* 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.
Stage #1: With sodium hydroxide In water for 1 h; Stage #2: With sulfuric acid; sodium nitrite In water at 0℃; Stage #3: With hydrogenchloride; tin(ll) chloride In water at 20℃; for 5 h;
The intermediate XIX was prepared according to the method reported (J Heterocyclic Chemistry, 1964, 1(5), 239-241). To a solution of 0.55 g of sodium hydroxide in 10 mL of water, 3.2 g of 5-bromoisatin (16.9 mmol) was added. After stirring for one hour the EPO <DP n="56"/>solution was cooled to 50C and treated, under stirring, with 1.0 g of sodium nitrite dissolved in 40 ml_ of water. It was then poured, in small portions and with vigorous stirring, into aqueous sulfuric acid (0.8 ml. of acid, d=1.84, in 30 mL of water) cooled at O0C, and sulfur dioxide was bubbled through until most of the yellow precipitate which had formed was dissolved. The golden-yellow liquid obtained after filtration was poured into a solution of 4.8 g of stannous chloride in 10 mL of hydrochloric acid, and the mixture left for 5 hours at room temperature. The precipitate obtained was collected, washed thoroughly with dilute hydrochloric acid, then with water, to give a yellow solid crude product XjX (1.4 g, 30percent yield). LC-MS (ESI, positive mode): [MH]+ = 241 , 243
6.21 g
Stage #1: With sodium hydroxide In water at 50℃; for 1 h; Stage #2: With sulfuric acid; sodium nitrite In water for 1 h; Cooling with ice Stage #3: With hydrogenchloride; tin(II) chloride dihdyrate In water at 20℃;
(a) Step 1 Aqueous sodium hydroxide (1.13 g, 28.3 mmol, 25 mL) was heated to 50°C, and added with 5-bromoisatin (6.22 g, 27.5 mmol). The reaction mixture was stirred at 50°C for 1 hour, and then cooled on ice. The reaction mixture was added dropwise with ice-cooled aqueous sodium nitrite (1.90 g, 27.5 mmol, 9 mL). Then, the mixture was added dropwise with concentrated sulfuric acid (5.26 g, 53.6 mmol) in ice-cooled water (44 mL), and the mixture was stirred for 1 hour under ice cooling. Then, the reaction mixture was added dropwise with an ice-cooled solution of tin(II) chloride dihydrate (14.9 g, 66.0 mmol) in concentrated hydrochloric acid (22 mL). The mixture was stirred overnight at room temperature, and then filtered, and the resulting solid was washed with water to obtain a pale brown solid (6.21 g).
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 2 h;
5-bromoisatin (II) (20.0 g, 88.49 mmol) was dispersed in dichloromethane (300 mL)At room temperature in batches to join betweenChloroperoxybenzoic acid (22.91 g, 132.73 mmol) and reacted at room temperature2h, TLC detection, the reaction is completed. After cooling to 10 ° C and stirring continued, the sodium bisulfite was added dropwise Solution until the starch test paper does not change color, spin to dichloromethane, add 50mL water and residual mixture of mixed Stir, and add saturated saturated sodium bicarbonate solution to no bubbles, filter, a small amount of water to wash,Dried at 50 ° C to obtain 20.99 g of 5-bromoisoin anhydride (III) in a yield of 98percent.
79%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 0 - 20℃; for 2 h;
Compound 1 ((500 mg, 2 . 2mmol) was suspended in 10 ml of dry methylene chloride, at zero-degree celsius added meta-chloroperoxybenzoic acid (0.76g, 4 . 4mmol, 85percent). Stirred under room temperature for 2 hours. TLC (CH 2 Cl 2/MeOH= 50/1, Rf0.4) detection after the reaction is complete, filtering white solid formed in the reaction, then with 10 ml of ethyl acetate after washing three times, to obtain compound 2 (420 mg, 79percent).
Reference：
[1] Patent: CN106632276, 2017, A, . Location in patent: Paragraph 0112; 0113; 0114
[2] Angewandte Chemie, 1980, vol. 92, # 3, p. 196 - 197
[3] Catalysis Science and Technology, 2015, vol. 5, # 10, p. 4830 - 4838
[4] Patent: CN103570726, 2016, B, . Location in patent: Paragraph 0085; 0086; 0087
[5] Journal fuer Praktische Chemie (Leipzig), 1886, vol. <2> 33, p. 36
10
[ 7664-93-9 ]
[ 7722-84-1 ]
[ 87-48-9 ]
[ 77603-45-3 ]
Reference：
[1] Patent: US5597922, 1997, A,
11
[ 541-50-4 ]
[ 87-48-9 ]
[ 5463-29-6 ]
Yield
Reaction Conditions
Operation in experiment
0.150 g
With sodium hydroxide In tetrahydrofuran; waterReflux
The title compound was prepared using the methods shown in Scheme 6. 5-bromoindoline-2,3-dione (0.250 g) was dissolved in THF (3 ml) in a round-bottomed flask and malonic acid (2 eq) was added. The vessel was connected to a reflux condenser and heated to reflux overnight by conventional heating. After 12 hours, solid precipitate was observed. Suspension was concentrated under reduced pressure to remove solvent, water was added, and the suspension was refluxed for 4 hours. The suspension was then filtered to provide 6-bromo-2-hydroxyquinoline-4-carboxylic acid (0.150 g) as a solid.
With sodium hydride; In N,N-dimethyl-formamide;Inert atmosphere;
General procedure: A mixture of 2-bromoaniline or 3-bromoaniline (110 mmol, 18.9 g), chloral hydrate (118.8 mmol,19.6 g), anhydrous sodium sulfate (880 mmol, 125 g), and hydroxylamine hydrochloride (347.6mmol, 24.2 g) in water (700 mL) was heated under reflux for 25 min to form a yellow precipitate. 50mL of ethanol was added after that and left to boil for another 4 min before filtration. The resultedisonitrosoacetanilide was then heated with sulfuric acid (150 mL) at 70 C for about 10 min thenpoured into ice water to form an orange precipitate. When using 3-bromoaniline, an extra step ofseparation is required by solving the resulted mixture in 0.25 M NaOH (1 L), filtering it, then addingacetic acid (100 mL) to afford 4-bromoistain as a precipitate. 6-Bromoistin can be then obtained whenlowering the pH of the solution to 1 by hydrochloric acid 37%.All substituted bromo-isatins were methylated by stirring (22 mmol, 4.97 g) with sodiumhydride (2 mmol, 0.968 g) and dimethylsulfate (23.1 mmol, 2.19 mL) in dried DMF (50 mL) undernitrogen atmosphere. The resulting mixture was poured after 2 h in ice water (100 mL) to form anorange precipitate.The methylated bromo-isatins (2 mmol, 0.480 g) were treated after that with oxindole (2 mmol,0.226 g) in a 100:1 mixture of glacial acetic acid and hydrochloric acid 37% (12 mL) in reflux for about 3 h. Then, they were poured in ice water (50 mL) to afford 5-, 6- and 7-bromomeisoindigo. While 4'-, 5'-, 6'- and 7'-bromomeisoindigo were obtained by reacting unmethylated bromo-isatins(2 mmol, 0.452 g) with 1-methyloxindole (2 mmol, 0.294 g) in the same conditions. The resultedprecipitates were washed with water, ethanol (2 x 10 mL), and diethylether (2 10 mL) then dried. 3.2.1. 5-Bromo-1-MeisoindigoYield: 70%. 1H-NMR (400 MHz, DMSO, d6) delta ppm 3.19 (s, 3H), 6.83 (dd, 3J = 7.8 Hz, 4J = 0.5 Hz, 1H)6.96 (m, 1H), 6.97 (d, 3J = 8.4 Hz, 1H), 7.35 (td, 3J = 7.6 Hz, 4J = 1.1 Hz), 7.58 (dd, 3J = 8.4 Hz, 4J = 2.1 Hz),9.06 (dd, 3J = 8.1 Hz, 4J = 0.5 Hz), 9.31 (d, 4J = 2.0 Hz, 1H), 10.94 (s, 1H). 13C-NMR (100 MHz, DMSO,d6) delta ppm 26.6, 110.2, 110.7, 114.0, 121.8, 121.9, 123.0, 130.2, 131.1, 131.5, 133.8, 134.8, 135.6, 144.4, 145.0,167.2, 169.3. Anal. calcd. for C17H11BrN2O2: C 57.49, H 3.12, N 7.89; found: C 57.44, H 3.18, N 793.HRMS (ESI) calculated m/z: 376.9896; found C17H11BrN2O2; m/z: 376.9896 [M + H]+.
General procedure: Isatin or 5-substituted isatin (7 mmol) and K2CO3 (10 mmol) were added to a dry CH3CN solution (25 mL) and stirred for 30 min at RT. Methyl iodide or benzyl chloride (7.5 mmol) was added to the solution and then refluxed at 80C for 3 hour. The mixture was cooled to RT and the solvent was removed. The residue was dissolved in CH2Cl2(30 mL) and then washed with H2O (3x30 mL). The organic extracts were dried over anh Na2SO4 and concentrated to give the crude brown solid. The purification of the crude solid using flash-column chromatography (silica gel, hexane/EtOAc (2:1) gave the pure compounds 3a-g.
General procedure: Isatins I (3.0 mmol) was dissolved in anhydrous DMF (15 mL), and the resultant solution was cooled to 0 C (ice bath), whereupon sodium hydride (60% dispersion in mineral oil, 140mg, 3.5 mmol, 1.17 equiv) was added in one portion and stirred for 5 minutes. Iodomethane (497 mg, 3.5 mmol, 1.17 equiv) or benzyl bromide (564.3 mg, 3.3 mmol, 1.1 equiv) was added and the reaction was stirred at 0 C for 30min. The reaction was monitored by TLC until I was fully consumed. The reaction mixture was then poured into saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic portions were washed with water and brine, dried (MgSO4), filtered, and concentrated to give N-methyl isatins and N-benzyl isatins II (90%-100% yield).
With sodium hydride; In N,N-dimethyl-formamide; at 0℃;
General procedure: Step 1: To a 250 mL flask equipped with a silicone oil bubbler was added commercially available isatin (7.7 g, 50 mmol) and anhydrous DMF (80 mL). the mixture was cooled down to 0 oC. To this solution was added NaH (1.32 g, 55 mmol), followed by the addition of CH3I in 15 min. Upon completion of the reaction (monitored by TLC), the mixture was diluted with saturated NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated to yield the crude N-methylindoline-2, 3-dione, which was used directly in the next step. Step 2: The N-methylindoline-2, 3-dione (7.58 g, 47 mmol) was refluxed in NH2·NH2-H2O ( 35 %) for 1h. Then the mixture was cooled to rt. The crude product was extracted with ethyl acetate. The combined organic layer was then dried over Na2SO4, purified by flash chromatography on silica gel (petroleum ether/ethyl acetate = 10:1). 1-Methylindolin-2-one was obtained as a pink solid.
With potassium carbonate; potassium iodide; for 3h;Reflux;
General procedure: Isatin derivatives 1a-c (0.005 mol) were stirred in acetonitrile(20 mL) with (0.007 mol) of the appropriate methyl iodide 2, propyliodide 3 or benzyl bromide 7a-d in the presence of catalytic amountof potassium iodide with (0.010 mol) of dry potassium carbonate atreflux temperature. The reaction was monitored with TLC. Aftercomplete of reaction, the mixture was poured into ice-water, theformed solid was collected, washed with water and recrystallizedfrom ethanol-water to furnish the final compounds 4a-f and 8a-l[58-61].
The intermediate XIX was prepared according to the method reported (J Heterocyclic Chemistry, 1964, 1(5), 239-241). To a solution of 0.55 g of sodium hydroxide in 10 mL of water, 3.2 g of 5-bromoisatin (16.9 mmol) was added. After stirring for one hour the EPO <DP n="56"/>solution was cooled to 50C and treated, under stirring, with 1.0 g of sodium nitrite dissolved in 40 ml_ of water. It was then poured, in small portions and with vigorous stirring, into aqueous sulfuric acid (0.8 ml. of acid, d=1.84, in 30 mL of water) cooled at O0C, and sulfur dioxide was bubbled through until most of the yellow precipitate which had formed was dissolved. The golden-yellow liquid obtained after filtration was poured into a solution of 4.8 g of stannous chloride in 10 mL of hydrochloric acid, and the mixture left for 5 hours at room temperature. The precipitate obtained was collected, washed thoroughly with dilute hydrochloric acid, then with water, to give a yellow solid crude product XjX (1.4 g, 30% yield). LC-MS (ESI, positive mode): [MH]+ = 241 , 243
The conversion of the substituted isatins to the corresponding indazole-3-carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H. R., et. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 C for 30 min. The burgundy solution was allowed to cool to rt and was maintained for lh. The reaction mixture was cooled to 0 C and was treated with a 0 C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0 C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the reaction mixture was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. This material was of sufficient purity ('H NMR and LC/MS) to use in the next step without further purification. Alternatively, the acid was recrystallized from acetic acid to provide pure material. The following acids were prepared using this method: 5-Bromoindazole-3-acid. 6-Bromoindazole-3-acid. 5-Trifluoromethoxyindazole-3-acid. 6-Trifluoromethylindazole-3-acid. 5-Methoxyindazole-3-acid.
The conversion of the substituted isatins to the corresponding indazole-3- carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H.R., e't. al. J. Am. Chem. Soc. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 mL) and was heated at 50 0C for 30 min. The burgundy solution was allowed to cool to it and was maintained for Ih. The reaction mixture was cooled to 0 0C and was treated with a 0 0C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 0C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0 0C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 mL) was added to the reaction mixture over 10 min and the slurry was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. The solid was recrystallized from acetic acid (20 mL/g) to provide the acid as a light yellow solid. . The acids were coupled with l,4-diazabicyclo[3.2.2]nonane according to procedure A.
The conversion of the substituted isatins to the corresponding indazole-3-carboxylic acids is essentially the same method as described for indazole-3-carboxylic acid: Snyder, H. R., et. al. J. AM. CHEM. SOC. 1952, 74, 2009. The substituted isatin (22.1 mmol) was diluted with 1 N sodium hydroxide (24 ml) and was heated at 50 C for 30 min. The burgundy solution was allowed to cool to rt and was maintained for 1h. The reaction mixture was cooled to 0 C and was treated with a 0 C solution of sodium nitrite (22.0 mmol) in water (5.5 mL). This solution was added through a pipet submerged below the surface of a vigorously stirred solution of sulfuric acid (2.3 mL) in water (45 mL) at 0 C. The addition took 15 min and the reaction was maintained for an additional 30 min. A cold (0 C) solution of tin (II) chloride dihydrate (52.7 mmol) in concentrated hydrochloric acid (20 ml) was added to the reaction mixture over 10 min and the reaction mixture was maintained for 60 min. The precipitated solids were isolated by filtration, washed with water, and dried to give a quantitative mass balance. 1H NMR (DMSO-d6) delta 13.9 (broad s, 1H), 8.23 (d, J= 1.3,1H), 7.67 (d, J= 8. 9,1H), 7.57 (dd, J= 8. 9,1. 8, 1H).
6.21 g
(a) Step 1 Aqueous sodium hydroxide (1.13 g, 28.3 mmol, 25 mL) was heated to 50C, and added with 5-bromoisatin (6.22 g, 27.5 mmol). The reaction mixture was stirred at 50C for 1 hour, and then cooled on ice. The reaction mixture was added dropwise with ice-cooled aqueous sodium nitrite (1.90 g, 27.5 mmol, 9 mL). Then, the mixture was added dropwise with concentrated sulfuric acid (5.26 g, 53.6 mmol) in ice-cooled water (44 mL), and the mixture was stirred for 1 hour under ice cooling. Then, the reaction mixture was added dropwise with an ice-cooled solution of tin(II) chloride dihydrate (14.9 g, 66.0 mmol) in concentrated hydrochloric acid (22 mL). The mixture was stirred overnight at room temperature, and then filtered, and the resulting solid was washed with water to obtain a pale brown solid (6.21 g).
To a solution of 5-bromoisatin (1.13 g, 4.98 mmol) and phenylboronic acid (0.67 g, 5.50 mmol) in degassed 1:1 toluene/ethanol solution (30 mL) was added 2 M potassium carbonate solution (5.0 mL). The solution mixture was stirred and degassed for 30 mm, followed by the addition of tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.059 mmol). The reaction mixture was then heated at 90 00 under nitrogen atmosphere for 18 hours. After completion of reaction, water (50 mL) was added to the reaction mixture. 2 M HCIwas then added to acidify the reaction mixture until pH 1. The organic layer was extracted into dichloromethane (3 x 30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the product 44a as a red solid (0.79 g, 71%); 1H NMR (400 MHz, DMSO-d6): O 11.13 (5, 1H, NH), 7.90 (d, J= 8.3 Hz, 1H, ArH), 7.75 (5, 1H, ArH), 7.64 (d, J= 7.8 Hz, 2H, ArH), 7.45 (t, J= 7.8 Hz, 2H, ArH), 7.35 (t, J= 7.4 Hz, 1H,ArH), 7.00 (d, J= 8.1 Hz, 1H, ArH); 130 NMR (100 MHz, DMSO-d6): O 184.4(00), 159.6 (00), 150.0 (ArC), 138.7 (ArC), 136.5 (ArCH), 134.9 (ArC), 129.0 (ArCH), 127.5 (ArCH), 126.2 (ArCH), 122.5 (ArCH), 118.4 (ArC), 112.7 (ArCH).
43%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 120℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation;
General procedure: The general procedure for the preparation of isatin derivatives was as follows. A mixture of 0.05mol substituted anilines, 0.15mol Hydroxylammonium chloride, 0.35mol Na2SO4, 2mol/L Hydrochloric acid at 5mL and Chloral hydrate at 0.06mol were stirred in 250mLH2O at 95C. The progress of the reaction was monitored by TLC (petroleum ether/ethyl acetate). After the reaction was completed, the reaction mixture was cooled to room temperature and the precipitate was filtered and dried. The crude product was used directly for the next step without further purification.To a flask (100mL) which contained concentrated sulfuric acid (20mL) was added N-2-(hydroxyimino)acetamide derivatives (7.0g) in portions at 50C with vigorous stirring. The reaction temperature was maintained at 50C-75C during the addition. After the addition was completed, the mixture was heated to 80C and stir at 80C for 30min. The reaction mixture was cooled to room temperature and then poured onto ice (250g). The solid which resulted was filtered out and dried over air to yield the crude which was purified 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 over air to provide the purified compounds 1a-1g. To a microwave reactor vial (5mL) which contained the solution of 5-bromoindoline-2,3-dione (1.0g, 4.4mmol) in 1,4-dioxane (5mL) were added PdCl2(dppf) (161mg, 0.22mmol), CH3COOK (0.6g, 6.2mmol) and substituted benzeneboronic acid (0.45g, 5.3mmol) under the atmosphere of argon. The microwave reactor vial was caped and placed into the microwave cavity. The reaction mixture was irradiated at high level for 30minat 120C. The reaction mixture was cooled to room temperature, poured onto 100mL ice-water and then extracted with dichloromethane (3×100mL). The combined organic layers were washed with water (2×100mL), brine (100mL) and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum to afford the crude which was purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 3:1) to yield the desired compound 1h-1k. To a flask (25mL) which contained the solution of compound 1i (0.2g, 0.79mmol) in dry N,N-dimethylformamide (2mL). The reaction temperature was maintained at 0C followed by addition K2CO3 (0.33g, 2.37mmol). Stirring 5min, was added alkyl or benzyl (1.0mmol) and the mixture allowed warm to room temperature. The reaction mixture was stirred at room temperature for 4h. The orange solution was poured water (25mL) and extracted with dichloromethane (3×100mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered and evaporated. Chromatography (petroleum ether/ethyl acetate 10:1-3:1) afforded the title compounds 2a-2v.
11%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In diethylene glycol dimethyl ether;Heating / reflux;
A mixture of 5-bromo isatin (2g, 8.85 MMOL), phenyl boronic acid (1. 13g, 9.29 MMOL), tetrakis triphenylphosphine palladium (307mg, 0.27 MMOL) and sodium carbonate (3.02g, 28 MMOL) in diglyme (85ML) under argon atmosphere was heated at reflux overnight. 2M hydrochloric acid (80ML) was added and the resulting precipitate removed by filtration. The filtrate was allowed to stand at room temperature overnight and then filtered. The solid was washed with water and dried under vacuum to give 212mg (11 %) of 5-phenyl isatin as a red solid, hplc/ms RT 2.16 min, m/z (positive ion) 223 (M+).
26%Chromat.
General procedure: A mixture of aryl halide (1mmol), catalyst (0.005mmol) and K2CO3 (2mmol) was stirred in EtOH-H2O (4:1) (5mL) for 5min. Phenylboronic acid (1.5mmol) was added to the above mixture and stirring was continued for required time at 82C. Then, reaction mixture was diluted with ethyl acetate and water, and the catalyst was separated by centrifugation. The centrifugate was dried over anhydrous sodium sulphate, filtered and evaporated. Then the product was analyzed by GC/GCMS.
With hydrogenchloride; methylmagnesium bromide; In tetrahydrofuran; toluene;
Step A 5-Bromo-3-methylindole To a stirred mixture of 5-bromoisatin (5 g., 22.1 mmol., 1 eq.) in dry THF (150 mL.) was added methylmagnesium bromide (32 mL. of a 1.4M solution in toluene, 44.2 mmol., 2 eq.) dropwise via syringe. After 45 minutes TLC analysis showed small amount of unreacted bromoisatin. Added 3.2 mL. of methylmagnesium bromide solution. Let stir 1 hour. Cooled reaction mixture to 0 C. Added lithium aluminum hydride (1.26 g., 33.15 mmol., 1.5 eq.) portionwise. Let stir 30 minutes at 0 C. Removed cooling bath and let stir overnight. Cooled mixture to 0 C. and carefully quenched reaction with 1N aqueous HCl. Acidified with 2N aqueous HCl. Removed cooling bath. Let stir for 3 hours. Filtered mixture through Celite. Washed Celite with THF. Concentrated filtrate in vacuo. Diluted residue with water and extracted 4* with CH2 Cl2. The organic extracts were combined, dried over anhydrous Na2 SO4, filtered and concentrated in vacuo. Loaded residue onto a silica gel plug in a fritted filter and eluted with 4:1 hexanes/acetone. Collected fractions containing the desired product and concentrated in vacuo giving 2.85 g. 5-bromo-3-methylindole.
With hydrogenchloride; methylmagnesium bromide; In tetrahydrofuran; toluene;
Step A: 5-Bromo-3-methylindole To a stirred mixture of 5-bromoisatin (5 g., 22.1 mmol., 1 eq.) in dry THF (150 mL.) was added methylmagnesium bromide (32 mL. of a 1.4M solution in toluene, 44.2 mmol., 2 eq.) dropwise via syringe. After 45 minutes TLC analysis showed small amount of unreacted bromoisatin. Added 3.2 mL. of methylmagnesium bromide solution. Let stir 1 hour. Cooled reaction mixture to 0 C. Added lithium aluminum hydride (1.26 g., 33.15 mmol., 1.5 eq.) portionwise. Let stir 30 minutes at 0 C. Removed cooling bath and let stir overnight. Cooled mixture to 0 C. and carefully quenched reaction with 1N aqueous HCl. Acidified with 2N aqueous HCl. Removed cooling bath. Let stir for 3 hours. Filtered mixture through Celite. Washed Celite with THF. Concentrated filtrate in vacuo. Diluted residue with water and extracted 4* with CH2 Cl2. The organic extracts were combined, dried over anhydrous Na2 SO4, filtered and concentrated in vacuo. Loaded residue onto a silica gel plug in a fritted filter and eluted with 4:1 hexanes/acetone. Collected fractions containing the desired product and concentrated in vacuo giving 2.85 g. 5-bromo-3-methylindole.
With piperidine; In ethanol; at 20℃; for 48 - 96h;
Example 39 Preparation of QR-0303 and QR-0289[00386] Compounds QR-0303 and QR-0289 were prepared by reactions depicted in Scheme 45 below. <n="120"/>Scheme 45[00387] The procedure was as follows.[00388] A solution of 5-substituted isatin (5 mmol), indole-7-carboxylic acidmethyl ester (5 mmol), and piperidine (0.5 mmol) were stirred in ethanol at roomtemperature for 2-4 d. When TLC indicated the reaction was complete, the reactionmixture was concentrated and the product washed with EtOAc and hexane. Theproduct was used in the next step without further purification. To a solution of theproduct (4 mmol) in dry THF at O0C was added BH3-THF (10 mL, 10 mmol)dropwise over 10 min. The solution was stirred at room temperature overnight, andthen quenched by the dropwise addition of MeOH (30 mL). The solvent wasremoved under vacuum, giving crude product which was stirred with LiOH (10 mmol) in MeOHZH2O ( 1 : 1 , 40 mL) at 70 0C for 2h. The mixture was concentrated and the pH adjusted to 2 with IN HCl. The aqueous layer was extracted with EtOAc (2 x 20 mL) and the organic layer dried with MgSO4. Final product was purified by flash column chromatography to yield the following compounds.[00389] QR-0303 (32percent yield). 1H NMR (DMSO): 7.19 (t, I H. J=7.7), 7.28(d, I H, J=8.6), 7.45 (d, I H, J=8.6), 7.62 (d, I H, J=2.3). 7.76 (d, I H. J=2.3), 7.79 (d. <n="121"/>111..1=1.7).7.83 (d. IH, J=8.6), 8.02 (d, IH. J=7.8).11.15 (s, IH), 11.49 (s, IH), 13.12 (s, IH); 13C NMR (DMSO): 109.09, 109.79, 112.07, 114.15, 114.22, 119.05.121.74, 123.96, 124.30, 124.57, 124.78, 125.40.128.13, 128.33, 135.53, 135.55, 168.47.[00390] QR-0289 (27percent yield). 1H NMR (DMSO): 3.76 (s, 3H), 6.82 (d. IH,J=8.7), 7.14 (d, IH. J=2.0), 7.19 (t, IH, J=7.6).7.36 (d, IH, J=8.7), 7.60 (d, IH,J=2.2).7.63 (d, IH, J=2.2), 7.82 (d, IH, J=7.3), 8.03 (d, 1H,J=7.8), 11.11 (s, 2H), 13.10 (s, IH); 13C NMR (DMSO): 55.82, 101.60.109.10, 110.72, 111.83, 112.81, 114.13, 118.85.123.58, 123.62, 124.64.125.54.126.87.128.31.132.06.135.56,153.97,168.52.
With choline chloride; oxalic acid; at 70℃; for 0.766667h;Green chemistry;
General procedure: A mixture of aminouracil (1 mmol), isatin (1 mmol), and carbonyl compound (1 mmol) in DES (1 ml) was stirred on magnetic stirrer at 70oC for nearly 35-55 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured on crushed ice.The DES remained in water and solid product was separated by filtration. The DES was recovered from the filtrate by evaporation. The recovered DES was reused three-four times with comparable yields.
With picolinaldehyde oxime-grafted SBA-15 supported zinc complex; In water; for 0.5h;Reflux; Green chemistry;
General procedure: A mixture of isatin 1 (1 mmol), 1,3-indandion 2 (1 mmol), aminouracil 3 (1 mmol) andSBA-oxime-Zn (0.1 g) was heated in refluxing water(5 mL) for appropriate time (Table 1). The reactionwas monitored by TLC (n-hexane-ethyl acetate 1:1),and after completion of the reaction, the reactionmixture was filtered for separation of solid productand catalyst from water. The remaining solid waswashed with ethanol (2×10 mL) for separation ofthe product from the catalyst. Finally, the productwas purified by recrystallization in hot EtOH. The desired pure products were characterized bycomparison of their melting point data with literature.All the products are known compoundsand their melting points are compared with reportedvalues [14]. Some selected samples were alsocharacterized by IR and NMR spectroscopic data.
INTERMEDIATE PREPARATION 6; methyl 3-methyl-6-(methylsulfonyl)-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylate6-bromo-3-methyl-2-r3-(trifluoromethyl)phenyll-4-quinolinecarboxylic acid5-Bromoisatin (198 g, 788 mmol) was dissolved in ethanol (1.2 L) in a 6L conical jacketed lab reactor equipped with a mechanical stirrer and an internal temperature probe. A solution of KOH (265 g, 4730 mmol) in water (0.480 L) was added slowly via addition funnel over ca. 1 hour, such that the vessel temperature was maintained at 20 °C. 1-[3- (Trifluoromethyl)phenyl]-1-propanone (159 g, 788 mmol) was added in one portion and the reactor was heated to reflux for 1 h. The reaction mixture was cooled to 20 °C and acidified to pH ~ 2 by addition of 450 mL of concentrated HCI. An additional 1.5 L of 50percent EtOH/H20 was added to facilitate filtration. The slurry was filtered and the filter cake was rinsed twice with 1 L portions of 50percent EtOH/water. The solid was dried in vacuo to give 6-bromo-3-methyl-2-[3- (trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (281.7 g, 87 percent yield) as a fine off-white solid. MS (m/z) 412.7 (M+H+).
With triethylamine; In methanol; at 60℃; for 3.0h;
General procedure: A mixture of isatin (0.1 mmol), methyl glycinate 2a (1.0 eq.), methyleneindolinone 3a (1.0 eq.), Et3N (1.0 eq.), in methanol (1.0 mL) was stirred for 3 h at 60 C. After completion of the reaction (TLC), the solvent was removed under vacuum. The crude product was subjected to column chromatography on silica gel using pet/ethyl acetate (2:1) as the eluent to give 4a (43.4 mg, 99% yield).
General procedure: To a mixture of 5-chloroisatin (182 mg, 1.0 mmol) and N-carboxyethylrhodanine (205 mg, 1.0 mmol) was added DMSO-d6 (3.0 mL). The reaction was followed by proton NMR until the disappearance of the starting material.
With copper(l) iodide; In acetonitrile; at 80℃; for 2.5h;Inert atmosphere;
General procedure: CuI (0.01mmol) was added to a mixture of isatin (1) (1.0 mmol), L-proline (2) (1.0 mmol) and alkyne (3)(1.0 mmol) in acetonitrile and the reaction mixture was stirred at 80 C for2-3 h under nitrogen. The solvent was then removed under reduced pressure andthe concentrated reaction mass was purified by column chromatography on silicagel using 50% hexane-ethyl acetate to afford the desired compound.
General procedure: A mixture of isatoic anhydride 1 (1 mmol), isatin 2 (1 mmol), phenyl hydrazine 3 (1 mmol), 0.3 g (0.6 mmol) alum, and 10 ml EtOH in a 50 ml flask was stirred at reflux for time period asindicated in Table 1. After completion of the reaction (monitored by TLC, ethylacetate/n-hexane,1:1), 25 ml EtOH was added to the reaction mixture, and recrystallized from ethanol to afford pure product.
5-bromo-1-(2-hexyldecyl)indoline-2,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With potassium carbonate; In N,N-dimethyl-formamide; at 70℃;Inert atmosphere;
General procedure: General procedure for the synthesis of a1-a6: To a solution of indoline-2,3-diones (10 mmol) in DMF (40 mL) was added K2CO3(15 mmol, 2.073 g) and <strong>[52997-43-0]7-(bromomethyl)pentadecane</strong> (11 mmol,3.358 g) under nitrogen. The mixture was stirred at 70 C and monitoredby TLC. After the reaction completed, water was added, andextracted with EtOAc. The organic layer was combined and dried withMgSO4. After evaporation of the solvent, the residue was purified bycolumn chromatograph (eluent: Petroleum/EtOAc=20:1) to give thetarget compound.
With choline chloride; oxalic acid; at 70℃; for 0.833333h;Green chemistry;
General procedure: A mixture of aminouracil (1 mmol), isatin (1 mmol), and carbonyl compound (1 mmol) in DES (1 ml) was stirred on magnetic stirrer at 70oC for nearly 35-55 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured on crushed ice.The DES remained in water and solid product was separated by filtration. The DES was recovered from the filtrate by evaporation. The recovered DES was reused three-four times with comparable yields.
With choline chloride; oxalic acid; at 70℃; for 0.966667h;Green chemistry;
General procedure: A mixture of aminouracil (1 mmol), isatin (1 mmol), and carbonyl compound (1 mmol) in DES (1 ml) was stirred on magnetic stirrer at 70oC for nearly 35-55 min. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured on crushed ice.The DES remained in water and solid product was separated by filtration. The DES was recovered from the filtrate by evaporation. The recovered DES was reused three-four times with comparable yields.
2-(2-(5-bromo-2-oxoindolin-3-ylidene)hydrazino)-6-fluorobenzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With acetic acid; In ethanol;Reflux;
General procedure: 6-Fluoro-2-(2-(5-(un)substituted-2-oxoindolin-3-ylidene)hydrazino)benzothiazoles 5a-c. General Procedure C. A mixture of compound 2 (0.183 g, 0.001 mol), the appropriate isatin (0.001 mol) and glacial acetic acid (0.1 mL) in ethanol (20 mL) was heated at reflux temperature for 4-6 h. The precipitated yellow to orange solid was collected by filtration, washed with ethanol, dried and crystallized from methanol to yield compounds 5a-c.
a. PREPARATION OF 5-(2-(2H-TETRAZOL-5-YL)ETHYL)-8-METHYL-5H- [l,2,5]OXADIAZOLO[3',4':5,6]PYRAZINO[2,3-B]lNDOLE (COMPOUND 39) [00308] To a solution of 39C (0.020 g, 0.072 mmol) in toulene (10 mL) was added nBu3SnN3 (0.12 g, 0.36 mmol). The resulting mixture was heated to reflux for 48 h. Then, it was cooled to room temperature, and the pH value was adjusted to 4-5 with HCl (1M), diluted with ethyl acetate (60 mL), and the organic phase was washed with brine (20 mLx 2), then dried over Na2SC>4 and concentrated. The residue was purified by column chromatography (silica gel, CH2C12 : MeOH = 10: 1 - 5: 1) to afford 39 (13.00 mg, 57% yield) as orange solid
5-bromo-6'-(4-fluorophenyl)-2',5'-diphenyl-1',2'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,3'(7'H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With acetic acid; In water; at 90℃; for 6h;Green chemistry;
General procedure: The mixture of isatin (1 mmol), 3-amino-1-phenyl-1H-pyrazol-5(4H)-one (1 mmol), 1,2-diarylethan-1-one, 2,3-dihydroinden-1-one (1 mmol) or 3,4-dihydronaphthalen-1(2H)-one (1 mmol), H2O (6 mL), HOAc (2 mL) was put in a reaction flask under 90 C about 5-7 h (monitored by TLC). After completion, the reaction mixture was cooled to room temperature and the products would be isolated out at same time. Then, compound 4 was recrystallized from DMF, however, the pure products of 6 and 8 were filtered from water, dried, without further recrystallization.
With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; for 3h;Reflux;
General procedure: To a stirred mixture of isatins 3a-c (3.4 mmol), potassium carbonate(0.94 g, 6.8 mmol) and catalytic amount of potassium iodidein dry DMF (10 mL), the appropriate alkyl halide 5a-d (3.7 mmol) or benzyl bromide 5e (0.63 g, 3.7 mmol) was added, and the mixture was heated under reflux for 3 h. Then, the reaction mixture was poured into ice-water, the obtained solid was collected, washed several times with water, and recrystallized from ethyl alcohol to afford the N-substituted isatin derivatives 6a-o [27].
5-bromo-3-hydroxy-3-(2-imino-3-methyl-5-oxoimidazolidin-4-yl)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With chloroauric acid; In water; for 0.5h;Reflux;
General procedure: Water (15 mL) was added to a mixture of 1.0 mmol of isatin derivative, 1.2 mmol of <strong>[60-27-5]creatinine</strong> (for 2p, 2.3 mmol of <strong>[60-27-5]creatinine</strong>) and 1 mol% of HAuCl4 and the resulting suspension was heated to reflux for 30 min. The clear reaction mixture was cooled to 15-20 C. The precipitated aldol product was filtered and washed with copious amount of water and then with methanol and ethyl acetate (EtOAc). The obtained product was thoroughly dried under vacuum to afford the pure product 2a-2p.
6-bromo-3-methyl-2-(2-methylphenyl)quinoline-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.17 g (5.19 mmol) of 5-bromo-1H-indole-2,3-dione were initially charged in 14.1 ml of acetic acid, and 0.77 g (5.19 mmol) of <strong>[2040-14-4]1-(2-methylphenyl)propan-1-one</strong> were added. The reaction mixture was stirred at 75 C. for 5 min. Thereafter, 4.7 ml of conc. hydrochloric acid were added, and stirring of the mixture was continued at 105 C. overnight. The reaction solution was then divided into two microwave vessels and successively heated in a microwave apparatus at 150 C. for 4.5 h. After cooling to RT, the mixture was introduced into water and the precipitate formed was filtered off. Filtrate and precipitate were then re-combined and purified by column chromatography (silica gel, mobile phase ethyl acetate/methanol 5:1). This gave 490 mg (23% of theory, purity 93%) of the title compound. 1H-NMR (400 Mhz, DMSO-d6): delta [ppm]=8.07 (d, 1H), 7.86 (d, 1H), 7.78 (dd, 1H), 7.40-7.24 (min, 3H), 7.18 (d, 1H), 2.08 (s, 3H), 2.00 (s, 3H). LC/MS (Method 1, ESIpos): Rt=0.76 min, m/z=356/358 [M+H]+.
6-Bromo-2-(3-methoxyphenyl)-3-methylquinoline-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.26 g (27.7 mmol) of 5-bromo-1H-indole-2,3-dione were added to a solution of 9.32 g (166 mmol) of potassium hydroxide in 55 ml of ethanol and 16 ml of water. 5.0 g (30.4 mmol) of <strong>[37951-49-8]1-(3-methoxyphenyl)propan-1-one</strong> were added and the reaction mixture was stirred under reflux for 3 h. After cooling to RT, the mixture was concentrated, 75 ml of water were added and the mixture was stirred at RT for 30 min. The mixture was then cooled to 0 C. and adjusted to a pH of about 3 using 11 ml (166 mmol) of conc. hydrochloric acid. The precipitate present was filtered off, washed with water and air-dried. This gave 9.46 g (81% of theory; purity 88%) of the title compound. 100 mg of this product batch were re-purified by preparative HPLC (Method 4). This gave 33 mg (purity 90%) of the title compound. 1H-NMR (400 Mhz, DMSO-d6): delta [ppm]=14.34 (br. s, 1H), 8.01 (d, 1H), 7.96-7.88 (min, 2H), 7.47-7.40 (m, 1H), 7.17-7.12 (m, 2H), 7.10-7.03 (min, 1H), 3.82 (s, 3H), 2.39 (s, 3H). LC/MS (Method 1, ESIpos): Rt=0.75 min, m/z=372/374 [M+H]+.
6-bromo-2-(3,5-difluorophenyl)-3-methylquinoline-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In ethanol; water; at 180℃; for 0.333333h;Microwave irradiation;
300 mg (1.33 mmol) of 5-bromo-1H-indole-2,3-dione were initially charged in 2 ml of 20% strength aqueous ethanol solution, and 565 mg (3.31 mmol) of <strong>[135306-45-5]1-(3,5-difluorophenyl)propan-1-one</strong> and 238 mg (4.25 mmol) of potassium hydroxide were added. The reaction mixture was then heated in the microwave (Biotage) at 180 C. for 20 min. After cooling to RT, the mixture was added to 100 ml of 1 M hydrochloric acid. The precipitated solid was then filtered off, washed with water and dried under reduced pressure. This gave 490 mg (69% of theory, purity 71%) of the title compound. LC/MS (Method 1, ESIpos): Rt=1.01 min, m/z=378/380 [M+H]+.
6-bromo-2-(2-chlorophenyl)-3-methylquinoline-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione was initially charged in 12.0 ml of acetic acid, and 746 mg (4.42 mmol) of <strong>[6323-18-8]1-(2-chlorophenyl)propan-1-one</strong> were added. The reaction mixture was stirred at 75 C. for 5 min. Subsequently, 4.0 ml of concentrated hydrochloric acid were added, and the mixture was stirred at 105 C. overnight. After cooling to RT, the reaction mixture was added to 200 ml of 1 M hydrochloric acid. The precipitated solid was then filtered off, washed with water and dried under reduced pressure. This gave 1.07 g (40% of theory; purity 63%) of the title compound. LC/MS (Method 1, ESIpos): Rt=0.94 min, m/z=376/378 [M+H]+.
6-bromo-2-(3-chlorophenyl)-3-methylquinoline-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.00 g (4.42 mmol) of 5-bromo-1H-indole-2,3-dione was initially charged in 12.0 ml of acetic acid, and 746 mg (4.42 mmol) of <strong>[34841-35-5]1-(3-chlorophenyl)propan-1-one</strong> were added. The reaction mixture was stirred at 75 C. for 5 min. Subsequently, 4.0 ml of concentrated hydrochloric acid were added, and the mixture was stirred at 105 C. overnight. After cooling to RT, the reaction mixture was added to 200 ml of 1 M hydrochloric acid. The precipitated solid was then filtered off, washed with water and dried under reduced pressure. This gave 1.26 g (49% of theory; purity 65%) of the title compound. LC/MS (Method 1, ESIpos): Rt=1.02 min, m/z=376/378 [M+H]+.
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In N,N-dimethyl-formamide; at 145℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation;
General procedure: To a microwave reactor vial (5 ml) which contained the solutionof 4 or 5 or 6 or 7-bromoindoline-2,3-dione (1.0 g, 4.4 mmol) inDMF (5 ml) were added PdCl2(PPh3)2 (155 mg, 0.22 mmol),CH3COOK (0.6 g, 6.2 mmol) and ethenyl (5.3 mmol) under the atmosphereof argon. The microwave reactor vial was caped andplaced into the microwave cavity. The reaction mixture was irradiatedat high level for 30 min at 145 C. The reaction mixture wascooled to room temperature, poured onto 100 ml ice-water andthen extracted with dichloromethane (3 x 100 ml). The combinedorganic layers werewashed withwater (2 x 100 ml), brine (100 ml)and dried over anhydrous magnesium sulfate. The solvent wasremoved under vacuum to afford the crude which was purified byflash column chromatography (silica gel, petroleum ether/ethylacetate 3:1) to yield the desired (2-Carboxyethenyl) isatinderivatives.
With 2-amino-2-hydroxymethyl-1,3-propanediol; In ethanol; at 20℃; for 3h;
General procedure: To a well-stirred solution of isatin and malononitrile(1 mmol each) in ethanol (95%, 4 mL) was added dimedone,4-hydroxycoumarin, 4-hydroxy-N-methylquinolin-2-one,or 2-methyl-pyrazol-2-one [generated in situ from ethylacetoacetate and hydrazine hydrate, 1 mmol each]. To thissolution was added THAM (30 mol %) and stirring wascontinued at ambient temperature. Upon completion of thereaction (TLC), water (5 mL) was added and stirring wascontinued for 10 min more. Resultant solid product wasfiltered, washed repeatedly with water, and dried. The dried solid was washed thrice with hexaneechloroformmixture (1:1, v/v) and dried again. Resultant product didnot require any further purification.
(Z)-3-amino-5-(5-bromo-2-oxoindolin-3-ylidene)-2-thioxothiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With acetic acid; In ethanol; at 100℃; for 0.0833333h;Microwave irradiation;
General procedure: A mixture of aminorhodanine (1 mmol), isatin (1 mmol) and 5 muL of acetic acid in 2mL of distilled ethanol was placed in a cylindrical quartz reactor (Phi = 4 cm). The reactor was introducedinto a monomode microwave (Anton Paar) apparatus, for 5 min at100 C and 50 Watts. The crude reaction mixture was allowed tocool down at room temperature and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartzreactor. The resulting precipitated product was filtered off and waspurified by recrystallization from ethanol if necessary.
5-bromo-10'-(3-fluoro-4-morpholinophenyl)-1'H-spiro[indoline-3,5'-pyrido[2,3-d:6,5-d']dipyrimidine]-2,2',4',6',8'(3'H,7'H,9'H,10'H)-pentaone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With urea; zinc(II) chloride; at 80℃; for 1.25h;
General procedure: A mixture of isatin derivatives 1a-c (1 mmol), 3-fluoro-4-morpholinoaniline 2 (1 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione 3/4-hydroxy-2H-chromen-2-one 4/1H-indene-1,3(2H)-dione 5/5,5-dimethylcyclohexane-1,3-dione 6 (2 mmol) were reacted in deep eutectic solvent ZnCl2 (3g) + Urea (10.5 g) at 80 C. The progress of all the reactions was monitored by TLC. After completion of the reaction, the crude mixture was transferred into crushed ice and the obtained precipitate was filtered, washed with water to remove the ZnCl2+Urea and dried. These products were washed with ethanol to get pure compounds.
5'-bromo-14-(3-fluoro-4-morpholinophenyl)-6H-spiro[dichromeno[4,3-b:3',4'-e]pyridine-7,3'-indoline]-2',6,8(14H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With urea; zinc(II) chloride; at 80℃; for 1.33333h;
General procedure: A mixture of isatin derivatives 1a-c (1 mmol), 3-fluoro-4-morpholinoaniline 2 (1 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione 3/4-hydroxy-2H-chromen-2-one 4/1H-indene-1,3(2H)-dione 5/5,5-dimethylcyclohexane-1,3-dione 6 (2 mmol) were reacted in deep eutectic solvent ZnCl2 (3g) + Urea (10.5 g) at 80 C. The progress of all the reactions was monitored by TLC. After completion of the reaction, the crude mixture was transferred into crushed ice and the obtained precipitate was filtered, washed with water to remove the ZnCl2+Urea and dried. These products were washed with ethanol to get pure compounds.
5'-bromo-5-(3-fluoro-4-morpholinophenyl)-10H-spiro[diindeno[1,2-b:2',1'-e]pyridine-11,3'-indoline]-2',10,12(5H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With urea; zinc(II) chloride; at 80℃; for 1.16667h;
General procedure: A mixture of isatin derivatives 1a-c (1 mmol), 3-fluoro-4-morpholinoaniline 2 (1 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione 3/4-hydroxy-2H-chromen-2-one 4/1H-indene-1,3(2H)-dione 5/5,5-dimethylcyclohexane-1,3-dione 6 (2 mmol) were reacted in deep eutectic solvent ZnCl2 (3g) + Urea (10.5 g) at 80 C. The progress of all the reactions was monitored by TLC. After completion of the reaction, the crude mixture was transferred into crushed ice and the obtained precipitate was filtered, washed with water to remove the ZnCl2+Urea and dried. These products were washed with ethanol to get pure compounds.
5'-bromo-10-(3-fluoro-4-morpholinophenyl)-3,3,6,6-tetramethyl-3,4,6,7-tetrahydro-2H-spiro[acridine-9,3'-indoline]-1,2',8(5H,10H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With urea; zinc(II) chloride; at 80℃; for 1.33333h;
General procedure: A mixture of isatin derivatives 1a-c (1 mmol), 3-fluoro-4-morpholinoaniline 2 (1 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione 3/4-hydroxy-2H-chromen-2-one 4/1H-indene-1,3(2H)-dione 5/5,5-dimethylcyclohexane-1,3-dione 6 (2 mmol) were reacted in deep eutectic solvent ZnCl2 (3g) + Urea (10.5 g) at 80 C. The progress of all the reactions was monitored by TLC. After completion of the reaction, the crude mixture was transferred into crushed ice and the obtained precipitate was filtered, washed with water to remove the ZnCl2+Urea and dried. These products were washed with ethanol to get pure compounds.
3-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-4-methoxybenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With acetic acid; In ethanol; at 180℃; for 1h;Microwave irradiation; Green chemistry;
General procedure: An equimolar mixture of isatin/5-bromoisatin and an aromatic primary amine were introduced into an Erlenmeyer flask. Ethanol (1 mL) and a few drops of acetic acid were added. The Erlenmeyer flask was placed in an ultrasonic bath filled with water (80 Hz,100%), the temperature was adjusted at 40C. At the end of the reaction (monitored by TLC), the product obtained by filtration was recrystallized from ethanol. For the reactions carried out in microwave Biotage, the reagents in 4 mL of ethanol were put in a magnetic stir bar for 2-5 mL vial and the temperature was set at 150C, 160C then 180C.
3-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylideneamino)-4-chlorobenzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With acetic acid; In ethanol; at 40℃; for 0.666667h;Sonication; Green chemistry;
General procedure: An equimolar mixture of isatin/5-bromoisatin and an aromatic primary amine were introduced into an Erlenmeyer flask. Ethanol (1 mL) and a few drops of acetic acid were added. The Erlenmeyer flask was placed in an ultrasonic bath filled with water (80 Hz,100%), the temperature was adjusted at 40C. At the end of the reaction (monitored by TLC), the product obtained by filtration was recrystallized from ethanol. For the reactions carried out in microwave Biotage, the reagents in 4 mL of ethanol were put in a magnetic stir bar for 2-5 mL vial and the temperature was set at 150C, 160C then 180C.
5-bromo-3-(5-bromo-2-methyl-phenylimino)-1,3-dihydroindol-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With acetic acid; In ethanol; at 180℃; for 2h;Microwave irradiation; Green chemistry;
General procedure: An equimolar mixture of isatin/5-bromoisatin and an aromatic primary amine were introduced into an Erlenmeyer flask. Ethanol (1 mL) and a few drops of acetic acid were added. The Erlenmeyer flask was placed in an ultrasonic bath filled with water (80 Hz,100%), the temperature was adjusted at 40C. At the end of the reaction (monitored by TLC), the product obtained by filtration was recrystallized from ethanol. For the reactions carried out in microwave Biotage, the reagents in 4 mL of ethanol were put in a magnetic stir bar for 2-5 mL vial and the temperature was set at 150C, 160C then 180C.
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