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With copper acetylacetonate; lithium hydroxide monohydrate; 1,3-bis(4-hydroxy-2,6-dimethylphenyl)urea In water; dimethyl sulfoxide at 130℃; for 24 h; Inert atmosphere
n 49. lmL dimethyl sulfoxide and 12.3 mL Water was added 10 g of a mixture of 61.35 mmol 8-chloroisoquinoline, 0.8], 3.07 mmol of copper acetylacetonate, 2.71 g, 64.42 mmol-hydrated hydroxide and 0.92 g, 3.07 mmol L-1,3-bis (4-hydroxy-2,6-dimethylphenyl) urea. The reaction solution was stirred at 130 ° C for 24 hours under nitrogen. After the reaction solution to be stirred was cooled, The solution was acidified with 2 mol / L HC1 to ρH- = 5, The mixture was extracted with ethyl acetate, The extracted organic phase was washed with saturated brine, Dried over anhydrous sodium sulfate and dried, The crude product was separated by column chromatography to give 8-hydroxyisoquinoline 6.41 g, the total yield was 72percent.
Reference：
[1] Patent: CN106966977, 2017, A, . Location in patent: Paragraph 0016; 0018-0019
3
[ 956003-79-5 ]
[ 34784-07-1 ]
Yield
Reaction Conditions
Operation in experiment
44%
With sodium tetrahydroborate; palladium 10% on activated carbon In 2-methyltetrahydrofuran; methanol at 25℃; for 1.16667 h; Inert atmosphere
A one-necked glass flask was charged with 12 (1.20 g, 4.95 mmol, 1.0equiv), 2-methyltetrahydrofuran (10 mL), and MeOH (10 mL), andthen N 2 gas was bubbled through the mixture. Under an inert atmo-sphere, 10percent Pd/C (530 mg, 0.5 mmol, 0.1 equiv) was added followed by careful addition of NaBH 4 (206 mg, 5.45 mmol, 1.1 equiv). The flaskwas closed by a gas bubbler filled with silicon oil. The mixture wasstirred for 70 min at 25 °C (longer reaction times resulted in an exten-sive formation of over-reduced products such as 1,2,3,4-tetrahy-droisoquinoline and 8-chloro-1,2,3,4-tetrahydroisoquinoline), andthen quenched with glacial AcOH (500 μL, 8.74 mmol, 1.75 equiv).The mixture was then stirred for another 10 min, followed by filtra-tion through Celite. The cake was washed with MeOH and CH 2 Cl 2 . Thefiltrate was evaporated and the residue was purified by flash chroma-tography (silica gel, hexane–EtOAc, 93:7), which afforded off-whitecrystals.Yield: 360 mg (44percent); mp 50–55 °C.IR (ATR): 1620, 1553, 1429, 1379, 1300, 1204, 1038, 970, 827, 748,686, 634, 534 cm –1 .1 H NMR (400 MHz, CDCl 3 ): δ = 9.66 (s, 1 H), 8.60 (d, J = 5.7 Hz, 1 H),7.73 (d, J = 7.9 Hz, 1 H), 7.69–7.56 (m, 3 H).13 C NMR (100 MHz, CDCl 3 ): δ = 149.4, 143.8, 137.1, 132.5, 130.3,127.5, 125.6, 125.7, 120.1.
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane for 3 h; Stage #2: With phosphorus pentachloride In toluene for 3 h; Heating / reflux
20a) 1, 8-DICHLORO-ISOQUINOLINE To a solution of 8-chloro-isoquinoline (J. Org. Chem. 1977,42 (19), 3208-9.) (11 G, 54 MMOL) in CH2CI2 (200 mL) is added MCPBA (25 g, 112 MMOL) in several portions. After stirring for 3 hours, ether (400 mL) is added, followed by addition of hexanes (1 L). Solution stirred overnight and conc in vacuo, ether (200 mL) and hexanes (400 mL) is added, stirred overnight. The ppt is filtered, air dried and mixed with 20 g of POS and toluene (150 mL). The solution is heated to reflux for 3 h, neutralized with NAHCO3. Extracted the solution with CH2CI2. Organic layer then dried with sodium sulfate and conc in vacuo, yield 8 g (72percent) of 1, 8-Dichloro-isoquinoline. MS: 198
Step 2: 8-chloro-5-nitroisoquinolineTo a solution of <strong>[34784-07-1]8-chloroisoquinoline</strong> (1 mmol) in concentrated sulfuric acid at 0 0C was added potassium nitrate (1.1 mmol) .The reaction mixture was warmed to room temperature and stirred at room temperature for 5 hours. The reaction mixture was basified .Solid precipitated was column purified to afford a pale yellow solid.1H NMR (DMSO- d6): delta /77.76 - 7.79 ( IH, d , J = 8.4 Hz ); 8.48 - 8.51 ( IH, d , J = 8.4 Hz ); 8.53 - 8.55 ( IH, d , J = 6 Hz ); 8.86 - 8.88 ( IH, d , J = 6.3 Hz ); 9.84 ( IH , s )
Intermediate 4: 8-chloroisoquinolin-5-amineStep 1: 8-ChloroisoquinolineTo a solution of 8-aminoisoquinoline (J. Med. Chem, 2005, 48, 744-52) (1 mmol) in concentrated hydrochloric acid was added a solution of sodium nitrite ( 1.2 mmol ) in water. The diazotization was carried out at 0 0C .The cold diazonium salt solution was added to a solution of cuprous chloride in concentrated hydrochloric acid at O0C. The cold solution was warmed to room temperature and stirred at room temperature for 3 hours. After 3 hours, the solution was heated at 600C for 30 min. Reaction mixture was basified and extracted with diethyl ether. Ether was washed with cold concentrated sulfuric acid, brine. Ether was dried over anhydrous sodium sulfate and evaporated under vacuum. Crude residue was column purified to afford a pale yellow liquid.1H NMR (DMSO- d6): delta £77.73 - 7.85 (2H, m); 7.93 - 7.95 (IH, d, J = 5.7 Hz ); 7.98 - 8.01 (IH, d, J = 7.8 Hz ); 8.64 - 8.66 ( lH,d, J = 5.4 Hz ); 9.55 ( lH,s )
Aminoacetaldehyde dimethyl acetal (10.54 g, 100.3 mmol, 1.54 equiv.) was added to a solution of 3-chlorobenzaldehyde (9.13 g, 65.0 mmol, 1.0 equiv.) in anhydrous toluene (125 mL). The mixture was refluxed using Dean-Stark trap to remove water. The solvent was then evaporated, and the resulting crude mixture was slowly added to H2SO4 (40 mL) stirred at 140 C. The reaction mixture was poured onto ice 20 minutes after the addition. The mixture was extracted with DCM, the aqueous layer was separated, carefully neutralized to pH=7, and then extracted with Et2O. The organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified with silica gel chromatography (EtOAc/Hexane=0->100%) to get the product as mixture of 7-isoquinoline 3-5a and 8-isoquinoline 3-5b (a/b=3/2). LRMS m/z (M+H) 164.1 found, 164.0 required.
20a) 1, 8-DICHLORO-ISOQUINOLINE To a solution of <strong>[34784-07-1]8-chloro-isoquinoline</strong> (J. Org. Chem. 1977,42 (19), 3208-9.) (11 G, 54 MMOL) in CH2CI2 (200 mL) is added MCPBA (25 g, 112 MMOL) in several portions. After stirring for 3 hours, ether (400 mL) is added, followed by addition of hexanes (1 L). Solution stirred overnight and conc in vacuo, ether (200 mL) and hexanes (400 mL) is added, stirred overnight. The ppt is filtered, air dried and mixed with 20 g of POS and toluene (150 mL). The solution is heated to reflux for 3 h, neutralized with NAHCO3. Extracted the solution with CH2CI2. Organic layer then dried with sodium sulfate and conc in vacuo, yield 8 g (72%) of 1, 8-Dichloro-isoquinoline. MS: 198
INTERMEDIATE 10 . 4-BROMO-8-CHLOROISOQUINOLINE25 To a solution of 8-chloroisoquinoHne (1.0 g, 6.1 mmol) in nitrobenzene (20 mL) at 18O0C was added bromine (0.35 mL, 6.7 mmol) over 10 min. Heating and stirring were continued for 2 hours. The mixture was allowed to cool to about 8O0C5 then 2M HCl in Et2O (5 mL) was added, followed by Et2O (5 mL) and hexanes (60 mL). The resulting slurry was filtered, washed with hexane and dried. The collected solid was dissolved in water, then the30 solution was adjusted to pH 9 with Na2CO3 (aq). The solution was extracted with EtOAc. The 3VfRL DOB-00006organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to afford the title compound as a white solid: 1H NMR (500 MHz, CDCl3): delta 9.62 (s, 1 H); 8.83 (s, 1 H); 8.13 (t, J - 5.0 Hz, 1 H); 7.74 (d, J = 5.0 Hz, 2 H). LC6: 4.08 rain, (M+H): 242.
With copper acetylacetonate; lithium hydroxide monohydrate; 1,3-bis(4-hydroxy-2,6-dimethylphenyl)urea; In water; dimethyl sulfoxide; at 130℃; for 24h;Inert atmosphere;
n 49. lmL dimethyl sulfoxide and 12.3 mL Water was added 10 g of a mixture of 61.35 mmol <strong>[34784-07-1]8-chloroisoquinoline</strong>, 0.8], 3.07 mmol of copper acetylacetonate, 2.71 g, 64.42 mmol-hydrated hydroxide and 0.92 g, 3.07 mmol L-1,3-bis (4-hydroxy-2,6-dimethylphenyl) urea. The reaction solution was stirred at 130 C for 24 hours under nitrogen. After the reaction solution to be stirred was cooled, The solution was acidified with 2 mol / L HC1 to rhoH- = 5, The mixture was extracted with ethyl acetate, The extracted organic phase was washed with saturated brine, Dried over anhydrous sodium sulfate and dried, The crude product was separated by column chromatography to give 8-hydroxyisoquinoline 6.41 g, the total yield was 72%.
With sodium tetrahydroborate; palladium 10% on activated carbon; In 2-methyltetrahydrofuran; methanol; at 25℃; for 1.16667h;Inert atmosphere;
A one-necked glass flask was charged with 12 (1.20 g, 4.95 mmol, 1.0equiv), 2-methyltetrahydrofuran (10 mL), and MeOH (10 mL), andthen N 2 gas was bubbled through the mixture. Under an inert atmo-sphere, 10% Pd/C (530 mg, 0.5 mmol, 0.1 equiv) was added followed by careful addition of NaBH 4 (206 mg, 5.45 mmol, 1.1 equiv). The flaskwas closed by a gas bubbler filled with silicon oil. The mixture wasstirred for 70 min at 25 C (longer reaction times resulted in an exten-sive formation of over-reduced products such as 1,2,3,4-tetrahy-droisoquinoline and 8-chloro-1,2,3,4-tetrahydroisoquinoline), andthen quenched with glacial AcOH (500 muL, 8.74 mmol, 1.75 equiv).The mixture was then stirred for another 10 min, followed by filtra-tion through Celite. The cake was washed with MeOH and CH 2 Cl 2 . Thefiltrate was evaporated and the residue was purified by flash chroma-tography (silica gel, hexane-EtOAc, 93:7), which afforded off-whitecrystals.Yield: 360 mg (44%); mp 50-55 C.IR (ATR): 1620, 1553, 1429, 1379, 1300, 1204, 1038, 970, 827, 748,686, 634, 534 cm -1 .1 H NMR (400 MHz, CDCl 3 ): delta = 9.66 (s, 1 H), 8.60 (d, J = 5.7 Hz, 1 H),7.73 (d, J = 7.9 Hz, 1 H), 7.69-7.56 (m, 3 H).13 C NMR (100 MHz, CDCl 3 ): delta = 149.4, 143.8, 137.1, 132.5, 130.3,127.5, 125.6, 125.7, 120.1.
With sodium tetrahydroborate; palladium 10% on activated carbon; In 2-methyltetrahydrofuran; methanol; at 25℃;Inert atmosphere;
A one-necked glass flask was charged with 12 (1.20 g, 4.95 mmol, 1.0equiv), 2-methyltetrahydrofuran (10 mL), and MeOH (10 mL), andthen N 2 gas was bubbled through the mixture. Under an inert atmo-sphere, 10% Pd/C (530 mg, 0.5 mmol, 0.1 equiv) was added followed by careful addition of NaBH 4 (206 mg, 5.45 mmol, 1.1 equiv). The flaskwas closed by a gas bubbler filled with silicon oil. The mixture wasstirred for 70 min at 25 C (longer reaction times resulted in an exten-sive formation of over-reduced products such as 1,2,3,4-tetrahy-droisoquinoline and 8-chloro-1,2,3,4-tetrahydroisoquinoline), andthen quenched with glacial AcOH (500 muL, 8.74 mmol, 1.75 equiv).The mixture was then stirred for another 10 min, followed by filtra-tion through Celite. The cake was washed with MeOH and CH 2 Cl 2 . Thefiltrate was evaporated and the residue was purified by flash chroma-tography (silica gel, hexane-EtOAc, 93:7), which afforded off-whitecrystals.Yield: 360 mg (44%); mp 50-55 C.IR (ATR): 1620, 1553, 1429, 1379, 1300, 1204, 1038, 970, 827, 748,686, 634, 534 cm -1 .1 H NMR (400 MHz, CDCl 3 ): delta = 9.66 (s, 1 H), 8.60 (d, J = 5.7 Hz, 1 H),7.73 (d, J = 7.9 Hz, 1 H), 7.69-7.56 (m, 3 H).13 C NMR (100 MHz, CDCl 3 ): delta = 149.4, 143.8, 137.1, 132.5, 130.3,127.5, 125.6, 125.7, 120.1.
With ammonium peroxydisulfate; caesium carbonate; In dimethyl sulfoxide; at 20℃; for 24h;Inert atmosphere; Irradiation; Green chemistry;
General procedure: Heterocycle (0.10mmol,1equiv)ammonium persulfate (0.30 mmol, 3 equiv), Cs2CO3(0.20mmol,2 equiv)were placed in a dry glass tube.Then, anhydrous DMSO1 mL) and2,2-diethoxyacetic acid (0.7mmol7equiv), wereinjected into the tube by syringe under a N2atmosphere.The solution was then stirred at roomtemperature under the irradiation of 15W blueLEDs strip for 24h.After completion of the reaction,the mixture was quenched by addition of1.2mL of 3.0 M HCl, stirred for 20hthen saturated Na2CO3solution was added to adjust pH tobasicextract with CH2Cl2,the combined organic layers was washed with brine, then dry overanhydrous Na2SO4. The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum and ethylacetate.
(8-chloroisoquinolin-1-yl)(phenyl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With ammonium peroxydisulfate; [Ir(2-(2,4-difluorophenyl)-5-methylpyridine)2(4,4?-di-tert-butyl-2,2?-bipyridine)]PF6; In dimethyl sulfoxide; at 20℃; for 12h;Inert atmosphere; Irradiation; Green chemistry;
General procedure: Heterocycle (0.10mmol, 1 equiv)ammonium persulfate (0.20 mmol, 2equiv),[Ir{dF(CF3ppy)}2(dtbbpy)]PF6 ( 0.2 mol%),alpha-keto acids(1.0mmol10equiv)wereplaced in a dry glass tube.Then, anhydrous DMSO1mLwereinjected into the tubeby syringe under a N2 atmosphere.The solution was then stirred at roomtemperatureunder the irradiation of 15W blue LEDs strip for 12h.After completion of thereaction,then saturated Na2CO3solution was added to adjust pH to basic.Thecombined organic layer was washed with brine and then dried overanhydrousNa2SO4.The desired products were obtained in thecorresponding yields afterpurification by flashchromatography on silica gel eluting with petroleum andethylacetate.
1-(8-(diphenylphosphino) naphthalen-1-yl)isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; lithium tert-butoxide; In toluene; at 150℃; for 24h;Inert atmosphere;
1-naphthyldiphenylphosphine (1 mmol), <strong>[34784-07-1]8-chloroisoquinoline</strong> (1 mmol), [Rh(cod)Cl]2 (0.025 mmol), lithium t-butoxide (3 mmol) and toluene (5 mL) were resistant Mix in a pressure tube, heat to 150 C under nitrogen protection, and at this temperatureReaction for 24 hours. After cooling to room temperature, it was isolated by silica gel column chromatography (the ratio of petroleum ether to dichloromethane: 1:20) to give the desired product yield of 65%.
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