* 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 triethylsilane; trifluoroacetic acid In 1,2-dichloro-ethane at 65℃; for 0.0833333 h; Stage #2: With sodium hydroxide In water; 1,2-dichloro-ethane
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65° C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32percent). The aqueous layer was extracted with tert-butyl methyl ether (3*200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27percent) as a white solid. MS m/e (percent): 164 (M-H+, 100).
27%
With triethylsilane; trifluoroacetic acid In 1,2-dichloro-ethane at 65℃; for 0.0833333 h;
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65° C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32percent). The aqueous layer was extracted with tert-butyl methyl ether (3*200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27percent) as a white solid. MS m/e (percent): 164 (M-H+, 100).
27%
Stage #1: With triethylsilane; trifluoroacetic acid In 1,2-dichloro-ethane at 65℃; for 0.0833333 h; Stage #2: With sodium hydroxide In water; 1,2-dichloro-ethane at 20℃;
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65° C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32percent). The aqueous layer was extracted with tert-butyl methyl ether (3*200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27percent) as a white solid. MS m/e (percent): 164 (M-H+, 100).
With lithium aluminium tetrahydride In diethyl ether at 0℃; for 0.75 h; Heating / reflux
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0° C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0° C. The aqueous layer was extracted with tert-butyl methyl ether (3*100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100percent) as a white solid. MS m/e (percent): 180 (M-H+, 100).
100%
Stage #1: With lithium aluminium tetrahydride In diethyl ether at 0℃; for 0.75 h; Heating / reflux Stage #2: With sodium hydroxide; water In diethyl ether at 0℃;
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0° C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0° C. The aqueous layer was extracted with tert-butyl methyl ether (3*100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100percent) as a white solid. MS m/e (percent): 180 (M-H+, 100).
100%
Stage #1: With lithium aluminium tetrahydride In diethyl ether at 0℃; for 0.75 h; Heating / reflux Stage #2: With sodium hydroxide; water In diethyl ether
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0° C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0° C. The aqueous layer was extracted with tert-butyl methyl ether (3*100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100percent) as a white solid. MS m/e (percent): 180 (M-H+, 100).
With lithium aluminium tetrahydride In tetrahydrofuran at 20℃; for 5 h; Cooling with ice
General procedure: A solution of indole-2-carboxylate 11 (1 mmol) in THF (10 mL)was added dropwise to a suspension of LiAlH4 (0.8 mmol) in THF(20 mL) under cooling with ice-water. After stirring at rt for 5 h, thereaction mixture was quenched with water, and then was filtratedthrough a Celite pad. The filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na2SO4, andevaporated in vacuo. The residue was purified by column chromatography using EtOAc-hexane as an eluent to give thealcohol 12.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 561 - 577
4
[ 89-59-8 ]
[ 53590-58-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 6, p. 1380 - 1400
5
[ 540523-98-6 ]
[ 53590-58-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 6, p. 1380 - 1400
6
[ 16732-75-5 ]
[ 53590-58-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 2, p. 364 - 377
7
[ 53590-58-2 ]
[ 53590-59-3 ]
Yield
Reaction Conditions
Operation in experiment
79%
With manganese(IV) oxide In N,N-dimethyl-formamide at 20℃; for 12 h; Inert atmosphere
General procedure: A suspension of the alcohol 12 (1 mmol) and active MnO2(10 mmol) in DMF (30 mL) was stirred at rt for 12 h. The reactionmixture was filtrated through a Celite pad. The filtrate was evaporatedin vacuo. The residue was purified by column chromatographyusing EtOAc-hexane as an eluent to give the indole-2-carbaldehyde 13.
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 121, p. 561 - 577
[2] Patent: US2003/144282, 2003, A1,
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 6, p. 1380 - 1400
[4] Patent: US2008/9485, 2008, A1, . Location in patent: Page/Page column 31
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 2, p. 364 - 377
[6] Journal of Organic Chemistry, 2015, vol. 80, # 16, p. 8122 - 8133
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 25℃; for 16.0h;
General procedure: 6-Fluoro-1-(p-toluenesulfonyl)indole-2-carboxylic acid (32.75 g, 98.25 mmol) was dissolved in tetrahydrofuran (400 mL) at 0 C. Lithium aluminum hydride (9.32 g, 245.63 mmol) was added to the mixture in batches and stirred at 25 C for 16 hours. TLC showed the reaction was complete, water (9.5 mL), 15% NaOH (9.5 mL) and water (28 mL) were added successively to the reaction mixture, and the mixture was filtered and the filtrate was concentrated to give the crude product. The product was purified by column chromatography (DCM: MeOH = 20: 1, 3: 1) to deliver the title compound (white solid, 5.11 g, yield 31.49%).
2
[ 27034-51-1 ]
[ 53590-58-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With lithium aluminium tetrahydride; In diethyl ether; at 0℃; for 0.75h;Heating / reflux;
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0 C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0 C. The aqueous layer was extracted with tert-butyl methyl ether (3*100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100%) as a white solid. MS m/e (%): 180 (M-H+, 100).
100%
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0 C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0 C. The aqueous layer was extracted with tert-butyl methyl ether (3*100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100%) as a white solid. MS m/e (%): 180 (M-H+, 100).
100%
To a solution of 2.00 g (8.94 mmol) 6-chlorindole-2-carboxylic acid ethyl ester in 50 ml diethyl ether were added 0.475 g (12.5 mmol) lithium aluminum hydride at 0 C. The reaction mixture was heated at reflux for 45 min and quenched by consecutive addition of 10 ml water, 10 ml aqueous 2 M sodium hydroxide solution and 10 ml water at 0 C. The aqueous layer was extracted with tert-butyl methyl ether (3*100 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.64 g; 100%) as a white solid. MS m/e (%): 180 (M-H+, 100).
In tetrahydrofuran;
Step 3: To 6-chloro-1H-indole-2-carboxylic acid ethyl ester (8.57 g) in THF at 0 C. was added lithium aluminum hydride solution (1M, in THF) dropwise and the reaction mixture was stirred for 3.5 h. The mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Evaporation of the solvent gave 7.77 g of the crude (6-Chloro-1H-indol-2-yl)-methanol which was used directly in the next step.
To 6-chloro-1H-indole-2-carboxylic acid ethyl ester (8.57 g) in THF at 0 C. was added lithium aluminum hydride solution (1M, in THF) dropwise and the reaction mixture was stirred for 3.5 h. The mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Evaporation of the solvent gave 7.77 g of the crude (6-chloro-1H-indol-2-yl)-methanol which was used directly in the next step.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3.5h;
General procedure: To ethyl 1H-indole-2-carboxylate (1.3 g, 6.89 mmol) in THF at 0 .was added lithium aluminumhydride solution (1M, in THF 0.29 g, 1.54 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at0 . The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed withTHF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 1.1 g (96% yield) of thecrude (1H-indol-2-yl)methanol which was used directly in the next step.
With manganese(IV) oxide; In N,N-dimethyl-formamide; at 20℃; for 12.0h;Inert atmosphere;
General procedure: A suspension of the alcohol 12 (1 mmol) and active MnO2(10 mmol) in DMF (30 mL) was stirred at rt for 12 h. The reactionmixture was filtrated through a Celite pad. The filtrate was evaporatedin vacuo. The residue was purified by column chromatographyusing EtOAc-hexane as an eluent to give the indole-2-carbaldehyde 13.
62%
In tetrahydrofuran;
Step 4: To <strong>[53590-58-2](6-chloro-1H-indol-2-yl)-methanol</strong> (37.7 mmol) in THF at 0 C. was added manganese (IV) oxide and the mixture was stirred at rt for 16 h. The mixture was filtered over celite and rinsed with THF and EtOAc and evaporated to near dryness. The solid was filtered and washed with cold EtOAc/hex to give 6-Chloro-1H-indole-2-carbaldehyde (62%, 2 steps).
With manganese(IV) oxide; In tetrahydrofuran; at 0 - 20℃; for 16.0h;
To <strong>[53590-58-2](6-chloro-1H-indol-2-yl)-methanol</strong> (37.7 mmol) in THF at 0 C. was added manganese (IV) oxide and the mixture was stirred at room temperature for 16 h. The mixture was filtered over celite and rinsed with THF and EtOAc and evaporated to near dryness. The solid was filtered and washed with cold EtOAc/hex to give 6-chloro-1H-indole-2-carbaldehyde (62%, 2 steps).
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65 C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32%). The aqueous layer was extracted with tert-butyl methyl ether (3*200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27%) as a white solid. MS m/e (%): 164 (M-H+, 100).
27%
With triethylsilane; trifluoroacetic acid; In 1,2-dichloro-ethane; at 65℃; for 0.08333330000000001h;
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65 C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32%). The aqueous layer was extracted with tert-butyl methyl ether (3*200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27%) as a white solid. MS m/e (%): 164 (M-H+, 100).
27%
A solution of 1.60 g (8.81 mmol) (6-chloro-1H-indol-2-yl)-methanol in 5 ml 1,2-dichloroethane was added to a mixture of 80.0 ml trifluoroacetic acid and 32.0 ml triethylsilane at 65 C. After 5 min, the reaction mixture was cooled to room temperature and quenched with water. The pH was adjusted to 14 by the addition of aqueous sodium hydroxide solution (32%). The aqueous layer was extracted with tert-butyl methyl ether (3*200 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.39 g; 27%) as a white solid. MS m/e (%): 164 (M-H+, 100).
With pyridinium chlorochromate; In dichloromethane; at 10 - 20℃; for 2h;
General procedure: To a stirred solution of the crude (1H-indol-2-yl)methanol (1.07 g, 7.3 mmol) in anhydrous CH2Cl2(10 mL) at coldbath temperature (~10 .) was added portionwise pyridinium chlorochromate (PCC) (1.89 g, 8.1mmol). Reaction was stirred at ambient temperature for 2 hours. Reaction was diluted with CH2Cl2 and filteredthrough a pad of celite and washed with CH2Cl2. After evaporation of solvent, crude product was silica-columnchromatographed (Biotage) using Acetone: Hexane as an eluent to yield 1H-indole-2-carbaldehyde (2d) (0.43 g,41% yield).
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 5.0h;Cooling with ice;
General procedure: A solution of indole-2-carboxylate 11 (1 mmol) in THF (10 mL)was added dropwise to a suspension of LiAlH4 (0.8 mmol) in THF(20 mL) under cooling with ice-water. After stirring at rt for 5 h, thereaction mixture was quenched with water, and then was filtratedthrough a Celite pad. The filtrate was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na2SO4, andevaporated in vacuo. The residue was purified by column chromatography using EtOAc-hexane as an eluent to give thealcohol 12.
(13R,13aS)-12-tert-butyl 13a-methyl 10-chloro-13-(2-methoxy-2-oxoethyl)-7-oxo-13,13a-dihydrobenzo[4',5']isothiazolo[2',3':1,6]pyrido[4,3-b]indole-12,13a(7H)-dicarboxylate 5,5-dioxide[ No CAS ]
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