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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. : | 17422-32-1 | MDL No. : | MFCD00005672 |
Formula : | C8H6ClN | Boiling Point : | - |
Linear Structure Formula : | (C6H3Cl)NHCHCH | InChI Key : | MYTGFBZJLDLWQG-UHFFFAOYSA-N |
M.W : | 151.59 | Pubchem ID : | 87110 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
79% | With yttrium(III) trifluoromethanesulfonate; at 100℃; for 0.166667h;Microwave irradiation; Ionic liquid; Green chemistry; | General procedure: A 10 mL glass vessel suited for the monomode microwave oven was charged with 1 mmol substrate,1 mmol acid anhydride, 0.01 mmol metal triflate, and 1 mmol ionic liquid. Next, the vessel was sealedwith a Teflon cap and irradiated in a monomode microwave oven at many different reaction conditions(temperature and time) to find the optimal condition. Upon completion, the vessel was cooled down toroom temperature and the mixture was extracted with Et2O (5 × 10 mL). The ether layer was decantedand washed with water (2 × 10 mL), saturated aqueous NaHCO3 (2 × 20 mL), and brine (2 × 10 mL).The organic layer was dried over MgSO4, filtered, and the solvent was removed by a rotary evaporator.The isolated yield was determined after purification by flash chromatography (silica gel, n-hexane/ethylacetate, gradient 10:0 to 8:2). |
45% | With acetic acid; for 20h;Reflux; | A mixture of compound 5a (9.1 g, 0.06 mol), glacial acetic acid (9.1 mL) and acetic anhydride (91 mL) was heated to reflux for 20 h. Upon cooling to room temperature, the solid was collected by filtration and purified by silica gel column chromatography. 6a was obtained as a white solid (5.2 g, 45%). m.p. 246-247 C. ESI-MS m/z: 194.1 (Cl = 35), 196.0 (Cl = 37) [M + H]+. 1H NMR (300 MHz, DMSO-d6) delta: 2.44 (s, 3H), 7.23-7.19 (m, 1H), 7.49 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 1.8 Hz, 1H), 8.37 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With silver perchlorate; niobium pentachloride; In dichloromethane; at 0 - 30℃; for 4.3h; | General procedure: In a round-bottom flask, an indole (153 mg, 1.3 mmol) was dissolved in a dry DCM (1.5 mL) at 0 C then the solution of acyl chloride (140 mg, 1 mmol) in DCM (1.5 mL) with syringe and 1 mol % of NbCl5 and 3 mol % of AgClO4 was added. The reaction temperature was then slowly increased to 30 C and the reaction was carried out at this constant temperature constantly. After 4 h the reaction was completed and monitored by TLC, then reaction mass was quenched by adding 5 mL water and extracted with ethyl acetate (2 x 15 mL). This subsequent extract was washed with water 10 mL, dried over anhydrous MgSO4 and evaported under vacuum. The purification of crude mass was done column chromatography on silica gel (100-200 mesh) by eluting with ethyl acetate and petroleum ether (10:90), which offered 3-benzoylindole (177 mg, 75 % yield) (Scheme-I). The yield of other indoles and acyl chlorides are given in Table-1. |
Take SnCl4 (20 mmol) in a flask, 15 mL of toluene was added and the mixture was stirred in an ice-water bath. To the system was added acetyl chloride (20 mmol). After stirring for 0.5 h in ice-water bath, 2 mL of toluene was dissolved in 5-chloroindole (l0mmol), Was added dropwise to the reaction system, and the ice-water bath was stirred for 2h. TLC monitoring reaction completely, vacuum distillation to remove toluene, water and ethyl acetate extraction, combined organic phase, anhydrous magnesium sulfate drying. The magnesium sulfate was removed by suction filtration, and the filtrate was concentrated to recrystallize from absolute ethanol to give Compound 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium nitrite; In 1,4-dioxane; water; for 2.0h;pH 2.5;Protection from light; | A 0.25 M aqueous solution of NaNO2 (1.0 equivalent) was brought to a pH of 2.5 by the addition of dilute HCl. Dioxane was added to the solution (10% by volume). The flask was protected from light with aluminum foil and 5-chloroindole (1.0 equivalent) was added slowly. The solution was stirred vigorously for 2 hours. The solution was then extracted with three portions of ethyl acetate. The organic layers were combined, washed with water, dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (ethyl acetate:hexane, 1: 1, v/v) yielding 5-chloro-1H-indazole-3-carbaldehyde as a purple solid. LC/MS (m/z) 181.3 (MH+), Rt 2.7 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; In N,N-dimethyl-formamide; at 100℃; for 34h; | General procedure: A mixture of CuI (0.6 mmol), indoles (0.5 mmol) and benzyl cyanide (0.6 mmol) in DMF (3.0 mL) was stirred under air at 100 C for 34 h and then cooled to room temperature. After the reaction mixture was quenched with 10 mL of water, it was extracted with DCM (3×10 mL). The combined organic layers were washed with the saturated aqueous solution of sodium chloride and dried over MgSO4. The solution was concentrated under reduced pressure and purified by column chromatography to afford 3-cyanoindoles. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate; at 20℃; for 12h;Cooling with ice; | General procedure: Synthesis of intermediates 4-6 was carried out following the previously reported procedure. Phosphoryl chloride (0.92ml, 10mmol) was added to ice cold dimethylacetamide (2.79ml, 30mmol) under stirring and cooling in ice. The suitable starting material (1-3) (1mmol) was added and the reaction mixture was stirred at room temperature for 12h, then poured over ice and basified with 4N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was powdered by treatment with diethyl ether and recrystallized from dichloromethane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | General procedure: A heterogeneous mixture of <strong>[521-73-3]isoquinoline-1,3,4-trione</strong>(17.5 mg, 0.1 mmol), indole (14.0 mg, 0.12 mmol) and alginic acid (1.76 mg,0.01 mmol, purchased from Sigma Aldrich) in H2O (0.2 mL) was stirred for 24 h(monitored by TLC). Afterwards, the reaction mixture was concentrated under reduced pressure to leave the crude residue which was purified by column chromatography over silica-gel using ethyl acetate/hexane as a mixture of solvent to give the pure compound 3aa in75% yield (21.9 mg) as a white solid.4-Hydroxy-4-(1H-indol-3-yl)isoquinoline-1,3(2H,4H)-dione (3aa): yield 75%; mp:188-190 C; Rf = 0.25 (EtOAc/hexane = 1:3); 1H NMR (400 MHz, acetone-d6) d10.24 (br s, 1H, NH), 10.10 (br s, 1H, NH), 8.14 (d, J = 7.8 Hz, 1H), 7.89 (d,J = 7.8 Hz, 1H), 7.76-7.79 (m, 2H), 7.59-7.63 (m, 1H), 7.36 (d, J = 8.2 Hz, 1H),7.06-7.10 (m, 1H), 6.96-7.00 (m, 1H), 6.65-6.66 (m, 1H), 5.66 (br s, 1H, OH); 13CNMR (100 MHz, acetone-d6) d 175.0 (CO), 164.7 (CO), 144.3, 138.0, 134.7,129.2, 128.2, 127.9, 125.8, 125.8, 124.8, 122.6, 122.4, 121.7, 120.1, 112.4, 74.7(C-4, quaternary); HRMS (ESI) m/z calcd For C17H12N2O3 [M+Na]+: 315.0897.Found 315.0953. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With isocyanate de chlorosulfonyle; In N,N-dimethyl-formamide; at 0℃; for 3.5h; | General procedure: To a solution of the indole 4b,c (5.10 mmol) in anhydrousacetonitrile (4.5 ml), chlorosulfonyl isocyanate (CSI) (0.44 ml,5.10 mmol) was added dropwise. The reaction mixture was stirredat 0 C for 2 h. Anhydrous dimethylformamide (DMF) (2.8 ml,36.39 mmol) was slowly added and the mixture was maintainedunder stirring at 0 C for 1.5 h. The reaction mixture was pouredinto crushed ice and the precipitate was filtered off (yields98e100%). | |
A solution of the suitable indole 8 (5.10 mmol) in anhydrousacetonitrile (4.5 mL) was treated dropwise with chlorosulfonylisocyanate (CSI) (0.44 mL, 5.10 mmol). The reaction mixture wasmaintained at 0 C under stirring for 2 h, then, anhydrous dimethylformamide(DMF) (2.8 mL, 36.39 mmol) was slowly added andthe mixture was stirred at 0 C for 1.5 h. The resulting solution waspoured into crushed ice. The solid obtained was filtered and dried(yields 98e100%). Analytical and spectroscopic data for compounds9b-e are in agreement with those previously reported [60]. |
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5-Chloro-2,3-dimethyl-1H-indole
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