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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
5-bromoindole is an inhibitor of glycogen synthase kinase 3 (GSK-3), it can be used as important pharmaceutical chemical intermediate.
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A tunable synthesis of indigoids: targeting indirubin through temperature
Shriver, James A. ; Kaller, Kaylie S. ; Kinsey, Ally L. ; Wang, Katelyn R. ; Sterrenberg, Summer R. ; Van Vors, Madison K. , et al.
Abstract: The spontaneous conversion of 3-indoxyl to indigo was a well-established process used to produce indigo dyes. It was recently shown that some indoles, when reacted with molybdenum hexacarbonyl and cumyl peroxide, proceed through an indoxyl intermediate to produce significant amounts of indirubin through a competing mechanism. Modulation of this system to lower temperatures allows for careful tuning, leading to selective production of indirubins in a general process. A systematic assay of indoles show that electron deficient indoles work well when substituted at the 5 and 7 positions. In contrast, 6-substituted electron rich indoles give the best results whereas halogeno indoles work well in all cases. This process shows broad functional group tolerance for generally reactive carbonyl-containing compounds such as aldehydes and carboxylic acids.
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Purchased from AmBeed: 1006-94-6 ; 3420-02-8 ; 1670-82-2 ; 10075-50-0 ; 3189-13-7 ; 933-67-5 ; 17422-33-2 ; 17422-32-1 ; 4769-96-4 ; 271-63-6 ; 6146-52-7 ; 614-96-0 ; 15861-24-2 ; 479-41-4 ; 25235-85-2 ; 1670-81-1 ; 120-72-9 ; 1074-88-0 ; 84-40-2 ; 19201-53-7 ; 482-89-3
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CAS No. : | 10075-50-0 |
Formula : | C8H6BrN |
M.W : | 196.04 |
SMILES Code : | C1=CC(=CC2=C1[NH]C=C2)Br |
MDL No. : | MFCD00005670 |
InChI Key : | VXWVFZFZYXOBTA-UHFFFAOYSA-N |
Pubchem ID : | 24905 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH; phosphoric acid; In tetrahydrofuran; N,N-dimethyl-formamide; | 1-(2-Hydroxyethyl)-5-bromoindole: Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.1 g, 141 mmol) were stirred in 71 mL of THF at 0 C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2*200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole. Tris[1-(2-t-Butyldimethylsilyloxyethyl)indol-5-yl]bismuthane: | |
With NaH; phosphoric acid; In tetrahydrofuran; N,N-dimethyl-formamide; | 1-(2-Hydroxyethyl)-5-bromoindole: Under a N2 atmosphere, 2-bromoethanol (17.6 g, 141 mmol) and 2-methoxypropene (10.1 g, 141 mmol) were stirred in 71 mL of THF at 0 C. for 30 minutes The resulting solution was added to a stirring mixture of 5-bromoindole (22.83 g, 116 mmol) and 60% NaH (4.62 g, 193 mmol) in 40 mL of DMF and 60 mL of THF. The solution was stirred at ambient temperature for 4 hours. The reaction mixture was worked up by quenching the excess of NaH with water and removing the aqueous layer. The organic layer was vigorously stirred with 200 mL of 2% aqueous phosphoric acid for 5 hours when the layers were separated. The organic layer was washed with water (2*200 mL) and the solvent removed. The residue was purified by column chromatography (30:70 EtOAc-Hex) to give 17 g of 1-(2-hydroxylethyl)-5-bromoindole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In dimethyl sulfoxide; | STEP 7A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). | |
With sodium hydroxide; In dimethyl sulfoxide; | STEP 1A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 tool) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). | |
With sodium hydroxide; In dimethyl sulfoxide; | STEP 25A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). |
With sodium hydroxide; In dimethyl sulfoxide; | STEP 25A 1-(2-Hydroxyethyl)-5-bromoindole A mixture of NaOH (4.4 gm, 0.011 mol) in DMSO (175 ml) was stirred at 100 C. for 5 hours at which time it was cooled to 20 C. To this mixture was added 5-bromoindole (20 gm, 0.102 mol) and the reaction was stirred for 8 hours at room temperature. A solution of ethylene oxide (5.1 gm, 0.125 mol) in DMSO (20 ml) was prepared by bubbling the gas into DMSO. To the bromoindole reaction mixture was slowly added the ethylene oxide solution and stirring was continued for another 2.5 hours. The reaction mixture was then poured into ice water and extracted twice with diethyl ether. The combined ether extracts were concentrated in vacuo whereupon crystallization took place. The crude product was recrystallized from diethyl ether:hexanes (3:2) to afford the title compound (6.25 gm). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With dmap; triethylamine; In 1,2-dichloro-ethane; at 20 - 60℃; for 8h; | General procedure: Triethylamine (3.8 mmol, 1.5 equiv), acetic anhydride (9.6 mmol, 3.8 equiv) and DMAP(0.5 mmol, 0.2 equiv) were added at rt to a solution of 5-bromo-1H-indole (2.5 mmol, 1 equiv) in1,2 dichloroethane (10 mL). The solution was heated to 60 C for 8 h. When the reaction wascomplete [TLC (EtOAc/hexane 2:5)], the mixture was extracted with EtOAc (2 × 20 mL) andwashed with water (2 × 20 mL). The organic layer was separated, dried over anhydrous Na2SO4,filtered and the solvent removed under reduced pressure. The residue was purified by flashcolumn chromatography [silica gel (230-400 mesh; Merck), EtOAc/hexane 2:5]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With copper(l) iodide; potassium carbonate; lithium chloride; In N,N-dimethyl-formamide; at 120℃; for 64h;Inert atmosphere; | Description 205-bromo-1-(3-fluoro-pyridin-4-yl)-1H-indole (D20)5-bromo-1H-indole [CA.S. 10075-50-0] (2 g, 10.202 mmol) was dissolved in DMF (16 ml). A nitrogen stream was bubbled through the mixture and then were added 3-Fluoro- 4-iodopyridine [CA.S. 22282-75-3] (2.502 g, 11.222 mmol), lithium chloride (0.432 g, 10.202 mmol), copper(I) iodide (0.0195 g, 0.102 mmol) and K2CO3 (4.23 g, 30.605 mmol). The reaction mixture was heated at 120 0C for 2 days. After cooling to room temperature, the reaction mixture was refilled with lithium chloride (0.100 g) and (copper(I) iodide (0.010) stirred at 1200C for 16 h. After cooling to room temperature, the reaction mixture was washed with NH3 (aqueous sat. solution) and extracted with DCM. The organic layer was separated, washed with water, dried (Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by column chromatography (silica gel; eluent: Heptane/EtOAc up to 15percent as eluent). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound D20 (1.37 g, 46 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tetra-(n-butyl)ammonium iodide; zinc trifluoromethanesulfonate; N-ethyl-N,N-diisopropylamine; In toluene; at 20℃;Inert atmosphere; | General procedure: Procedure A: To a solution of 1H-indole-5-sulfonamide/5-(methylsulfonyl)-1H-indole (2 equiv.), zinc triflate (1.2 equiv.) and tetrabutylammonium iodide (1 equiv.) in dry toluene (ca. 3 mL per mmol of indole) was added N,N-diisopropylethylamine (2.2 equiv.) under argon. The reaction mixture was heated at 50 °C for 30 min, followed by addition of the p-halo-benzyl bromide (1 equiv.). The mixture was stirred overnight at 50 °C under argon. The reaction was quenched with saturated aqueous NH4Cl, diluted with distilled water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate anhydrous, filtered and concentrated. The samples were further purified with silica flash chromatography then PTLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With lithium tert-butoxide; In N,N-dimethyl-formamide; at 100℃; under 760.051 Torr; for 24h; | General procedure: In a dried two-necked test tube was charged with LiOtBu (160 mg, 2.00 mmol) and indole 1a (23.4 mg, 0.4 mmol). The reaction vessel was evacuated under high vacuum and the atmosphere was replace with a balloon of CO2. Then DMF (2 mL) was added and the mixture was stirred for 24 h at 100C. Then the result mixture was cooled and carefully quenched with a solution of HCl (2 N) and extracted with EtOAc (5x). The combined organic layers were washed with water (2x), brine (1x) and dry over MgSO4. The dried organics were concentrated under reduce pressure and the residue was purified by preparative TLC (hexane:acetone = 1:1) to afford the desired product 2a (153.0 mg, 95%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With manganese(III) triacetate dihydrate; acetic acid; at 80℃; for 2h;Inert atmosphere; | General procedure: Manganese triacetate (2 mmol) is added portion wise to a pre dissolved solution of Indole (1mmol) and benzimidazolethiol (1mmol) in acetic acid (10mL) at room temperature under Nitrogen atmosphere. The reaction mixture is stirred at 80 C for 2 hours. After completion of reaction, as monitored by T.L.C analysis, the reaction mixture was quenched by the addition of water 20 ml. The organic compounds are extracted with ethyl acetate (3x20ml). The combined layers are dried over anh.Na2SO4. The required product is purified by column chromatography, eluted with 8% methanol in DCM to get the product. The product is confirmed by 1H, 13C, NMR, IR and mass |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium carbonate; In acetonitrile; at 120℃; for 24h;Schlenk technique; | General procedure: A mixture of indole 1 (0.50 mmol), Na2CO3 (10.6 mg, 0.10 mmol, 20 mol%), and alkenyl carboxylate 2 (2.0 mmol, 4.0 equiv) in MeCN (3 mL) was added into a Schlenk flask (25 mL) and stirred at 120 C until completion of the reaction. Then the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/EtOAc 20:1 to 5:1) to afford the desired acylindoles 3 (Tables 2 and 3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-bromo-1H-indole (700 mg, 3.57 mmol) was dissolved in anhydrous DMF (10 mL), NaH (60%, 429 mg, 10.71mmol) was added at 0 C, the reaction solution was slowly warmed to room temperature, and allowed to proceedovernight. Then TDI01286-2 (579 mg, 4.29 mmol) was added at room temperature, and the reaction was further stirredfor 3 hours at room temperature. LC-MS indicated the reaction was complete. The reaction solution was slowly addedto 100 mL water, and stirred at room temperature for 30 min. A large amount of solid precipitated, and was filtered bysuction. The filter cake was washed, collected and dried to afford TDI01286-3 (800 mg, crude product).1H NMR (400 MHz, DMSO-d6) delta 8.17 (d, J = 7.2 Hz, 1H), 7.61 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H),7.15 (d, J = 8.4 Hz, 1H), 6.46 (d, J = 2.8 Hz, 1H), 4.77 (s, 2H), 3.88-3.80 (m, 1H), 1.09 (d, J = 6.4 Hz, 6H). MS m/z (ESI):297.2 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(II) tungstate; In water; at 60℃;Green chemistry; | General procedure: To a mixture of isatin (1 equiv.) and indole (1 or 2 equiv.) in water (3 mL), CuWO4 (10 mol%) was added and the mixture was stirred at room temperature for 2 h or heated at 60 C for 2 h. After completion of the reaction (monitoring by TLC), the mixture was cooled (in the case of bis-indolyl-2-oxindoles) and extracted with EtOAc (2×10 mL). The organic layers were washed with brine, dried using sodium sulfate. Evaporation of the solvent gave the desired product which was purified by silica gel column chromatography. Elution of the column with PE:EtOAc gave the desired products (5 or 6). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
> 99% | With potassium carbonate; In ethanol; at 140℃;Schlenk technique; | General procedure: A mixture of indole-3-carboxylic acid 1 (0.50 mmol) and K2CO3 (13.8 mg, 0.10 mmol, 20 mol%) in EtOH (3 mL) was added into a Schlenk flask (25 mL) and stirred at 140 C. The reaction was monitored by thin layer chromatography until the disappearance of starting material 1. Then the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate 20:1 to 10:1). |
Tags: 5-Bromoindole | Indoles | GSK-3 | Bromides | Heterocyclic Building Blocks | PI3K/AKT/mTOR | Stem Cells | Parkinson'S Disease and Alzheimer'S Disease | Hedgehog (Hh) | Tumor Development and Microenvironment Evolution | Organic Building Blocks | Wnt Signaling Pathway | 10075-50-0
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H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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