* 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.
Stage #1: With diisobutylaluminium hydride In toluene at -78℃; for 0.25 h; Stage #2: With water; acetic acid In diethyl ether; toluene at -78 - 20℃;
Isoquinoline-3-carbaldehyde; A solution of methyl 3-isoquinolinecarboxylate (2. 0 g, 10.7 mmol) in toluene was cooled to-78°C. To the solution was added diisobutylaluminum hydride (1M in toluene, 21.4 mL, 21.4 mmol) slowly over 15 minutes via syringe. While still at-78°C, the reaction was quenched with a solution of ether (80 mL), acetic acid (20 mL) and water (8 mL) and then the mixture was allowed to slowly warm to room temperature overnight. The organics were decanted and the solvent was evaporated. Flash column chromatography (gradient 1: 4 ethyl acetate/hexanes to 1: 3 ethyl acetate/hexanes) provided 1.1 grams of the title compound (65percent yield).'H-NMR (CDC13, 300 MHz) 8 10.24 (s, 1H), 9.35 (s, 1H), 8.36 (s, 1H), 8.07-7. 98 (m, 2H), 7.82-7. 32 (m, 2H). Mass spec.: 158 (MH) +.
54%
With diisobutylaluminium hydride In tetrahydrofuran at 0℃; for 2 h;
To a cooled solution 0°C of isoquinoline-3-carboxylic acid methyl ester (l. Og, 5.34mmol) in anhydrous tetrahydrofuran (100ml), is added a solution of DIBAL-H (11. 8ml, 11. 8mmol). The reaction mixture is stirred at 0°C for 2 hours and then quenched with saturated aqueous sodium potassium tartrate and stirred for 2 hours. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with 1N HCl, 2N NaOH, and dried over anhydrous Na2S04, filtered, and concentrated ira vacuo. The crude reaction mixture is purified on silica gel eluting with 20percent ethyl acetate/hexanes to give isoquinoline-3-carboxaldehyde (0.46g, 54percent).'H NMR (CDC13) : 8 = 10.24 (1H, brs), 9.32 (1H, brs), 8.35 (1H, brs), 8. 02 (2H, brd), 7.77 (2H, brs).
33%
Stage #1: With diisobutylaluminium hydride In toluene at 0 - 10℃; for 3 h; Stage #2: With water; Rochelle's salt In toluene for 0.25 h;
Example 11;: 3-Amino-6- [4- (2-hydroxy-2-isoquinolin-3-yl-ethylamino)-piperidin-1-yl]- 4-propyl-thieno [2, 3-b] pyridine-2-carboxylic acid amide Methyl 3-isoquinoline carboxylate (1.50 g, 8.01 mmol) was placed in 60 mL anhydrous toluene and cooled to 0 °C. The solution was treated dropwise with 1M DIBAL solution in toluene (8.2 mL, 8.2 mmol). The solution gradually changed from colorless to yellow and then orange during addition. After 2 h another 2 mL 1M DIBAL solution in toluene was added and the mixture was left stirring another 1 h at 0-10 °C. The mixture was then quenched with aqueous Na K tartrate solution, stirred 15 min then diluted with brine and EtOAc. The layers were separated and the aqueous was extracted twice with EtOAc. The combined organics were washed with brine repeatedly (emulsion), dried (MgS04), filtered and the solvent was removed in vacuo. An orange oil was thus obtained, which was purified by flash column chromatography on Si02 using CH2Cl2/MeOH eluent mixtures. The desired isoquinoline carboxaldehyde was isolated as a yellow solid, 420 mg (33percent of theory).
Reference：
[1] Journal of Organic Chemistry, 1958, vol. 23, p. 900
[2] Journal of the Chemical Society, 1951, p. 1145,1147
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 688
7
[ 1532-97-4 ]
[ 82102-37-2 ]
[ 5470-80-4 ]
Reference：
[1] Journal of Organic Chemistry, 2013, vol. 78, # 12, p. 6112 - 6120
Isoquinoline-3-carbaldehyde; A solution of <strong>[27104-73-0]methyl 3-isoquinolinecarboxylate</strong> (2. 0 g, 10.7 mmol) in toluene was cooled to-78C. To the solution was added diisobutylaluminum hydride (1M in toluene, 21.4 mL, 21.4 mmol) slowly over 15 minutes via syringe. While still at-78C, the reaction was quenched with a solution of ether (80 mL), acetic acid (20 mL) and water (8 mL) and then the mixture was allowed to slowly warm to room temperature overnight. The organics were decanted and the solvent was evaporated. Flash column chromatography (gradient 1: 4 ethyl acetate/hexanes to 1: 3 ethyl acetate/hexanes) provided 1.1 grams of the title compound (65% yield).'H-NMR (CDC13, 300 MHz) 8 10.24 (s, 1H), 9.35 (s, 1H), 8.36 (s, 1H), 8.07-7. 98 (m, 2H), 7.82-7. 32 (m, 2H). Mass spec.: 158 (MH) +.
54%
With diisobutylaluminium hydride; In tetrahydrofuran; at 0℃; for 2h;
To a cooled solution 0C of <strong>[27104-73-0]isoquinoline-3-carboxylic acid methyl ester</strong> (l. Og, 5.34mmol) in anhydrous tetrahydrofuran (100ml), is added a solution of DIBAL-H (11. 8ml, 11. 8mmol). The reaction mixture is stirred at 0C for 2 hours and then quenched with saturated aqueous sodium potassium tartrate and stirred for 2 hours. The layers are separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with 1N HCl, 2N NaOH, and dried over anhydrous Na2S04, filtered, and concentrated ira vacuo. The crude reaction mixture is purified on silica gel eluting with 20% ethyl acetate/hexanes to give isoquinoline-3-carboxaldehyde (0.46g, 54%).'H NMR (CDC13) : 8 = 10.24 (1H, brs), 9.32 (1H, brs), 8.35 (1H, brs), 8. 02 (2H, brd), 7.77 (2H, brs).
33%
Example 11;: 3-Amino-6- [4- (2-hydroxy-2-isoquinolin-3-yl-ethylamino)-piperidin-1-yl]- 4-propyl-thieno [2, 3-b] pyridine-2-carboxylic acid amide Methyl 3-isoquinoline carboxylate (1.50 g, 8.01 mmol) was placed in 60 mL anhydrous toluene and cooled to 0 C. The solution was treated dropwise with 1M DIBAL solution in toluene (8.2 mL, 8.2 mmol). The solution gradually changed from colorless to yellow and then orange during addition. After 2 h another 2 mL 1M DIBAL solution in toluene was added and the mixture was left stirring another 1 h at 0-10 C. The mixture was then quenched with aqueous Na K tartrate solution, stirred 15 min then diluted with brine and EtOAc. The layers were separated and the aqueous was extracted twice with EtOAc. The combined organics were washed with brine repeatedly (emulsion), dried (MgS04), filtered and the solvent was removed in vacuo. An orange oil was thus obtained, which was purified by flash column chromatography on Si02 using CH2Cl2/MeOH eluent mixtures. The desired isoquinoline carboxaldehyde was isolated as a yellow solid, 420 mg (33% of theory).
With lithium aluminium tetrahydride; acetic acid; In tetrahydrofuran;
(a) 3-Isoquinolinecarboxaldehyde (7 g, 84%) was prepared by reduction of 3-isoquinolinecarboxylic acid methyl ester (10 g, 52 mmol) with 1M LAH (27 ml in THF, 27 mmol) in 300 ml of dry THF at -78 C. for 30 minutes. The mixture was quenched with 7 ml of acetic acid, concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate, 2:1) to afford 7 g (84%) of 3-iso-quinolinecarboxaldehyde.
General procedure: To a solution of beta-lapachone (1.1 mmol) in acetic acid (6 mL), the desired aldehyde (2.5 mmol) was added, and the mixture was heated to 70 C; at this point, ammonium acetate (16.5 mmol) was slowly added, and reflux was maintained for a determined time. All the reactions were monitored by thin layer chromatography. At the end of the reaction, after addition into water, the precipitate was purified by column chromatography using as eluent a mixture of hexane/ethyl acetate, with a gradient of increasing polarity, as previously described.16
(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(isoquinolin-3-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
Stage #1: 1-(benzenesulfonyl)-4-chloro-1H-pyrrolo[2,3-b]pyridine With lithium diisopropyl amide In tetrahydrofuran; hexane at -45℃; for 1h;
Stage #2: 3-formylisoquinoline In tetrahydrofuran at -45℃; for 1h;
19.1 Step 1: (4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)(isoquinolin-3-yl)methanol
To a cooled solution (-45° C.) of 4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (270 mg, 0.92 mmol) in anhydrous THF (4 mL) was added a solution of LDA (1M in hexanes, 1.01 mmol). The reaction was stirred at -45° C. for 1 hr, and isoquinoline-3-carbaldehyde (160 mg, 1.01 mmol) was added. The reaction was stirred at -45° C. for 1 hr and quenched with aqueous NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with water and concentrated. The crude product was purified with column chromatography using 20-50% EtOAc/hexanes to give the title compound (220 mg, 53%).
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