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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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CAS No. : | 6146-52-7 |
Formula : | C8H6N2O2 |
M.W : | 162.15 |
SMILES Code : | O=N(=O)C1=CC2=C(NC=C2)C=C1 |
MDL No. : | MFCD00005673 |
InChI Key : | OZFPSOBLQZPIAV-UHFFFAOYSA-N |
Pubchem ID : | 22523 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H341 |
Precautionary Statements: | P501-P202-P201-P280-P308+P313-P405 |
* 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 |
---|---|---|
100% | at 0℃; for 0.0833333 h; | Nitro-lH-indole (325 mg, 2.0 mmol)In dichloromethane (6 mL) was added di-tert-butyl dicarbonateEster (524 mg, 2.4 mmol),Stirred at 0 ° C for 5 minutes,A further catalytic amount of 4-dimethylaminopyridine (3 mg, 0.025 mmol) was added,Stirring is then continued for 30 minutes at room temperature.Quenched by adding water (2 mL)Extract with dichloromethane (15 mL x 3).The combined organic phase was washed with water (20 mL)Saturated brine (15 mL × 2)Dried over anhydrous sodium sulfate,The solvent was distilled off under reduced pressure,Obtained as a gray solid (526 mg, 100percent),Directly used for the next reaction. |
99% | With dmap In tetrahydrofuran at 0 - 20℃; for 3 h; | Di-tert-butyl dicarbonate (8.07 g, 37.0 mmol)was siowly added to a stirred solution of 5-nitroindole (6.00 g, 37.0 mmol) and 4-dimethyianiinopyridine (226 Ing, 185 mmol) in THF (60 niL) at 0 °C. The mixture was then stirred for 3h at 20 °C. The reaction solution was concentrated in vacuo and the residue was dissolved in DCM (150 rnL). The organic layer was washed with water, brine, dried (MgSO4), filtered, and the solvent evaporated in vaeuo to yield the title compound (9.60 g, 99percent). |
98% | With triethylamine In dichloromethane at 0 - 20℃; | Triethylamine (3.1 mL, 22.2 mmol) and 4-dimethylaminopyridine (226 mg, 1.85 mmol) were added to a solution of 5-nitro-1H-indole (3 g, 18.5 mmol) in DCM (30 mL) at 0° C., di-tert-butyl dicarbonate (4.3 g, 19.7 mmol) was then added. The resulting mixture was warmed to room temperature and it was stirred overnight, it was then quenched by addition of water and extracted with DCM. The organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure; the crude residue was filtered through a silica pad and the filtrate was evaporated under reduced pressure to give 4.77 g (98percent yield) of 5-nitro-indole-1-carboxylic acid tert-butyl ester. |
89% | With dmap In dichloromethane at 20℃; for 1 h; | 4-DMAP (414.4 mg, 3.4 mmol) and di-tert-butyl dicarbonate (740.3 mg, 3.4 mmol) were added to 5-nitro- l //-indole (500.0 mg, 3.1 mmol) in DCM (5 mL), stirred for 1 h at ambient temperature, 2 M HCL was added followed by extraction with DCM, organic phase was collected and the solvent was removed un- der reduced pressure. Yield 724.0 mg (89percent). HPLC 100percent. LC-MS 263 (M+H)+. |
78% | With dmap In tetrahydrofuran; ethyl acetate | Part F. 5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF. The solution was stirred for 12 h at rt under N2 and was then concentrated. The residue was taken up in EtOAc and the mixture was filtered. The filtered solid was washed with 100 mL of hexanes and dried to give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid (3.1 g, 78percent). LRMS (AP+): 304.2 (M+H+ACN)+. 1H NMR (CDCl3) δ8.51 (d, 1H), 8.23-8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H). |
78% | With dmap In tetrahydrofuran at 20℃; for 12 h; Inert atmosphere | Part F. 5-Nitro-1H-indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (3.6 g, 17 mmol), and DMAP (190 mg, 1.5 mmol) were dissolved in 150 mL of THF. The solution was stirred for 12 h at rt under N2 and was then concentrated. The residue was taken up in EtOAc and the mixture was filtered. The filtered solid was washed with 100 mL of hexanes and dried to give tert-butyl-5-nitro-1H-indole-1-carboxylate as an off-white solid (3.1 g, 78percent). LRMS (AP+): 304.2 (M+H+ACN)+. 1H NMR (CDCl3) δ 8.51 (d, 1H), 8.23-8.29 (m, 2H), 7.75 (d, 1H), 6.73 (d, 1H), 1.71 (s, 9H). |
1 g | With dmap; triethylamine In dichloromethane at 20℃; for 16 h; | 1(1.0 g, 6.17 mmol), DCM (30 mL). DMAP (cat.), TEA (3 eq), (Boc)20 (1.2 eq) reacted at RT. After 16 h anon-polar product was observed by TLC. The reaction was quenched with ice cold water and extracted with DCM (2X10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by silica gel column chromatography [using 100-200 mesh, eluting with 10percent EtOAc-hexanej to afford 1 g of 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With tetrabutylammomium bromide; copper(ll) bromide; In ethanol; at 45℃; | General procedure: A round bottom flask was charged with Bu4NBr (2 mmol, 0.64 g), EtOH (8 mL) and 2-methylaniline (2 mmol, 0.21 g) followed by CuBr2 (3 mmol, 0.67 g). The resulted mixture was stirred at 25 C. After the completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure. To the residue was added ammonium hydroxide (5 mL, 25% w/v) and water (5 mL) with stirring, and the suspension was extracted with DCM(10 mL×4) The organic phase was washed with saturated brine and dried over anhydrous Na2SO4. The product 2b was obtained using flash chromatograph column eluted with PE : EA (5 : 1). |
87% | With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 0℃; for 1h; | To a stirred solution of 5-nitro-lH-indole (1) (100 g, 0.61 mol) in DMF (1 L) was added NBS (131.1 g, 0.74 mol) at 0 C and the solution was stirred for 1 h. After completion of reaction the mixture was diluted with cold water, filtered. The solid was washed with hexanes & product (130.0 g, 87%) used directly to the next step without further purification. |
83% | With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; In 1,4-dioxane; at 10℃; | General procedure: DBDMH (157 mg, 0.55 mmol) was added in five potion to a solution ofindoles (1.0 mmol) in dioxane at 10 C over two minutes with stir, and the resulting solution was stirred for 5to 10 minutes. TLC indicate that the reaction is completed. The reactionsolution was poured into the saturated NaHCO3 solution (10 mL), themixtures was extracted by ethyl acetate (15 mL*2). The organic phase was dried over Na2SO4,filtered, concentrated under reduced pressure. The residue was then purified byflash chromatography on 200~300 mesh silica gel to provide the correspondingproduct 2. |
74% | With pyridinium hydrobromide perbromide; In pyridine; at -4 - 0℃; for 0.0833333h; | Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine (200 rnL) at -40C was added a solution of pyridinium bromide perbromide (10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen with stirring. After complete addition, the reaction mixture was stirred for 5 min at O0C. The reaction mixture was diluted in O0C water (200 mL) and extracted with 200 mL OfEt2O. The organic layer was washed with 6 M HCl (300 mL), 5% NaHCO3 (300 mL), and brine (300 mL). The organic phase was dried over MgSO4 and solvent was removed to give 3-bromo-5-nitroindole as a yellow powder, 80% pure with 20% 5-nitroindole (6.80 g, 74%yield). |
67% | With pyridine; pyridinium tribromide; at -10℃; for 0.166667h; | To a solution of 5-nitro-indole (200 mg, 1.2 mmol) in pyridine (5 mL) was added Py.HBr3 (474 mg, 1.4 mmol) at -10 C. and mixture was stirred for 10 min. Then reaction mixture was quenched by addition of water at 0 C. and then the reaction mixture was extracted with diethyl ether. The organic layer was washed successively with 6N HCl (20 mL), 5% NaHCO3 (20 mL) followed by brine. The combined organic layers were dried (Na2SO4), filtered and concentrated to obtain the title compound (200 mg, 67%) as yellow colored solid. 1H NMR (400 MHz, CDCl3): delta 8.58-8.57 (m, 2H), 8.16 (dd, J=2.0, 8.8 Hz, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.41 (d, J=2.8 Hz, 1H). LCMS: m/e 240.80 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.72 g (4.1 mmol, 80%) | With methylmagnesium bromide; chloranil; In tetrahydrofuran; | 4-Methyl-5-nitroindole To a solution of 5-nitroindole (from Aldrich, 0.82 g, 5.1 mmol) in 20 mL of dry THF was added 5.0 mL (15 mmol) of methylmagnesium bromide for 0.5 h period and the resulting reaction mixture was stirred for 1 h at 25 C. Reaction was the quenched by adding a THF solution of tetrachloro-1,4-benzoquinone (1.2 g, 4.9 mmol). Reaction mixture was concentrated in vacuo, yielding a dark solid which was subjected to column chromatography (30% EtOAc/n-Hexane) to yield 0.72 g (4.1 mmol, 80%) of the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With zinc; In water; acetic acid; ethyl acetate; tert-butyl alcohol; | EXAMPLE 6 Preparation of FCE 28901 To a stirred solution of 5-nitroindole (4 g, 24.6 mmol) in 200 ml of t-Butanol was added, portionwise, pirydinium bromide perbromide (30 g, 93 mmol) over a period of 0.5 h. The reaction mixture was stirred at room temperature overnight, then t-Butanol was removed and the resulting residue dissolved in ethyl acetate/water (500/500 ml). The organic layer was separated and the aqueous layer was extracted with 300 ml of ethyl acetate. The organic extracts were washed with water, dried over sodium sulphate anhydrous and concentrated in vacuo to give 8.5 g of a less polar compound that was recrystallized from ethyl acetate to give 7.5 g of dibromoderivative. Hydrogenation of this compound with 10 equivalents of zinc dust in 80 ml of acetic acid at room temperature for 3 h gave 5-amino oxindole in good yields (3 g, 82percent yield). EI-MS: m/z 148 (100, [M]+); 120 (56, [M-CO]+); 119 (94, [M-CO--H]+); 105 (22, [M-HNCO]+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyrrolidine; In ethanol; at 20℃; for 72h;Heating / reflux; | (4-(5-Nitro-1H-indol-3-yl)-5,6-dihydropyridin-1(2H)-yl)(phenyl)methanone (68) A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.77 mL, 9.250 mmol), 1-benzoyl-4-piperidone (1.0 g, 4.933 mmol) at room temperature and resulting solution was refluxed for 3 days. The reaction cooled to room temperature and the solid was filtered off. The product was washed with cold ethanol (2*10 mL) and dried under vacuum to obtain compound 68 (1.05 g, 98percent) as a solid. mp 280-282° C.; 1H NMR (DMSO-d6) delta 2.55-2.61 (m, 2H), 3.54-3.58 (m, 1H), 3.86-3.90 (m, 1H), 4.15-4.34 (m, 2H), 6.14-6.30 (m, 1H), 7.39-7.55 (m, 5H), 7.67 (d, 1H, J=9.6 Hz), 7.72 (s, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70-8.78 (m, 1H), 11.94 (s, 1H); ESI-MS m/z (percent): 348 (M+, 100), 276 (83), 244 (40). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With tris(bipyridine)ruthenium(II) dichloride hexahydrate; N,N-diphenyl-4-methoxyaniline; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere; Irradiation; | General procedure: An oven dried 10 mL round bottom flask was equipped with a rubber septum and magnetic bar and was charged with the heteroaromatic substrate (0.5 mmol, 1.0 equiv), tris(2,2-bipyridyl)ruthenium(II) chloride hexahydrate (5.0 mumol, 3.70 mg, 1.0 mol %), 4-methoxytriphenylamine (1.0 mmol, 0.274 g, 2.0 equiv), diethyl bromomalonate (1.0 mmol,0.239 g, 2.0 equiv) and DMF (2.0 mL). The mixture was degassed by the freeze-pump-thaw method and the reaction vessel was filled with argon. A 1 Watt blue light emitting diode(LED) strip was placed around the reaction vessel at a distance of approximately 2-4 cm. The reaction was stopped by removing the LED lamps and the mixture was poured into a separatory funnel containing ethyl acetate (10 mL) and water (10 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (2 × 10 mL). The combinedorganic phases were washed with brine (10 mL), dried (anhydrous Na2SO4), filtered and concentrated on a rotary evaporator. The residue was purified by preparative HPLC on a C18 column, using water and acetonitrile as eluent. Appropriate fractions were collected, frozen and lyophilized to afford derivatives of substrates as pure compounds. |
Tags: 5-Nitroindole | Nitroes | Indoles | Heterocyclic Building Blocks | Organic Building Blocks | 6146-52-7
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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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The concentration of the dissolution solution you need to prepare is mg/mL