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The evaluation of isatin analogues as inhibitors of monoamine oxidase
Prinsloo, Izak F. ; Petzer, Jacobus P. ; Cloete, Theunis T. , et al. Chem. Biol. Drug Des.,2023,102(5):1067-1074. DOI: 10.1111/cbdd.14304 PubMed ID: 37500571
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Abstract: The small mol., isatin, is a well-known reversible inhibitor of the monoamine oxidase (MAO) enzymes with IC50 values of 12.3 and 4.86μM for MAO-A and MAO-B, resp. While the interaction of isatin with MAO-B has been characterized, only a few studies have explored structure-activity relationships (SARs) of MAO inhibition by isatin analogs. The current study therefore evaluated a series of 14 isatin analogs as in vitro inhibitors of human MAO-A and MAO-B. The results indicated good potency MAO inhibition for some isatin analogs with five compounds exhibiting IC50 < 1μM. 4-Chloroisatin (1b) and 5-bromoisatin (1f) were the most potent inhibitors with IC50 values of 0.812 and 0.125μM for MAO-A and MAO-B, resp. These compounds were also found to be competitive inhibitors of MAO-A and MAO-B with Ki values of 0.311 and 0.033μM, resp. Among the SARs, it was interesting to note that C5-substitution was particularly beneficial for MAO-B inhibition. MAO inhibitors are established drugs for the treatment of neuropsychiatric and neurodegenerative disorders, while potential new roles in prostate cancer and cardiovascular disease are being investigated.
Keywords: competitive ; inhibition ; isatin ; monoamine oxidase ; structure-activity relationship
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CAS No. : | 39603-24-2 | MDL No. : | MFCD00047219 |
Formula : | C10H9NO2 | Boiling Point : | - |
Linear Structure Formula : | (CH3)2C8H3NO2 | InChI Key : | HFZSCCJTJGWTDZ-UHFFFAOYSA-N |
M.W : | 175.18 | Pubchem ID : | 38296 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 52.09 |
TPSA : | 46.17 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) : | -6.34 cm/s |
Log Po/w (iLOGP) : | 1.36 |
Log Po/w (XLOGP3) : | 1.45 |
Log Po/w (WLOGP) : | 0.87 |
Log Po/w (MLOGP) : | 0.79 |
Log Po/w (SILICOS-IT) : | 2.44 |
Consensus Log Po/w : | 1.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.18 |
Solubility : | 1.15 mg/ml ; 0.00659 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.03 |
Solubility : | 1.65 mg/ml ; 0.00943 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.55 |
Solubility : | 0.0495 mg/ml ; 0.000282 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.66 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P273-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319-H412 | 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 |
---|---|---|
66% | With sulfuric acid In water at 50 - 90℃; for 0.5 h; | General procedure: To a flask (100 mL) which contained concentrated sulfuricacid (20 mL) was added N-2-(hydroxyimino)acetamidederivatives (7.0 g) in portions at 50 °C with vigorous stirring.The reaction temperature was maintained at 50 °C-75 °Cduring the addition. After the addition was completed, themixture was heated to 80 °C and stirred for 30 min. The reactionmixture was cooled to room temperature and thenpoured onto ice (250 g). The solid which resulted was filteredout and dried over air to yield the crude which waspurified by dissolving in dilute sodium hydroxide (5percent, 100mL) followed by acidified with 4N hydrochloric acid (20mL). The solid which formed was filtered out and dried overair to provide the purified compounds 15a-g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | at 80℃; for 0.666667 h; Cooling with ice | General procedure: A round-bottom flask is charged with concentrated sulfuric acid (33 ml) and is magnetically stirred at 50 °C open to the atmosphere. To the acid was added 2-[(benzyloxy)imino]-N-(4-n-hexylphenyl) (11 g, 32.5 mmole) in portions over 30 minutes. On completion of the addition the mixture was heated at 80 °C for an additional 10 minutes then allowed to cool to room temperature. The dark viscous solution was subsequently added in portions with rapid stirring to ice (750 ml). The crude product was isolated by vacuum filtration, and the filter cake washed with water. The crude product was dried under vacuum to give 6.3 g (85 percent) of an orange solid.#10;#10; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 1-butyl-3-methylimidazolium Tetrafluoroborate; at 20℃; for 0.233333h;Green chemistry; | General procedure: A mixture of aromatic diamine derivatives (2 mmol) and a 1,2-dicarbonyl compound (2 mmol) in ionic liquid (2 mL) was stirred atroom temperature for the appropriate time. The progress of the reaction was monitored by TLC (n-Hexane: EtOAc, 7:3), after completion of the reaction, the reaction mixture was diluted with water and extracted using diethyl ether (30 ml). The combined organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to afford the corresponding product. The residual ionic liquid was dried under vacuum and reused. The same procedure was repeated for the reaction of aromatic anilines with isatin and acenaphthoquinone and phenaacylbromide. All the products obtained were characetrised by IR,1HNMR, 13CNMR and Mass studies. |
91% | In ethylene glycol; at 80℃; for 0.233333h;Microwave irradiation; Green chemistry; | General procedure: Indole-2,3-dione 1 (1 mmol) and 1,2-diamine 2 (1 mmol) and 5 mol% of Cu doped CdS NPs in ethylene glycol (10 ml) was introduced in a 50 ml round-bottomed flask. The flask was placed in the microwave cavity and subjected to irradiation for appropriate time at 80 C using a maximum power of 300 W. When the reaction was complete, the reaction mixture was extracted with ethylacetate; the organic layer was removed under reduced pressure to afford the crude product. The pure products were obtained by crystallization from ethanol. |
91% | With aminosulfonic acid; In ethanol; at 20℃; for 1.5h; | General procedure: To a 25 ml round bottom flask, a mixture of isatin / acenaphthoquinone / 2-hydroxynaphthoquinone/ ninhydrin (1 mmol), o-phenylene diamine (1 mmol) in ethanol (95 %, 10 mL) and sulfamic acid (20 mol %) was added. The reaction mixture was stirred at ambient temperature for time mentioned in Table II, monitored by TLC. After completion of reaction, the mixture was filtered washed with ethanol and dried to furnish the desired pure products in high yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sulfuric acid; In water; at 50 - 90℃; for 0.5h; | General procedure: To a flask (100 mL) which contained concentrated sulfuricacid (20 mL) was added N-2-(hydroxyimino)acetamidederivatives (7.0 g) in portions at 50 C with vigorous stirring.The reaction temperature was maintained at 50 C-75 Cduring the addition. After the addition was completed, themixture was heated to 80 C and stirred for 30 min. The reactionmixture was cooled to room temperature and thenpoured onto ice (250 g). The solid which resulted was filteredout and dried over air to yield the crude which waspurified by dissolving in dilute sodium hydroxide (5%, 100mL) followed by acidified with 4N hydrochloric acid (20mL). The solid which formed was filtered out and dried overair to provide the purified compounds 15a-g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With borane-THF; In tetrahydrofuran; at 0 - 20℃; | 45. A. SYNTHESIS OF 5, 7-DIFNETHYL-IH-INDOLE To solution of 5, 7-dimethyl-lH-indole-2, 3-dione in tetrahydrofuran at 0 C was added 1. 0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (40 mL). After stirred at room temperature overnight, a 5% HCl solution was added to the mixture and it was stirred 20 minutes. It was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. Extracts were dried over magnesium sulfate and evaporated to dryness to afford the title compound as oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In ethanol at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In ethanol at 80℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With indium(III) chloride; In water; at 100℃; for 0.166667h; | General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With indium(III) chloride; In water; at 100℃; for 0.166667h; | General procedure: A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile (1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin (1 mmol) and the reaction mixture heated under reflux at 100 C for 10 min. After completion of the reaction (TLC), the reaction mixture was cooled to room temperature; the precipitate was filtered off and washed with methanol to obtain pure 13 as a colorless solid. Spectroscopic data for all the compounds are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium acetate; In neat (no solvent); at 25℃; for 0.25h;Green chemistry; | General procedure: Isatin 1 (3 mmol), 0.198 g malononitrile (3 mmol),0.420 g dimedone (3 mmol), and 0.025 g sodium acetate(0.3 mmol) were grinded with the pestle in mortar atambient temperature for 15 min. The resulting mixture wasair dried. Crude solid was then put on filter, rinsed withwater (2 9 2 cm3), and dried with water pump. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; for 24h;Reflux; | General procedure: To a mixture of the protecting reagent RBr (0.2 mmol) and K2CO3 (0.138 g) in MeCN (10 mL), isatin (6) was added (0.147 g) at room temperature. After that, the reaction mixture was stirred 24 h at reflux. Then, the solvent was evaporated under vacuum, and the reaction crude was purified by column chromatography (SiO2, Hex:EtOAc 8:2), giving rise to the corresponding product 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 9-epi-9-amino-9-deoxyquinine; water; benzoic acid; In tetrahydrofuran; at 5℃; for 12h; | General procedure: To a mixture of isatin 1a (14.7 mg, 0.1 mmol), H2O (5.4 muL, 0.3 mmol), quinine-derived amine 3 (3.3 mg, 0.01 mmol), and benzoic acid (3.66 mg, 0.03 mmol) in THF (1.0 mL) at 5 C was added acetaldehyde (22.0 mg, 0.5 mmol). After the reaction mixture was stirred for 15 h at this temperature, it was cooled to 0 C. Methanol (2 mL) and NaBH4 (20.0 mg, 0.5 mmol) were then added sequentially. The resulting reaction mixture was stirred for an additional 30 min at 0 C. Water (5.0 mL) was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent under reduced pressure, the crude product was purified by column chromatography on silica gel (ethyl acetate/hexane 1:2 to 2:1) to give the pure product 2a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With nano structured silica bonded 1,4-diaza-bicyclo[2.2.2]octane sulfonic acid chloride; In water; for 1.5h;Reflux; | General procedure: A mixture of isatin derivatives or acenaphthenquinone(1 mmol), barbituric acid (1 mmol), 1, 3-dicarbonyl compounds(1 mmol), SBDBSAC (0.02 g) and H2O (5 mL) was added to a in a25 mL round-bottomed flask connected to a reflux condenser, andstirred under reflux conditions. After completion of the reaction, asmonitored by TLC, the reaction mixture was cooled to room temper-ature. Methanol (20 mL) was added, stirred and refluxed for 3 min.Then, the resulting mixture was centrifuged for the separation of the catalyst from the product and remaining starting materials.After the separation of catalyst from the reaction mixture, methanolwas removed and the solid residue (crude product) was trituratedby a mixture of ethanol and water (9/1) to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With toluene-4-sulfonic acid; In water; at 70℃; for 24h; | General procedure: A solution of isatin (1 mmol), barbituric acid (1 mmol), 3-amino-5-methyl isoxazole (1 mmol), and p-TsOH (0.2 mmol) in water (10 mL) was stirred for 24 h at 70 C in oil bath. After completion of the reaction, which was followed by TLC (n-hexane/EtOAc), the warm reaction mixture was filtered. The residue was washed with water and then recrystallized from ethanol to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With cetyltrimethylammonim bromide; In water; at 80℃; for 0.5h;Green chemistry; | General procedure: A mixture of isatin derivative (1.0 mmol), trans-4-hydroxy-L-proline (0.131 g,1 mmol), and CTAB (4 mmol) in water (50mL) was stirred at 80 C for 30 min. After completion of the reaction (monitored by TLC), the contents were filtered and the residue was washed thoroughly with water until free from CTAB. Finally, the residue was crystallized from a chloroform-petroleum ether mixture to afford the desired products in excellent yields. The characterizations of the products were accomplished by spectroscopic analysis (1H, 13C NMR, FTIR, and ESI-mass) and also by comparison of the data reported in the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sulfuric acid; at 80℃; for 0.666667h;Cooling with ice; | General procedure: A round-bottom flask is charged with concentrated sulfuric acid (33 ml) and is magnetically stirred at 50 C open to the atmosphere. To the acid was added 2-[(benzyloxy)imino]-N-(4-n-hexylphenyl) (11 g, 32.5 mmole) in portions over 30 minutes. On completion of the addition the mixture was heated at 80 C for an additional 10 minutes then allowed to cool to room temperature. The dark viscous solution was subsequently added in portions with rapid stirring to ice (750 ml). The crude product was isolated by vacuum filtration, and the filter cake washed with water. The crude product was dried under vacuum to give 6.3 g (85 %) of an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In methanol at 100℃; for 0.333333h; Microwave irradiation; Green chemistry; stereoselective reaction; | |
for 0.25h; Microwave irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 0℃; | General procedure: To a stirred solution of tetraethyl methylenebis(phosphonate) (0.69 mmol, 200 mg) in anhydrousTHF (10 mL) was added NaH (1.52 mmol, 60 mg) slowly at 0 C. After 10 minutes, a solution ofisatine (0.69 mmol) in anhydrous THF (2 mL) was added. After completion (monitored by TLC),water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The combinedorganic phases were dried with anhydrous Na2SO4 and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (hexane/ethyl acetate). To a stirredsolution of the above product (0.65 mmol, 182 mg) in anhydrous THF (10 mL) was added DMAP(0.13 mmol) and TEA (0.98 mmol) at 0 C. Then (Boc)2O (0.78 mmol, 170 mg) was added. Aftercompletion, water was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). Thecombined organic phases were dried with anhydrous Na2SO4 and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel (hexane/ethyl acetate). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With antimony(III) chloride; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | General procedure: A magnetically stirred mixture of naphthalene-2-amine (1.0mmol), isatin (1.0 mmol), dialkyl acetylenedicarboxylate (1.2 mmol) andanhydrous antimony trichloride (0.10 mmol) in dry acetonitrile (3 mL) taken in a 10 mL round bottom flask fitted with a reflux condenser under argonatmosphere and was refluxed for 5 h. After completion of the reaction, the reaction mixture was allowed to cool, quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and volatiles were removed in vacuo. The crude residue was purified by column chromatography over silica gel (100-200mesh), eluting with 25 % ethyl acetate in petroleum ether to afford compound (4). |
78% | With antimony(III) chloride; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | General procedure: A magnetically stirred mixture of naphthalene-2-amine (1.0mmol), isatin (1.0 mmol), dialkyl acetylenedicarboxylate (1.2 mmol) andanhydrous antimony trichloride (0.10 mmol) in dry acetonitrile (3 mL) taken ina 10 mL round bottom flask fitted with a reflux condenser under argonatmosphere and was refluxed for 5 h. After completion of the reaction, thereaction mixture was allowed to cool, quenched with water (10 mL) and extractedwith DCM (3 x 20 mL). The combined organic extracts were dried over anhydrousNa2SO4, filtered and volatiles were removed in vacuo. Thecrude residue was purified by column chromatography over silica gel (100-200mesh), eluting with 25 % ethyl acetate in petroleum ether to afford compound (4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With antimony(III) chloride; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | General procedure: A magnetically stirred mixture of naphthalene-2-amine (1.0mmol), isatin (1.0 mmol), dialkyl acetylenedicarboxylate (1.2 mmol) andanhydrous antimony trichloride (0.10 mmol) in dry acetonitrile (3 mL) taken in a 10 mL round bottom flask fitted with a reflux condenser under argonatmosphere and was refluxed for 5 h. After completion of the reaction, the reaction mixture was allowed to cool, quenched with water (10 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and volatiles were removed in vacuo. The crude residue was purified by column chromatography over silica gel (100-200mesh), eluting with 25 % ethyl acetate in petroleum ether to afford compound (4). |
81% | With antimony(III) chloride; In acetonitrile; at 80℃; for 8h;Inert atmosphere; | General procedure: A magnetically stirred mixture of naphthalene-2-amine (1.0mmol), isatin (1.0 mmol), dialkyl acetylenedicarboxylate (1.2 mmol) andanhydrous antimony trichloride (0.10 mmol) in dry acetonitrile (3 mL) taken ina 10 mL round bottom flask fitted with a reflux condenser under argonatmosphere and was refluxed for 5 h. After completion of the reaction, thereaction mixture was allowed to cool, quenched with water (10 mL) and extractedwith DCM (3 x 20 mL). The combined organic extracts were dried over anhydrousNa2SO4, filtered and volatiles were removed in vacuo. Thecrude residue was purified by column chromatography over silica gel (100-200mesh), eluting with 25 % ethyl acetate in petroleum ether to afford compound (4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With acetic acid; at 80℃; for 24h; | General procedure: A solution of an isatin (3) (1 mmol), a C-H acidderivative (2) (1 mmol), and naphthalen-1-amine (1)(1 mmol) was heated at 80 C in acetic acid (5 mL)for 24 h. After completion of the reaction as indicatedby TLC (MeOH/AcOEt, 1:4), the residue wasfiltered and washed successively with gl. acetic acid andCHCl3 (3 × 10 ml). The crude product thus obtainedwas crystallized from MeOH or EtOH and dried atroom temperature. The final product was obtained as a powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of isatin 1 (0.5 mmol) in THF (2 mL) was added quinine (0.017 g, 10 mol%). The mixture was cooled to -78 C and stirred at this temperature for 15 minutes. Then the solution of 2-(trimethylsilyloxy)furan 2 (0.156 g, 1 mmol) in THF (1 mL) was added dropwise. The mixture was stirred at -78 C for 15 minutes. The reaction was monitored by TLC. After the completion ofthe reaction it was quenched by addition of 10% aqueous HCl (2.0 mL) and the mixture wasextracted with ethyl acetate (3×5 mL). The combined organic layer was washed with brine solution,dried over MgSO4, and concentrated under reduced pressure (rotary evaporator). The crude products were purified by silica gel column chromatography (AcOEt/hexane) to afford the product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1,4-diaza-bicyclo[2.2.2]octane; In methanol; for 12h;Reflux; | General procedure: A solution of an isatin or 9,10-Phenanthrenequinone (1mmol), koijc acid (1 mmol), malononitrile or ethyl and/or methyl cyanoacetate (1 mmol) and DABCO (20 mol %) in MeOH (5 ml) was stirred for 12 h under reflux in oil bath. After completion of the reactions, which has been followed by TLC (EtOAc:n-hexane, 5:1), the reaction mixture was remained for 12 h at room temperature to get white and pure crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 0.25h; | General procedure: A mixture of the isatin 1 or acenaphthenequinone 4 (1 mmol), indole 2 (2 mmol), p-TSA (10mol %), CH2Cl2 (10 mL) was added to 50 mL flask and stirred at room temperature until the thecompletion of the reaction (Scheme 1, 2). Then the solid was filtered and washed with CH2Cl2 (5mL) and ethanol (5 mL) in turns, affording the product in excellent yields, which wasrecrystallized from ethanol to produce pure crystalline products. The products were identified byelemental analysis, MS, 1H NMR, 13C NMR, and IR spectra. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With 1-butyl-3-methylimidazolium Tetrafluoroborate In toluene at 100℃; for 0.666667h; Inert atmosphere; Combinatorial reaction / High throughput screening (HTS); Microwave irradiation; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In glycerol; at 40℃; for 3h;Green chemistry; | General procedure: To a round bottom flask containing 5 ml glycerol was added respective isatin (1 mmol) and respective thiosemicarbazide/semicarbazide (1 mmol) under stirring. The temperature of the reaction was set at 40 oC and the resulting mixture was stirred till completion and progress of reaction was monitored with TLC (Hexane/EtOAc 2:1). The reaction was quenched with hot water whence glycerol got dissolved in water and the resulting insoluble solid precipitate was filtered and dried to obtain the crude product which was as good as pure (1H NMR). The aqueous phase containing glycerol was extracted with methyl t-butyl ether (4 × 25 mL) to remove any trace of organic compounds and then evaporated in vacuo to give pure glycerol which was used for the next cycle. |
82% | With C10H16NO4S(1+)*HO4S(1-); In water; at 20℃; for 0.2h;Green chemistry; | General procedure: A mixture of isatin (1 mmol), thiosemicarbazide/4-methyl-3-thiosemicarbazide (1 mmol) was taken in 5 cm3 watercontaining 20 mol% of [2-HMPyBSA]HSO4 and stirred atroom temperature for the time specified in Table 2. Theprogress of reaction was monitored by TLC. After completionof the reaction, the reaction mixture was filteredand washed with ethanol to yield corresponding product inpure form. Products were characterized by usual spectraltechniques. (i.e. IR, 1H, 13C NMR, and MS). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In glycerol; at 40℃; for 3h;Green chemistry; | General procedure: To a round bottom flask containing 5 ml glycerol was added respective isatin (1 mmol) and respective thiosemicarbazide/semicarbazide (1 mmol) under stirring. The temperature of the reaction was set at 40 oC and the resulting mixture was stirred till completion and progress of reaction was monitored with TLC (Hexane/EtOAc 2:1). The reaction was quenched with hot water whence glycerol got dissolved in water and the resulting insoluble solid precipitate was filtered and dried to obtain the crude product which was as good as pure (1H NMR). The aqueous phase containing glycerol was extracted with methyl t-butyl ether (4 × 25 mL) to remove any trace of organic compounds and then evaporated in vacuo to give pure glycerol which was used for the next cycle. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethylene glycol; at 80℃; for 0.233333h;Microwave irradiation; Green chemistry; | General procedure: Indole-2,3-dione 1 (1 mmol) and 1,2-diamine 2 (1 mmol) and 5 mol% of Cu doped CdS NPs in ethylene glycol (10 ml) was introduced in a 50 ml round-bottomed flask. The flask was placed in the microwave cavity and subjected to irradiation for appropriate time at 80 C using a maximum power of 300 W. When the reaction was complete, the reaction mixture was extracted with ethylacetate; the organic layer was removed under reduced pressure to afford the crude product. The pure products were obtained by crystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-(pyridin-2-ylmethyl)pyrrolidine-2-carboxamide; ytterbium(III) triflate; In dichloromethane; at 20℃; for 288h; | General procedure: A mixture of Yb(OTf)3 (0.01 mmol) and ligand L6 (0.02 mmol) wasstirred at r.t. for 2 h in CH2Cl2 (2 mL). The appropriate enones 1 (1mmol) and isatins 2 (0.1 mmol) were then added. The resulting mixturewas stirred at r.t. After the reaction was completed as monitoredby TLC (eluent: hexane-EtOAc, 1:1), the reaction mixture was purifiedby column chromatography (silica gel, eluent: mixture ofhexane and EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 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 |
---|---|---|
89% | With 2,2,2-trifluoroethanol; for 0.666667h;Reflux; | General procedure: An equimolar mixture of dipolarophile 1/7 (1 mmol), isatin 2a-e/acenaphthenequinone 11 (1 mmol) and sarcosine 3/1,3-thiazolane-4-carboxylic acid 5 (1 mmol) in 2,2,2-trifluoroethanol (10 ml) was refluxed forthe appropriate time (30-40 min). After completion of the reaction asindicated by (TLC), the solid precipitates were filtered and washed withethanol to furnish pure corresponding dispiropyrrolidine/thiapyrrolizidinederivatives. Synthesized compounds were well characterized by 1H NMR, 13CNMR, Mass and single crystal X-ray analysis of representative compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 2,2,2-trifluoroethanol; for 0.65h;Reflux; | General procedure: An equimolar mixture of dipolarophile 1/7 (1 mmol), isatin 2a-e/acenaphthenequinone 11 (1 mmol) and sarcosine 3/1,3-thiazolane-4-carboxylic acid 5 (1 mmol) in 2,2,2-trifluoroethanol (10 ml) was refluxed forthe appropriate time (30-40 min). After completion of the reaction asindicated by (TLC), the solid precipitates were filtered and washed withethanol to furnish pure corresponding dispiropyrrolidine/thiapyrrolizidinederivatives. Synthesized compounds were well characterized by 1H NMR, 13CNMR, Mass and single crystal X-ray analysis of representative compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With 2,2,2-trifluoroethanol; for 0.666667h;Reflux; | General procedure: An equimolar mixture of dipolarophile 1/7 (1 mmol), isatin 2a-e/acenaphthenequinone 11 (1 mmol) and sarcosine 3/1,3-thiazolane-4-carboxylic acid 5 (1 mmol) in 2,2,2-trifluoroethanol (10 ml) was refluxed forthe appropriate time (30-40 min). After completion of the reaction asindicated by (TLC), the solid precipitates were filtered and washed withethanol to furnish pure corresponding dispiropyrrolidine/thiapyrrolizidinederivatives. Synthesized compounds were well characterized by 1H NMR, 13CNMR, Mass and single crystal X-ray analysis of representative compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 2,2,2-trifluoroethanol; for 0.666667h;Reflux; | General procedure: An equimolar mixture of dipolarophile 1/7 (1 mmol), isatin 2a-e/acenaphthenequinone 11 (1 mmol) and sarcosine 3/1,3-thiazolane-4-carboxylic acid 5 (1 mmol) in 2,2,2-trifluoroethanol (10 ml) was refluxed forthe appropriate time (30-40 min). After completion of the reaction asindicated by (TLC), the solid precipitates were filtered and washed withethanol to furnish pure corresponding dispiropyrrolidine/thiapyrrolizidinederivatives. Synthesized compounds were well characterized by 1H NMR, 13CNMR, Mass and single crystal X-ray analysis of representative compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With ammonium acetate; In ethanol; at 20℃; for 1.5h;Green chemistry; | General procedure: A mixture of 2-amino benzophenone (1 mmol), corresponding isatin or aldehyde (1 mmol) and ammonium acetate (2 mmol) in ethanol (5 mL) was stirred at room temperature. The progress of reaction was monitored by TLC. After completion of the reaction ice-cold water was added and stirred for a while. The solid product obtained was filtered and washed with water. This was further purified by crystallization from ethanol or by short column chromatographyon silica gel using ethyl acetate-petroleum ether as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With ammonium acetate; In ethanol; water; at 20℃; for 6h;Green chemistry; | General procedure: Isatin (1mmol), 1,3-indanedione (1mmol), ethyl acetoacetate (1mmol), and NH4OAc (1mmol) were placed in a 25-mL round-bottomed flask in ethanol:water (9:1) (5mL). The resulting mixture was stirred at room temperature for time mentioned in Table 2, until completion of the reaction as monitored by thin-layer chromatography (TLC). After completion of the reaction, the mixture was filtered and washed with a small quantity of ethanol to furnish pure spiro[4H-indeno-[1,2-b]pyridine-4,3'-[3H]indoles]. The structure of products was confirmed by IR, 1H and 13C NMR, GCMS, HRMS, and elemental analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With aminosulfonic acid; In ethanol; at 20℃; for 0.5h;Green chemistry; | General procedure: To a mixture of isatin(s)/acenaphthoquinone/cyclic ketone(s) (1 mmol) and anthranilamide (1mmol) in ethanol(96%, 2 mL), sulfamic acid (0.2 mmol) was added. Thereaction mixture was stirred at ambient temperature forthe time mentioned in table 2 until completion of reaction,as monitored by TLC. After the completion ofreaction, the precipitated products was just filtered. Theconfirmation of isolated products was done by spectraltechniques such as 1H, 13C NMR, IR and massspectrometry. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,4-diaza-bicyclo[2.2.2]octane; In ethanol; water; at 20℃; for 0.416667h; | General procedure: In a 25 cm3 round bottom flask, to a mixture of isatin(1 mmol), malononitrile (2 mmol), and cyclohexanone (1 mmol) in 10 cm3 30 % ethanol, DABCO (20 mol%)was added. The reaction mixture was stirred at room temperature for time mentioned in Table 2 until completionof reaction, monitored by TLC. After completion ofreaction, the mixture was cooled and filtered to furnish thedesired product in good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With acetic acid; In ethanol; for 6h;Reflux; | General procedure: A mixture of the compounds 11a-d (1 mmol) and substituted indolinone 15a-g (1.1 mmol) or appropriate aromatic aldehydes 12a-c (1.1 mmol) with catalyst amount of glacial acetic acid in ethanol (10 mL) was heated at reflux for 6 h and then cooled to room temperature and filtered. The obtained cake was washed with diethyl ether to get a white to light yellow solid. The crude product was purified by chromatography on silica gel using MeOH/CH2Cl2 to afford the desired compounds 16a-d and 17a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With perchloric acid; In butan-1-ol; for 8h;Reflux; | General procedure: To asolution of isatin 3 (1.0mmol), 2-aminopyridine 2 (1.35mmol)andisocyanide 4 (1.35mmol) in 4mL of n-butyl alcohol was added HClO4 (1.0mmol), and the reaction mixture was stirred under refluxfor 8 h. After cooling to room temperature, the precipitate was collected by filtration, rinsed with ethanol and dried to afford the target compound 1. |
40% | With perchloric acid; In butan-1-ol; for 8h;Reflux; | Will be perchloric acid (70%, 1 mmol, 142 mg) was added 5-methoxyisatin (1 mmol, 177 mg), 2-amino-5-chloro-pyridine (1.35 mmol, 174 mg) And tert-butylisocyanide (1.35 mmol, 112 mg) in n-butanol (4 mL) The reaction was stirred at reflux for 8 hours. When the reaction solution was cooled to room temperature, Filtration and washing the filter cake with a small amount of ethanol gave the desired product in 39% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With perchloric acid; In butan-1-ol; for 8h;Reflux; | General procedure: To asolution of isatin 3 (1.0mmol), 2-aminopyridine 2 (1.35mmol)andisocyanide 4 (1.35mmol) in 4mL of n-butyl alcohol was added HClO4 (1.0mmol), and the reaction mixture was stirred under refluxfor 8 h. After cooling to room temperature, the precipitate was collected by filtration, rinsed with ethanol and dried to afford the target compound 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: In a 50 mL flask, a mixture of hydrazine hydrate 1 (1 mmol), beta-keto ester 2 (acetylacetic ether or ethyl benzoylacetate) (1 mmol) was stirred at room temperature (78C) for 5 minutes. And then, 2-hydroxynaphthalene-1,4-dione 3 (1 mmol), isatins 4 (1 mmol), MgCl2 (0.1 mmol) and 5 mL ethanol were added to it. The mixture was stirred at 78C for the appropriate time. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to room temperature, 5 mL water was added to it. Then the precipitated products were filtered and washed with cold ethanol (3 mL×2) to afford the pure products as solid powder in good to excellent yields without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid; In ethanol; for 2h;Reflux; | General procedure: To a stirred solution of the appropriate indolin-2,3-dione derivative1a-f (1 mmol) in absolute ethyl alcohol (10 mL), 4-(2-aminoethyl)benzenesulfonamide 2 (0.2 gm, 1 mmol) and catalyticamount of glacial acetic acid were added. After refluxing for 2 h, theformed precipitate was collected by filtration while hot, washedwith methanol, dried and crystallized from ethanol to furnishcompounds 3a-f with 62e75% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In 2,2,2-trifluoroethanol; at 150℃; for 0.133333h;Microwave irradiation; Green chemistry; | General procedure: A mixture of substituted isatins 1 (1mmol), sarcosine 2/1,3-thiazoles-4-carboxylic acid 5 (1 mmol) and Knoevenagel adduct (1 mmol) was refluxed for 10 min. in 2,2,2-trifluoroethanol (4 mL) under microwaves. All these reactions were carried out by microwave irradiation for 10 min at the power level 250 W and at the temperature of 150C which was recorded by the temperature probe of the microwave. Progress of the reaction was checked after a regular interval of one minute till the completion of reaction by TLC using hexane: ethylacetate (8:2) as mobile. Product was collected by the same way as in conventional methods. The TFE was distilled off (to recover for the next run). All the synthesized compounds were well characterized by IR, 1H NMR, 13C NMR, Mass and single crystal X-ray analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In 2,2,2-trifluoroethanol; at 150℃; for 0.166667h;Microwave irradiation; Green chemistry; | General procedure: A mixture of substituted isatins 1 (1mmol), sarcosine 2/1,3-thiazoles-4-carboxylic acid 5 (1 mmol) and Knoevenagel adduct (1 mmol) was refluxed for 10 min. in 2,2,2-trifluoroethanol (4 mL) under microwaves. All these reactions were carried out by microwave irradiation for 10 min at the power level 250 W and at the temperature of 150C which was recorded by the temperature probe of the microwave. Progress of the reaction was checked after a regular interval of one minute till the completion of reaction by TLC using hexane: ethylacetate (8:2) as mobile. Product was collected by the same way as in conventional methods. The TFE was distilled off (to recover for the next run). All the synthesized compounds were well characterized by IR, 1H NMR, 13C NMR, Mass and single crystal X-ray analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In 2,2,2-trifluoroethanol; at 150℃; for 0.1h;Microwave irradiation; Green chemistry; | General procedure: A mixture of substituted isatins 1 (1mmol), sarcosine 2/1,3-thiazoles-4-carboxylic acid 5 (1 mmol) and Knoevenagel adduct (1 mmol) was refluxed for 10 min. in 2,2,2-trifluoroethanol (4 mL) under microwaves. All these reactions were carried out by microwave irradiation for 10 min at the power level 250 W and at the temperature of 150C which was recorded by the temperature probe of the microwave. Progress of the reaction was checked after a regular interval of one minute till the completion of reaction by TLC using hexane: ethylacetate (8:2) as mobile. Product was collected by the same way as in conventional methods. The TFE was distilled off (to recover for the next run). All the synthesized compounds were well characterized by IR, 1H NMR, 13C NMR, Mass and single crystal X-ray analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In 2,2,2-trifluoroethanol; at 150℃; for 0.133333h;Microwave irradiation; Green chemistry; | General procedure: A mixture of substituted isatins 1 (1mmol), sarcosine 2/1,3-thiazoles-4-carboxylic acid 5 (1 mmol) and Knoevenagel adduct (1 mmol) was refluxed for 10 min. in 2,2,2-trifluoroethanol (4 mL) under microwaves. All these reactions were carried out by microwave irradiation for 10 min at the power level 250 W and at the temperature of 150C which was recorded by the temperature probe of the microwave. Progress of the reaction was checked after a regular interval of one minute till the completion of reaction by TLC using hexane: ethylacetate (8:2) as mobile. Product was collected by the same way as in conventional methods. The TFE was distilled off (to recover for the next run). All the synthesized compounds were well characterized by IR, 1H NMR, 13C NMR, Mass and single crystal X-ray analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | 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 |
---|---|---|
32% | With ethanol; potassium hydroxide; at 80℃; for 16h; | j0309j A. 6,8-Dimethyl-2-(3-methyl-1-benzofuran-2-yl)quinoline-4-carboxylic acid. To a100 ml. round-bottom flask was placed a solution of 1-(3-methyl-1-benzofuran-2-yl)ethan-1-one (1 g,5.74 mmol) in EtOH (20 mL) then 5,7-dimethyl-2,3-d1H ydro-1H -indole-2,3-dione(800 mg,4.57 mmol) and KOH (800 mg) were added. The resulting solution was heated to80C and stirred for 16 h. The reaction was cooled to rt and concentrated under reducedpressure. The residue was dissolved in 100 mL of H20,washed with MTBE (3x50 mL),and the pH of the solution was adjusted to 2-3 with 2N HC1. The resulting precipitate was isolated by filtration and washed with MeOH (3x50 mL) affording 485 mg (32%) of the title compound as a yellow solid. Mass Spectrum (LCMS,ESI pos): Calcd. for C2,H,8NO3: 332.1 (M+H); Found: 332.0. 1H NMR (300 MHz,DMSO-d6): oe 13.95 (s,1H ),8.43 (s,1H ),8.33 (s,1H ),7.80-7.77 (d,J= 7.5 Hz,1H ),7.73-7.70 (d,J= 8.1H z,1H ),7.61 (s,1H ),7.47-7.42 (t,J= 7.5 Hz,1H ),7.38-7.33 (t,J= 7.5 Hz,1H ),2.85 (s,3H),2.73 (s,3H),2.52 (s,3H). HPLC purity(254 nm): 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | General procedure: A mixture of isatins 1a-g (1 mmoL) with an equimolar amount of N,N'-diphenyl/(p-tolyl)thiourea2a,b (1 mmoL) and bromoacetic acid 3 (0.14 g, 1 mmoL) in glacial acetic acid (10 mL) in the presenceof sodium acetate (0.16 gm, 2 mmoL), was heated under reflux for 3 h. The formed solid was filteredoff while hot, washed with hot ethanol, dried and recrystallized from DMF to furnish the targethybrids 4a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium acetate; acetic acid; for 2h;Reflux; | General procedure: A mixture of isatins 1c, e-g (1 mmoL) with an equimolar amount of 2-mercaptobenzimidazole6 (0.15 gm, 1 mmoL) and bromoacetic acid 3 (0.14 g, 1 mmoL) in glacial acetic acid (10 mL) in thepresence of sodium acetate (0.16 g, 2 mmoL), was heated under reflux for 2 h. The obtained solid wasfiltered off while hot, washed with hot ethanol, dried and recrystallized from DMF to afford the targethybrids 7a-d. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | General procedure: A mixture of isatins 1a-g (1 mmoL) with an equimolar amount of N,N'-diphenyl/(p-tolyl)thiourea2a,b (1 mmoL) and bromoacetic acid 3 (0.14 g, 1 mmoL) in glacial acetic acid (10 mL) in the presenceof sodium acetate (0.16 gm, 2 mmoL), was heated under reflux for 3 h. The formed solid was filteredoff while hot, washed with hot ethanol, dried and recrystallized from DMF to furnish the targethybrids 4a-n. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic acid; for 6h;Reflux; | General procedure: To a hot solution of 4-(hydrazinecarbonyl)benzenesulfonamide 3 (0.25g, 1.16mmol) in glacial acetic acid (15mL), the appropriate isatin derivative 4a-h, 8a-g or 9a-c (1.2mmol) was added. This mixture was heated under reflux for 6h. The formed precipitate was filtered off while hot and washed with ethanol and petroleum ether then recrystallized from DMF/ethanol to obtain the target compounds 5a-h, 10a-g and 11a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1,7-bis(((pyridin-2-ylmethyl)amino)methyl)-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine-2,8-diol; potassium hydroxide; palladium dichloride; In dimethyl sulfoxide; at 110℃; | isatin(1.0 mmol) was added to a 50 mL dry round bottom flask in turn.O-iodophenylacetonitrile (1.0 mmol), 4-hydroxycoumarin (1.0 mmol),Catalyst 3e (5 mol%), palladium dichloride (5 mol%),KOH (20 mol%), DMSO 3 mL, mix well, stir at 110 C,After the reaction was completed (TLC tracking), an appropriate amount of water was added and extracted with ethyl acetate.The organic phases are combined, and the excess solvent in the system is distilled off under reduced pressure.The crude product was separated by column chromatography (V petroleum ether: V ethyl acetate = 1:1 gradient elution) to give the title compound 12b in a yield of 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With caesium carbonate In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium fluoride on basic alumina; In ethanol; for 6h;Reflux; | General procedure: To a solution of DHEA (0.5 mmol, 1.0 eq) and isatin derivative(0.75 mmol, 1.5 eq) in EtOH (10 mL) was added Al2O3/KF (0.5 mmol,1.0 eq), the resulting mixture was stirred at reflux temperature for 6 h.Upon completion of the reaction indicated by the TLC, the mixture wasfiltered and the solid was washed with dichloromethane (DCM) forseveral times. The filtrate was then evaporated under vacuum, followedby addition of DCM and H2O. The mixture was then acidified with 4MHCl (pH=1-2). The aqueous layer was washed with DCM for severaltimes. The combined organic layers were then dried over Na2SO4 andevaporated under vacuum to the crude product, which was then subjectedto column chromatography, affording the corresponding product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With Amberlyst-15; In methanol; at 80℃; for 5h; | General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With Amberlyst-15; In methanol; at 80℃; for 5h; | General procedure: In a 25 mL round bottom flask, isatins 1 (1 mmol), 3-phenylisoxazol-5(4H)-one 2 (1 mmol) or 3-ethylisoxazol-5(4H)-one 7 (1 mmol), pyrazol-5-amine 3 (1 mmol) or 6-aminopyrimidine-2,4-(1H,3H)-dione 5 (1 mmol), and Amberlyst-15 (100 mg) were stirred in CH3OH (5.0 mL) at 80 C. When the reaction was completed (detected by TLC), the spherical catalyst was separated by a sieve at once under hot condition. Then, the reaction mixture was cooled to room temperature, and solid precipitation occurred. After filtration, the crude product was recrystallized from EtOH and DMF to give pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | 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 |
---|---|---|
84% | 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 |
---|---|---|
73% | With acetic acid; In ethanol; for 2h;Reflux; | General procedure: To a hot stirred solution of key intermediate 1H-indole-2-carbohydrazide 5 (0.18 gm, 1 mmoL) inabsolute ethyl alcohol (7 mL) and glacial acetic acid (catalytic amount), the appropriate N-unsubstituted1H-indole-2,3-dione 6a-f, N-substituted 1H-indole-2,3-dione 8a-h, or 1-tetralone 10 (1 mmoL) wasadded. The resulting mixture was refluxed for 2 hours, and then the formed solid was filtered owhile hot, washed with cold isopropyl alcohol, dried and recrystallized from DMF to aord targetbis-indoles (7a-f and 9a-h), and 11, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With acetic acid; for 4h;Reflux; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With air In toluene at 25℃; UV-irradiation; Green chemistry; | 2.3. General procedure for the preparation of 3-alkyl-3-hydroxyindolin-2-ones General procedure: A quartz tube equipped with a stirring bar was charged with isatin derivative (0.20 mmol, 1.0 equiv.), benzophenone compound (0.30 mmol, 1.5 equiv.), and toluene (2 mL). The mixture was stirred at room temperature under irradiation of a 15 W black LEDs (Philips) in the air atmosphere. After completion of the reaction (detected by TLC), the toluene was removed from the reaction mixture. The residue was purified by flash chromatography on silica gel with petroleum ether/ethyl acetate (5:1 to 2:1) as the eluent to give desired product. |
65% | In toluene at 20℃; for 36h; UV-irradiation; | 13 Example 13 Dissolve 0.2mmol of compound III-13 (5,7-dimethylindoline-2,3-dione) and 0.3mmol of compound II-13 (phenyl(o-tolyl)methanone) in 2ml of organic solvent (toluene), irradiate with an ultraviolet lamp with a power of 15W, react at room temperature for 36h, and purify by chromatography after removing the organic solvent (using a volume ratio of 2:1 petroleum ether and ethyl acetate mixed solvent as eluent, R f value=0.2) to obtain a white solid compound I-13 (3-(2-benzoylbenzyl)-3-hydroxy-5,7-dimethylindolin-2-one) (Mp is 191.6-193.3 ) 48.3mg, the yield is 65%, |
Tags: 39603-24-2 synthesis path| 39603-24-2 SDS| 39603-24-2 COA| 39603-24-2 purity| 39603-24-2 application| 39603-24-2 NMR| 39603-24-2 COA| 39603-24-2 structure
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P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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