* 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.
Step 2: 6-Chloroisatin 3,3-Dibromo-6-chloro-1,3-dihydro-indol-2-one (21.34 g, 59.7 mmol) was suspended in a 4:1 (v:v) mixture of MeOH (172 mL): water (43 mL) and heated at reflux for 19 hr. The reaction was cooled in an ice bath and filtered. The red solid was washed once with cold CH3OH and dried to give the title compound as a red solid (10.49 g, 88percent yield). NMR (400 MHz, DMSO-d6): consistent. MS: (API-ES+) m/z 182/184 [M+H], 1 chlorine pattern observed.
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.
With hydrogenchloride; hydroxylamine hydrochloride; sodium sulfate In water at 90℃; for 0.0833333 h;
General procedure: To a solution of 120mL water, chloral hydrate (8.93g, 0.054mol), anhydrous sodium sulfate (130g, 0.40mol), aniline or substituted aniline 5 (0.05mol), hydroxylammonium chloride (10.98g, 0.158mol) and concentrated hydrochloric acid (43mL) were added respectively. Subsequently, the resulting suspension was heated to 90°C for 5min and cooled to room temperature. After filtration and washing with water (2×20mL), the crude material was obtained. The crude was added in batches to a 250mL, three mouth flask filled with concentrated sulfuric acid (32.6mL) at the temperature of 65°C and then heated up to 80°C for 20min. The reaction solution was cooled to room temperature and poured onto 500g of ice water and stirred vigorously for 4h. Intermediates 6a–i were isolated by filtration, washing with water, and recrystallization from ethanol with yields from 25.7percent to 73.2percent.
Reference：
[1] Chinese Chemical Letters, 2013, vol. 24, # 10, p. 929 - 933
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 20, p. 5630 - 5633
General procedure: 4.2 General procedure for the synthesis of 5 and 10a–g: (a) A 500 ml, three-necked, round-bottomed flask fitted with a condenser and a thermometer was charged with chloral hydrate (16.50 g, 0.1 mol) and 220 ml of water. Then anhydrous sodium sulfate (15.00 g), aniline derivative (0.1 mol), HCl solution (5.2 percent, 70 ml), and hydroxylamine hydrochloride (20.81 g, 0.3 mol, in 95 ml of water) were added in successively. After being heated to reflux for 1 h, the reaction mixture was cooled to room temperature. The intermediate compound (anilide derivative) was collected by filtration and dried, which was used for next step without further purification. (b) A 100 ml, three-necked, round-bottomed flask fitted with a thermometer was charged with concentrated sulfuric acid (10 equiv). After heating to 50 °C with stirring, the dried product (1 equiv) from the above step was added in over a period of 20 min. The resulting solution was heated to 65 °C and kept for 1 h and then cooled down to room temperature with an ice bath. The precipitate was filtered out and dried to get the target compounds. The dried product from the above step (15.4 g, 0.095 mol) was added into concentrated sulfuric acid (50 ml) in a period of 20 min at 50 °C. Then the resulted mixture was heated to 65 °C and kept for 1 h. The mixture was poured into ice water. The precipitate in the mixture was filtered out and dried.
Reference：
[1] European Journal of Pharmacology, 2007, vol. 556, # 1-3, p. 200 - 206
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[3] Tetrahedron, 2014, vol. 70, # 4, p. 906 - 913
[4] Medicinal Chemistry Research, 2014, vol. 23, # 5, p. 2161 - 2168
[5] Heterocycles, 2014, vol. 89, # 8, p. 1923 - 1932
[6] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6371 - 6379
6
[ 17122-55-3 ]
[ 6341-92-0 ]
[ 6344-05-4 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 6, p. 578 - 581
[2] Synthetic Communications, 2010, vol. 40, # 21, p. 3125 - 3134
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 11, p. 2085 - 2094
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 935 - 946
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 2, p. 494 - 499
[6] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 4, p. 764 - 769
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 10, p. 1881 - 1885
16
[ 141-85-5 ]
[ 6341-92-0 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 6, p. 578 - 581
17
[ 1261152-95-7 ]
[ 6341-92-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
18
[ 98591-63-0 ]
[ 6341-92-0 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 614,619
19
[ 17422-33-2 ]
[ 6341-92-0 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 516 - 530
20
[ 79-37-8 ]
[ 141-85-5 ]
[ 6341-92-0 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 647
21
[ 98591-63-0 ]
[ 7664-93-9 ]
[ 7732-18-5 ]
[ 6341-92-0 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 614,619
22
[ 17122-55-3 ]
[ 6341-92-0 ]
[ 6344-05-4 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 6, p. 578 - 581
[2] Synthetic Communications, 2010, vol. 40, # 21, p. 3125 - 3134
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 11, p. 2085 - 2094
[4] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 935 - 946
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2006, vol. 45, # 2, p. 494 - 499
[6] Journal of the Brazilian Chemical Society, 2010, vol. 21, # 4, p. 764 - 769
23
[ 302-17-0 ]
[ 108-42-9 ]
[ 6341-92-0 ]
[ 6344-05-4 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 2014, vol. 51, # 1, p. 1 - 10
24
[ 108-42-9 ]
[ 6341-92-0 ]
[ 6344-05-4 ]
Reference：
[1] Patent: US6576656, 2003, B1,
25
[ 6341-92-0 ]
[ 6958-39-0 ]
Reference：
[1] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
26
[ 6341-92-0 ]
[ 1677-48-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 19, p. 5536 - 5549
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 2697,2700
[3] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
27
[ 6341-92-0 ]
[ 89-77-0 ]
Reference：
[1] Journal of the American Chemical Society, 1956, vol. 78, p. 1251,1254
With titanium tetrachloride; zinc In tetrahydrofuran at 20℃; for 0.0833333 h; Inert atmosphere
General procedure: TiCl4 (0.7 mL, 6 mmol)was added to a stirred suspension of Zn powder (0.78 g, 12 mmol) in freshlydistilled anhydrous THF (15 mL) at room temperature (rt) under a dry N2atmosphere. After completion of the addition, the mixture was refluxed for 2 h.The suspension of the low-valent titanium reagent thus-formed was cooled tort. A solution of isatin or its derivatives 1 or 3 (2 mmol) in THF (10 mL) wasadded dropwise. The mixture was stirred at room temperature for about 5 minunder N2. After this period, the thin layer chromatography (TLC) analysis of themixture showed the reaction completed. The reaction mixture was quenchedwith 3percent HCl (15 mL) and extracted with CHCl3 (3 50 mL). The combinedextracts were washed with water (3 50 mL) and dried over anhydrousNa2SO4. After evaporation of the solvent under reduced pressure, the crudeproduct was purified by column chromatography (petroleum ether/ethylacetate = 5:1) to give the pure products 2 or 4.
Reference：
[1] Tetrahedron Letters, 2014, vol. 55, # 14, p. 2238 - 2242
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 13, p. 2033 - 2042
[3] Patent: US4658037, 1987, A,
[4] Patent: US4652658, 1987, A,
[5] Patent: US4730004, 1988, A,
[6] Patent: US4721712, 1988, A,
[7] Patent: US4725616, 1988, A,
[8] Patent: US4556672, 1985, A,
[9] Patent: US4569942, 1986, A,
[10] Patent: US4690943, 1987, A,
[11] Patent: EP208510, 1991, B1,
[12] Tetrahedron, 2011, vol. 67, # 5, p. 982 - 989
[13] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[14] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6371 - 6379
[15] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 1071 - 1082
31
[ 6341-92-0 ]
[ 20776-61-8 ]
Reference：
[1] Journal of Organic Chemistry, 1952, vol. 17, p. 149,153
With sulfuric acid In water at 50 - 65℃; for 2.33333h;
General procedure: A 100 mL, three-neck round-bottom flask fitted with a thermometer was charged with concentrated sulfuric acid (10 equiv.). After heating to 50 °C with stirring, the dried product (1 equiv.) from the above step was added over a period of 20 min.The resulting solution was heated to 65 °C, which was maintained for 1 h followed by cooling to room temperature in an ice bath. The precipitate was filtered and dried to yield the target compounds.
General procedure: A mixture of <strong>[608-08-2]1H-indol-3-yl acetate</strong> (5 g, 29 mmol), isatin derivative (5.2 g), and KOH (22 g) in water (200 mL) was stirred for 10 days at rt, filtered and the filtrate was acidified to pH 1 with concentrated HCl. The precipitate of quindoline-11-carboxylic acid derivative 13 was collected, washed with water, dried, and used for the next step without further purification.
With nickel dichloride In PEG 600 at 100℃; for 3.5h;
4.2. General procedure for synthesis of pyrazolophthalazinyl spirooxindoles
General procedure: A mixture of isatin 1 (1.0 mmol), malononitrile or cyanoacetic ester 2 (1.0 mmol), phthalhydrazide (1.0 mmol), and NiCl2 (0.2 mmol) in PEG 600 (5 mL) was stirred at 100 °C for the appropriate time (refPreviewPlaceHolderTable 2). After complete conversion as indicated by TLC, water was added and the product was extracted with ethyl acetate (2×10 ml). The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was recrystallized from ethanol to afford the pure product.
Example 109 2-(6-Chloro-2,3-dioxo-2,3-dihydro-indol-1-yl)-4-methyl-pentanoic acid thiazol-2-ylamide A mixture of sodium hydride (60% in oil, 264 mg) in N,N-dimethylformamide at 0 C. was treated with a solution of 6-chloro-1H-indole-2,3-dione (1.0 g) in N,N-dimethyl formamide (total volume is 25 mL). The reaction mixture was then stirred for 30 min at 0 C. After this time, the reaction mixture was treated with 2-bromo-4-methyl-pentanoic acid methyl ester (prepared as in Example 9, 1.38 g) and stirred for another 1 h at 0 C. The reaction mixture was then allowed to warm to room temperature and stirred for 3 h. After this time, the reaction was diluted with water and extracted with methylene chloride. The organic layers were combined and then dried over sodium sulfate, filtered to remove the drying agent and the filterate concentrated in vacuo. The residue obtained was then purified by silica gel column chromatography to afford 2-(6-chloro-2,3-dioxo-2,3-dihydro-indol-1-yl)-4-methyl-pentanoic acid methyl ester (1.3 g, 76%).
3.2. Experimental Procedures
General procedure: A mixture of isatin 1a (0.1 mmol), (E)-4-phenylbut-3-en-2-one (2a, 0.1 mmol), arginine (0.01 mmol) in MeOH (1.0 mL) was stirred for 48 h at 25 °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 petroleum ether/ethyl acetate = 1:1 as the eluent to give 3a.
rac-(3S,3'S,4'S,5'S)-6-chloro-3'-(3-chlorophenyl)-5'-(2-hydroxyethyl)-4'-nitro-1,2-dihydrospiro[indole-3,2'-pyrrolidine]-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; for 0.666667h;Reflux;
6-Chloroisatin A-la (1.00 g, 5.4 mmol), 1-(3-chlorophenyl)-2-nitroethene (0.99 g, 5.4 mmol) and <strong>[672-15-1]L-homoserine</strong> (0.64 g, 5.4 mmol) are refluxed in MeOH for 40 min. The reaction mixture is concentrated in vacuo and purified by chromatography if necessary.
(2E)-N-(3-chlorophenyl)-2-hydroxyiminoacetamide[ No CAS ]
[ 6341-92-0 ]
[ 6344-05-4 ]
Yield
Reaction Conditions
Operation in experiment
With sulfuric acid In water at 60 - 80℃; for 0.5h; Inert atmosphere; Overall yield = 67 %; Overall yield = 7.18 g; regioselective reaction;
General Procedure 1: Isatin formation
General procedure: To a stirred solution of aqueous 18.1 M sulfuric acid (0.68 mL/mmol) at 60 °C was added the isonitrosoacetanilide (1 equiv.) portionwise. The reaction mixture was stirred in a heating block for 30 minutes at an internal temperature of 80 °C, then the mixture was cooled to room temperature. The solution was added slowly to a saturated water/ice mixture (5 mL/g)and stirred for 10 minutes at room temperature. The resultant solid was filtered, dried and purified as specified
6-chloro-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
89%
With acetic acid; In water; at 90℃; for 5h;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 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.
1-(3-chloro-2-fluorophenyl)-2-nitroethene[ No CAS ]
(3S,3'S,4'S,5'S)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2-hydroxyethyl)-4'-nitro-1,2-dihydrospiro[indole-3,2'-pyrrolidine]-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In methanol; for 4h;Reflux;
6-Chloroisatin S-la (31.5 g, 174 mmol), 1-(3-chloro-2-fluoro-phenyl)-2-nitroethene B-2a(35 g, 174 mmol) and <strong>[672-15-1]L-homoserine</strong> B-5a (20.7 g, 174 mmol) are refluxed in MeOH for4 h. The reaction mixture is concentrated in vacuo and purified by crystallization orchromatography if necessary.
5-hydroxy-5-(4-chloro-2-(isoindolin-2-yl-1,3-dione)phenyl)-1,3-dimethylhydantoin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With toluene-4-sulfonic acid In acetonitrile at 80℃; for 5h;
General procedures for the synthesis of polysubstituted 5-hydroxyhydantoins
General procedure: The mixture of substituted isatins 1 (1 mmol), phthalic anhydride or succinic anhydride 2 (1 mmol), 1,3-dimethylurea (1,3-diethylurea) 3 (1.5 mmol), p-TSA•H2O (0.2 mmol), and CH3CN (3 mL) was put in a 25 mL flask and reacted under 80 °C (monitored by TLC) about 5 h. After completion, the reaction the mixture was cooled to room temperature and the precipitate was obtained by filtration. Compound 4 was purified by recrystallization from EtOH.
5-hydroxy-5-(4-chloro-2-(pyrrolidin-1-yl-2,5-dione)phenyl)-1,3-dimethylhydantoin[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With toluene-4-sulfonic acid In acetonitrile at 80℃; for 5h;
General procedures for the synthesis of polysubstituted 5-hydroxyhydantoins
General procedure: The mixture of substituted isatins 1 (1 mmol), phthalic anhydride or succinic anhydride 2 (1 mmol), 1,3-dimethylurea (1,3-diethylurea) 3 (1.5 mmol), p-TSA•H2O (0.2 mmol), and CH3CN (3 mL) was put in a 25 mL flask and reacted under 80 °C (monitored by TLC) about 5 h. After completion, the reaction the mixture was cooled to room temperature and the precipitate was obtained by filtration. Compound 4 was purified by recrystallization from EtOH.
With ammonium hydroxide; dihydrogen peroxide; In dimethyl sulfoxide; at 20 - 30℃; for 4h;Sealed tube;
General procedure: A sealed tube was charged with isatin 1 (1a 147 mg, 1.0 mmol), ammonia hydrate 2 (25percent, 421 mg, 3.0 mmol) and H2O2 (30percent, 227 mg, 2.0 mmol) at room temperature, and then solvent DMSO (4 mL) was added. The resulting mixture was stirred at 30 °C in a sealed vessel under air after 4 h, then added 50 mL water to the mixture, extracted with CH3COOC2H5 3 times (3 x 50 mL). The extract was washed with 30percent NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate = 3:1) to yield the desired product 3a as a yellow solid (89percent yield).
Weigh rapamycin (0.05mmol), isatin 3h (0.10mmol) and rhodium octanoate dimer(0.0005mmo),They were placed in a reaction flask, 2.0 mL of dry dichloromethane was added, and after stirring at room temperature for 5 minutes,Phenyldiazo 2a (0.10 mmol) was weighed and dissolved in dry dichloromethane (1.0 mL), and slowly added dropwise to the reaction system (about 1 hour), and stirring was continued for half an hour.The solvent was removed by rotary distillation to give a crude product. The rapamycin analog I-h was obtained by column chromatography (eluent: petroleum ether: ethyl acetate = 1:10 to 1:4).The yield was 82%.
2-bromo-9-chloroindole[2,1-b]quinazoline-6,12-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66.2%
With triethylamine; In chloroform; at 80℃; for 3h;
Weigh6-chloroguanidine0.35g (0.0019mol),5-bromoindole anhydride0.48 g (0.0020 mol) was added to a 100 ml three-necked flask containing magnetons, and then 40 ml of chloroform was added to the three-necked flask.1.5 ml of triethylamine, heated to reflux in an oil bath at 80 C for 3 h,After the reaction is over, stop heating and wait for cooling.The crude product was obtained as a yellow solid powder by suction filtration.The product was washed 3 times with 10 ml of ethanol to obtain a pure product of a yellow solid powder.drying,Weigh 0.45 g and the yield was 66.2%.
6-chloro-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one[ 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.
6-chloro-3'-ethyl-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
87%
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-chloro-5'-methyl-3'-phenyl-7',8'-dihydrospiro[indoline-3,4'-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
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.
7-chloro-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
85%
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.
With NBS In N,N-dimethyl-formamide at 25℃; for 12h; Inert atmosphere;
4.1.2. General Procedure II: Synthesis of Multi-Substituted Isatin Derivatives (4a-4c)
General procedure: To a solution of compound 3 (3.0 mmol) in N, N-dimethylformamide (2.5 mL) wasadded NBS (3.3 mmol). The resulting reaction mixture was stirred at 25 C for 12 h. Afterthe reaction finished, the mixture was diluted with water (10 mL), the resultant precipitatefiltered, and the precipitate was dried in vacuo. The crude product was chromatographedgradiently on silica gel with PE/EA (10:14:1) to give the compounds 4a-4c.
45%
With NBS In N,N-dimethyl-formamide at 60℃; for 3h; Inert atmosphere;
37.1 Step 1: 5-Bromo-6-chloroisatin
After dissolving 6-chloroisatin (10.0 mmol) with N,N-dimethylformamide (15 mL) under argon atmosphere, N-bromosuccinimide (12.0 mmol) was added. After the feeding, the reaction solution was stirred for 3 hours under an argon atmosphere at 60°C. After TLC detected the completion of the reaction, the heating was stopped, and after cooling, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution (200 mL), and extracted with ethyl acetate. The organic phase was dried with anhydrous sodium sulfate and filtered, and the filtrate was concentrated in vacuo to obtain an orange-yellow solid as 5-bromo-6-chloroisatin with a yield of 45%.
6-chloro-2-oxo-1′,3′,6′-triphenyl-1′,7′-dihydrospiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-5′-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With magnetic biochar sulfonic acid In ethanol for 1h; Reflux;
General procedure for synthesis of spiro-pyrazolo[3,4-b]pyridines
General procedure: CoFe2O4/BC-SO3 (10 mg) was added to a mixture of isatin (1.0 mmol), 3-oxo-3-phenylpropanenitrile (1.0 mmol), 1H-pyrazol-5-amine (1.0 mmol) in ethanol (2 mL). The reaction mixture was stirred under reflux conditions for the appropriate time. After the completion of the reaction as monitored with TLC, the catalyst was separated by an external magnet and washed with ethanol. The filtrate was cooled to room temperature, and water (2 mL) was added, the product was precipitated and isolated by filtration.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
