* 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.
Reference：
[1] Journal of the American Chemical Society, [2] Journal of the American Chemical Society, 2009, vol. 131, p. 1662 - 1663
2
[ 60313-92-0 ]
[ 20780-76-1 ]
Yield
Reaction Conditions
Operation in experiment
83%
at 65 - 80℃; for 0.25 h;
A solution of concentrated sulfuric acid (275 mL) was heated at 60 °C, then the heating was stopped and p-iodoisonitrosoacetanilide (45)[9] (22.0 g, 75.9 mmol) was added portionwise under stirring while maintaining the temperature below 65 °C. The resulting solution was heated at 80°C for 15 min. After cooling to room temperature and then to 0 °C, the reaction mixture was poured on crushed ice (550 g) and stirred at 0 °C for 1 h. The orange formed precipitate was filtered, washed with water (110 mL) and dissolved in a 10percent aqueous sodium hydroxide solution (55 mL), previously warmed to 60 °C. Acetic acid was then added (16.5 mL), and the solution was heated at 60 °C for 30 min. After cooling to room temperature and then to 0 °C, the formed precipitate was filtered, washed with water (11 mL) and dried under vacuum to give 5-iodoisatine (46) (17.1 g, 62.7 mmol) as an orange solid. Yield 83percent; mp 272-274 °C (litt.[10]: 272-274 °C); IR (KBr) ν 1198, 1458, 1606, 1731-1751, 3241 cm-1; 1H NMR (200 MHz, DMSO-d6) δ 6.75 (d, 1H, J = 8.2 Hz, H-7), 7.76 (d, 1H, J = 1.8 Hz, H-4), 7.88 (dd, 1H, J = 1.8, 8.2 Hz, H-6), 11.11 (s, 1H, NH); 13C NMR (50 MHz, DMSO-d6) δ 85.8 (C-5), 115.2 (C-7), 120.4 (C-3a), 132.9 (C-4), 142.0 (C-6), 150.7 (C-7a), 159.3 (C-2), 183.7 (C-3).
64%
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.
Reference：
[1] European Journal of Medicinal Chemistry, 2015, vol. 92, p. 818 - 838
[2] Tetrahedron, 2005, vol. 61, # 25, p. 6082 - 6087
[3] Medicinal Chemistry, 2016, vol. 12, # 5, p. 489 - 498
[4] Chemische Berichte, 1924, vol. 57, p. 1773
[5] European Journal of Pharmacology, 2007, vol. 556, # 1-3, p. 200 - 206
[6] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 292 - 302
3
[ 114144-16-0 ]
[ 20780-76-1 ]
Yield
Reaction Conditions
Operation in experiment
87%
With iodine pentoxide In dimethyl sulfoxide at 80℃;
General procedure: Indoles 1 (0.5 mmol), DMSO (3mL) and I2O5 (1 mmol) were added into a flask and vigorously stirred at 80oC under air. The reaction was stopped until indoles were completely consumed as monitored by TLC analysis. After the completion of reaction, saturated Na2S2O3 solution (20 mL) was added to the mixture. The mixture was extracted with EtOAc (3×20 mL) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator. Then, the crude product was purified by column chromatography on silica gel using ethyl acetate and petroleum ether as the eluent to give the products 2.
Reference：
[1] European Journal of Pharmacology, 2007, vol. 556, # 1-3, p. 200 - 206
[2] Tetrahedron, 2005, vol. 61, # 25, p. 6082 - 6087
[3] Chemische Berichte, 1924, vol. 57, p. 1773
[4] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 292 - 302
[5] Medicinal Chemistry, 2016, vol. 12, # 5, p. 489 - 498
7
[ 302-17-0 ]
[ 540-37-4 ]
[ 20780-76-1 ]
Reference：
[1] Pharmazie, 1980, vol. 35, # 1, p. 14 - 16
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 8, p. 1882 - 1885
8
[ 7647-01-0 ]
[ 91-56-5 ]
[ 7790-99-0 ]
[ 20780-76-1 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1773
[2] Chemische Berichte, 1924, vol. 57, p. 2116
[3] Journal of the Chemical Society, 1926, p. 2908
[4] Journal of the American Chemical Society, 1932, vol. 54, p. 1917
[5] Chemische Berichte, 1924, vol. 57, p. 1773
[6] Chemische Berichte, 1924, vol. 57, p. 2116
[7] Journal of the Chemical Society, 1926, p. 2908
[8] Journal of the American Chemical Society, 1932, vol. 54, p. 1917
9
[ 91-56-5 ]
[ 7790-99-0 ]
[ 64-19-7 ]
[ 20780-76-1 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1773
[2] Chemische Berichte, 1924, vol. 57, p. 2116
[3] Journal of the Chemical Society, 1926, p. 2908
[4] Journal of the American Chemical Society, 1932, vol. 54, p. 1917
[5] Chemische Berichte, 1924, vol. 57, p. 1773
[6] Chemische Berichte, 1924, vol. 57, p. 2116
[7] Journal of the Chemical Society, 1926, p. 2908
[8] Journal of the American Chemical Society, 1932, vol. 54, p. 1917
10
[ 7664-93-9 ]
[ 60313-92-0 ]
[ 20780-76-1 ]
Reference：
[1] Chemische Berichte, 1924, vol. 57, p. 1773
3-hydroxy-6-iodo-quinoline-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 127; 2-((3-methoxyquinolin-6-yl)methyl)-6-phenylpyridazin-3(2H)-one <n="172"/>(1) S-Hydroxy--iodoquinoline^-carboxylic acid. Iodoindoline-2,3-dione (50 g, 183 mmol) was dissolved in a hot solution containing potassium hydroxide (82 g, 1465 mmol) and water (250 mL). The homogeneous solution precipitated out completely 5 min. Enough ethanol (30 mL) was added to redissolve the reaction mixture. After cooled to rt and mechanically stirred, <strong>[1113-59-3]3-bromo-2-oxopropanoic acid</strong> hydrate (47 g, 256 mmol) was added portionwise , causing temperature to rise (> 80 C). After the addition, the reaction mixture was cooled to rt and continued to stir for 3 days. The reaction mixture was treated with saturated solution OfNaHSO3 (sodium bisulfite, 12 g, 115.32 mmol) in order to prevent the development of color in the product. The resulting mixture was then acidified to pH=2 using concentrated HCl. After stirred for Ih, the yellow solid that was formed in the solution mixture was collected by filtration. The solid was washed with water and suspended in water with SO2 bubbling in the solution. After 30 minutes the solid again was separated by filtration. This wet solid was suspended in water, stirred, and dissolved by gradual addition of solid Na2CO3. The solution was treated with a saturated solution OfNaHSO3 and filtered. The filtrate was <n="173"/>acidified to pH=2 using concentrated HCl. The solid was collected by filtration and was washed with water. It was resuspended in water, and again filtered. The solid was suspended in EtOH, separated by filtration, and air dried to afford the desired product (brown solid, 22.0 g). MS (ESI pos. ion) m/z (M+l): 316.2. Calc'd exact mass for Ci0H6INO3: 315.06. 1H NMR (300 MHz, DMSO-d6) delta ppm 7.65 - 7.72 (m, 1 H) 7.75 - 7.84 (m, 1 H) 8.70 (s, 1 H) 8.81 (s, 1 H).
With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 12h;
Preparation Example 30; Preparation of Compound (30); In DME (600 mL, 0.305 M), dissolved were 5-iodoisatin (50 g, 183 mmol) and phenylboronic acid (24.5 g, 201.3 mmol), and the solution was stirred. After adding Pd(PPh3)4 (6.34 g, 5.49 mmol) and 2M NaHCO3 (200 mL) thereto, the resultant mixture was stirred at 100 C. under reflux for 12 hours. The reaction mixture containing 5-phenylisatin was dried under low vacuum, and 5% NaOH (120 mL) was added to the residual aqueous solution. After removing the impurities by extracting with CH2Cl2, added was H2O2 (120 mL) to the aqueous layer, and the resultant mixture was stirred at 50 C. for 30 minutes. The mixture was cooled to room temperature, and filtered. The filtrate was adjusted to have pH of 4. Filtration of the solid compound gave 2-amino-5-phenylbenzoic acid (24.3 g, 114 mmol, 62%).While maintaining the temperature at 5 C., NaNO2 (7.9 g, 114 mmol) was dissolved in water (30 mL), and a solution of 2-amino-5-phenylbenzoic acid (24.3 g, 114 mmol) dissolved in water (60 mL), and concentrated HCl (23 mL) were slowly added thereto. At the same time, Na2S9H2O (28.8 g, 120 mmol) and refined sulfur (3.85 g, 120 mmol) were dissolved in water (30 mL), and 10 M NaOH (11 mL) was added thereto. The mixture was cooled to 5 C., and added to the solution containing 2-amino-5-phenylbenzoic acid. The resultant mixture was stirred while slowly raising the temperature to room temperature. Concentrated HCl was added to generate solid, and the mixture was washed with NaHCO3 (250 mL). The solid generated was filtered and dried, and then added to glacial acetic acid (100 mL) along with Zn dust (7 g, 107 mmol). The mixture was stirred under reflux for 48 hours. After quenching with concentrated HCl, the solid was filtered and washed with EtOH (100 mL) to obtain 2-mercapto-5-phenylbenzoic acid (17.3 g, 75 mmol, 66%).In polyphosphoric acid (40 g), dissolved were 2-mercapto-5-phenylbenzoic acid (17.3 g, 75 mmol) and 2-aminobenzenethiol (10.3 g, 82.5 mmol), and the solution was stirred at 140 C. for 12 hours. After cooling to room temperature, the reaction was quenched by adding NaOH. Washing with water and drying under reduced pressure gave 2-(benzo[d]thiazol-2-yl)-4-phenylbenzenethiol (12.8 g, 40 mmol, 53%).Compound (30) (1.7 g, 1.6 mmol, 76%) was obtained by repeating the same procedure as described in Preparation Example 1, but using 2-(benzo[d]thiazol-2-yl)-4-phenylbenzenethiol (2.0 g, 6.3 mmol), ZnCl2 (558.8 mg, 4.1 mmol), EtOH (80 mL, 0.026 M), NH4OH (2.0 mL) and water (20 mL).mp. >300 C.1H NMR (300 MHz, CDCl3): d=8.23-8.10 (m, 2H), 7.55-7.22 (m, 12H)MS/FAB: 1081.98 (found), 1086.09 (calculated)
Stage #1: 5-iodoisatin; 2-oxo-propionic acid With potassium hydroxide In water at 40℃; for 12h;
Stage #2: With hydrogenchloride In water
12.A
To 5-Iodoisatin (1) (10.0 g, 44.24 mmol) in hot 33% aqueous KOH (66 mL) was added pyruvic acid (5.40 mL, 77.42 mmol). The very thick and heterogenous reaction mixture was heated to 40° C. and allowed to stand for 12 h. The reaction mixture was diluted with cold 33% aqueous KOH (100 mL). The potassium salt was filtered off, washed with 33% aqueous KOH (50 mL) and cold ethanol (100 mL). The potassium salt was then dissolved in water (300 mL), acidified to pH 3 with conc. HCl which resulted in the formation of a precipitate. The white precipitate 2 was removed by filtration and dried under vacuum for 10 h to yield an off white solid (9.56 g, 73%). 1H NMR (DMSO-d6, 400 MHz): δ 9.05 (d, 1H, J=2.0 Hz), 8.51 (s, 1H), 8.16 (d, 1H, J=9.0 Hz), 8.04 (dd, 1H, J=2.1, 2.1 Hz).
73%
With potassium hydroxide In water at 40℃; for 12h;
12.A Part A
To 5-lodoisatin (1) (10.0 g, 44.24 mmol) in hot 33% aqueous KOH (66 mL) was added pyruvic acid (5.40 mL,77.42 mmol). The very thick and heterogenous reaction mixture was heated to 40 °C and allowed to stand for 12 h. Thereaction mixture was diluted with cold 33% aqueous KOH (100 mL). The potasssium salt was filtered off, washed with33% aqueous KOH (50 mL) and cold ethanol (100 mL). The potassium salt was then dissolved in water (300 mL),acidified to pH 3 with conc. HCl which resulted in the formation of a precipitate. The white precipitate 2 was removed byfiltration and dried under vacuum for 10 h to yield an off white solid (9.56 g, 73 %). 1H NMR (DMSO-d6, 400MHz): δ 9.05(d, 1H, J = 2.0 Hz), 8.51 (s, 1H), 8.16 (d, 1H, J = 9.0 Hz), 8.04 (dd, 1H, J = 2.1, 2.1 Hz)
Stage #1: 5-iodoisatin With sodium hydroxide In water Heating / reflux;
Stage #2: With sulfuric acid; sodium nitrite In water at 0 - 4℃; for 0.25h;
Stage #3: With hydrogenchloride; tin(ll) chloride In water at 4℃;
9 5-Iodo-1H-indazole-3-carboxylic acid
5-Iodoisatin (5 g, 18.3 mmol) is heated in the presence of sodium hydroxide (0.77 g, 19.2 mmol in 12 ml H2O) until dissolution is obtained and then the reaction mixture is cooled to 0° C. A sodium nitrite solution cooled beforehand to 0° C. (1.26 g, 18.3 mmol in 5.5 ml H2O) is added. The paste obtained is added in small portions, with vigorous stirring, to a sulphuric acid solution (3.40 g, 34.8 mmol in 37 ml H2O) precooled to 0° C. so that the temperature does not exceed 4° C. The stirring is maintained for 15 min and then a tin chloride solution (SnCl2.2H2O, 9.91 g, 43.9 mmol in 15 ml concentrated HCl) is slowly added such that the temperature does not exceed 4° C. The medium is allowed to react for several hours. The reaction mixture is filtered. The solid is washed with boiling water and then taken up in ethanol in the hot state. The insoluble impurities are removed by filtration. 2 g of product are obtained.
Stage #1: 5-iodoisatin With sodium hydroxide In water at 35℃; for 0.5h;
Stage #2: With sodium nitrite In water at 5 - 10℃; for 0.5h;
Stage #3: With hydrogenchloride; sulfuric acid; tin(ll) chloride more than 3 stages;
11 EXAMPLE [11]; Preparation of [N-PHENYL-5-IODO-LH-INDAZOLE-3-CARBOXAMIDE]
To a suspension of 5-iodoisatin (Lancaster Synthesis) (2.2 g, 8.0 mmol, 1.0 equiv) or 5-chloroisatin (Lancaster Synthesis) (1.0 equiv. ) in water (20 ml) was added [NAOH] (0.34 g, 8.48 mmol, 1.06 equiv) and the mixture was warmed to approximately 35 °C for 30 minutes to form a solution. The solution was cooled to [5 °C] and a solution of sodium nitrite (0.62 g, 8.98 mmol, 1.12 equiv) was added dropwise over approximately 30 minutes, keeping the temperature below 10 °C. The whole mixture was added dropwise via a cannula to a vigorously stirred solution of concentrated sulphuric acid (1.53 g, 15.6 mmol, [1.] 95 equiv) in water (20 ml) keeping the temperature below [10 °C.] The mixture was stirred for 20 minutes and a solution of tin [(II)] chloride (3.7 g, 19.52 mmol, 2.44 equiv) in concentrated hydrochloric acid (8 ml) was added dropwise. The mixture was stirred at [5 °C] for 2 hours and the resulting crude 5-iodo or 5-chloro indazole-3-carboxylic acid (a yellow solid) was isolated by filtration and washed several times with water. The yellow solid was then azeotroped with toluene (3 x 100 ml) to remove water prior to the next step. The crude product was dissolved in dichloromethane (36 ml) and split into four 8 ml portions. To the separate solutions of crude 5-iodo or 5-chloro indazole-3-carboxylic acid in dichloromethane (8 ml) was added the appropriate [AMINE/ANILINE] (2.4 mmol, 1.2 equiv), [N, N DIISOPROPYLETHYLAMINE] (1.2 ml, 7.2 mmol, 3.6 equiv) and [0-(7-AZABENZOTRIAZOL-1-YL)-N, N, N', N'-TETRAMETHYLURONIUM] hexafluorophosphate (0.84 g, 2.20 mmol, 1.1 equiv). The mixture was stirred for a period of 24-72 hours and was then quenched with water (8 ml) and dichloromethane (8 ml). The compounds were purified as described in the examples below, and characterised by liquid chromatography and mass spectrometry using either of the systems described above. Procedure B was followed. Water and dichloromethane were removed by filtration and the solid was triturated with water and dichloromethane. The title compound was dried in vacuo to afford 53 mg (7%); LCMS 4.11 min, mlz [M+H] + 364.
Stage #1: 5-iodoisatin With sodium hydroxide In water at 35℃; for 0.5h;
Stage #2: With sodium nitrite In water at 5 - 10℃; for 0.5h;
Stage #3: With hydrogenchloride; sulfuric acid; tin(ll) chloride more than 3 stages;
2
EXAMPLE 2 General Amide Preparative Procedure B; To a suspension of 5-iodoisatin (Lancaster Synthesis) (2.2 g, 8.0 mmol, 1.0 equiv) or 5-CHLOROISATIN (Lancaster Synthesis) (1.0 equiv. ) in water (20 ml) was added NAOH (0.34 g, 8.48 mmol, 1.06 equiv) and the mixture was warmed to approximately 35 °C for 30 minutes to form a solution. The solution was cooled to 5 °C and a solution of sodium nitrite (0.62 g, 8.98 mmol, 1.12 equiv) was added dropwise over approximately 30 minutes, keeping the temperature below 10 °C. The whole mixture was added dropwise via a cannula to a vigorously stirred solution of concentrated sulphuric acid (1.53 g, 15.6 mmol, 1.95 equiv) in water (20 ml) keeping the temperature below 10 °C. The mixture was stirred for 20 minutes and a solution of tin (II) chloride (3.7 g, 19.52 mmol, 2.44 equiv) in concentrated hydrochloric acid (8 ml) was added dropwise. The mixture was stirred at 5 °C for 2 hours and the resulting crude 5-iodo or 5-chloro indazole-3-carboxylic acid (a yellow solid) was isolated by filtration and washed several times with water. The yellow solid was then azeotroped with toluene (3 x 100 ml) to remove water prior to the next step. The crude product was dissolved in dichloromethane (36 ml) and split into four 8 ml portions. To the separate solutions of crude 5-iodo or 5-chloro INDAZOLE-3-CARBOXYLIC acid in dichloromethane (8 ML) was added the appropriate AMINE/ANILINE (2.4 mmol, 1.2 equiv), N, N-DIISOPROPYLETHYLAMINE (1.2 ml, 7.2 mmol, 3.6 equiv) and 0- (7-AZABENZOTRIAZOL-1-YL)-NNN, N -TETRAMETHYLURONIUM hexafluorophosphate (0.84 g, 2.20 mmol, 1.1 equiv). The mixture was stirred for a period of 24-72 hours and was then quenched with water (8 ml) and dichloromethane (8 ml). The compounds were purified as described in the examples below, and characterised by liquid chromatography and mass spectrometry using either of the systems described above. By following either preparative Procedure A or Procedure B, compounds of the formula (1) were prepared as described in Examples 3 to 14.
Stage #1: 5-iodoisatin With sodium hydroxide; sulfuric acid; sodium nitrite In water at 0 - 4℃; for 0.25h;
Stage #2: With hydrogenchloride; tin(IV) chloride In water at 4℃;
1
5-Iodoisatin (5 g, 18.3 mmol) is heated in the presence of sodium hydroxide (0.77 g, 19.2 mmol in 12 ml of H2O) until it is dissolved, and the reaction mixture is then cooled to 0° C. A solution of sodium nitrite precooled to 0° C. (1.26 g, 18.3 mmol in 5.5 ml of H2O) is added. The paste obtained is added portionwise, with vigorous stirring, to a solution of sulphuric acid (3.40 g, 34.8 mmol in 37 ml of H2O) precooled to 0° C. such that the temperature does not exceed 4° C. The stirring is maintained for 15 min and then a tin chloride solution (SnCl2.2H2O, 9.91 g, 43.9 mmol in 15 ml of concentrated HCl) is added slowly such that the temperature does not exceed 4° C. The mixture is left to react for several hours. The reaction mixture is filtered. The solid is washed with boiling water and then taken up with ethanol under hot conditions. The insoluble impurities are eliminated by filtration. 2 g of product are obtained.
EXAMPLE 1 N-fi-Cyano-i-fP^-dimethoxyphenyQsulphonyll-S-p-ethoxypyridin-S-yO^-oxo^S- dihydro- 1 H-indol-3-yl]-4-(1 -methylpiperidin-4-yl)piperazine- 1 -carboxamide; 1 a) 3-(2-Ethoxypyridin-3-yl)-3-hydroxy-5-iodo- 1, 3-dihydro-2H-indol-2-oneWith ice-bath cooling, 20.86 g (76.40 mmol) of 5-iodoisatin were stirred in 400 ml of anhydrous tetrahydrofuran (THF), and 3.22 g (80.50 mmol, 60% w/w) of sodium hydride were added a little at a time, the temperature being kept between 0-100C. With ice-bath cooling, the suspension was stirred for one hour, during which the pyridine Grignard reagent was prepared. At room temperature, 20 g (80.30 mmol) of the 2-ethoxy-3- iodopyridine were dissolved in 400 ml of anhydrous THF, and over a period of 5-10 minutes 95.6 ml (1 M solution in THF, 95.60 mmol) of ethylmagnesium bromide were added to this solution with cooling, at a temperature between 22 and 15C. The solution was stirred for 20 minutes, during which time the colour changed from colourless to slightly yellowish. The solution of the pyridine Grignard reagents was then, over a period of 5-10 minutes, added to the solution, cooled in an ice-bath, of the 5-iodoisatin sodium salt, the temperature fluctuating between 5 and 18C. After the addition of the Grignard reagent had ended, the ice-bath was removed, and the reaction mixture was stirred at room temperature for another 2 hours. Excess saturated ammonium chloride solution was added, followed by ethyl acetate, and the mixture was stirred for another 5 minutes. The aqueous phase was removed and extracted with ethyl acetate (2 x). The combined organic phases were washed with water (2 x), and the solvent was removed under <n="16"/>reduced pressure. Initially, unreacted 5-iodoisatin precipitated from the still dilute solution and was removed, and after further concentration the product, too, crystallized out. The suspension was stored in a refrigerator at 5C for two hours and the slightly yellowish solid was then filtered off and washed with a little ethyl acetate. The desired 3-(2- ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1 ,3-dihydro-2/-/-indol-2-one (17.1 g, 43.16 mmol, 57%) was isolated after drying at 400C.ESI-MS [M+H+] = 397.05 Calculated for Ci5H13IN2O3 = 396.19
57%
An excess of saturated ammonium chloride solution was added, followed by ethyl acetate, the mixture being stirred for 5 minutes. The aqueous phase was separated off and extracted with ethyl acetate (2*). The combined organic phases were washed with water (2*), and the solvent was removed in vacuo. During this, unreacted 5-iodoisatin precipitated first from the still dilute solution and was separated off. After further concentration, finally the title compound also crystallized. The suspension was stored in a refrigerator at 5 C. for 2 hours. The precipitated, pale yellow solid was then filtered off and washed with a little ethyl acetate. After drying at 40 C., (±)-3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one (17.1 g, 43.16 mmol, 57%) was isolated. ESI-MS [M+H+]=397.05 calculated for C15H13IN2O3=396.19
With hydrazine hydrate; potassium hydroxide; In ethylene glycol; at 100.0℃; for 1.0h;
General procedure: A mixture of substituted isatin (12.3 mmol), hydrazine hydrate (368 mmol), potassium hydroxide (245 mmol), and ethylene glycol (242 mmol) were heated at 100 C for 1 h. The reaction mixture was cooled on ice bath and acidified using concd HCl (drop wise addition) along with vigorous stirring. The precipitated product was vacuum filtered and washed with hexanes to give substituted indolin-2-ones in 90-95% 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 1,4-diaza-bicyclo[2.2.2]octane In tetrahydrofuran at 20℃; for 5.2h; Inert atmosphere; regioselective reaction;
4.2. General procedure for DABCO catalyzed regioselective gadditionof β-keto esters to isatins
General procedure: To the stirred solution of β-keto ester 2(aei) (1.0 mmol) and DABCO (30 mol %) in 5 mL THF was added isatin 1(aeh) (1 mmol).The mixture was then stirred at room temperature for stipulated time (5-8 h). After completion of reaction as indicated by TLC, thesolvent was removed at reduced pressure on a BUCHI rotary evaporator. The residue was then purified by column chromatography on silica gel (hexane/ethyl acetate4:1 to 1:1) to afford thedesired product 3(a-w).
ethyl 2-chloro-4-(3-hydroxy-5-iodo-2-oxo-2,3-dihydro-1H-indol-3-yl)-3-oxobutanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With 1,4-diaza-bicyclo[2.2.2]octane In tetrahydrofuran at 20℃; for 6h; Inert atmosphere; regioselective reaction;
4.2. General procedure for DABCO catalyzed regioselective gadditionof β-keto esters to isatins
General procedure: To the stirred solution of β-keto ester 2(aei) (1.0 mmol) and DABCO (30 mol %) in 5 mL THF was added isatin 1(aeh) (1 mmol).The mixture was then stirred at room temperature for stipulated time (5-8 h). After completion of reaction as indicated by TLC, thesolvent was removed at reduced pressure on a BUCHI rotary evaporator. The residue was then purified by column chromatography on silica gel (hexane/ethyl acetate4:1 to 1:1) to afford thedesired product 3(a-w).
With 1,4-diaza-bicyclo[2.2.2]octane In tetrahydrofuran at 20℃; for 7h; Inert atmosphere; regioselective reaction;
4.2. General procedure for DABCO catalyzed regioselective gadditionof β-keto esters to isatins
General procedure: To the stirred solution of β-keto ester 2(aei) (1.0 mmol) and DABCO (30 mol %) in 5 mL THF was added isatin 1(aeh) (1 mmol).The mixture was then stirred at room temperature for stipulated time (5-8 h). After completion of reaction as indicated by TLC, thesolvent was removed at reduced pressure on a BUCHI rotary evaporator. The residue was then purified by column chromatography on silica gel (hexane/ethyl acetate4:1 to 1:1) to afford thedesired product 3(a-w).
With 2,2'-iminobis[ethanol] In water at 20℃; Green chemistry;
Typical experimental procedure for Friedal-Crafts reaction of isatins
General procedure: To the reaction mixture containing isatin (0.5mmol) in water (2mL), indole (0.5mmol), diethanolamine (20mol %) was slowly added at room temperature. After thecompletion of reaction as monitored by TLC, the reaction mixture was washed with brine solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and the product was purified by flash chromatography on the silica gel column using a gradient of petroleum ether/ethyl acetate, as eluent to afford pure products 1-41.
Stage #1: 5-iodoisatin; malononitrile With piperidine In methanol at 20℃; for 0.166667h;
Stage #2: 4-methyl-5,7-dihydroxycoumarin In methanol at 65℃; for 3h; regioselective reaction;
General experimental procedure for the synthesis of pyranocoumarin fused spirooxindoles
General procedure: To a stirred mixture of isatins (1mmol) and malononitrile/ethyl cyanoacetate (1mmol) in methanol (3ml), was added piperidine (10mol%) and the reaction mixture was stirred at room temperature for 10min. Then 5,7-dihydroxy-4-methyl-2H-chromen-2-one (1mmol) was added to it. The resulting mixture was stirred at reflux until the reaction was completed as indicated by TLC. The resulting precipitate was treated with dilute HCl and washed with water to afford the pure product for analysis.
(±)-(7R,7a'S)-5'-amino-5-iodo-1',2,3'-trioxo-1',2',3′,7a'-tetrahydrospiro[indoline-3,7'-pyrrolo[1,2-c]imidazole]-6'-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium hydrogencarbonate In water for 24h; Reflux;
(±)-(7R,7a'S)-5'-amino-5-iodo-1',2,3'-trioxo-1',2',3′,7a'-tetrahydrospiro[indoline-3,7'-pyrrolo[1,2-c]imidazole]-6'-carbonitrile (4m):
General procedure: A mixture of isatin 1(2 mmol), hydantoin 2/2-thiohydantoin 2a (2 mmol), malononitrile 3 (2 mmol) and NaHCO3 (0.2 mmol) were stirred in water for the appropriate time under reflux conditions. After completion of the reaction (TLC), the solid that separated from the reaction mixture was filtered and washed with ethanol (5 mL) without further purification.
85%
With nano tungsten(IV) on N,N'-(ethane-1,2-diyl)bis(2-aminobenzamide)-SBA-15 In ethanol; water at 80℃; for 5h; diastereoselective reaction;
79%
With piperidine In water at 80℃; diastereoselective reaction;
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; oxygen; In acetonitrile; at 20.0℃; for 24.0h;
General procedure: An oven-dried flask was charged with stir bar, oxindole (0.5 mmol), PIDA (0.25 mmol) in dry acetonitrile (4.0 mL). Then to the reaction mixture TEMPO (0.5 mmol) was added in presence of air and the mixture was stirred at room temperature until complete conversion takes place as indicated by TLC analysis. The resulting reaction mixture was extracted with ethyl acetate (3 10 mL). The combined organics were dried with Na2SO4 and dried under vacuum to afford crude solid. Then the crude product was purified by column chromatography on silica gel.
5-iodo-3-hydroxy-3-(2-imino-3-methyl-5-oxoimidazolidin-4-yl)indolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
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.
1,3-dihydroxy-7-iodo-2-methylacridine-9-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With sodium hydroxide; In water; for 4h;Reflux;
General procedure: A mixture of <strong>[88-03-9]methylphloroglucinol</strong> (MPHG) 1 (0.7 g, 0.005 mol), isatin 2 (0.68 g, 0.0046 mol), and an aqueous solution of sodium hydroxide (0.68 g, 0.017 mol in water (5.5 mL)) was refluxed for 4 h, using a reflux condenser. The resulting mixture was cooled to room temperature, acidified with a 10% solution of hydrochloric acid to pH ? 6-7. A precipitate formed was collected by filtration on a Buchner funnel, washed with water and acetone on the filter, and dried in air to obtain the product (1.21 g, 97%) as a light orange powder, m.p. 270 C.
N-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-(5-iodo-2,3-dioxo-2,3-dihydroindol-1-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
Stage #1: 5-iodoisatin With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Cooling with ice;
Stage #2: 2‐chloro‐N‐(2‐(2,6‐dioxopiperidin‐3‐yl)‐1,3‐dioxoisoindolin‐4‐yl)acetamide With potassium iodide In N,N-dimethyl-d<SUB>6</SUB>-formamide at 80℃;
3'-ethyl-5-iodo-6',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With Amberlyst-15 In methanol at 80℃; for 5h;
Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives
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.
6-iodo-1',3'-dimethyl-3-phenyl-9H-spiro[isoxazolo[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H,3'H,7'H)-trione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With Amberlyst-15 In methanol at 80℃; for 5h;
Synthesis of spiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo-[5,4-b]quinoline-4,5'-pyrrolo[2,3-d]pyrimidine]-2',4',6'(1'H, 3'H, 7'H)-trione, spiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(5'H)-dione derivatives
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.
12-(4-chlorophenyl)-8-iodo-1-methyl-2,3-dihydro-1H-3a,9b-(methanooxymethano)pyrrolo[3,2-c]quinoline-4,10(5H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
With copper(l) iodide In N,N-dimethyl-formamide at 80℃; for 0.166667h; Sealed tube; Microwave irradiation;
General procedure for the reaction between 1, 2 and 3 under microwave conditions in DMF
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.
3-(2-benzoylbenzyl)-3-hydroxy-5-iodoindolin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
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.
92%
In toluene at 20℃; for 36h; UV-irradiation;
4 Example 4
Dissolve 0.2mmol of compound III-4 (5-iodoindole-2,3-dione) and 0.3mmol of compound II-4 (phenyl(o-tolyl)methanone) in 2ml of organic solvent (toluene) , irradiated with an ultraviolet lamp with a power of 15W, reacted at room temperature for 36h, and purified by chromatography after removing the organic solvent (using a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 2:1 as the eluent, R f value=0.2 ) to obtain a white solid compound I-4(3-(2-benzoylbenzyl)-3-hydroxy-5-iodoindolin-2-one) (Mp is 199.8-203.0) 86.3mg, the yield is 92%,
3′-(3-chlorophenyl)-5-iodo-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With toluene-4-sulfonic acid In ethanol at 70℃; for 0.5h; regioselective reaction;
4.2. general synthetic procedure for the compounds 3a-k
General procedure: The synthesis of spiro indolinone-dihydroquinazolinone 3a-k was accomplished by employing a simple one-pot two components condensationapproach. In first step, an equimolar mixture of isatin derivatives(1) (1.0 mmol) and 2-aminobenzamides (2) (1.0 mmol) was taken into50 mL round-bottom flask. The entire reaction mixture was dissolved in10 mL ethanol and then to catalyze the reaction 10 mol% of p-TsOH was added. The resulting mixture was stirred at 70 C in an oil-bath for 30min. The progress of the reaction was screened by thin layer chromatography(TLC). After completion of the reaction the ethanol solvent was removed under reduced pressure to obtain the crude product. Thereafter,the crude product was taken out with ethyl acetate (20 mL) whichwas washed with brine several times to eliminate the acidic impurities.The organic layer was allowed to dry over anhydrous sodium sulfate(Na2SO4) and concentrated by evaporating ethyl acetate under vacuumto afford the crude product. Finally, the crude was purified by column chromatography on silica gel (60-120 mesh) by employing ethyl acetate/hexane (3:7) as the eluent to obtain pure spiro indolinone dihydroquinazolinone derivatives 3. All the synthesized compounds were characterized based on their spectroscopic data.
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