CH2Cl2 and basified with triethylaminefollowed by silica gel column chromatography using hexane-EtOAc (6:1) as an eluate. The product2-chloroquinoline (204 mg, 82%) was obtained.
With piperazine; In DMF (N,N-dimethyl-formamide); at 110℃; for 6h;
To a solution of <strong>[13676-02-3]2-chloro-6-methoxy-quinoline</strong> of Step C (2.5 g, 12.91 [MMOL)] in N, N-dimethylformamide (50 mL) is added piperazine (12 g) and the mixture is heated at [110C] under nitrogen for 6 hours. The solution is diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel [MERCK-60] using a gradient of methanol (4-10%) in dichloromethane containing 0.2% ammonium hydroxide to provide the title compound (1.6 g) as an off-white solid, m. p. [95-97C.] MS [(+) ES, m/z] : 244.1 [M+H] +
Step 1a A solution of 6-methoxyquinoline N-oxide (5.0 g, 29 mmol) in CHCl3 (30 mL) was treated by slow addition of POCl3 (5.3 mL, 57 mmol) at 0 C. The mixture was heated at 80 C. for 14 hours. The mixture was cooled and poured onto ice. After stirring for 30 min., the aqueous layer was adjusted to pH 9 by Na2CO3 addition. The mixture was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 2.5 g (46%) of 2-chloro-6-methoxyquinoline as a white solid, (M+) 193(100).
Step 2a A solution of <strong>[13676-02-3]2-chloro-6-methoxyquinoline</strong> (4.4 g, 22 mmol) in CH2Cl2 (60 mL) was treated by slow addition of Br2 (3.5 mL, 11 g, 68 mmol). After 14 hours, the mixture was partitioned between NaCl and CH2Cl2. The aqueous layer was extracted with CH2Cl2. The organic layer was worked-up. HPLC (1:10 EtOAc/hexane) gave 6.1 g (99%) of 5-bromo-<strong>[13676-02-3]2-chloro-6-methoxyquinoline</strong> as a light yellow solid, (M+) 273(100).
<strong>[13676-02-3]2-Chloro-6-methoxyquinoline</strong> (52.0 mmoles, 10.0 g), 4-aminothiophenol (52.0 mmoles, 6.5 g) and dimethylaminopyridine (52.0 mmoles, 6.3 g) were stirred for 16 hr in 250 ml ethanol. The reaction was condensed and purified by HPLC over silica gel eluted with 25-30% ethyl acetate/hexane to yield 2-(4-aminophenylthio)-6-methoxyquinoline. 8.5 g, 58% product. Mass spec (FD) 282. Calculated for C16 H14 N2 OS: C, 68.06; H, 5.00, N, 9.92. Found: C, 68.04; H, 4.97; N, 10.02.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 100℃; for 24h;
3-Methylphenyl borate (1.3 mmol), <strong>[13676-02-3]2-chloro-6-methoxyquinoline</strong> (1 mmol), tetrakis(triphenylphosphine) palladium(O) (0.05 mmol) and potassium carbonate (3 mmol) were dissolved in THF (30 mL) and H2O (10 mL). The resulting solution was stirred in a bath at 100C for 24 hours. After completion of the reaction, the solvents were removed. The reaction mixture was extracted with dichloromethane and water and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether, and filtered to yield 2-(3-methylphenyl)-6-methoxyquinoline as a solid.
Step 1: 1-benzyl-4-(2-chloro-6-methoxy-quinolin-3-yl)-piperidin-4-ol Under an argon atmosphere 5.0 g (25 mmol) <strong>[13676-02-3]2-chloro-6-methoxyquinoline</strong> in a small amount of THF were added dropwise at -78 C. to 14 mL (28 mmol) of a 2 M lithium diisopropylamide solution (in THF) in 50 mL THF. Then the mixture was stirred for 1.5 h at -78 C. and 4.5 mL (25 mmol) N-benzylpiperidone was added dropwise. The mixture was stirred for a further 15 min with cooling before slowly being heated to RT. The reaction mixture was stirred overnight, evaporated down and purified by flash chromatography on aluminium oxide. The product-containing fractions were combined and evaporated down. Yield: 2.1 g (13% of theory) ESI-MS: m/z=383 (M+H)+
Step 1: 1-benzyl-4-(<strong>[13676-02-3]2-chloro-6-methoxy-quinoline</strong>-3-yl)-piperidin-4-ol Under an argon atmosphere 14.0 mL (28.0 mmol) of a 2 M lithium diisopropylamide solution in 50 mL THF were cooled to -78 C. and combined with stirring with a solution of 5.00 g (25.1 mmol) of <strong>[13676-02-3]2-chloro-6-methoxy-quinoline</strong> in THF. After 1 h stirring at -78 C., 4.5 mL (25.2 mmol) N-benzylpiperidone were added dropwise. After 1 h stirring at -78 C. the mixture was allowed to come up to RT and stirred overnight. The mixture was evaporated down i. vac. and purified by flash chromatography through Alox. The fractions containing the product were combined and evaporated down. Yield: 2.10 g (13% of theoretical) Purity: 60% ESI-MS: m/z=383 (M+H)+
With caesium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; for 24h;Inert atmosphere; Reflux;
General procedure: To a stirred mixture of 21 (0.25 g, 1.21 mmol), 4-bromo-1-methylindole (0.31 g, 1.45 mmol), cesium carbonate (0.79 g, 2.41 mmol) and copper oxide (0.01 g, 0.12 mmol) in DMF (2 mL) was refluxed for 24 h. After cooling, the reaction was quenched with water and extracted with EtOAc. The combined organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure and purified by silica gel flash column chromatography (EtOAc : n-hexane = 1 : 3) to afford compound 13 as a pale white solid (0.12 g, 30%)
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