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A tunable synthesis of indigoids: targeting indirubin through temperature
Shriver, James A. ; Kaller, Kaylie S. ; Kinsey, Ally L. , et al. RSC Adv.,2022,12(9):5407-5414. DOI: 10.1039/d2ra00400c PubMed ID: 35425542
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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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CAS No. : | 1670-81-1 | MDL No. : | MFCD00005678 |
Formula : | C9H7NO2 | Boiling Point : | No data available |
Linear Structure Formula : | - | InChI Key : | IENZCGNHSIMFJE-UHFFFAOYSA-N |
M.W : | 161.16 | Pubchem ID : | 74280 |
Synonyms : |
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Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* 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 |
---|---|---|
93% | With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 24h; | A solution of 1H-indole-5-carboxylic acid (1.6 g, 10 mmol), sodium hydride (1.2 g, 30 mmol), iodomethane (6.2 mL, 100 mmol) and DMF (40 mL) was stirred and room temperature for 24 hr. The reaction mixture was then quenched with water (5 mL) and diluted with ether (150 mL) and ethyl acetate (50 mL). After washing with aq. NH4Cl (100 mL), water (100 mL) and then brine (100 mL), the organic layer was dried over MgSO4, filtered and concentrated. The remaining material was subjected to flash chromatography (ethyl acetate/hexane 1:4) to provide 1-methyl-1H-indole-5-carboxylic acid methyl ester as a crystalline solid (1.77 g, 93% yield). 1H NMR (400 MHz, CDCl3) delta 8.40 (s, 1H), 7.94 (d, 1H, J=9.0 Hz), 7.34 (d, 1H, J=9.0 Hz), 7.12 (d, 1H, J=2.9 Hz), 6.60 (d, 1H, J=2.9 Hz), 3.94 (s, 3H), 3.83 (s, 3H). |
93% | A solution of l//-indole-5-carboxylic acid (1.6 g, 10 mmol), sodium hydride (1.2 g, 30 mmol), iodomethane (6.2 mL, 100 mmol) and DMF (40 mL) was stirred and room temperature for 24 hr. The reaction mixture was then quenched with water (5 mL) and diluted with ether (150 mL) and ethyl acetate (50 mL). After <n="94"/>washing with aq. NH4Cl (100 mL), water (100 mL) and then brine (100 mL), the organic layer was dried over MgSO4, filtered and concentrated. The remaining material was subjected to flash chromatography (ethyl acetate/hexane 1:4) to provide 1 -methyl- l//-indole-5-carboxylic acid methyl ester as a crystalline solid (1.77 g, 93% yield). 1H NMR (400 MHz, CDCl3) delta 8.40 (s, IH), 7.94 (d, IH, J = 9.0 Hz), 7.34 (d, IH, J = 9.0 Hz), 7.12 (d, IH, J = 2.9 Hz), 6.60 (d, IH, J = 2.9 Hz), 3.94 (s, 3H), 3.83 (s, 3H). | |
66.43% | With sodium hydride; In N,N-dimethyl-formamide; for 1h;Inert atmosphere; Cooling with ice; | In the atmosphere of nitrogen and ice bath conditions,Compound 5-carboxylic acid hydrazine (0302-104) (1 g, 6.2 mmol, 1 eq.)Dissolved in 10 ml of DMF,Sodium hydride (744 mg, 18.6 mmol, 3 eq) was slowly added.After stirring the mixture for 15 minutes,Methyl iodide (2.2 g, 15.5 mmol, 2.5 eq.) was added dropwise thereto.The mixture was stirred at ice bath for 1 hour. After the reaction is completed, add water to quench and filter to obtain the targetCompound 1-methyl-1H-indole-5-carboxylic acid methyl ester (780 mg, yield: 66.43%) was a yellow solid. |
56% | To a stirred suspension of 0.99 g (24.8 mmol) of sodium hydride (60% oil dispersion), which had been previously washed 3X with hexanes, in anhydrous DMF (50 mL) is added lH-indole-5-carboxylic acid (2.0 g, 12.4 mmol). The mixture is stirred at rt for 30 min and methyl iodide (3.09 mL, 49.7 mmol) is added. The mixture is stirred overnight and diluted with water, extracted with EtOAc (3x). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel. Elution with hexanes-EtOAc (90: 10) gives methyl 1-METHYL-LH-INDOLE-5-CARBOXYLATE as a white solid (1.32 g, 56%) : LH NMR (400 MHz, CDC13) 8 8.44, 7.97, 7. 37, 7D6, 6.63, 3.97, 3.87. | |
With NaH; In water; N,N-dimethyl-formamide; | (192-1) Under nitrogen atmosphere, a solution of indole-5-carboxylic acid (1.05 g) in DMF (40 mL) was cooled to 0 C., and thereto was added NaH (544 mg, 60%), and the mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 30 minutes. The mixture was cooled to 0 C., and thereto was added iodomethane (3.68 g), and the mixture was stirred at room temperature for 48 hours. Water was added to the mixture, and the mixture was extracted three times with ethyl acetate-toluene, and dried over MgSO4. The solvent was evaporated under reduced pressure to give a crude methyl 1-methylindole-5-carboxylate. | |
With NaH; In water; N,N-dimethyl-formamide; | (192-1) Under nitrogen atmosphere, a solution of indole-5-carboxylic acid (1.05 g) in DMF (40 mL) was cooled to 0C, and thereto was added NaH (544 mg, 60 %), and the mixture was stirred at the same temperature for 10 minutes, and stirred at room temperature for 30 minutes. The mixture was cooled to 0C, and thereto was added iodomethane (3.68 g), and the mixture was stirred at room temperature for 48 hours. Water was added to the mixture, and the mixture was extracted three times with ethyl acetate-toluene, and dried over MgSO4. The solvent was evaporated under reduced pressure to give a crude methyl 1-methylindole-5-carboxylate. | |
To a solution of indole-carboxylic acid (5 g, 1 eq.) in DMF (250 ml) was added dry NaH (3.75 g, 5 eq.), freshly prepared by washing 60% NaH in mineral oil with hexane. After the mixture was stirred at room temperature for 40 minutes, iodomethane (20 mL, 10 eq.) was added. After being stirred for 20 hours, the reaction mixture was poured into a IM NaHSO4 aqueous solution (30 mL), and extracted with ethyl acetate. The organic layer was back-extracted sequentially with water, a saturated aqueous NaHCtheta3 solution, dried over MgSO4, filtered, and concentrated to afford a crude product as an oil 1-37. |
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