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Synonyms: 6-Methylindole
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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. : | 3420-02-8 |
Formula : | C9H9N |
M.W : | 131.17 |
SMILES Code : | CC1=CC2=C(C=C1)C=CN2 |
Synonyms : |
6-Methylindole
|
MDL No. : | MFCD00005682 |
InChI Key : | ONYNOPPOVKYGRS-UHFFFAOYSA-N |
Pubchem ID : | 137928 |
GHS Pictogram: | ![]() |
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 |
---|---|---|
94% | Example 4; 1. Synthesis of indole derivatives; 1) Synthesis of 3-cyanoindole derivatives; [Show Image] Nine objective compounds were prepared by (1) formylation of 3-position of the corresponding indole using phosphorus oxychloride in the presence of dimethylformamide (Vilsmeier method), (2) cyanation by dehydrating reaction with hydroxylamine in sodium formate and formic acid, (3) coupling with ethyl 4-fluorobenzoate in the presence of potassium fluoride on almina and 18-crown-6-ether in dimethyl sulfoxide and then, (4) hydrolysis with lithium hydroxide in total 4 steps in that order (the following Table 2). In addition, XO-CH172 and XO-CH183 (R is a 2-methyl group or a 5-methoxy group, respectively) were prepared from the step (2) using the corresponding aldehydes purchased.; 1) Synthesis of XO-CH200; XO-CH180 Under an argon atmosphere, 6-methylindole (1.004 g, 7. 62 mmol) was dissolved in dimethylformamide (10 mL), and to the solution was added phosphorus oxychloride (2 mL) under ice-cooling. The mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added dropwise an aqueous sodium hydroxide solution (5g/15mL) under ice-cooling. The mixture was heated for reflux for 1.5 hours. To the reaction mixture was added water under ice-cooling, and the mixture was adjusted to pH3 with concentrated hydrochloric acid. The solid was collected by filtration and dried at 60C under reduced pressure to give XO-CH180 as a pale brown solid (1.14 g, 94% yield). | |
89.38% | Add 30 mL of N,N-dimethylformamide (DMF) to a 250 mL three-necked flask, cool to below 0 C, and slowly add phosphorus oxychloride (6.30 mL, 67 mmol). After the addition is complete, let stand at room temperature and continue to stir. After 30 min, 25 mL of 6-methyl-1H-indole (II-3, 8.00 g, 61 mmol) in DMF was added dropwise in an ice bath. The temperature was controlled below 10 C. After the addition was completed, the temperature was raised to 35 C and stirred for 1 h.The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched by adding 60 g of crushed ice under ice cooling, and then slowly added dropwise.1mol/L NaOH solution, adjust pH=89, and control the temperature in the dropping process to not exceed 40C. After the addition is completed, the mixture is heated to reflux for 1 hour.Stirring was carried out, cooled to room temperature, 55 mL of water was added dropwise, filtered, and the filter cake was washed with water until neutral. After drying, 8.67 g of a yellow solid was obtained.III-3, 89.38%. | |
79% | General procedure: The Vilsmeier-Haack reagent was prepared by adding POCl3 (60 mmol, 6 mL) dropwise to ice-cold dry DMF (30 mL) whilst stirring. The mixture was then stirred for 10-15 min at 0 C. Compound 3b or 3e (10 mmol) was added as a solution in DMF (5 mL) to the above Vilsmeier-Haack reagent. The stirred mixture was then heated at 35 C for 1 h. After cooling, ice water (6 mL) and a 30% aqueous solution of NaOH (13 mL) were added successively, and the mixture was heated at reflux for 20 min and allowed to cool. The mixture was extracted with CH2Cl2 (20 mL*3). The extracts were dried over Na2SO4, evaporated under reduced pressure to remove the solvent, and the crude product was purified by flash column chromatography using 15-25% acetone/petroleum ether (60-90 C) as eluent to give the corresponding intermediate compound 4b or 4e, respectively. |
With sodium hydroxide; In water; | 6-Methyl indole-3-carboxaldehyde Phosphorus oxychoride (3.2 ml, 34.3 mmol) was added dropwise to dimethyl formamide (26 ml) over ten minutes at ~5 C. To this solution was added a dimethyl formamide (32 ml) solution of 6-methylindole (3.307 g, 25.2 mmol) over 10 minutes. The mixture was slowly warmed to ambient temperature, then heated to 50 C. for four hours. The mixture was cooled to ambient temperature, then poured onto ice (500 g). The aqueous solution was left to stand for 16 hours. Sodium hydroxide (6.0 g) was dissolved in water (22 ml) and added dropwise to the brown solution. The resultant yellow precipitate was boiled and filtered hot. It was left to cool to room temperature, then to 5 C. The precipitate was filtered off and washed with water (800 ml), dried at the pump, then further dried in vacuo at 50 C. for 16 hours to yield a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With iodine; oxygen; pyrographite; In N,N-dimethyl-formamide; at 120℃; for 0.8h; | General procedure: A 50 mL round bottom flask equipped with a magnetic stirring bar was charged with substituted indole 1 (1.0 mmol, 1.0 equiv), HMTA (2.0 mmol, 0.2803 g, 2.0 equiv), activated carbon (0.1 g) and DMF (2 mL). Then I2 (0.2 mmol, 0.0507g, 20 molpercent) was added and the flask was equipped with a reflux condenser. The reaction mixture was stirred at 120 oC under open air and monitored by TLC. Upon completion of the reaction, the reaction mixture was cooled to room temperature. The resultant mixture was filtered through a pad of celite and the filter cake was washed thoroughly with EtOAc (4 × 6 mL). The filtrate was washed with 0.5 M aqueous HCl (10 mL), saturated NaHCO3 solution (10 mL) and saturated NaCl solution ( 10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with hexane and ethyl acetate to give the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iron(III) chloride; ammonia; In water; N,N-dimethyl-formamide; at 130℃; for 1h; | General procedure: A 50 mL round-bottomed flask equipped with a magnetic stirringbar was charged with the appropriate indole 1 (0.5 mmol,1.0 equiv), 37percent aq HCHO (0.5 mmol, 0.0406 g, 1.0 equiv), 25percent aqNH3 (1.0 mmol, 0.0681 g, 2.0 equiv), FeCl3 (0.01 mmol, 0.0016 g,2 molpercent), and DMF (2 mL). The flask was fitted with a reflux condenser,and the mixture was stirred at 130 °C under open air.When the reaction was complete (TLC), the mixture was cooledto r.t., diluted with sat. aq NaCl (10 mL) and 0.5 M aq HCl (2 mL),and extracted with EtOAc (3 x 7 mL). The organic layers werecombined, washed with sat. aq NaHCO3 (10 mL) and sat. aq NaCl(10 mL), dried (Na2SO4), and concentrated under reduced pressure.The residue was purified by flash column chromatography(silica gel, hexane?EtOAc). |
Tags: 6-Methyl-1H-indole | Indoles | Heterocyclic Building Blocks | 3420-02-8
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