Structure of 18372-22-0
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| CAS No. : | 18372-22-0 |
| Formula : | C11H9NO3 |
| M.W : | 203.19 |
| SMILES Code : | O=C(OC)C(C1=CNC2=C1C=CC=C2)=O |
| MDL No. : | MFCD00047173 |
| InChI Key : | VFIJGAWYVXDYLK-UHFFFAOYSA-N |
| Pubchem ID : | 588944 |
| GHS Pictogram: |
|
| Signal Word: | Warning |
| Hazard Statements: | H315-H319-H335 |
| Precautionary Statements: | P261-P305+P351+P338 |
| Num. heavy atoms | 15 |
| Num. arom. heavy atoms | 9 |
| Fraction Csp3 | 0.09 |
| Num. rotatable bonds | 3 |
| Num. H-bond acceptors | 3.0 |
| Num. H-bond donors | 1.0 |
| Molar Refractivity | 54.59 |
| TPSA ? Topological Polar Surface Area: Calculated from |
59.16 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.65 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.2 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.52 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.47 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.24 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.62 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.73 |
| Solubility | 0.377 mg/ml ; 0.00185 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-3.08 |
| Solubility | 0.17 mg/ml ; 0.000838 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.31 |
| Solubility | 0.0986 mg/ml ; 0.000485 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.98 cm/s |
| Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
| Ghose? Ghose filter: implemented from |
None |
| Veber? Veber (GSK) filter: implemented from |
0.0 |
| Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
| Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
| PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
| Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
| Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
| Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.67 |
* 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 |
|---|---|---|
| 91% | To a solution of methyl 2-(1H-indol-3-yl)-2-oxoacetate (1.04 g, 5.12mmol, 1.00 equiv) in anhydrous DMF (25.0 mL, 0.205 H) was added sodiumhydride (57-63% suspension in mineral oil, 225 mg, 5.63 mmol, 1.10 equiv) at 0 C. The reaction mixture was stirred at 0 C for 30 mm before iodomethane (872 mg, 6.14 mmol, 1.20 equiv) was added. The reaction mixture was stirred overnight at room temperature. Thereaction was quenched with ice water (50.0 mL) and the aqueous layer was extracted with EtOAc (6 x 30.0 mL) . The organic extracts were combined, washed with 5% LiC1(aq) (5.00 mL), and then dried over Na2SO4. After being concentrated in vacuo, the residue was purified by flash chromatography on silica gel (EtCAc:hexanes = 1:1) to affordthe title compound as a white solid (1.01 g, 4.65 mmol, 91% yield) NMR Spectroscopy: H NHR (400 MHz, CDCl, 25 C, 6): 8.40-8.46 (m, lH), 8.29 (s, 1H), 7.31- 7.40 (m, 3H>, 3.95 (5, 3H), 3.84 (s, 3H) . NMR (100 MHz, CDC13, 25 C, 6): 177.0, 163.5, 140.6, 137.5, 127.1, 124.3, 23.7, 122.8, 112.9, 110.1, 52.8, 33.9. The 1H NMR data werein good agreement with values reported in the literature (N. Wang etal. 2011). | |
| 76.4% | Add 1.0 g (4.9 mmol) of 5a and 10 mL of anhydrous DMF in a three-necked flask, cool to 0 0C, add 0.17 g (4.9 mmol) of 70% NaH, add to room temperature for 30 min and then cool to 0 (5.3 mmol) of CH3I was added dropwise and the reaction was allowed to proceed to room temperature for 1 h. After the reaction was completed, the reaction solution was poured into 100 mL of ice water and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined, Washed with saturated brine (3 x 150 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure,The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to give 0.81 g of a white solid 6b, yield: 76.4% | |
| 33% | Synthesisof2-(1-methylindole-3-yl)-2-oxoacetic acid, methyl ester The 3-indole glyoxylic acid, methyl ester (5.88 g) obtained in the step 1 was dissolved in N,N-dimethylformamide (180 mL), and thereto was added hydrogenated sodium (dispersed in oil at 60%, 1.4 g) in small portions while stirring at 0C. After stirring the reaction mixture for 1 hour, methyl iodide (1.2 mL) was added thereto, and stirred at 20C for 20 hrs. After adding ice-cooled water to the reaction fluid, the pH value was adjusted with 1 mol/L hydrochloric acid to become 5. Thus deposited crystals were filtrated, and washed with water. The crystals were dried under a reduced pressure to obtain 2-(1-methylindole-3-yl)-2-oxoacetic acid, methyl ester (1.96 g, 33%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80.2% | A. Chemical Examples; Example 1; 3,4-Di-(1 H-indol-3-yl)pyrrole-2,5-dione (Compound 1); Potassium tert-butoxide (0.976 g, 8.7 mmol) was added to a stirred suspension of (1 H-indol-3-yl)acetamide (0.5 g, 2.8 mmol) and methyl 3-indolylglyoxylate (0.650, 3.15 mmol) in anhydrous tetrahydrofuran (15 ml), under argon at -10C. After 15 minutes the resultant dark red solution was allowed to warm to 20C over 3.5 hours. Concentrated hydrochloric acid (2ml) was added with cooling, and the orange-red precipitate then dissolved in ethyl acetate by stirring overnight. The organic phase was washed with water and brine, dried (magnesium sulphate) and evaporated to give the title compound as red crystals (0.780 g, 80.2% yield), mp 234C. ¹H-NMR (DMSO-d6, No./ppm) : 11.6 (br s, 1 H), 10.95 (br s, 1 H), 7.68 (s, 1 H), 7.38 (d, 1 H), 6.98 (t, 1 H), 6.8 (d, 1 H), 6.6 (t, 1 H). | |
| 75% | With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 4.5h;Inert atmosphere; | A three-necked flask equipped with a magnetic stirrer and two addition funnels was charged with indole (10.1 g, 0.086 mol) and 100 mL of diethyl ether. Oxalyl chloride (7.3 mL, 0.086 mol) was added dropwise to the solution at 0 C under nitrogen in 0.5 h. Yellow precipitate were formed and the reaction mixture was stirred for another 0.5 h. The reaction mixture was cooled to -70 C by dry-ice, then sodium methylate (25 % solution in methanol, 37.3 g, 0.173 mol) was added dropwise to the reaction mixture in 1 h. After that the reaction mixture was warmed to 0 C and 50 mL of water was added. The precipitate were filtered, washed with water several times, and then dried at 60 C under vacuum. The product of methyl indolyl-3- glyoxylate was obtained as a yellow powder and used without further purification. Yield 90 %. A three-necked flask equipped with a magnetic stirrer and an addition funnel was charged with 3-indoleacetamide (8.0 g, 0.046 mol), methyl indolyl-3-glyoxylate (10.0 g, 0.049 mol) and 80 mL of tetrahydrofuran. A solution of potassium tert-butoxide (15.2 g, 0.135 mol) in 130 mL of tetrahydrofuran was added dropwise to the reaction mixture at 0 C under nitrogen in 1.5 h. Then the reaction mixture was warmed to room temperature and stirred for 3 h. A solution of Hydrochloric acid (35 % in water, 64 mL) was added dropwise to the reaction mixture in 1 h. Then 200 mL of ethyl acetate and 100 mL of water were added and stirred for dissolving. The organic phase was separated, washed with water several times until neutral, and then washed with brine once, dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the solution was concentrated. The product was crystallized by adding a 1:1 (v/v) mixture of ethyl acetate and n-hexane dropwise to the concentrated solution at 50~60 C. The pure product of 3,4-bisindolylmaleimide was obtained as a red crystal. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69% | Synthesis of 3-indole glyoxylic acid, methyl ester Commercially available 3-indole glyoxylic acid (9.55 g) was suspended in methylene chloride (300 mL), and cooled on ice. Thereafter, to the suspension was added oxalyl chloride (8.8 mL), followed by stirring at 20C for 20 hrs. The reaction fluid was cooled on ice, and after adding methanol (190 mL) thereto, the reaction fluid was stirred at 25C for 1 hour. To the reaction fluid were added water and methylene chloride, and thus deposited crystals were filtrated, followed by washing of the crystals with methylene chloride. The crystals were dried under a reduced pressure to obtain 3-indole glyoxylic acid, methyl ester (7.07 g, 69%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 2.5 g | In methanol; diethyl ether; at -78 - 20℃; | To a solution of indole (2.0 g, 17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL, 17.2 mmol) dropwise at 0 C. The yellow slurry was stirred at same temperature for 0.5 h and then cooled to -78 C. A solution of NaOMe in MeOH (25 wt %, 7.8 mL, 34.1 mmol) was added to this slurry at same temperature. After addition, the reaction mixture was allowed to warm to ambient temperature, and quenched by addition of H2O (10 mL). The precipitate was collected by filtration, washed with H2O and dried to give 12 (2.5 g, 73%) as a yellow solid: mp 160 C (dec.); 1H NMR (DMSO-d6) δ 12.42 (s, 1H), 8.45 (d, J = 3.5 Hz, 1H), 8.16 (dd, J = 1.5, 6.0 Hz, 1H), 7.55 (dd, J = 1.5, 6.0 Hz, 1H), 7.32-7.27 (m, 2H), 3.89 (s, 3H). |
| 2.53 g | In methanol; diethyl ether; at -78 - 20℃; | To a stirred solution of indole (2.0 g, 17.1 mmol) in Et2O (20 mL) was added oxalyl chloride (1.5 mL,17.2 mmol) dropwise at 0 C. After the resultant yellow slurry was stirred at 0 C for 0.5 h, it was cooled to -78 C. A solution of NaOMe in MeOH (25 wt %, 7.8 mL, 34.1 mmol) was added to this slurry at -78 C. The reaction mixture was allowed to warm to room temperature and quenched by addition of water (10 mL). The solid was collected by filtration, rinsed with water and dried to give 4a (2.53 g, 73%) as a yellow solid |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | A three-necked flask equipped with a magnetic stirrer and two addition funnels was charged with indole (10.1 g, 0.086 mol) and 100 mL of diethyl ether. Oxalyl chloride (7.3 mL, 0.086 mol) was added dropwise to the solution at 0 C under nitrogen in 0.5 h. Yellow precipitate were formed and the reaction mixture was stirred for another 0.5 h. The reaction mixture was cooled to -70 C by dry-ice, then sodium methylate (25 % solution in methanol, 37.3 g, 0.173 mol) was added dropwise to the reaction mixture in 1 h. After that the reaction mixture was warmed to 0 C and 50 mL of water was added. The precipitate were filtered, washed with water several times, and then dried at 60 C under vacuum. The product of methyl indolyl-3- glyoxylate was obtained as a yellow powder and used without further purification. Yield 90 %. A three-necked flask equipped with a magnetic stirrer and an addition funnel was charged with 3-indoleacetamide (8.0 g, 0.046 mol), methyl indolyl-3-glyoxylate (10.0 g, 0.049 mol) and 80 mL of tetrahydrofuran. A solution of potassium tert-butoxide (15.2 g, 0.135 mol) in 130 mL of tetrahydrofuran was added dropwise to the reaction mixture at 0 C under nitrogen in 1.5 h. Then the reaction mixture was warmed to room temperature and stirred for 3 h. A solution of Hydrochloric acid (35 % in water, 64 mL) was added dropwise to the reaction mixture in 1 h. Then 200 mL of ethyl acetate and 100 mL of water were added and stirred for dissolving. The organic phase was separated, washed with water several times until neutral, and then washed with brine once, dried over anhydrous sodium sulfate. The sodium sulfate was filtered and the solution was concentrated. The product was crystallized by adding a 1:1 (v/v) mixture of ethyl acetate and n-hexane dropwise to the concentrated solution at 50~60 C. The pure product of 3,4-bisindolylmaleimide was obtained as a red crystal. | |
| 86.3% | To a three-necked flask was added 3.0 g (0.026 mol) of indole,30 mL of anhydrous ether, stirring dissolved, control the temperature 0-5 oC,A solution of 3.4 g (0.026 mol) of oxalyl chloride in anhydrous ethyl ether (5 mL) was slowly added dropwise, followed by incubation for 1 h and then cooled to about -25 C,A solution of 16.3 g of sodium methoxide in methanol (17.5%, 0.052 mol)After dripping for 30 min, the reaction solution was poured into 100 mL of ice water, filtered, washed with water (3 x 10 mL)Dichloromethane (2 x 10 mL),Dried to give 4.5 g of a pale yellow solid 5a in a yield of 86.3% | |
| 86% | To a solution of 1H-indole (6.00 g, 51.2 mmol, 1.00 equiv) in Et20(60.0 mL, 0.850 M) was added oxalyl chloride (5.27 mL, 61.4 mmol, 1.20equiv) dropwise at 0 C. The yellow slurry was stirred at 0 C for 30mm and then cooled to -78 C. A solution of NaOMe in MeOH (25%, 23.0mL) was added to this slurry at the same temperature. The reaction mixture was then allowed to warm up to room temperature, and was quenched by addition of water (40.0 ml) . The precipitate was collected by filtration, washed with water and dried to afford the title compoundas a gray solid (8.96 g, 44.0 mmol, 86% yield).NMR Spectroscopy: 1H NMR (700 MHz, (CD,)2S0, 25 C, 5): 12.50 (s, 1H),8.44 (d, J = 3.2 Hz, 1H), 8.16 (d, J = 7.6 Hz, 1H), 7.55 (d, J 7.7Hz, 1H), 7.25 - 7.33 (m, 2H), 3.89 (s, 3H) . “C NMR (175 MHz, (CD3)2S0,25 C, 5): 178.7, 164.0, 138.4, 136.7, 125.5, 123.8, 122.9, 121.1,112.8, 112.4, 52.5. The ‘H NMR data were in good agreement with values reported in the literature (Ye, Q. et al. 2015) |
[ 18372-22-0 ]
[ 6343-93-7 ]
[ 18372-22-0 ]
[ 74860-13-2 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 90% | In a reaction flask,7 g ( 60 mmol ) indole and 300 mL of dry diethyl ether were add, and 16.1 mL of oxalyl chloride was added dropwise to the reaction solution at 0 C. The reaction was continued for 6 h at room temperature to form a yellow suspension. It was further placed at 0 C, 12 mL of methanol was added dropwise to the reaction, and the mixture was stirred for 30 min. The resulting mixture was filtered and washed with ice ether to finally obtain a yellow solid 1 ( 10.93 g , 90% yield). | |
| 90% | 7g (60mmol) of indole and 300mL of dry ether were added to a reaction flask, and 16.1mL of oxalyl chloride was added dropwise to the reaction solution at 0C. After the drop was completed, the reaction was carried out at room temperature for 6 hours to form a yellow suspension. It was placed at 0 C., 12 mL of methanol was added dropwise thereto, and stirred for 30 min. The resulting mixture was filtered and washed with glacial ether. Finally, 10.93 g of yellow solid 1 was obtained with a yield of 90%. | |
| To a solution of indole (10.0 mmol, 1.0 equiv) in dry Et2O (50 mL) was added dropwise oxalyl chloride (2.7 mL, 30.0 mmol, 3.0 equiv) at 0 C. Then the ice bath was removed and the resulting yellow slurry was stirred for 6 h at room temperature. The reaction mixture was then cooled to 0 C and quenched with MeOH (2.0 mL, 50.0 mmol, 5.0 equiv). The crude precipitate was collected by filtration and was washed with cold Et2O. The solid 3 was dried under vacuum and useddirectly for the next step without further purification.A solution of compound 3 in THF (20 mL) was added dropwise to a suspension of LiAlH4 (1.5 g, 4.0equiv) in THF (40 mL) at 0 C. The reaction mixture was stirred for 4 h at room temperature and quenched with H2O (1.5 mL), 10% aqueous NaOH (3.0 mL), and H2O (4.5 mL) slowly at 0 C. Thereaction mixture was then filtered and the filtrate was extracted with EtOAc. The combined organic layerswere dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel (petroleum ether:EtOAc, v/v = 1:1) to give tryptophol 5 (1.3 g, 80% for two steps) as a yellow solid. NMR data were in consistent with thosereported.15 |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h; | A mixture of Compound 1d (4.00 g, 19.7 mmol), Compound 1b (5.19 g, 21.7 mmol) and cesium carbonate (7.06 g, 21.7 mmol) in DMF (40 mL) was stirred at 50 C. for 4 h and then filtered. The filtrate was evaporated in vacuo and the residue was separated by flash column chromatography (EtOAc/heptane, 1:2) to give Compound 1e as a viscous oil. 1HNMR (CDCl3) δ 8.61 (m, 2H), 7.51 (m, 3H), 4.45 (t, J=5.1 Hz, 2H), 4.13 (m, 2H), 4.10 (s, 3H), 0.96 (s, 9H), 0.1 (s, 6H). ES-MS m/z 362 (MH+). |
[ 18372-22-0 ]


| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 47% | With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20 - 50℃; | Compound 1b (4.0 g, 0.0197 mole) and 1,2-dibromoethane (18.5 g, 0.0985 mole) were combined in anhydrous DMF (80 mL) and treated with cesium carbonate (12.8 g, 0.0394 mole). The mixture was stirred under an argon atmosphere at rt for 1 h, then the temperature was raised to 50 C for 4 h. The mixture was stirred at rt overnight. The resulting white solids were removed by filtration, then partitioned between 600 mL of ether and 300 mL of water. The organic layer was washed with water (3X) and brine, then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the resulting oily residue triturated with hexane to give a crude solid product. The crude solid was RECRYSTALLIZED from ethyl acetate/hexane and flash chromatographed on silica eluted with ethyl acetate/hexane to give Compound 1c (5.5 g, 47%). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 70℃; for 5h;Inert atmosphere; | In a three-necked flask, 47 mL lithium aluminum hydride (4.44 g, 117 mmol, 2.5 mol/L THF solution) was injected under Nitrogen at 0 C. 10.15 g (50 mmol) 1 was dissolved in 36 mL of dry THF. The above solution was added dropwise for a period of 1 h, then heated to 70 C for 4 hours. The reaction was complete and quenched by the Fisher treatment for a suspension. The suspension was filtered and the filter cake washed with ethyl acetate. The combined organic layer was wash with brine, dry over Na2SO4 and concentrated in vacuum. The residue was purified by flash silica gel column chromatography(ethyl acetate / petroleum ether, 25%) to obtain a white solid 2 (6.44 g, 80% yield). |
| 80% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 70℃; for 5h;Inert atmosphere; | In a three-necked flask, under nitrogen protection, inject 47mL lithium aluminum hydride (4.44g, 117mmol, 2.5mol/L THF solution), place it at 0, and dissolve 10.15g (50mmol) yellow solid 1 in 36mL THF , Added dropwise to the above solution for 1 hour, then heated to 70C to keep the reaction for 4 hours, the reaction was complete, the reaction was quenched by Fieser treatment, the resulting suspension was filtered, the filter cake was washed with ethyl acetate, saturated salt The filtrate was washed with water, the organic layer was separated, concentrated, and finally purified by silica gel column chromatography to obtain 6.44 g of white solid 2 with a yield of 80%. |
| With sodium borohydrid; In isopropyl alcohol; | EXAMPLE 1 3-(2-Hydroxyethyl)indole A vigorously-stirred mixture of isopropanol (3 1), methyl 3- indolylglyoxylate (305 g) and sodium borohydride (125 g) was warmed to 40 - 50 and held at that temperature until the initial exothermic reaction was complete. The mixture was then heated to reflux for 4 hours, cooled and diluted with water (5 l). After acidification with hydrochloric acid the product was extracted into dichloromethane. The separated extract was washed with sodium carbonate solution to remove 3-indolylacetic acid and then with water. Evaporation of the solvent gave the crude product as a brown oil. This was distilled at 0.5 - 1 mm pressure (vapour temperature 160 - 190) and crystallized from toluene (1 l) to give the title compound as white to pale brown crystals m.p. 57 - 59. Yield 170 g. (70% of theory). |
| 1.3 g | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 4h;Inert atmosphere; | To a solution of indole (10.0 mmol, 1.0 equiv) in dry Et2O (50 mL) was added dropwise oxalyl chloride (2.7 mL, 30.0 mmol, 3.0 equiv) at 0 C. Then the ice bath was removed and the resulting yellow slurry was stirred for 6 h at room temperature. The reaction mixture was then cooled to 0 C and quenched with MeOH (2.0 mL, 50.0 mmol, 5.0 equiv). The crude precipitate was collected by filtration and was washed with cold Et2O. The solid 3 was dried under vacuum and useddirectly for the next step without further purification.A solution of compound 3 in THF (20 mL) was added dropwise to a suspension of LiAlH4 (1.5 g, 4.0equiv) in THF (40 mL) at 0 C. The reaction mixture was stirred for 4 h at room temperature and quenched with H2O (1.5 mL), 10% aqueous NaOH (3.0 mL), and H2O (4.5 mL) slowly at 0 C. Thereaction mixture was then filtered and the filtrate was extracted with EtOAc. The combined organic layerswere dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography on silica gel (petroleum ether:EtOAc, v/v = 1:1) to give tryptophol 5 (1.3 g, 80% for two steps) as a yellow solid. NMR data were in consistent with those reported.15 |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 16.1 (1H-indol-3-yl)-oxo-acetic acid A mixture of 610 mg of methyl indolyl-3-glyoxylate and 3.3 cm3 of 1N soda in 3.3 cm3 of water is heated for 1 h at 80 C., then it is cooled on an ice bath and 3.5 cm3 of 1N hydrochloric acid is added. The mixture is extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 554 mg of (1H-indol-3-yl)-oxo-acetic acid in the form of a yellow solid. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 3.21 g (93%) | With sodium methylate; In diethyl ether; water; | Preparation 6 Methyl indolyl-3-glyoxylate A solution of indole (2.0 g, 1.70 mmol) in Et2 O (20 mL) was cooled to 0-5 C. under N2 and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5 C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65 C. and a 25% wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at <-58 C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93%) of the titled compound. NMR. MS (FD) m/z=203 (M+, 100%). Analytical calculated for C11 H9 NO3 C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03. |
| 3.21 g (93%) | With sodium methylate; In diethyl ether; water; | Preparation 6 Methyl indolyl-3-glyoxylate A solution of indole (2.0 g, 1.70 mmol) in Et2O (20 mL) was cooled to 0-5C under N2and oxalyl chloride (1.5 mL 1.70 mmol) was added dropwise at <5C. The resultant yellow slurry was stirred 30 min. in the ice bath and was then cooled to -65C and a 25% wt. solution of sodium methoxide (7.8 mL, 3.4 mmol) was slowly added at <-58C. The reaction was then allowed to warm to room temperature, water was added (10 mL), and the resultant mixture filtered. The solid was dried at room temperature to give 3.21 g (93%) of the titled compound. NMR. MS (FD) m/z= 203 (M+, 100%). Analytical calculated for C11H9NO3C, 65.02; H, 4.46; N, 6.89. Found C, 64.93; H, 4.25; N, 7.03. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 47℃; for 24h; | Compound 1b (1.50 g, 7.4 mm) and 1,3-dibromopropane (3.75 mL, 37.0 mm) were dissolved in dry DMF (30 mL) followed by the addition of cesium carbonate (4.89 g, 15.0 mm). The mixture was stirred at 47 C for 24 hrs, then cooled to rt and filtered. The filtrate was diluted with ethyl acetate, washed with water (4x) and brine (1X), then dried (NA2SO4) and evaporated in vacuo. The crude product was chromatographed (SILICA GEL-10% EtoAc/90% Hex to 20% EtoAC/80% Hex) to afford Compound 5a (0.890 G). HNMR (CDOS) 8 2.39- 2.47 (m, 2H, CH2), 3.33 (t, 2H, CH2), 3.96 (s, 3H, CH3), 4.44 (t, 2H, CH2), 7.35- 7.46 (m, 3H, aromatics), 8.45-8. 47 (m, 2H, aromatics). ES-MS M/Z 324 (MH+). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 28h; | Compound 1 B (2.50 g, 12.3 mm) was dissolved in dry DMF (50 mL) followed by the addition of 3-dimethylaminopropyl chloride hydrochloride (2.34 g, 14.8 mm) and cesium carbonate (10.00 g, 30.7 mm). The mixture was stirred at 60 C for 24 hrs. Additional 3-dimethylaminopropyl chloride hydrochloride (0.5848 g, 3.7 mm) was added and the reaction was stirred at 60 C C for 4 hrs. The mixture was filtered and the filtrate was diluted with ethyl acetate, washed with water (4x) and brine (1X), then dried (NA2SO4) and evaporated in vacuo. The crude product was chromatographed (silica gel 97% DCM/3% MeOH to 95% DCM/5% MeOH) to afford Compound 4c (1.35 G). HNMR (DMSO) 6 1.88- 2.00 (m, 2H, CH2), 2.12 (s, 8H, CH2 and CH3), 3.89 (s, 2H, CH3), 4.34 (t, 2H, CH2), 7.29-7. 38 (m, 2H, H-5 and H-6), 7.67 (d, 1H, H-7), 8.17 (d, 1H, H-4) and 8.49 (s, 1 H, H-2). ES-MS M/Z 289 (MH). Compound 4b (0.060 g, 0.26 mm) and Compound 4c (0.1124 g, 0.39 mm) were dissolved in dry THF (1 mL) followed by the addition of 60% NaH (0.104 g, 2.6 mm). The mixture was stirred at ambient temperature for 3 hrs and then the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with water (1X15 mL) and brine (1x15 mL), then dried (NA2SO4), and evaporated in vacuo. The crude product was chromatographed (silica gel-97% DCM/ 1% MeOH/2% NH40H) to afford Compound 31 (0.0275 g, 23%). HNMR (CD30D) 8 0.3793-0. 4566 (m, 2H, CH2), 0. 6618 (s, 6H, CH3), 0.759 (t, 2H, CH2), 2.71 (t, 2H, CH2), 4.85-4. 99 (m, 2H, aromatics), 5.42-5. 61 (m, 3H, aromatics), 5.80 (d, 2H, aromatics), 6.19 (d, 1H, aromatics), 6.38 (d, 2H, aromatics). ES-MS M/Z 464 (MH+). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | In methanol; hexane; dichloromethane; at 0 - 20℃; | A suspension of Compound 1a (10.0 g, 0.053 mole) in dichloromethane : methanol (6: 1 ratio; 350 mL) was stirred and cooled in an ice bath while a solution of TMSCHN2 (79 mL, 2.0 M) in hexane was added dropwise over a 1 hr period. The mixture was allowed to warm to rt and was stirred overnight. The resulting light yellow solid was filtered and washed with ether to yield Compound 1B (7.5 g, 70%). 1H NMR (DMSO-d6) â 12.5 (s, 1H), 8.45 (d, 1H), 8.2 (d, 1H), 7.55 (d, 1H), 7.3 (m, 2H), 3.95 (s, 3H). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium hydride; In tetrahydrofuran; at 20℃; for 5h; | Potassium carbonate (2.42 g, 17.5 MMOL) and 3-dimethylaminopropyl chloride hydrochloride (1.03 g, 6.51 MMOL) were added to phenol Compound 9a (0.92 g, 4.34 MMOL) in DMF (20 mL) and heated in an oilbath at 60 C for 3 h. The mixture was cooled and partitioned between DCM (75 mL) and water (25 mL); the DCM was washed twice with water and once with brine, then dried (K2CO3) and evaporated in vacuo to an oil Compound 9b (1. 08 G). H NMR (CDCI3) 8 1.95 (m, 2 H), 2.30 (s, 3H), 2.45 (m, 2H), 3.80 (s, 2H), 4.0 (m, 2H), 6.78 (bd d, J = 8. 0 Hz, 1 H), 7.05 (bd s, 1 H), 7.45 (d, J = 8. 0 Hz, 1 H). ES-MS MLZ 297 (MH+). This was dissolved in t-butanol (30 mL) and potassium hydroxide (1.02 g, 17.5 MMOL) was added and the reaction REFLUXED for 45 min. The reaction was cooled and evaporated in vacuo to a brown oil Compound 9c (0.35 g); ES- MS m/z 315 (MH+). A portion of the amide Compound 9c (350 mg, 1.11 MMOL) and the ester Compound 1b (250 mg, 1.22 MMOL) in THF (20 mL) were stirred at rt as 60% NaH (266 mg, 6.66 MMOL) was added. After 5 h, the reaction was quenched with 12 N HCI (4.0 mL, 48 mmol), stirred for 10 min and then partitioned between EA and saturated sodium bicarbonate. The organic layer was washed once with sodium bicarbonate and twice with brine, then dried (NA2SO4) and evaporated in vacuo to give the crude product of Compound 24 (250 mg) as a yellow oil. The product was purified by preparative TLC to give Compound 24. 1H NMR (CDC13) 8 1.90 (m, 2 H), 2.30 (s, 3H), 2.45 (m, 2H), 3.95 (m, 2H), 6.65 (d, J = 8.0 Hz, 1 H), 6.80 (m, 1 H), 6.85 (s, 1 H), 7.10-7. 60 (m, 4H), 8.05 (s, 1 H), 8.80 (s, 1 H) ; ES-MS M/Z 468 (MH+). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 56% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20℃; for 1h; | 3-BUTYNYL P-TOSYLATE Compound 2a (0.90 g, 4.0 MMOL) and 2-METHYLAMINOETHANOL (0.30 g, 4.0 mmol) were dissolved in DMF (2 mL) and sodium bicarbonate (0.34 g, 4.0 MMOL) was added. The mixture was heated to 75 C under argon for 2 h then cooled to rt and partitioned between DCM (30 mL) and saturated sodium bicarbonate (15 mL). The organic layer was washed once with sodium bicarbonate (15 mL), once with brine (10 mL), then dried (NA2SO4) and evaporated in vacuo to give Compound 2b as a colorless oil (0.98 g). Compound 2b was added to Compound 1b (0.43 g, 2.1 MMOL) followed by triphenyl phosphine (0.73 g, 2.8 MMOL) in THF (15 mL) and DIETHYLAZODICARBOXYLATE (0.49 g, 2.8 MMOL) and the mixture was stirred at ambient temperature for 1 h. The product was evaporated in vacuo to an oil, which was purified via flash column chromatography (ethyl acetate) to give Compound 2c (0.37 g, 56%) as a tan solid. ES-MS m/z 313 (MH+). A portion of the indole Compound 2c (34 mg, 0.11 MMOL) and 1-naphthalene acetamide (Compound 2d, 18 mg, 0.11 MMOL) in THF (1 mL) were treated with 1 M potassium t-butoxide in THF (0.33 mL, 0.33 MMOL) while being cooled in an ice bath. The mixture was stirred at ambient temperature for 3 h, then treated with 12 N HCI (0.15 mL), stirred for 10 min and evaporated in vacuo to give an oil. The oil was partitioned between chloroform and saturated sodium bicarbonate. The organic layer was washed again with saturated sodium bicarbonate, once with brine, then dried (NA2SO4) and evaporated in vacuo to give a mixture of Compound 17 and Compound 18 (50 mg) as an orange oil. The material was purified by preparative TLC to separate Compound 17 and Compound 18. Compound 17 : H NMR (CDCI3) 5 1.81 (s, 3 H), 2.31 (s, 3H), 2.81 (m, 2H), 3.30 (BD S, 2H), 4.22 (m, 2H), 6.18 (d, J=8. 0HZ, 1H), 6.52 (m, 1 H), 7.0 (m, 1 H), 7.15-8. 0 (m, 8H), 8.07 (s, 1 H) ; ES-MS M/Z 448 (MH+). Compound 18: 1H NMR (CDCI3) 61. 97 (m, 1 H), 2.24 (m, 2H), 2.29 (s, 3H), 2.61 (t, J = 7.3 Hz, 2H), 2.77 (m, 2H), 4.19 (m, 2H), 6.18 (d, J = 8.2 Hz, 1H), 6.51 (m, 1 H), 7.0 (m, 1 H), 7.20-7. 93 (m, 8H), 8.04 (s, 1 H) ; ES-MS M/Z 448 (MH+). |
[ 870274-22-9 ]
[ 18372-22-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 1h; | Example 2: 3-[2-Amino-5-(4-methyl-piperazin-I -yl)-phenyl]-4-(l H-indol-3-yl)-pyrrole-2,5-dione; To a solution of 2-[2-amino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (124 mg, 0.50 mmol) and (1 H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (4.0 mL) is added a solution of 1.0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at 0 C under argon. After stirring for 30 min at 0 C and 30 min at RT, TLC indicates the complete consumption of the acetamide. The dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat. , aqueous NH4CI solution. The aqueous layer is extracted with EtOAc (2 x 25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2S04, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc / AcOH / H20 5.5 : 1 : 1) to afford the title compound as its water soluble acetate salt. Red solid. ¹H NMR (DMSO-d6, 400 MHz): 8 1.70 (s, 9H, CH3COO-), 2.25 (s, 3H), 2.22 - 2.38 (m, 4H), 2.78 - 2.84 (m, 4H), 6.51 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1 H), 6.64 - 6.68 (m, 2H), 6.77 (dd, J = 8.7 Hz, J = 2.8 Hz, 1 H), 6.97 - 7.02 (m, 1 H), 7.35 (d, J = 8.0 Hz, 1H), 7.90 (s, 1 H), 11.91 (bs, 1H). ES+-MS: 402 [M + H]+. |
[ 870274-25-2 ]
[ 18372-22-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 18h; | Example 3:; N-[2-[4-(1 H-Indol-3-yl)-2,5-dioxo-2,5-dihydro-1 H-pyrrol-3-yl]-4-(4-methyl-piperazin-I -yl)- phenyl] -acetamide; To a suspension of 2-[2-Acetylamino-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide (145 mg, 0.50 mmol) and (1 H-indol-3-yl)-oxo-acetic acid methyl ester (183 mg, 0.90 mmol) in dry THF (6.0 m L) is a dded a s olution of f 1 .0 M t-BuOK in THF (2.0 mL, 2.0 mmol) at O under argon. The resulting yellow suspension is stirred for 18 h at RT. The now dark red reaction mixture is partitioned between EtOAc (25 mL) and brine (25 mL), and the layers are separated. The pH of the aqueous layer is adjusted to 6 with a sat. , aqueous NH4CI solution. The aqueous layer is extracted with EtOAc (2 x 25 mL) and the combined organic layers are washed with brine (25 mL), dried over Na2S04, and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/ AcOH / H20 5.5 : 1 : 1) to afford the title compound as its water soluble acetate salt. Orange solid. ¹H NMR (DMSO-d6, 400 MHz) : No. 1.75 (s, 12H, CH3COO-), 2.16 (s, 3H), 2.31 - 2.38 (m, 4H), 2.92 - 2.99 (m, 4H), 6.61 (d, J = 7.8 Hz, 1 H), 6.66 (t, J = 7.4 Hz, 1 H), 6.75 (d, J = 2.5 Hz, 1 H), 6.92 (dd, J = 9.0 Hz, J = 2.7 Hz, 1 H), 6.99 (t, J = 7.5 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.47 (d, J = 8.9 Hz, 1 H), 7.75 (s, 1 H), 8.69 (s, 1 H), 11.86 (bs, 1 H). ES+-MS: 444 [M + H]+. |
[ 870274-19-4 ]
[ 18372-22-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium tert-butylate; In tetrahydrofuran; at 0 - 20℃; for 1.5h; | Example 1:; 3-(l H-Indol-3-yl)-4-[5-(4-methyl-piperazin-I -yl)-2-nitro-phenyl]-pyrrole-2,5.dione ; To a solution of 2-[5-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-acetamide (278 mg, 1.00 mmol) and (1 H-indol-3-yl) -oxo-acetic acid methyl ester (366 mg, 1.80 mmol) in dry THF (8.0 mL) is added a solution of 1.0 M t-BuOK in THF (4.0 mL, 4.0 mmol) at 0 C under argon. After stirring for 30 min at 0 C and 1 h at RT, TLC indicates the complete consumption of the acetamide. The purple reaction mixture is partitioned between EtOAc (50 mL) and brine (50 mL), the layers are separated, and the aqueous layer is extracted with EtOAc (50 mL). The combined organic layers are dried over Na2S04 and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc / AcOH / H20 7 : 1 : 1) to afford the title compound as its water soluble acetate salt. Orange solid. (at)H NMR (DMSO-d6, 400 MHz) : No. 1.84 (s, 6H, CH3COO-), 1.97 - 2.15 (m, 4 H), 2.03 (s, 3H), 2.95 - 3.21 (m, 4H), 6.51 (d, J = 7.8 Hz, 1 H), 6.54 (d, J = 2.7 Hz, 1 H), 6.73 (t, J = 7.8 Hz, 1 H), 7.01 - 7.07 (m, 2H), 7.41 (d, J = 8.1 Hz, 1 H), 8.00 (s, 1 H), 8.13 (d, J = 9.4 Hz, 1 H), 10.8 - 11.4 (br, 1 H), 11.95 (bs, 1 H). ES+-MS: 431 [M + H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With NaH; In N,N-dimethyl-formamide; | EXAMPLE 19 3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-[1-(3-pyridinyl)-1H-indazol-3-yl]-1H-pyrrole-2,5-dione (Compound 59) The indol-3-yl-glyoxylic methyl ester (0.50 g, 2.46 mmol) Compound 2b and 3-dimethylamino propyl chloride hydrochloride (0.44 g, 2.78 mmol) were combined in DMF (5 mL) and cooled to 0 C. as 95% NaH (135 mg, 5.34 mmol) was added. The reaction vessel was placed in an oilbath at 55 C. for 20 h and then cooled to ambient temperature. The solution was diluted with DCM (30 mL), washed with water, 3 times with saturated NaHCO3 and once with brine, then dried (K2CO3) and evaporated in vacuo to give an oil (0.44 g, 62%). The oil was purified via flash column (DCM:MeOH; 10:1) to afford Compound 19a. ES-MS m/z 289 (MH+). |

[ 18372-22-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium tert-butylate; In tetrahydrofuran; at 20 - 50℃; for 1.03333h; | Example 1: 3-(1H-indol-3yl)-4-[6-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-pyridin-2-yl]-pyrrole-2,5-dione 2-[6-(4-methyl-piperazin-1-yl)-3-trifluoromethyl-pyridin-2-yl]-acetamide (60 mg, 0.132 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (40 mg, 0.199 mmol) are azeotroped twice are dry THF and then dissolved in dry THF (2 ml). A solution of 1.0 M KOtBu in THF (0.73 ml) is added dropwise over 2 minutes at RT. The reaction mixture is warmed to 50C for 1 hour, after which TLC analysis indicates complete conversion of starting materials. The reaction is quenched by the addition of water (5 ml). The mixture is diluted with EtOAc and washed twice with saturated aq. NH4Cl. The aqueous layers are backextracted twice with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 800:55:45 to 750:83:68 to 700:110:90 to 600:150:150) to afford the title compound as its acetate salt. After azeotroping with MeOH/toluene, the product is obtained as its acetate-methanol complex. 1H NMR (DMSO, 400 MHz) δ 2.10 (s, 3H), 2.10-2.22 (m, 4H), 3.47-3.52 (m, 4H), 6.58 (d, J = 8.9 Hz, 1H), 6.73-6.76 (m, 1H), 7.02 (d, J = 10.0 Hz, 1H), 7.04-7.08 (m, 1H), 7.40 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 10.0, 1 H), 8.03 (s, 1 H); ES-MS: 456.5 [M+H]+. |

[ 18372-22-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 1.01667h; | Example 29: 3-(5-Chloro-2-dimethylaminomethyl-1H-indol-4-yl)-4-(1H-indol-3-yl)-pyrrole-2,5-dione 2-(5-chloro-2-dimethylaminomethyl-1H-indol-4-yl)-acetamide (50 mg, 0.19 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (57 mg, 0.28 mmol) are dissolved under an atmosphere of argon in 3 ml of dry THF. Molecular sieves (3Å, 100 mg) are added. A solution of 1.0 M KOtBu in THF (0.57 ml) is added dropwise at RT over a period of 1 minute. After 1 hour, TLC analysis indicates complete consumption of starting materials. The reaction mixture was diluted with EtOAc and washed twice with saturated aq. NH4Cl and once with saturated aq. NaCl. The aqueous layers are backextracted with EtOAc. The combined organic layers are dried over Na2SO4 and the solvent evaporated to give a quantitative yield of crude 4-(5-chloro-2-dimethylaminomethyl-1H-indol-4-yl)-3-hydroxy-3-(1H-indol-3-yl)-pyrrolidine-2,5-dione. This product is dissolved in dry DMF (4 ml) under an atmosphere of argon, and DBU (141 microL, 0.94 mmol) is added at RT. The reaction flask is then immersed in a oil-bath preheated to 120C for 10 minutes. TLC analysis indicates complete conversion of the starting material. The reaction mixture is diluted with EtOAc and washed with saturated aq. NaCl. The organic layer is dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (EtOAc/AcOH/H2O 700:110:90 to afford the title compound as its acetate salt. 1H NMR (DMSO, 400 MHz) δ 1.96 (s, 6H), 3.30-3.42 (m, 2H), 5.86 (s, 1H), 6.38 (d, J = 8.4 Hz, 1H), 6.51 (t, J = 8.4 Hz, 1H), 6.94 (t, J = 8.4 Hz, 1H), 7.29 (d, J = 9.0 Hz, 1H), 7.32 (d, 8.4 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 11.3 (s, 1H), 12.0 (br s, 2H); ES-MS: 419.1 [M+H]+. |


[ 18372-22-0 ]

[ 244086-64-4 ]| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 54.5 mg (79%) | With potassium tert-butylate; In ethyl acetate; N,N-dimethyl-formamide; | 3-[4-(1H-imidazol-1-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indole (19) To a stirred solution of t-BuOK (140 mg, 1.25 mmol) in DMF (2.0 mL) at 0 C. was added a solution of 20 (31.1 mg, 0.249 mmol) and <strong>[18372-22-0]methyl indole-3-glyoxylate</strong> (21) (101.1 mg, 0.498 mmol) in DMF (3.0 mL). The reaction mixture was stirred for 12 h at rt and then heated to 45 C. for 3 h. The reaction mixture was then cooled and treated with saturated aqueous NH4Cl (5 mL) and EtOAc (20 mL). The phases were separated and the aqueous layer was extracted with EtOAc (2*20 mL). The combined organic extracts were washed with brine (4*10 mL), dried (MgSO4), and concentrated. Flash chromatography (25 g of silica gel, 10:1 then 6:1 CH2Cl2-MeOH) of the crude material afforded 54.5 mg (79%) of 19 as a red solid that exhibited IR (KBr) 3121, 2729, 1767, 1719, 1651, 1495, 1340, 1239, 746 cm-1; 1H NMR (400 MHz) 10.75 (bs, 1H), 10.00 (bs, 1H), 8.03 (d, 1 H, J=3.1 Hz), 7.78 (s, 1H), 7.48 (d, 1H, J=8.2 Hz), 7.29 (s, 1H), 7.11 (dd, 1H, J=8,8 Hz), 7.04 (s, 1H), 6.80 (dd, 1H, J=8,8 Hz), 6.21 (d, 1H, J=7.6 Hz); 13C NMR (100 MHz) 170.4, 168.4, 137.8, 136.4, 131.6, 128.8, 125.8,124.3,124.1, 122.5, 120.6, 120.1, 119.6,112.3,102.3; HREIMS calcd for C15H10N4O2 278.0804, found 278.0804. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With acetic acid; acetyl chloride; In ethanol; for 18h;Heating / reflux; | Example 2 2-Ethyl-4-oxo-4,5-dihydro-2H-pyrazolo[3,4-c]quinoline-l-carbaldehyde EPO <DP n="53"/>Part AAcetyl chloride (0.7 mL, 9.8 mmol), acetic acid (1 mL), and ethylhydrazine (1.5 g, 9.8 mmol) were added sequentially to a suspension of methyl (l/f-indol-3-yl)gly oxalate (1.0 g, 4.9 mmol) in ethanol (25 mL). The reaction mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was combined with acetonitrile. A pink solid was isolated by filtration and then purified by automated flash chromatography (Biotage, eluted with a gradient of 0 - 30% CMA in chloroform) to provide a white solid. This material was recrystallized from acetonitrile to provide 360 mg of 2-ethyl-2,5-dihydro-4H- pyrazolo[3,4-c]quinolin-4-one as white crystals, mp >250 0C. MS (APCI) m/z 214 (M + H)+; Anal, calcd for C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C, 67.52; H, 5.14; N, 19.90. |

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