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CAS No. : | 169037-23-4 | MDL No. : | MFCD00192524 |
Formula : | C9H4F3NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XHAJMVPMNOBILF-UHFFFAOYSA-N |
M.W : | 231.13 | Pubchem ID : | 2732752 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 48.84 |
TPSA : | 55.4 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.42 cm/s |
Log Po/w (iLOGP) : | 1.21 |
Log Po/w (XLOGP3) : | 1.82 |
Log Po/w (WLOGP) : | 2.41 |
Log Po/w (MLOGP) : | 0.35 |
Log Po/w (SILICOS-IT) : | 2.05 |
Consensus Log Po/w : | 1.57 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.57 |
Solubility : | 0.629 mg/ml ; 0.00272 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.6 |
Solubility : | 0.576 mg/ml ; 0.00249 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.41 |
Solubility : | 0.0895 mg/ml ; 0.000387 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
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 |
---|---|---|
General procedure: Substituted aniline (1 mmol), 1N HCl (1 mL), H2O (6 mL), hydroxylamine hydrochloride (226 mg, 3.25 mmol), and anhydrous Na2SO4 (900 mg) was added in 25 ml seal tube, heat to boiling, andthen added chloral hydrate (198 mg, 1.2 mmol), kept boiling for 40 min, cooled, and then extracted with Ethyl acetate. The Ethyl acetate extracts were dried (Na2SO4) and evaporated. The residuewas added to a stirred solution of concentrated H2SO4 (1 mL) and H2O (0.1 mL) during 10 min at 65 C. The mixture was then kept at 80 C for 10 min and then poured onto cracked ice. Then the mixture was extracted with Ethyl acetate, and, the organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure to afford the substituted isatins as crude product,and then compound 11a-j was obtained by substituted isatins through the General procedure A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With dihydrogen peroxide; sodium hydroxide; In water; at 10 - 35℃; for 0.333333h; | Step 1 5-(Trifluoromethoxy)isatin (2.00 g, 8.65 mmol) was dissolved in 1N aqueous sodium hydroxide solution (150 mL) and aqueous hydrogen peroxide (30-35%, 2.45 mL) was added dropwise at room temperature to this solution. The reaction mixture was stirred at room temperature for 20 min., and adjusted to pH 3-4 by adding 1N hydrochloric acid. The precipitated insoluble material was collected by filtration, and washed with water to give 5-(trifluoromethoxy) anthranilic acid as a brown powder (1.88 g, 98%). |
With potassium hydroxide; dihydrogen peroxide; In water; acetic acid; | EXAMPLE 162 STR184 Step 1. Preparation of 2-amino-5-(trifluoromethoxy)benzoic acid. 5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassium hydroxide pellets (4 g) were mixed in water (35 mL) and cooled to 0 C. With vigorous stirring, a solution of 30% aqueous hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g), and water (80 mL) was added drop-wise keeping the temperature below 10 C. After stirring 1 hour at 0 C., glacial acetic acid (22 mL) was added drop-wise, causing foaming and formation of a precipitate. The contents were stirred overnight and filtered to afford the 2-amino-5-trifluoromethoxybenzoic acid as an amber solid (12.5 g, 87%). A small amount was recrystallized from ethyl acetate-hexanes to afford amber needles for an analytical sample and the remaining compound was used without further purification: mp 142.5-144.2 C. 1 H NMR (CDCl3, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H, J=8.0 Hz) 6.62 (d, 1H, J=8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd for C8 H6 NO3 F3: C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35. | |
With potassium hydroxide; dihydrogen peroxide; In water; acetic acid; | Step 1. Preparation of 2-amino-5-(trifluoromethoxy)benzoic Acid 5-(Trifluoromethoxy)isatin (15.0 g, 65 mmol) and potassium hydroxide pellets (4 g) were mixed in water (35 mL) and cooled to 0 C. With vigorous stirring, a solution of 30% aqueous hydrogen peroxide (11.7 g), potassium hydroxide pellets (5.8 g), and water (80 mL) was added drop-wise keeping the temperature below 10 C. After stirring 1 hour at 0 C., glacial acetic acid (22 mL) was added dropwise, causing foaming and formation of a precipitate. The contents were stirred overnight and filtered to afford the 2-amino-5-trifluoromethoxybenzoic acid as an amber solid (12.5 g, 87%). A small amount was recrystallized from ethyl acetate-hexanes to afford amber needles for an analytical sample and the remaining compound was used without further purification: mp 142.5-144.2 C. 1 H NMR (CDCl3, 300 MHz) 7.98 (s, 1H), 7.18 (d, 1H, J=8.0 Hz) 6.62 (d, 1H, J=8.0 Hz), 6.40 (brs, 2H). Anal. Calc'd for C8 H6 NO3 F3: C, 43.45; H, 2.73; N, 6.33. Found: C, 43.40; H, 2.65; N, 6.35. |
With sodium hydroxide; dihydrogen peroxide; In water; at 17 - 20℃; for 1.33333h; | 5-TRIFLUOROMETHOXY-1H-INDOLE-2, 3-dione (3.48g, 15.0 MMOL) was dissolved in 2N aqueous sodium hydroxide (90MI) and cooled to 17 C before adding 30% aqueous hydrogen peroxide solution (2. 75ml, 27 MMOL) dropwise over 20 minutes. The mixture was stirred at room temperature for 1 hour before adding concentrated hydrochloric acid (7ml). The resulting brown precipitate was filtered off and DRIED IN VACUO at 50 C for 66 hours to give the title compound (1.83g) as a brown solid. APCI MS M/Z 220 [M-H] + 1H NMR (400MHZ, DMSO): 8 6.80 (d, 1H) 7.24 (dd, 1H), 7.53 (d, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Information Example 2: 5-Trifluoromethoxy-1H-indole Lithium aluminum hydride (10.4 mL,1M in THF, 10.4 mmol) was added to a solution of 5-trifluoromethoxyistatin (0.8 g, 3.45 mmol) in THF at room temperature and the mixture was refluxed overnight. The reaction mixture was cooled, and Na2SO4·10H2O was added very carefully portionwise, followed by ethyl acetate. The reaction mixture was then filtered, and the filtrate was evaporated. The residual oil was purifed by column chromatography with ethyl acetate in hexanes (2:98) to yield 5-trifluoromethoxy-1H-indole (0.162 g, 23%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Step c: 5 -(trifluoromethoxy)indo lin-2-one[0514] A solution of <strong>[169037-23-4]5-(trifluoromethoxy)indoline-2,3-dione</strong> (0.2 g, 0.87 mmol) in hydrazine hydrate (85%, 2.0 mL) was heated at 130C for 4 h. After the mixture was cooled to room temperature, it was poured into ice-water (10.0 mL). The resulting mixture was adjusted to pH=2 and stirred at room temperature for 2 d. The precipitate was collected by filtration, washed with water and dried under vacuum to give 130 mg of the title compound (69%> yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrogenchloride; In ethanol;Reflux; | General procedure: General method: The Schiff bases were obtained by adding an ethanolic solution of the hydrazinyl component to the solution of the keto component in equimolar amounts, refluxing the mixture in the presence of catalytic amounts of acid. If not indicated otherwise, purification was carried out by recrystallization. Carbazides were prepared by adding an equimolar amount of hydrazine to the methanolic solution of the respective isothiocyanate [53]. For the picolinylidene derivatives with ethyl group in 5-position of the pyridine moiety (2e, 2k), 5-Ethylpicolinaldehyde was prepared from 5-ethyl-2-methyl-pyridine as reported previously [13,115]. The reaction of 5-trifluoromethoxyisatin (50mg, 0.22mmol) with N-(4-methoxyphenyl)hydrazinecarbothioamide C-1 (43mg, 0.22mmol) in ethanolic solution under HCl-catalysis resulted in a yellow fluffy precipitate, which was identified as the product in 70% yield (65.7mg, 0.16mmol). 1H NMR (500MHz, DMSO-d6): delta=12.60 (s, 1H), 11.36 (s, 1H), 10.78 (s, 1H), 7.78 (s, 1H), 7.49-7.41 (m, 2H), 7.41-7.31 (m, 1H), 7.02 (d, 1H, 3J(H,H)=5.0Hz), 7.01-6.95 (m, 2H), 3.78 (s, 3H). 13C NMR (126MHz, DMSO-d6): delta=176.6, 162.7, 157.5, 143.5, 141.2, 131.1, 130.9, 127.3 (2C), 124.0, 121.5, 120.7 (d {121.19, 119.15}, 1J(C,F)=255.7Hz), 114.4 (2C), 113.6, 112.1, 55.3. Anal. Calcd. for C17H13N4SO3F3: C: 49.76; H: 3.19; N: 13.65. Found: C: 49.61; H: 3.477; N: 13.53 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; for 0.5h; | To a solution of 5-trifluoromethoxyisatin (12A, 0.46g, 2.00mmol) in CH2Cl2 (15mL) was added mCPBA (70% pure, 0.54g, 2.2mmol). The resulting solution was allowed to stir for 30 minutes. A solid precipitate formed and was filtered, rinsed with CH2CI2, and dried to yield compound 12B as a solid (0.39g, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With orthoformic acid triethyl ester;Amberlite FPC22H; In ethanol;Inert atmosphere; Reflux; | A lL, four-necked, jacketed flask equipped with a thermocouple, nitrogen inlet/bubbler, condenser and a mechanical stirrer was charged with 50.0 g of 5-trifluoromethoxyisatin (4) (commercially available from, for example, Aldrich), and 25 g of Amberlite FPC22H resin. The resin was distilled over toluene (200ml/100g) three times and dried at 40 0C under vacuum overnight. A quantity of 43 ml of HC(OEt)3 and 400 ml of absolute ethanol was used. The reaction mixture was heated to reflux. The batch temperature was 76.5 0C and the jacket was set at 90 0C. The mixture was held at reflux and a quantity of 21.5 ml OfHC(OEt)3 was charged at 90 minute, 180 minute, and 300 minute intervals. The mixture was held for another 2 hrs and the batch was cooled to 20 0C and filtered through a celite bed. The solution was collected and distilled to dryness under vacuum. The crude residue was re-slurried in 80 ml of 1 : 10 EtO Ac/heptane and stirred at 0 0C for an hour and filtered to collect the product. Intermediate (7) was obtained in 80% yield and >99% HPLC purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53.4% | In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere; Cooling with ice; | General procedure: 1M solution of phenylmagnesium bromide in THF (20.40mL, 20.40mmol) was added dropwise to a stirred ice-cold solution of isatin (1g, 6.80mmol) in anhydrous THF (20mL) that was kept under nitrogen. The reaction was stirred at room temperature for 2h and then quenched with a saturated aqueous solution of NH4Cl (20mL). Water was then added (30mL) and the aqueous phase was extracted twice with dichloromethane (2×60mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuum and the crude was purified by crystallization from EtOAc/Hexane to afford 1 (1.18g, 77.1%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In water; at 30℃; for 0.333333h; | Preparation of 3-hydroxy-5-trifluoromethoxy-3-(nitromethyl)indolin-2-one 5-trifluoromethoxy isatin ((0.115 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30 C. for 20 minutes. The obtained product was extracted with ethyl acetate and the solvent was removed to give pure product. |
86% | With 1,4-diaza-bicyclo[2.2.2]octane; at 20℃; for 0.075h;Neat (no solvent); | General procedure: To a solution of isatin 1 (1 mmol), nitromethane/nitroethane (3 mmol) was added DABCO (5 mol %). The mixture was stirred at rt this temperature for 1-5 min. The reaction was monitered by TLC. After completion of the reaction, the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure (rotary evaporator). The crude products were purified by silica gel column chromatography (ethyl acetate/hexanes: 30:70). All novel compounds were characterized by M.P., NMR, Mass and IR spectral data. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | EXAMPLE 133-(1 ,4'-bipiperidin-1 '-ylmethyl)-//-(1 -phenylcvclopropyl)-6-r(trifluoromethyl)oxyl-2-r3- (trifluorometh l)phenyll-4-quinolinecarboxamide3-methyl-6-r(trifluoromethyl)oxyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acidTo a suspension of 5-[(trifluoromethyl)oxy]-1 /-/-indole-2,3-dione (5.0 g, 21 .63 mmol) in ethanol (50 mL) was added a solution of potassium hydroxide (7.28 g, 130 mmol) in water (20.00 mL) slowly. 1 -[3-(Trifluoromethyl)phenyl]-1 -propanone was added (4.37 g, 21.63 mmol) and the mixture was heated to reflux for 1 h. The ethanol was removed under reduced pressure and the residue was dissolved in water and washed with diethyl ether. The aqueous mixture was chilled and adjusted to pH 3 with concentrated HCI. The solid was collected by filtration, washed with H20, and air dried to afford 3-methyl-6- [(trifluoromethyl)oxy]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (8.5 g, 95% yield). MS (m/z) 416.1 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Example 37 2-(2,3-Dioxo-5-trifluoromethoxy-2,3-dihydro-indol-1-yl)-4-methyl-pentanoic acid pyrazin-2-ylamide A stirred suspension of sodium hydride (60% dispersion in oil, 208 mg) in N,N-dimethylformamide (25 mL) at 0 C. was treated with a solution of 5-trifluoromethoxy-1H-indole-2,3-dione (1.0 g) in N,N-dimethylformamide. The reaction mixture was stirred for 30 min at 0 C. and then 2-bromo-4-methyl-pentanoic acid methyl ester (prepared as in Example 9, 1.1 g) was added and it was stirred for 1 h at 0 C. It was then slowly allowed to warm to room temperature and stirred for another 3 h at room temperature. After this time, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layers were combined and dried over sodium sulfate, filtered and the filterate concentrated in vacuo. The crude material was purified by column chromatography (silica gel) to afford 2-(2,3-dioxo-5-trifluoromethoxy-2,3-dihydro-indol-1-yl)-4-methyl-pentanoic acid methyl ester (1.0 g, 64%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Example 29 3-Cyclopentyl-2-(2,3-dioxo-5-trifluoromethoxy-2,3-dihydro-indol-1-yl)-N-pyrazin-2-yl-propionamide A stirred suspension of sodium hydride (60% dispersion in oil, 208 mg) in N,N-dimethylformamide (20 mL) at 0 C. was treated with a solution of <strong>[169037-23-4]5-trifluoromethoxy-1H-indole-2,3-dione</strong> (1.0 g) in N,N-dimethylformamide. The reaction mixture was stirred for 30 min at 0 C. and then 2-bromo-3-cyclopentyl-propionic acid methyl ester (prepared as in Example 1, 1.22 g) was added and it was stirred for 1 h at 0 C. It was then slowly allowed to warm to room temperature and stirred for another 3 h at room temperature. After this time, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layers were combined and dried over sodium sulfate, filtered and the filterate concentrated in vacuo. The crude material was purified by column chromatography (silica gel) to afford 3-cyclopentyl-2-(2,3-dioxo-5-trifluoromethoxy-2,3-dihydro-indol-1-yl)-propionic acid methyl ester (1.0 g, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In methanol; at 100℃; for 0.0666667h;Irradiation; | General procedure: A mixture of 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone (1, 0.364 mmol), thiazolidine-4-carboxylic (3, 0.364 mmol) and <strong>[169037-23-4]1-morpholinoindoline-2,3-dione</strong> (2,0.364 mmol) was dissolved in methanol (1 mL) and irradiated for 2-3.5 min in a CEM microwave synthesizer (100 0C, 100 W). After completion of the reaction as evident from TLC, the mixture was poured into water. The precipitated solid was filtered and washed with water to afford the products 4a-i which was purified by recrystallisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In methanol; at 100℃; for 0.0833333h;Irradiation; | General procedure: A mixture of 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone (1, 0.364 mmol), thiazolidine-4-carboxylic (3, 0.364 mmol) and <strong>[169037-23-4]1-morpholinoindoline-2,3-dione</strong> (2,0.364 mmol) was dissolved in methanol (1 mL) and irradiated for 2-3.5 min in a CEM microwave synthesizer (100 0C, 100 W). After completion of the reaction as evident from TLC, the mixture was poured into water. The precipitated solid was filtered and washed with water to afford the products 4a-i which was purified by recrystallisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In methanol; at 100℃; for 0.0833333h;Irradiation; | General procedure: A mixture of 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone (1, 0.364 mmol), thiazolidine-4-carboxylic (3, 0.364 mmol) and <strong>[169037-23-4]1-morpholinoindoline-2,3-dione</strong> (2,0.364 mmol) was dissolved in methanol (1 mL) and irradiated for 2-3.5 min in a CEM microwave synthesizer (100 0C, 100 W). After completion of the reaction as evident from TLC, the mixture was poured into water. The precipitated solid was filtered and washed with water to afford the products 4a-i which was purified by recrystallisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In methanol; at 100℃; for 0.0666667h;Irradiation; | General procedure: A mixture of 5,6-dimethoxy-2-[(E)-1-arylmethylidene]-1-indanone (1, 0.364 mmol), thiazolidine-4-carboxylic (3, 0.364 mmol) and <strong>[169037-23-4]1-morpholinoindoline-2,3-dione</strong> (2,0.364 mmol) was dissolved in methanol (1 mL) and irradiated for 2-3.5 min in a CEM microwave synthesizer (100 0C, 100 W). After completion of the reaction as evident from TLC, the mixture was poured into water. The precipitated solid was filtered and washed with water to afford the products 4a-i which was purified by recrystallisation. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With D-gluconic acid; In water; at 100℃; for 0.5h;Green chemistry; | General procedure: A mixture of isatin (0.15 g, 1 mmol), 5,5-dimethylcyclohexane-dione (0.14 g, 1 mmol), barbituric (0.13 g, 1 mmol) in gluconic acid aqueous solution (3 ml) was stirred at 100 C. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction mixture was cooled to room temperature. Then, the precipitated product was filtered and washed with water. The crude product was crystallized from ethanol to give 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With D-gluconic acid; In water; at 100℃; for 0.416667h;Green chemistry; | General procedure: A mixture of isatin (0.15 g, 1 mmol), 5,5-dimethylcyclohexane-dione (0.14 g, 1 mmol), barbituric (0.13 g, 1 mmol) in gluconic acid aqueous solution (3 ml) was stirred at 100 C. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction mixture was cooled to room temperature. Then, the precipitated product was filtered and washed with water. The crude product was crystallized from ethanol to give 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With D-gluconic acid; In water; at 100℃; for 0.416667h;Green chemistry; | General procedure: A mixture of isatin (0.15 g, 1 mmol), 5,5-dimethylcyclohexane-dione (0.14 g, 1 mmol), barbituric (0.13 g, 1 mmol) in gluconic acid aqueous solution (3 ml) was stirred at 100 C. The reaction progress was monitored by thin-layer chromatography. After completion of the reaction, the reaction mixture was cooled to room temperature. Then, the precipitated product was filtered and washed with water. The crude product was crystallized from ethanol to give 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.638 g | (a) Step 1 Aqueous sodium hydroxide (0.0888 g, 2.22 mmol, 2 mL) was heated to 50C, and added with 5-trifluoromethoxyisatin (0.500 g, 2.16 mmol). The mixture was stirred at 50C for 1 hour, and then cooled on ice. The reaction mixture was added with sodium nitrite (0.149 g, 2.16 mmol), and then added dropwise with a solution of concentrated sulfuric acid (0.413 g, 4.21 mmol) in ice-cooled water (3.5 mL), and the mixture was stirred for 1 hour under ice cooling. Then, the mixture was added dropwise with an ice-cooled solution of tin(II) chloride dihydrate (1.17 g, 5.18 mmol) in concentrated hydrochloric acid (1.7 mL). The mixture was stirred overnight at room temperature, and then filtered to obtain a pale brown solid (0.638 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; potassium iodide; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; | General procedure: The title compound was synthesized in one step from commercially available starting materials according to the following procedure. Into a 20mL microwave reaction vial, containing a magnetic stir bar, were weighed 5-(trifluoromethoxy)isatin (460mg, 2.0mmol), K2CO3 (550mg, 4.0mmol), KI (33mg, 0.20mmol), followed by acetonitrile (20mL, 0.1M) and 2-bromoethyl phenyl ether (480mg, 2.4mmol). After being sealed with a crimp cap, the vessel was placed in a microwave reactor and heated to 160C for 10min, with magnetic stirring. After cooling to ambient temperature, the reaction was diluted with CH2Cl2 (?20mL) and washed with brine. The organic layer was separated and dried over Na2SO4. Solvent was removed under reduced pressure and the crude product was purified via flash column chromatography (silica gel, hexane/ethyl acetate, 0-50% ethyl acetate gradient). Product containing fractions were combined and the solvents removed under reduced pressure to obtain 583mg of ML326 (83% yield) as a red-orange powder. TLC Rf=0.79 (hexane/ethyl acetate 1:1); 1H NMR (400MHz, CDCl3 calibrated to 7.26) delta 7.52-7.46 (m, 2H), 7.31-7.25 (m, 3H), 6.98 (t, J=7.4Hz, 1H), 6.82 (d, 2H), 4.28 (t, J=5.0Hz, 2H), 4.17 (t, J=5.0Hz, 2H); 13C NMR (125MHz, CDCl3 calibrated to 77.16) delta 182.25, 158.27, 157.93, 150.01, 145.44, 131.02, 129.78, 121.75, 118.32, 114.39, 112.89, 65.94, 40.62; HRMS calcd for C17H13NO4F3[M+H+]; 352.0797 found: 352.0795. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; potassium iodide; In acetonitrile; at 160℃; for 0.166667h;Microwave irradiation; | General procedure: The title compound was synthesized in one step from commercially available starting materials according to the following procedure. Into a 20mL microwave reaction vial, containing a magnetic stir bar, were weighed 5-(trifluoromethoxy)isatin (460mg, 2.0mmol), K2CO3 (550mg, 4.0mmol), KI (33mg, 0.20mmol), followed by acetonitrile (20mL, 0.1M) and 2-bromoethyl phenyl ether (480mg, 2.4mmol). After being sealed with a crimp cap, the vessel was placed in a microwave reactor and heated to 160C for 10min, with magnetic stirring. After cooling to ambient temperature, the reaction was diluted with CH2Cl2 (∼20mL) and washed with brine. The organic layer was separated and dried over Na2SO4. Solvent was removed under reduced pressure and the crude product was purified via flash column chromatography (silica gel, hexane/ethyl acetate, 0-50% ethyl acetate gradient). Product containing fractions were combined and the solvents removed under reduced pressure to obtain 583mg of ML326 (83% yield) as a red-orange powder. TLC Rf=0.79 (hexane/ethyl acetate 1:1); 1H NMR (400MHz, CDCl3 calibrated to 7.26) δ 7.52-7.46 (m, 2H), 7.31-7.25 (m, 3H), 6.98 (t, J=7.4Hz, 1H), 6.82 (d, 2H), 4.28 (t, J=5.0Hz, 2H), 4.17 (t, J=5.0Hz, 2H); 13C NMR (125MHz, CDCl3 calibrated to 77.16) δ 182.25, 158.27, 157.93, 150.01, 145.44, 131.02, 129.78, 121.75, 118.32, 114.39, 112.89, 65.94, 40.62; HRMS calcd for C17H13NO4F3[M+H+]; 352.0797 found: 352.0795. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In toluene; at 70℃; for 3.5h; | General procedure: To a solution of isatin 1 (1 mmol) in toluene (5 mL) was added the solution of trialkyl/aryl Al 2 (2 mmol, 2 M in toluene) dropwise at RT. Then the mixture was heated at 70 C and stirred for additional 3-3.5 h (see Table 2). The reaction was monitored by TLC. After completion of the reaction, toluene was evaporated and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure (rotary evaporator). The crude products were purified by silica gel column chromatography using ethyl acetate/hexanes (4:1-1:1). All compounds were characterized by (MP, NMR, Mass, and IR) spectral data.18 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In toluene; at 70℃; for 3.5h; | General procedure: To a solution of isatin 1 (1 mmol) in toluene (5 mL) was added the solution of trialkyl/aryl Al 2 (2 mmol, 2 M in toluene) dropwise at RT. Then the mixture was heated at 70 C and stirred for additional 3-3.5 h (see Table 2). The reaction was monitored by TLC. After completion of the reaction, toluene was evaporated and extracted with ethyl acetate (3 × 5 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure (rotary evaporator). The crude products were purified by silica gel column chromatography using ethyl acetate/hexanes (4:1-1:1). All compounds were characterized by (MP, NMR, Mass, and IR) spectral data.18 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere; Cooling with ice; | General procedure: 1M solution of phenylmagnesium bromide in THF (20.40mL, 20.40mmol) was added dropwise to a stirred ice-cold solution of isatin (1g, 6.80mmol) in anhydrous THF (20mL) that was kept under nitrogen. The reaction was stirred at room temperature for 2h and then quenched with a saturated aqueous solution of NH4Cl (20mL). Water was then added (30mL) and the aqueous phase was extracted twice with dichloromethane (2×60mL). The organic phase was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuum and the crude was purified by crystallization from EtOAc/Hexane to afford 1 (1.18g, 77.1%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | A solution of Ca(OH)2 (38.5 g, 519 mmol) and 5-(trifluoromethoxy)isatin (40 g, 173 mmol) in water (150 ml) was heated at 80C for 1 h. The heating bath was removed followed by slow addition of chloroacetone (34.5 ml, 433 mmol). The reaction was then heated at 80C for another 5 h then cooled to RT and quenched with IN aq. HCl until pH=2. The solid was filtered over fritted disk, washed with water and dried overnight at 50C under high vacuum to afford the product intermediate (47.0 g, 95% yield) as a slightly yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 2,2'-iminobis[ethanol]; In water; at 20℃;Green chemistry; | General procedure: To the reaction mixture containing isatin (0.5mmol) in water (2mL), indole (0.5mmol), diethanolamine (20mol %) was slowly added at room temperature. After thecompletion of reaction as monitored by TLC, the reaction mixture was washed with brine solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the product was purified by flash chromatography on the silica gel column using a gradient of petroleum ether/ethyl acetate, as eluent to afford pure products 1-41. |
With pyridine; potassium carbonate; at 40℃; for 2h; | General procedure: To a solution of isatin (0.2 mmol) and indole (0.2 mmol) in pyridine (0.5 mL) was added K2CO3 (0.2 mmol) under an airatmosphere and the mixture was stirred at 40C for 2 h. Then,morpholine (0.3 mmol), CuI (0.04 mmol), and benzoic acid(0.1 mmol) were added to the reaction mixture and the resultingmixture was heated at 80C for another 5 h. The reaction mixturewas concentrated under reduced pressure. The residue was puriedby ash chromatography on silica gel (eluent: EtOAc/PE 1:1) toyield the corresponding product 4a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 2,2'-iminobis[ethanol]; In water; at 20℃;Green chemistry; | General procedure: To the reaction mixture containing isatin (0.5mmol) in water (2mL), indole (0.5mmol), diethanolamine (20mol %) was slowly added at room temperature. After thecompletion of reaction as monitored by TLC, the reaction mixture was washed with brine solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the product was purified by flash chromatography on the silica gel column using a gradient of petroleum ether/ethyl acetate, as eluent to afford pure products 1-41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2,2'-iminobis[ethanol]; In water; at 20℃;Green chemistry; | General procedure: To the reaction mixture containing isatin (0.5mmol) in water (2mL), indole (0.5mmol), diethanolamine (20mol %) was slowly added at room temperature. After thecompletion of reaction as monitored by TLC, the reaction mixture was washed with brine solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the product was purified by flash chromatography on the silica gel column using a gradient of petroleum ether/ethyl acetate, as eluent to afford pure products 1-41. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In 1,4-dioxane; at 20℃; | General procedure: (The reagents were purchased fromAdamas and used without further purification.) A dry 3-mL flask was chargedwith relevant isatin 5 (0.3 mmol), tert-butyl 2-aminoacetate hydrochloride 7(0.3 mmol) and benzophenone imine 8 (0.36 mmol). The reaction mixture wasstirred at room temperature for the corresponding time. After the completionof the reaction, the reaction mixture was directly purified by silica gelchromatography (ethyl acetate/petroleum ether = 1:4) to give product 6. Asolution of 6 in EA/TFA (10:1) was stirred in a 10-mL flask under roomtemperature for 3 h. The solvent was removed under vacuum. The residue wasrecrystallized in diethyl ether/petroleum ether to give product 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium acetate; acetic acid; potassium hydroxide; In water; at 120℃; for 1h;pH Ca.5;Microwave irradiation; Sealed tube; | Intermediate 1 A6-bromo-2-(trifluoromethyl)quinoline-4-carboxylic acid 300 mg (1.33 mmol) of 5-bromo-1 H-indole-2,3-dione was suspended in 3 mL water in a microwave vial. 82 mg ( 1.46 mmol) potassium hydroxide, 152 muL (2.65 mmol) acetic acid and 152 mg (1.86 mmol) sodium acetate were added so that the pH was around 5. The solution was cooled to 10 C and 238 muL (2.65 mmol) 1 ,1,1 -trifluoroacetone was added rapidly, the microwave vial was sealed and heated in the microwave for 2 h at 120 C. The reaction was stopped by the addition of 10% aqueous hydrochloric acid solution and the resulting precipitate was isolated by filtration, washed with water and dried in a vacuum drying cabinet at 50 C overnight to obtain 409 mg (1.28 mmol, 96%) of the desired title compound .In analogy to intermediate 1A, 200 mg (0.87 mmol) 5-(trifluoromethoxy)-1 H-indole-2,3-dione was heated with 388 muL (4.33 mmol) 1,1,1 -trifluoroacetone, 53 mg (0.95 mmol) potassium hydroxide, 99 muL (1.73 mmol) acetic acid and 99 mg (1.21 mmol) sodium acetate in 2 mL water for 1 h at 120 C in the microwave to obtain 269 mg (0.83 mmol, 96%) of the desired title compound after aqueous work-up.1 H NMR (400 MHz, DMSO d6): delta (ppm) = 8.01 (dd, 1 H), 8.38 (s, 1 H), 8.44 (d, 1 H), 8.85 - 8.89 (m, 1 H), 14.57 (br. s. , 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0℃; for 14h;Inert atmosphere; | Diethylcyanomethylphosphonate (279 mg, 1.58 mmol) was dissolved in dry THF (6 mL) at 0oC. Sodium hydride (66 mg, 1.15 mmol) was added and, to the resulting suspension, 5-trifluoromethoxyistain (347 mg, 1.50 mmol) was added slowly. Upon completion of the reaction as shown by TLC analysis, water (10 mL), brine (10 mL) and ethyl acetate (10 mL) were added and the aqueous layer extracted with ethyl acetate (3 x 5 mL) and dried with Na2SO4. The solvent was evaporated in vacuo and the resulting solid was purified by column chromatography (PSp:EtOAc 1:0 to 1:1) to yield a yellow product (31%), 1H NMR (400 MHz, CDCl3): d 6.39 (s, 1H), 6.91 (d, J 8.7, 1H), 7.26-7.31 (m, 1H), 7.84 (br s, 1H), 7.94 (d, J 1.9, 1H); 13C NMR (100 MHz, CDCl3): d 99.8, 111.3, 115.3, 118.9, 120.43 (q, J 258), 120.6, 126.9, 141.3, 142.5, 144.8 (q, J 2.1), 165.9; IR (neat, cm-1): 3254, 2228, 1760, 1728, 1624, 1473, 1245, 1124; HRMS: m/z: [M+Na]+ calcd for C11H5N2O2F3Na, 277.0195; found, 277.0188. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.8% | With potassium borohydride; In methanol; for 1h;Reflux; | General procedure: The isatin ( 0.01 mol scale) was dissolved in 50 ml of CH3OH in a 150 ml round bottomed flask equipped with a reflux condenser and a stir bar. The mixture was brought to reflux that was followed by gradual addition of KBH4 (0.27 g, 0.005 mol). The reaction mixture continued to stir under reflux for 1 hour. While heating, the stopper of the round bottomed flask was removed 2-3 times and the flask was shaken to saturate the reaction mixture with air. After 1 hour, the solution was cooled to room temperature and the indirubin precipitated out of the solution. The solid was isolated by filtration and was further purified by recrystallization from 95% C2H5OH or by column chromatograph on silica gel. Indirubin and 10 indirubin derivatives in Z form were synthesized by this method. The structures of the indirubins were determined by 1H NMR, 13C NMR, MS, IR, UV and elemental analysis, and the stereochemistry was assigned by comparing the spectra data to published reports or comparing to authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sulfuric acid; In ethanol; for 4h;Reflux; | General procedure: N-(4-Sulfamoylphenyl)hydrazinecarbothioamide (2) (3.5mmol) was added to a solution of 1H-indole-2,3-diones 3a-m (3.5mmol) in ethanol (20mL). After addition of a drop of concentrated sulfuric acid, the mixture was refluxed on a water bath for 4h. The product formed after cooling was filtered and washed with ethanol or recrystallized from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With sulfonated beta-cyclodextrin; In water; at 80℃;Green chemistry; | General procedure: Sulfonated-beta-cyclodextrin (beta-CD-SO3H) (76 mg, 0.06 mmol) was dissolved in water (5 mL) at RT by stirring to get the clear solution in 50 mL round bottom ask. Further, isatin 2 (0.31 mmol) and tryptamine 1a/isotryptamine 1b (0.31 mmol) were added to the solution under constant stirring and mixture was heated at 80 C for 8-12 h. The progress of the reaction was monitored by TLC. After completion of reaction, it was cooled to room temperature, water was added to it. The aqueous phase was extracted with ethylacetate. The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the crude product obtained was puried by column chromatography using chloroform/methanol (99:1) as an eluent furnishing the product. The spectral and analytical data of all the reported products is consistent with the previous (6c,d,f) reports. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With triethylamine; In toluene; at 110℃; for 0.666667h;Microwave irradiation; | General procedure: Following the procedure described by Pandey etal. [17] with some modifications. A mixture of the isatin derivative (1 eq), the corresponding amine derivative (1 eq) and MMT-K10 (20mg for 1mmol of the isatin derivative) and toluene if necessary, was heated under microwave irradiation (6-90min, 100-110C). After cooling to room temperature, ethyl acetate (50mL) was added and the mixture was extracted with a saturated solution of NaHCO3 (50mL x 3). Finally, the organic phase was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was chromatographed as indicated in each case. In case the amine was in hydrochloride form, the amine derivative (1 eq) was stirred with triethylamine (1 eq) and toluene (3mL) for 1hat room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In ethanol; for 1h;Reflux; | General procedure: The NiO-SiO2 catalyst (6.5 mol%) was added to a mixture of isatin (1 mmol), malononitrile (1 mmol), and 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol) in EtOH, and the reaction flask was placed in an oil bath and refluxed for the appropriate time. The progress of reaction was monitored by TLC. After the completion of the reaction, the heterogeneous catalyst was recovered from the reaction mixture by filtration. The filtrate was evaporated to afford the crude solid product which was later purified by column chromatography. The solid catalyst was washed with hot EtOH and then dried in oven to reuse. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(m-tolyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(methylphenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5h): Melting point 234-236 C; white solid, 88%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.99 (d, J = 14.5 Hz, 1H), 4.63-4.68 (m, 1H), 4.34 (d, J = 10.0 Hz, 1H), 3.77 (d, J = 14.00 Hz, 1H), 3.68 (d, J = 15.00 Hz, 1H), 3.38-3.47 (dd, J = 15 Hz, 1H), 3.00-3.03 (dd, J = 14.5 Hz,1H), 2.72-2.76 (m, 1H), 2.56 (d, J = 14.0 Hz, 1H), 2.33 (s, 3H), 2.27 (s, 3H), 6.60 (d, J = 14.5 Hz, 2H), 6.79-7.71 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 21.1, 21.4, 39.4, 47.4, 52.8, 52.9, 61.1, 66.9, 70.8, 100.8, 109.5, 119.5, 120.9, 121.5, 122.4, 123.9, 124.3, 126.3, 128.4, 128.5, 128.6, 129.2, 129.4, 129.5, 130.5, 131.7, 133.6, 135.3, 136.2, 136.8, 138.3, 138.5, 138.8, 139.7, 139.8. 140.0, 144.3, 179.7, 197.1. EI-MS: m/z 739 (M+). Anal. Calcd for C46H40F3N3O3: C, 74.68; H, 5.45; N, 5.68. Found: C, 74.77; H, 5.55;N, 5.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(p-tolyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(methylphenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5i): Melting point 222-224 C; white solid, 95%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 5.00 (d, J = 14.5 Hz, 1H), 4.66-4.70 (m, 1H), 4.30 (d, J = 10.0 Hz, 1H), 3.77 (d, J = 14.00 Hz, 1H), 3.67 (d, J = 15.00 Hz, 1H), 3.41-3.50 (dd, J = 15 Hz, 1H), 3.00-3.04 (dd, J = 14.5 Hz,1H), 2.70-2.75 (m, 1H), 2.55 (d, J = 14.0 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 6.52 (d, J = 14.5 Hz, 1H), 6.58-7.48 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 21.1, 21.4, 39.5, 47.4, 52.8, 52.9, 61.1,66.9, 70.8, 100.7, 109.6, 119.5, 120.9, 121.5, 122.3, 123.9, 124.3, 126.3, 128.4, 128.5, 129.2, 129.4, 129.38, 130.5, 131.6, 133.7, 136.9, 138.3, 138.4, 138.7, 139.6, 139.8. 140.0, 144.3, 179.8, 197.1. EI-MS: m/z 739 (M+). Anal. Calcd for C46H40F3N3O3: C, 74.68; H, 5.45; N, 5.68. Found: C, 74.76; H, 5.53; N, 5.79. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(o-methoxyphenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(o-methoxyphenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5j): Melting point 295-297 C; White solid, 92%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 5.00 (d, J = 14.64 Hz, 1H), 4.69-4.72 (m, 1H), 4.41 (d, J = 10.24 Hz, 1H), 3.87 (d, J = 13.92 Hz, 1H), 3.83 (s, 3H), 3.81 (s, 3H), 3.72 (d, J = 16.92 Hz, 1H), 3.55 (d, J = 15.4 Hz, 1H), 3.05 (d, J = 11.72 Hz, 1H), 2.84-2.90 (dd, J = 13.96, 8.08 Hz, 1H), 2.75 (d, J = 13.92 Hz, 1H), 6.62-6.68(m, 2H), 6.99-7.58 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 39.7, 47.4, 52.7, 53.3, 55.4, 55.5, 61.2, 67.4, 70.9, 100.9, 109.8, 114.1, 114.3, 121.3, 122.4, 124.6, 124.9, 126.5, 127.4, 128.6, 128.7, 128.6, 128.7, 129.4, 129.8, 130.2, 130.5, 131.7, 134.5, 136.8, 138.4, 138.5, 138.7, 139.8, 139.9, 140.2, 144.4, 179.3, 197.5. EI-MS: m/z 771 (M+). Anal. Calcd for C46H40F3N3O5: C, 71.58; H, 5.22; N, 5.44. Found: C, 71.69; H,5.36; N, 5.58. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(m-methoxyphenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(m-methoxyphenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5k): Melting point 285-287 C; white solid, 94%;1H-NMR (CDCl3, 400 MHz): delta/ppm 4.99 (d, J = 14.64 Hz, 1H), 4.68-4.71 (m, 1H), 4.39 (d, J = 10.24 Hz, 1H), 3.85 (d, J = 13.92 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.70 (d, J = 16.92 Hz, 1H), 3.53 (d, J = 15.4 Hz, 1H), 3.03 (d, J = 11.72 Hz, 1H), 2.79-2.86 (dd, J = 13.96, 8.08 Hz, 1H), 2.72 (d, J = 13.92 Hz, 1H), 6.60-6.67 (m, 2H), 7.13-7.63 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 39.6, 47.3, 52.6, 53.3, 55.4, 55.5, 61.2, 67.4, 70.9, 100.8, 109.7, 114.2, 114.3, 121.5, 122.3, 122.4, 124.5, 124.6, 124.8, 126.5, 127.4, 128.6, 128.8, 128.5, 128.7, 129.4, 129.9, 130.2, 130.6, 134.6, 136.8, 138.4, 138.4, 138.7, 139.8, 139.7, 144.3, 179.4, 197.5. EI-MS: m/z 771 (M+). Anal. Calcd for C46H40F3N3O5: C, 71.58; H, 5.22; N, 5.44. Found: C, 71.66; H, 5.32; N, 5.55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(p-methoxyphenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(p-methoxyphenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5l): Melting point 270-272 C; White solid, 92%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 5.00 (d, J = 14.64 Hz, 1H), 4.67-4.70 (m, 1H), 4.33 (d, J = 10.24 Hz, 1H), 3.86 (d, J = 13.92 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.76 (d, J = 16.92 Hz, 1H), 3.47 (d, J = 15.4 Hz, 1H), 3.06 (d, J = 11.72 Hz, 1H), 2.75-2.79 (dd, J = 13.96, 8.08 Hz, 1H), 2.72 (d, J = 13.92 Hz, 1H), 6.59-6.66 (m, 2H), 7.14-7.63 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 39.6, 47.3, 52.7, 53.1, 55.3, 55.4, 61.1, 67.3, 70.9, 100.8, 109.7, 114.1, 114.4, 121.1, 122.2, 124.7, 124.9, 126.5, 127.4, 128.5, 128.6, 128.7, 129.3, 129.9, 130.1, 130.4, 134.5, 136.9, 138.3, 138.5, 138.7, 139.8, 139.8, 144.4, 179.6, 197.2. EI-MS: m/z 771 (M+). Anal. Calcd for C46H40F3N3O5: C, 71.58; H, 5.22; N, 5.44. Found: C, 71.71; H, 5.34; N, 5.56. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(m-nitrophenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(m-nitrophenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5l): Melting point 296-298 C; white solid, 94%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 5.05 (d, J = 14.64 Hz, 1H), 4.75-4.77 (m, 1H), 4.30 (d, J = 10.24 Hz, 1H), 3.86 (d, J = 13.92 Hz, 1H), 3.83 (d, J = 16.92 Hz, 1H), 3.49 (d, J = 15.4 Hz, 1H), 3.10 (d, J = 11.72 Hz, 1H), 2.73-2.77 (dd, J = 13.96, 8.08 Hz, 1H), 2.74 (d, J = 13.92 Hz, 1H), 7.01-6.68 (m, 2H), 7.18-7.82 (m, 21H,Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 40.6, 47.4, 52.1, 53.3, 62.8, 65.6, 70.9, 98.8, 110.2, 121.9, 122.4, 122.5, 112.5, 123.6, 124.4, 124.5, 126.4, 126.5, 126.7, 128.7, 128.8, 128.9, 129.2, 129.4, 129.9, 132.4, 132.9, 135.6, 136.3, 137.7, 138.7, 139.9, 144.4, 179.8, 198.7. EI-MS: m/z 801 (M+). Anal. Calcd for C44H34F3N5O7: C, 65.91; H, 4.27; N, 8.73; Found: C, 65.99; H, 4.39; N, 8.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-phenyl-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-phenyl-1?-styryl-5-benzylidenespiro[3'.3?]piperidin-4?-one (5a): Melting point 210-212 C; white solid, 94%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 5.00 (d, J = 14.64 Hz, 1H), 4.68-4.72 (m, 1H), 4.34 (d, J = 10.24 Hz, 1H), 3.80 (d, J = 13.92 Hz, 1H), 3.68 (d, J = 16.92 Hz, 1H), 3.47 (d, J = 5.4 Hz, 1H), 3.02 (d, J = 11.72 Hz, 1H), 2.72-2.77 (dd, J = 13.96, 8.08 Hz, 1H), 2.54 (d, J = 13.92 Hz, 1H), 6.56-6.63 (m, 2H), 6.92-7.42 (m, 23H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 39.6, 47.3, 52.8, 53.1, 61.0, 67.3, 70.8, 100.9, 109.7, 121.1, 122.5, 124.1, 124.4, 126.4, 127.3, 128.5, 128.6, 128.7, 128.8, 129.3, 129.6, 130.1, 130.4, 134.5, 136.9, 138.3, 138.4, 138.7, 139.7, 139.8, 144.4, 179.8, 197.1. EI-MS: m/z 711 (M+). Anal. Calcd for C44H36F3N3O3: C, 74.25; H, 5.10; N, 5.90. Found: C, 74.38; H, 5.17; N, 5.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(o-bromophenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(o-bromophenyl-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5b): Melting point 247-249 C; white solid, 96%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.82 (d, J = 13.96 Hz, 1H), 4.58-4.61 (m, 1H), 4.49 (d, J = 10.24 Hz, 1H), 3.79 (d, J = 13.2 Hz, 1H), 3.60 (d, J = 16.82 Hz, 1H), 3.39 (d, J = 5.4 Hz, 1H), 2.94 (d, J = 13.96 Hz, 1H), 2.71-2.77 (m, 1H), 2.41 (d, J = 13.92 Hz, 1H), 6.56-6.61 (m, 2H), 6.98-7.65 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 40.6, 47.4, 52.7, 53.2, 61.3, 67.2, 70.9, 100.8, 110.1, 121.9, 122.4, 122.5, 123.8, 124.5, 126.4, 126.5, 127.2, 128.3, 128.4, 128.5, 128.6, 128.7, 128.9, 129.1, 131.4, 131.6, 131.8, 133.2, 136.3, 138.2, 138.5, 138.6, 144.6, 179.5, 197.1. EI-MS: m/z 869 (M+). Anal. Calcd for C44H34Br2F3N3O3: C, 60.77; H, 3.94; N, 4.83; Found: C, 60.85; H, 3.83; N, 4.72. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(p-bromophenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(p-bromophenyl-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5c): Melting point 255-257 C White solid, 97%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.98 (d, J = 3.96 Hz, 1H), 4.56-4.62 (m, 1H), 4.22-4.29 (m, 1H), 3.74 (d, J = 13.2 Hz, 1H), 3.63 (d, J = 16.82 Hz, 1H), 3.37 (d, J = 15.4 Hz, 1H), 2.90 (d, J = 13.96 Hz, 1H), 2.72-2.78 (m, 1H), 2.53 (d, J = 13.92 Hz, 1H), 6.53-6.62 (m, 2H), 6.88-7.55 (m, 21H, Ar); 13C-NMR(CDCl3, 100 MHz): delta/ppm 39.7, 47.3, 52.8, 53.2, 61.4, 67.2, 70.8, 100.8, 110.0, 121.9, 122.4, 122.5, 123.8, 124.3, 126.4, 126.5, 128.5, 128.6, 129.1, 129.2, 130.7, 131.5, 131.7, 131.9, 133.2, 136.2, 136.3, 138.1, 138.4, 138.6, 140.2, 144.6, 179.6, 197.1. EI-MS: m/z 869 (M+). Anal. Calcd for C44H34Br2F3N3O3: C, 60.77; H, 3.94; N, 4.83; Found: C, 60.89; H, 3.81; N, 4.75. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(o-chlorophenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(o-chlorophenyl-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5d): Melting point 276-278 C White solid, 93%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.91 (d, J = 14.00 Hz, 1H), 4.61-4.68 (m, 1H), 4.20-4.27 (m, 1H), 3.87 (d, J = 13.2 Hz, 1H), 3.62 (d, J = 16.82 Hz, 1H), 3.35 (d, J = 15.4 Hz, 1H), 2.98 (d, J = 13.96 Hz, 1H), 2.77-2.84 (m, 1H), 2.45 (d, J = 13.92 Hz, 1H), 6.52-6.61 (m, 2H), 6.89-7.54 (m, 21H, Ar); 13C-NMR(CDCl3, 100 MHz): delta/ppm 40.5, 47.3, 51.9, 53.2, 62.9, 65.7, 73.2, 98.8, 110.1, 120.4, 122.5, 123.9, 124.1, 126.4, 126.5, 127.0, 128.0, 128.1, 128.2, 128.3, 128.4, 128.6, 128.9, 129.1, 129.7, 129.8, 130.5, 132.4, 132.9, 135.5, 136.3, 137.7, 138.8, 139.9, 144.4, 179.7, 198.9. EI-MS: m/z 780 (M+). Anal. Calcd for C44H34Cl2F3N3O3: C, 67.70; H, 4.39; N, 5.38; Found: C, 67.57; H, 4.47; N, 5.28. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(o,p-dichlorophenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(o,p-dichlorophenyl-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5e): Melting point 288-290 C White solid, 94%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.86 (d, J = 14.00 Hz, 1H), 4.68 (d, J = 13.92 Hz, 1H), 4.49-4.53 (m, 1H), 3.85 (d, J = 13.2 Hz, 1H), 3.58 (d, J = 16.82 Hz, 1H), 3.26 (d, J = 15.4 Hz, 1H), 2.95 (d, J = 13.96 Hz, 1H), 2.77-2.85 (m, 1H), 2.38 (d, J = 13.92 Hz, 1H), 6.49-6.59 (m, 2H), 6.00-7.76 (m, 19H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 40.6, 46.3, 51.9, 52.3, 63.3, 65.5, 70.4, 99.3, 110.5, 121.8, 122.4, 123.9, 124.2, 126.4, 126.6, 126.5, 127.1, 128.4, 128.5, 128.6, 129.0, 129.2, 130.6, 132.4, 133.5, 134.2, 135.6, 135.8, 135.9, 136.8, 137.4, 138.1, 138.5, 132.9, 144.5, 177.8, 199.7. EI-MS: m/z 849 (M+). Anal. Calcd for C44H32Cl4F3N3O3: C, 62.21; H, 3.80; N, 4.95; Found: C, 62.36; H, 3.99; N, 4.83. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(p-chlorophenyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(p-chlorophenyl-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5f): Melting point 259-261 C; white solid, 95%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.60 (d, J = 13.92 Hz, 1H), 4.18-4.23 (m, 1H), 3.86 (d, J = 10.28 Hz, 1H), 3.24-3.38 (m, 2H), 2.92-3.00 (m, 2H), 2.50-2.54 (m, 1H), 2.33-2.39 (m, 1H), 6.53-6.56 (m, 2H), 6.67-7.02 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 39.8, 46.9, 52.3, 53.1, 61.5, 65.9, 70.7, 100.4, 109.8, 123.9, 124.1, 126.0, 128.1, 128.2, 128.4, 128.7, 128.8, 129.0, 130.4, 131.4, 132.5, 132.6, 135.8, 135.9, 136.4, 140.6, 143.7, 136.2, 137.6, 138.5, 139.9, 144.4, 179.1, 196.9. EI-MS: m/z 780 (M+). Anal. Calcd for C44H34Cl2F3N3O3: C, 67.70; H, 4.39; N, 5.38; Found: C, 67.59; H, 4.51; N, 5.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of bisarylidenepiperidin-4-one (1.36 mmoL), isatin (2.72 mmoL) and L-phenylalanine (2.72 mmoL) were heated with stirring in [bmim]Br medium (3 mL) for 1 h at 100 C. After completion of the reaction (TLC), ethyl acetate (2 x 5 mL) was added and the reaction mixture was stirred for 10 min. The organic layer was removed under reduced pressure and the crude product was purified by column chromatography (ethyl acetate:hexane v/v 3:7). 5'-Benzyl-4'-(o-tolyl)-5-(trifluoromethoxy)spiro[3,2']oxindolopyrrolidino-4'-(o-methylphenyl)-1?-styryl-5-benzylidene-spiro[3'.3?]piperidin-4?-one (5g): Melting point 229-231 C; white solid, 89%; 1H-NMR (CDCl3, 400 MHz): delta/ppm 4.96 (d, J = 14.5 Hz, 1H), 4.53-4.62 (m, 1H), 4.21 (d, J = 10.0 Hz, 1H), 3.64 (d, J = 14.00 Hz, 1H), 3.59 (d, J = 15.00 Hz, 1H), 3.37-3.42 (dd, J = 15 Hz, 1H), 2.98-3.02 (dd, J = 14.5 Hz,1H), 2.66-2.71 (m, 1H), 2.48 (d, J = 14.0 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H), 6.49-6.58 (m, 2H), 6.99-7.39 (m, 21H, Ar); 13C-NMR (CDCl3, 100 MHz): delta/ppm 21.1, 21.5, 39.5, 47.4, 52.8, 52.9, 61.1, 66.9, 70.8, 100.7,109.6, 119.6, 120.9, 121.5, 122.4, 123.9, 124.2, 126.4, 128.4, 128.5, 129.1, 129.3, 129.35, 130.4, 131.6, 133.7, 135.2, 135.8, 136.2, 136.8, 138.2, 138.4, 138.7, 139.6, 139.8. 140.0, 144.3, 179.9, 197.1. EI-MS: m/z 739 (M+). Anal. Calcd for C46H40F3N3O3: C, 74.68; H, 5.45; N, 5.68. Found: C, 74.78; H, 5.51; N, 5.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃;Ionic liquid; | General procedure: A mixture of indoline-2,3-dione 1 (1mmol), l-tryptophan (2a) or l-histidine 2b (1mmol) and (E)-(2-nitrovinyl)benzene 3 (1.1mmol) was heated while stirred in [bmim]Br as the reaction medium (3mL) for 1hat 100C. After completion of the reaction (TLC), EtOAc (5mL) was added and the reaction mixture was stirred for 10min. This treatment was repeated and the combined ethyl acetate layers were removed in vacuo. The crude product was purified by recrystallization of the residue from EtOH (compounds 4) or by column chromatography (compounds 5). After extraction of the product, the ionic liquid was dried under vacuum at 80C for 2h to eliminate any water and could be reused for subsequent runs of the reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In ethanol; at 50℃; | 3beta-hydroxy-5alpha,8alpha-peroxyandrost-6-ene-17-hydrazine obtained in the step (f)(100 mg, 0.30 mmol) and 5-trifluoromethoxy-isatin (76.2 mg, 0.30 mmol) dissolved in 20 mLIn absolute ethanol, placed in a 50 mL single-necked flask, and the system was heated to 50 C for 2 to 4 hours.The reaction was terminated until no starting material was reacted. Decomposition under reduced pressure, purification by silica gel column,The product was obtained as a pale yellow solid, 114.2 mg, yield: 70%. |
70% | With acetic acid; In ethanol; at 50℃; | General procedure: To a suspension of intermediate 6 (0.2mmol) in anhydrous EtOH (30mL) was added different substituent (0.2mmol). The mixture was continually stirred under 50C for 2~3h until no starting material. Then the solvent was evaporated by rotary evaporation. The residue was purified by flash chromatography to afford compounds 7a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h; | General procedure: A mixture of beta-nitrostyrenes, isatin and tyrosine (1:1:1) was stirredunder heating at 100 C for 1 h in [bmim]Br (200 mg). After the reaction was completed, 10 mL of ethyl acetate was added to the reaction mixture and stirred for 15 min. The organic layer was separated, washed with water, and dried. The cycloadduct was further purified using hexane: ethyl acetate (3:2 v/v) as eluent employing column chromatography technique. After extraction of the cycloadduct, [bmim]Br wasdried under vacuum at 80 C for 2 h to exclude any water trapped from moisture and reused for subsequent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h; | General procedure: A mixture of beta-nitrostyrenes, isatin and tyrosine (1:1:1) was stirredunder heating at 100 C for 1 h in [bmim]Br (200 mg). After the reaction was completed, 10 mL of ethyl acetate was added to the reaction mixture and stirred for 15 min. The organic layer was separated, washed with water, and dried. The cycloadduct was further purified using hexane: ethyl acetate (3:2 v/v) as eluent employing column chromatography technique. After extraction of the cycloadduct, [bmim]Br wasdried under vacuum at 80 C for 2 h to exclude any water trapped from moisture and reused for subsequent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h; | General procedure: A mixture of beta-nitrostyrenes, isatin and tyrosine (1:1:1) was stirredunder heating at 100 C for 1 h in [bmim]Br (200 mg). After the reaction was completed, 10 mL of ethyl acetate was added to the reaction mixture and stirred for 15 min. The organic layer was separated, washed with water, and dried. The cycloadduct was further purified using hexane: ethyl acetate (3:2 v/v) as eluent employing column chromatography technique. After extraction of the cycloadduct, [bmim]Br wasdried under vacuum at 80 C for 2 h to exclude any water trapped from moisture and reused for subsequent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h; | General procedure: A mixture of beta-nitrostyrenes, isatin and tyrosine (1:1:1) was stirredunder heating at 100 C for 1 h in [bmim]Br (200 mg). After the reaction was completed, 10 mL of ethyl acetate was added to the reaction mixture and stirred for 15 min. The organic layer was separated, washed with water, and dried. The cycloadduct was further purified using hexane: ethyl acetate (3:2 v/v) as eluent employing column chromatography technique. After extraction of the cycloadduct, [bmim]Br wasdried under vacuum at 80 C for 2 h to exclude any water trapped from moisture and reused for subsequent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h; | General procedure: A mixture of beta-nitrostyrenes, isatin and tyrosine (1:1:1) was stirredunder heating at 100 C for 1 h in [bmim]Br (200 mg). After the reaction was completed, 10 mL of ethyl acetate was added to the reaction mixture and stirred for 15 min. The organic layer was separated, washed with water, and dried. The cycloadduct was further purified using hexane: ethyl acetate (3:2 v/v) as eluent employing column chromatography technique. After extraction of the cycloadduct, [bmim]Br wasdried under vacuum at 80 C for 2 h to exclude any water trapped from moisture and reused for subsequent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-n-butyl-3-methylimidazolim bromide; at 100℃; for 1h; | General procedure: A mixture of beta-nitrostyrenes, isatin and tyrosine (1:1:1) was stirredunder heating at 100 C for 1 h in [bmim]Br (200 mg). After the reaction was completed, 10 mL of ethyl acetate was added to the reaction mixture and stirred for 15 min. The organic layer was separated, washed with water, and dried. The cycloadduct was further purified using hexane: ethyl acetate (3:2 v/v) as eluent employing column chromatography technique. After extraction of the cycloadduct, [bmim]Br wasdried under vacuum at 80 C for 2 h to exclude any water trapped from moisture and reused for subsequent runs. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60.1% | With triethylamine; In chloroform; at 80℃; for 3h; | Weigh5-trifluoromethoxy ruthenium0.95g (0.0041mol),0.85 g (0.0043 mol) of 4-chloroindole anhydride was added to a 100 ml three-necked flask containing a magnet, and then 40 ml of chloroform was added to the three-necked flask.1.5 ml of triethylamine, heated to reflux in an oil bath at 80 C for 3 h, after the reaction is over,The heating was stopped, and the mixture was cooled, and suction filtered to obtain a crude yellow solid powder.The product was washed 3 times with 10 ml of ethanol to obtain a pure product of a yellow solid powder.Dry and weigh 0.92g,The yield was 60.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.6% | With triethylamine; In chloroform; at 80℃; for 3h; | Weigh out 0.35 g (0.0015 mol) of 5-trifluoromethoxy ruthenium,0.39 g (0.0016 mol) of 5-bromoanthoic anhydride was added to a 100 ml three-necked flask containing a magnet, and then 40 ml of chloroform was added to the three-necked flask.1.5 ml of triethylamine, heated to reflux in an oil bath at 80 C for 3 h, after the reaction is over,The heating was stopped, and the mixture was cooled, and suction filtered to obtain a crude yellow solid powder.The product was washed 3 times with 10 ml of ethanol to obtain a pure product of a yellow solid powder.It was dried and weighed 0.45 g, and the yield was 72.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.9% | With triethylamine; In chloroform; at 80℃; for 3h; | Weigh 5-trifluoromethoxyBlush1.0g (0.0043mol),5-chloroindole anhydride 0.9g (0.0045mol) was added to a 100ml three-necked flask containing magnetons.Then add 40 ml of chloroform to the three-necked flask.1.5 ml of triethylamine, heated to reflux in an oil bath at 80 C for 3 h,After the reaction is over, stop heating and wait for cooling.The crude product was obtained as a yellow solid powder by suction filtration.The product was washed 3 times with 10 ml of ethanol.Obtaining a pure product yellow solid powder,drying,Weighing 1.12g,The yield was 70.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 1H-imidazole; In water; at 80℃; for 29h; | 0.4 mmol of 5-trifluoromethoxyisatin, 0.2 mmol of antipyrine, 0.04 mmol of imidazole and 1 mL of water were mixed, and the reaction was stirred under an oil bath of 80 C for 29 hours.Then, the obtained reaction system was cooled to room temperature, extracted with dichloromethane, and the organic phase was collected. The obtained organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (mobile phase: petroleum ether / ethyl acetate volume ratio) In the order of 4/1, 3/1, 2/1 and 1/1), the title compound I-7 (yellow solid, yield 65%, purity 99.8%) was obtained. |
65% | With 1H-imidazole; In water; at 80℃; for 29h;Green chemistry; | General procedure: The mixture of isatin 1 (58.9 mg, 0.4 mmol), antipyrine 2 (37.6 mg, 0.2 mmol) andimidazole (20 mol %, 0.04 mmol) in 1 mL H2O were stirred at 80 . Once thereaction completed, the solid mixture was filtered, washed by water and dried undervacuum to afford the analytically pure products 3. In some cases, the desired pureproducts were obtained by silica gel chromatography using ethyl acetate as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In water; at 120℃; for 48h;Green chemistry; | General procedure: The mixture of isatin 1 (29.4 mg, 0.2 mmol), antipyrine 2a (84.7 mg, 0.45 mmol) in 1mL H2O were stirred at 120 . Once the reaction completed (indicated by colorchange from red to white), the mixture was then cooled down to the room temperature.The insoluable solid mixture was filtered, washed by water and dried under vacuum to afford the desired product 4a in high pure form. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(l) iodide; In N,N-dimethyl-formamide; at 80℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in an Anton Paar Monowave 200 apparatus. Isatin 1 (1.0 equiv.) L-proline, 2 (1.0 equiv.), Baylis-Hillman adduct 3 (1.0 equiv.) and CuI (20 mol%) were suspended in DMF (2 mL) and placed in a 10 mL reaction vial, which was sealed with a septum and irradiated with microwave 200 for 10 min at 80 C. The reaction mixture was allowed to cool to r.t. and then diluted with CH2Cl2 (10 mL) and filtered. The organic layer was separated and the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography to afford the pure polycyclic pyrrolidine- and piperidinoquinolinone derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With copper(l) iodide; In N,N-dimethyl-formamide; at 80℃; for 0.166667h;Sealed tube; Microwave irradiation; | General procedure: All microwave irradiation experiments were carried out in an Anton Paar Monowave 200 apparatus. Isatin 1 (1.0 equiv.) L-proline, 2 (1.0 equiv.), Baylis-Hillman adduct 3 (1.0 equiv.) and CuI (20 mol%) were suspended in DMF (2 mL) and placed in a 10 mL reaction vial, which was sealed with a septum and irradiated with microwave 200 for 10 min at 80 C. The reaction mixture was allowed to cool to r.t. and then diluted with CH2Cl2 (10 mL) and filtered. The organic layer was separated and the solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography to afford the pure polycyclic pyrrolidine- and piperidinoquinolinone derivatives. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In ethanol; at 20℃; for 3h; | General procedure: A round bottom flask equipped with a magnetic stirrer was charged with isatin derivative (0.3 mmol), absolute ethanol (1.5 mL), NHS-diazoacetate (1.2 equiv) and triethylamine (20 mol%). The mixture was stirred for 3 hours at room temperature until formation of a precipitated (intermediate 14). The reaction mixture was centrifuged to recover the solid which was then washed with hexane. The isolated diazo compound was then dissolved in 2.5 mL of dry DCM and reacted with Rh2(OAc)4 (1 mol%) at room temperature over a period of 20 minutes. The ring expansion product precipitated from the reaction mixture and was collected by filtration and then washed with hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | General procedure: Ethyl diazoacetate (1.2 eq) and DBU (15 mol%) were added to a stirring solution of isatin (0.3 mmol) in absolute ethanol (1.5 ml). The reaction mixture was stirred for 3 hours at room temperature and then Rh2(OAc)4 (1 mol%) was added to afford the ring expansion product, which readily precipitated from the reaction mixture and was isolated by filtration. The collected solid was washed with Et2O, and dried under reduced pressure to furnish the expected 3-hydroxy-4-ethylesterquinolin-2-(1H)-ones.5 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With acetic acid for 4h; Reflux; | 3.1.3. Synthesis of Final Compounds 6a-i, 9a-f, and 11a,b General procedure: A solution of indole-2-carbohydrazide 4 (210 mg, 1.2 mmol) in glacial acetic acid (15 mL) was treated with the appropriate isatin derivative 5a-i and 8a-f (1.2 mmol), or ketones 10a and 10b (1.2 mmol). The resulting reaction mixture was refluxed for four hours then cooled to r.t. The obtained precipitate was collected by filtration and dried to get a powder that was recrystallized from glacial acetic acid to furnish the titled conjugates 6a-i, 9a-f, and 11a,b. |
Tags: 169037-23-4 synthesis path| 169037-23-4 SDS| 169037-23-4 COA| 169037-23-4 purity| 169037-23-4 application| 169037-23-4 NMR| 169037-23-4 COA| 169037-23-4 structure
[ 345-32-4 ]
5-(Trifluoromethyl)indoline-2,3-dione
Similarity: 0.74
[ 21544-81-0 ]
4,6-Dimethoxyindoline-2,3-dione
Similarity: 0.81
[ 21544-81-0 ]
4,6-Dimethoxyindoline-2,3-dione
Similarity: 0.81
[ 21544-81-0 ]
4,6-Dimethoxyindoline-2,3-dione
Similarity: 0.81
[ 345-32-4 ]
5-(Trifluoromethyl)indoline-2,3-dione
Similarity: 0.74
[ 21544-81-0 ]
4,6-Dimethoxyindoline-2,3-dione
Similarity: 0.81
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