* 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.
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 12, p. 2074 - 2077
2
[ 1670-81-1 ]
[ 917-54-4 ]
[ 53330-94-2 ]
Yield
Reaction Conditions
Operation in experiment
72.9%
at 0 - 20℃; Inert atmosphere
To a solution of indole-5-acid (2.5 g, 15.5 mmol) in 30 mL anhydrous THF, a solution of CH3Li (1.6 M, 30 mL, 51.2 mmol) in diethyl ether was added dropwise at 0 °C under N2 atmosphere. The mixture was stirred at room temperature for 4 h, the reaction was quenched by NH4Cl aqueous, and extracted with CH2Cl2 (3 * 50 mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide 1.8 g 5-acetylindole (24) as white solid.
50.6%
Stage #1: at 20℃; for 41 h; Stage #2: With water In tetrahydrofuran; diethyl ether at 0℃;
To a solution of indole-5-carboxylic acid [10G, 62.05 mmol, Intermediate (16) ] in anhydrous tetrahydrofuran (1000 mL) is added methyl lithium (1.6M in diethyl ether, 150 mL) drop wise over 60 minutes periods. The resulting precipitate is stirred at ambient temp for 40 hours. The reaction is cooled to 0°C and quenched by the cautious addition of water (5 ML) until boiling stopped. The solvent is removed in vacuo and the slurry mixture is partitioned between dichloromethane (500 ML) and water (100 mL). Dichloromethane layer is washed with 1N hydrochloric acid (20 mL), saturated NAHC03 (20 ML), brine and dried over sodium sulfate. The residue is chromatographed on 110 g silica gel cartridge (30 to 50percent ethyl acetate gradient in heptane) to afford L- (LH-INDOL-5-Y)-ETHANONE [5. 0G, 50.6percent, Intermediate (17) ] as colorless oil. Oil solidified on standing; 1H NMR (CDC13) : 8 8.846 (1H, br s), 8.356 (1H, s), 7.917 (1H, d), 7.449-7. 297 (2H, m), 6.690 (1H), 2.713 (3H, s); LC/MS : 160 (M + H).
Reference：
[1] European Journal of Medicinal Chemistry, 2019, p. 428 - 442
[2] Patent: WO2005/26175, 2005, A1, . Location in patent: Page/Page column 73
[3] Patent: EP2287173, 2011, A1, . Location in patent: Page/Page column 40-41
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 12, p. 2074 - 2077
5
[ 99-92-3 ]
[ 53330-94-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 12, p. 2074 - 2077
6
[ 97776-06-2 ]
[ 53330-94-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2007, vol. 46, # 12, p. 2074 - 2077
7
[ 1056442-76-2 ]
[ 75-16-1 ]
[ 53330-94-2 ]
Yield
Reaction Conditions
Operation in experiment
323 mg
at 20 - 50℃; for 1 h;
[001241j Step B: The crude product from Step A was dissolved in THF (20 mL). A 1.4 M solution of methylmagnesium bromide (11.2 mL, 15.6 mmol) in THF:toluene (3:1), was added drop wise to the solution. The solution was allowed to warm to room temperature. The solution was stirred at 50 °C for 1 hour, upon which iN aqueous HC1 (50 mL) was slowly added. The mixture was partitioned into EtOAc (200 mL) and aqueous iN NaOH (200 mL). The organic layer was washed with brine, dried over Na2504, filtered and concentrated. The residue was chromatographed on silica, eluting with EtOAc (0percent to 50percent) in hexanes to afford 1-(1H-indol-5- yl)ethanone as a white powder (323 mg, 33percent).
Reference：
[1] Synlett, 2003, # 10, p. 1447 - 1450
16
[ 16078-35-6 ]
[ 53330-94-2 ]
Reference：
[1] Bulletin de la Societe Chimique de France, 1982, vol. 2, # 7/8, p. 249 - 256
[2] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 2875,2880; engl. Ausg. S. 2835, 2840
In tetrahydrofuran; diethyl ether; at 0 - 20℃;Inert atmosphere;
To a solution of indole-5-acid (2.5?g, 15.5?mmol) in 30?mL anhydrous THF, a solution of CH3Li (1.6?M, 30?mL, 51.2?mmol) in diethyl ether was added dropwise at 0?C under N2 atmosphere. The mixture was stirred at room temperature for 4?h, the reaction was quenched by NH4Cl aqueous, and extracted with CH2Cl2 (3?*?50?mL). The combined organic layers were then washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to provide 1.8?g 5-acetylindole (24) as white solid.
50.6%
To a solution of indole-5-carboxylic acid [10G, 62.05 mmol, Intermediate (16) ] in anhydrous tetrahydrofuran (1000 mL) is added methyl lithium (1.6M in diethyl ether, 150 mL) drop wise over 60 minutes periods. The resulting precipitate is stirred at ambient temp for 40 hours. The reaction is cooled to 0C and quenched by the cautious addition of water (5 ML) until boiling stopped. The solvent is removed in vacuo and the slurry mixture is partitioned between dichloromethane (500 ML) and water (100 mL). Dichloromethane layer is washed with 1N hydrochloric acid (20 mL), saturated NAHC03 (20 ML), brine and dried over sodium sulfate. The residue is chromatographed on 110 g silica gel cartridge (30 to 50% ethyl acetate gradient in heptane) to afford L- (LH-INDOL-5-Y)-ETHANONE [5. 0G, 50.6%, Intermediate (17) ] as colorless oil. Oil solidified on standing; 1H NMR (CDC13) : 8 8.846 (1H, br s), 8.356 (1H, s), 7.917 (1H, d), 7.449-7. 297 (2H, m), 6.690 (1H), 2.713 (3H, s); LC/MS : 160 (M + H).
(1) Indole-5-carboxylic acid (2.0 g) was dissolved in tetrahydrofuran (20 ml), a 1.09 M solution of methyllithium in diethyl ether (39.8 ml) was slowly added dropwise to the solution under ice cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. Distilled water was added to the reaction mixture, the resulting mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a methyl ketone compound (1.35 g).
1.8 g
In tetrahydrofuran; diethyl ether; at 20℃;Inert atmosphere;
(A) Indole-5-carboxylic acid (2.5 g, 15.5 mmol) was dissolved in anhydrous 20 mL of THF. Under a nitrogen atmosphere, a 1.6 M solution of methyl lithium in diethyl ether (30 mL, 51.2 mmol) was slowly poured. After being slowly added, a saturated aqueous solution of ammonium chloride was added, and ethyl acetate (50 mL × 3) was evaporated.Concentrated to obtain 1.8 g of 5-acetyl indole;
To a solution of 1- (lH-indol-5-yl)-ethanone [5g, 31.41 mmol, Intermediate (17) ] and 4- (DIMETHYLAMINO) pyridine (39.4 mg) in tetrahydrofuran (60 mL) is added di-tert-butyl- dicarbonate (1M in tetrahydrofuran, 32 mL) drop wise at 0C over 55 minutes. Stirred 10 minutes then water (30 mL) is added and the product extracted three times with ethyl acetate (50 ML). The combined ethyl acetate layers are washed with brine and dried over sodium sulfate. The residue is chromatographed on 1 LOG silica gel cartridge (15-20% ethyl acetate gradient in heptane) afforded 5-acetyl-indole-l-carboxylic acid tert-butyl ester [1.28g, 81%, Intermediate (18)] as colorless oil. Oil solidified on standing; 1H NMR (CDCL3) : B 8.201 (2H), 7.966 (1H), 7.657 (1H), 6.661 (1H), 2.672 (3H), 1.701 (9H) ; LC/MS: 260 (M+H).
79.9%
To a solution of 24 (500 mg, 3.14 mmol) in 20 mL anhydrous THF,NaH (60%, 188 mg, 4.71 mmol) was added and the mixture wasstirred for 15 min. Then, (Boc)2O (822 mg, 4.71 mmol) was addeddropwise. After stirring for 1 h, the mixture was diluted with 50 mLEtOAc, then washed with water (20 mL x 3), saturated brine, driedover anhydrous Na2SO4, and concentrated in vacuo to afford thecrude product, which was purified by column chromatographywith petroleum/ethyl acetate (5:1) to give intermediate 21a(650 mg, 79.9%). The spectral data of 21c was in accordance withliterature report [36].
REFERENCE EXAMPLE 1 Ethyl 3-(indol-5-yl)isocrotonate (Compound A) After 12.5 g of sodium hydride (60percent oil) was washed with pentane under nitrogen stream, 180 ml of tetrahydrofuran (THF) was added. 2-3 drops of ethanol were added to the suspension ethyl diethylphosphonoacetate (70.4 g) was added dropwise at 0° C. After the mixture was stirred at 0° C. for 30 minutes, 10.0 g of <strong>[53330-94-2]5-acetylindole</strong> in 70 ml of THF was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then refluxed for 8 hour. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate=5:1) to give 9.6 g of compound A as a yellow syrup. IR (liquid film) cm-1: 1680, 1603, 1195, 1101. 1 H-NMR (CDCl3) (delta, ppm): 1.32(t, 3H, J=7 Hz), 2.67(d, 3H, J=1 Hz), 4.22 (q, 2H, J=7 Hz), 6.21(d, 1H, J=1 Hz), 6.56(dd, 1H, J=2 and 3 Hz), 7.33 (s, 2H), 7.79(s, 1H), 8.3 (brs, 1H).
General procedure: The method adopted for the synthesis of 1-(4-bromobutyl)indole (3a) is described. Potassium hydroxide (3.83 g, 68.3 mmol) and tetrabutylammonium iodide (0.2 g, 0.54 mmol) were added, under mechanical stirring, to a solution of indole (2a) (2 g, 17.1 mmol) in anhydrous DMF (25 mL). The reaction mixture was stirred at room temperature for 45 min and cooled to 0 °C. 1,4-Dibromobutane was then added and the mixture was stirred for 15 min at 0 °C and for 1 h at room temperature. The mixture was poured into 70 mL of water, extracted with methylene chloride (3 .x. 50 mL), and the combined organic layers were washed with brine and dried. The solvent was removed in vacuo, and the residue was chromatographed on a silica gel column using a gradient of hexanes/ethyl acetate (10:0 to 9:1) as the eluent to give 2.92 g (68percent) of 1-(4-bromobutyl)indole as a pale yellow oil.
methyl 3-(1H-indol-5-yl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
With sodium hydride; In tetrahydrofuran; mineral oil;
[001242j Step C: Following the procedure in Example 5, Step E, the methyl ketone from Step B, dimethyl carbonate (0.46 mL, 5.5 mmol) and sodium hydride (220 mg, 60percent dispersion in mineral oil, 5.5 mmol) in THF (6 mL) afforded methyl methyl 3-(1H-indol-5-yl)-3- oxopropanoate as an off white powder (120 mg, 27percent). MS m/z 216.1 [M-Hf.
[001241j Step B: The crude product from Step A was dissolved in THF (20 mL). A 1.4 M solution of methylmagnesium bromide (11.2 mL, 15.6 mmol) in THF:toluene (3:1), was added drop wise to the solution. The solution was allowed to warm to room temperature. The solution was stirred at 50 °C for 1 hour, upon which iN aqueous HC1 (50 mL) was slowly added. The mixture was partitioned into EtOAc (200 mL) and aqueous iN NaOH (200 mL). The organic layer was washed with brine, dried over Na2504, filtered and concentrated. The residue was chromatographed on silica, eluting with EtOAc (0percent to 50percent) in hexanes to afford 1-(1H-indol-5- yl)ethanone as a white powder (323 mg, 33percent).
General procedure: To a slurry of tBuONa (1.00 g, 5.36 mmol) in dry THF under N2 (8 mL) a solution of starting material aldehyde (19a-27a, Table S1) in 2.0 mL anhydrous THF was added and via syringe. The mixture was stirred at room temperature for 30 min. and then dimethyl oxalate (2.2 equiv, 11.8 mmol, 1.39 g) was added. After 48 hours, the reaction mixture was quenched with 2.0 mL of 2 M HCl (aq) and extracted with EtOAc. The combined organic layer was washed with 10 mL brine solution, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude mixture was purified by a silica gel column chromatography to afford the desired methyl-ester as an amorphous solid. Methyl-ester of 19-27 was dissolved in 4 mL of 2:1:1 mixture of (THF/CH3OH/H2O) and xx mg(0.212 mmol) of LiOH monohydrate was added. The yellow solution was stirred for 6 h, and after completion of hydrolysis the reaction mixture was acidified to pH 4 with 2 M HCl (aq), and the resulting mixture was extracted with 2x5 mL EtOAc. The combined organic phase was dried (Na2SO4), filtered, and concentrated to afford the desired acid product (19-27) as a solid.
methyl 5-(3-methoxy-3-oxopropanoyl)-1H-indole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With sodium hydride; In mineral oil;Reflux;
General procedure: A 100 mL round bottom flask fitted with magnetic stirrer is charged with appropriate commercial arylethanone and dimethylcarbonate. Sodium hydride (60percent in mineral oil) is added slowly with stirring and the whole is refluxed overnight. The mixture is poured into water, acidified with HCl (2M) and extracted with ethyl acetate. The organic layer is washed with water (50 mL) and saturated brine solution (50 mL). The organic layer is dried over anhydrous Na2SO4 and the solvent is removed under reduced pressure. The crude material is purified by silica gel column chromatography using suitable solvent to give the corresponding methyl 3-oxo-3-arylpropanoate.
1-[1-(toluene-4-sulfonyl)-1H-indol-5-yl]ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 2h;Inert atmosphere;
1-(1H-Indol-5-yl)ethan-1-one (1 g, 6.28 mmol, commercially available from, for example, Fluorochem) was taken up in DMF (10 mL) and cooled to 0 °C. NaH (0.302 g, 7.54 mmol, 60percent dispersion in mineral oil) was added in small portions and allowed to stir for 15 min. tosyl-Cl (1.437 g, 7.54 mmol) was added, and the reaction was allowed to warm to rt and left to stir for 1.5 h. Additional NaH (63 mg, 0.25 eq., 60percent dispersion in mineral oil) was added, and the reaction was left to stir for 30 min. The reaction was quenched with water (40 mL). The reaction mixture was extracted with ethyl acetate (2 x 50 mL) and the combined organics were washed with brine (75 mL), dried with Na2SO4, filtered and concentrated in vacuo to yield a brown solid. The crude product was applied to a 100 g ULTRA SNAP cartridge in the minimum of DCM and eluted with 0-5percent ethyl acetate in DCM. The appropriate fractions were combined and concentrated in vacuo to yield 1-(1-tosyl-1H-indol-5-yl)ethan-1-one (1.408 g, 4.27 mmol, 68 percent yield) as a cream solid. (0455) LCMS (2 min High pH): Rt = 1.20 min, [MH]+ = 314.3.
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