* 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] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1982, vol. 18, # 8, p. 871 - 872[2] Khimiya Geterotsiklicheskikh Soedinenii, 1982, vol. 18, # 8, p. 1130
4
[ 91-56-5 ]
[ 117-57-7 ]
Reference：
[1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 22, p. 482
[2] Journal of the American Chemical Society, 1939, vol. 61, p. 2730,2732
5
[ 592-20-1 ]
[ 91-56-5 ]
[ 117-57-7 ]
Reference：
[1] Journal of Pharmacology and Experimental Therapeutics, 1949, vol. 95, p. 185,186
Reference：
[1] Organic Letters, 2015, vol. 17, # 6, p. 1373 - 1376
[2] Organic Letters, 2016, vol. 18, # 20, p. 5232 - 5235
[3] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 7622 - 7632
[4] Tetrahedron Letters, 2018, vol. 59, # 37, p. 3409 - 3412
[5] Journal of Fluorine Chemistry, 2018, vol. 215, p. 44 - 51
8
[ 91-56-5 ]
[ 20876-36-2 ]
Reference：
[1] Archiv der Pharmazie, 2015, vol. 348, # 10, p. 715 - 729
9
[ 91-56-5 ]
[ 20780-76-1 ]
Reference：
[1] Tetrahedron Letters, 2001, vol. 42, # 11, p. 2089 - 2092
[2] Heterocyclic Communications, 2003, vol. 9, # 1, p. 31 - 34
[3] Organic Letters, 2009, vol. 11, # 13, p. 2844 - 2847
[4] Inorganic Chemistry, 2013, vol. 52, # 23, p. 13779 - 13790
[5] Chemische Berichte, 1924, vol. 57, p. 1773
[6] Journal of the Chemical Society, 1925, vol. 127, p. 773[7] Journal of the Chemical Society, 1926, p. 644
[8] Chemische Berichte, 1924, vol. 57, p. 2116
[9] Journal of the Chemical Society, 1926, p. 2908
10
[ 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
11
[ 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
12
[ 91-56-5 ]
[ 20198-19-0 ]
[ 86-96-4 ]
Reference：
[1] Gazzetta Chimica Italiana, 1956, vol. 86, p. 119,125
13
[ 101080-38-0 ]
[ 20780-74-9 ]
[ 91-56-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3715 - 3723
14
[ 91-56-5 ]
[ 3597-63-5 ]
Reference：
[1] Angewandte Chemie, 1980, vol. 92, # 3, p. 196 - 197
[2] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1990, vol. 29, # 7, p. 603 - 605
15
[ 91-56-5 ]
[ 3597-63-5 ]
Reference：
[1] Patent: US4297491, 1981, A,
[2] Patent: US4297491, 1981, A,
16
[ 141-82-2 ]
[ 91-56-5 ]
[ 15733-89-8 ]
Yield
Reaction Conditions
Operation in experiment
97.3%
for 6 h; Reflux; Large scale
400 kg of recovered glacial acetic acid was placed in a 1000 L reactor and 100 kg of isatin, 160 kg of malonic acid, and 15 kg of sodium acetate were added under stirring. The mixture was heated to reflux and refluxed for 6 hours. After the reaction is completed, the acetic acid is distilled off under reduced pressure. 300 kg of deionized water are added to stir the crystals. The filtered solids are first washed with cold 30 kg glacial acetic acid and then rinsed with cold 30 kg methanol to obtain 2-hydroxy-. 4-Carboxyquinoline wet product, after filtering and drying at 45-70°C for 24 hours,125 kg of 2-hydroxy-4-carboxyquinoline was obtained with a yield of 97.3percent and a liquid phase purity of 99.6percent.
40%
for 16 h; Reflux
A stirred suspension of isatin, also called 1H-indole-2,3-dione, available from Sigma-Aldrich, (3.80 g, 25 mmol) and malonic acid (8.06 g, 77 mmol) in acetic acid (150 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (150 ml), filtered and washed with water (100 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (200 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 withconcentrated HCl and the precipitate was filtered, washed with water and dried to obtainthe desired product as a grey solid (2.2 g, 11.6 mmol, Yield 40percent). 1H NMR (500 MHz; d6-DMSO) δ 6.87 (5, 1H), 7.23 (ddd, 1H, J= 1.2 Hz, J= 7.2 Hz, J=8.3 Hz), 7.41 (dd, 1H, J= 0.7 Hz, J= 8.3 Hz), 7.55 (ddd, 1H, J= 1.4 Hz, J= 7.2 Hz, J=8.4 Hz), 8.15 (dd, 1H, J= 1.2 Hz, J= 8.3 Hz), 12.13 (brs, 1H) ppm. Purity by LCMS (UV Chromatogram, 190-450nm) 90percent, rt = 2.96 min m/z 190 (M+H)+
40%
for 16 h; Reflux
Preparation 10 2-hydroxyquinoline-4-carboxylic acid A stirred suspension of isatin, also called 1H-indole-2,3-dione, available from Sigma-Aldrich, (3.80 g, 25 mmol) and malonic acid (8.06 g, 77 mmol) in acetic acid (150 ml) was refluxed for 16 h. Acetic acid was removed under reduced pressure, the residue was suspended in water (150 ml), filtered and washed with water (100 ml) to give a brown solid. The solid was stirred in NaHCO3 saturated aqueous solution (200 ml) and the insoluble material was filtered off. The filtrate was acidified to pH 1-2 with concentrated HCl and the precipitate was filtered, washed with water and dried to obtain the desired product as a grey solid (2.2 g, 11.6 mmol, Yield 40percent). 1H NMR (500 MHz; d6-DMSO) δ 6.87 (s, 1H), 7.23 (ddd, 1H, J=1.2 Hz, J=7.2 Hz, J=8.3 Hz), 7.41 (dd, 1H, J=0.7 Hz, J=8.3 Hz), 7.55 (ddd, 1H, J=1.4 Hz, J=7.2 Hz, J=8.4 Hz), 8.15 (dd, 1H, J=1.2 Hz, J=8.3 Hz), 12.13 (brs, 1H) ppm. Purity by LCMS (UV Chromatogram, 190-450 nm) 90percent, rt=2.96 min, m/z 190 (M+H)+
Reference：
[1] Patent: CN108101842, 2018, A, . Location in patent: Paragraph 0021; 0023
[2] Synthetic Communications, 2005, vol. 35, # 17, p. 2243 - 2250
[3] Patent: WO2013/153357, 2013, A1, . Location in patent: Page/Page column 44
[4] Patent: US2015/45354, 2015, A1, . Location in patent: Paragraph 0271-0274
[5] Chemische Berichte, 1914, vol. 47, p. 358
[6] Journal of the Chemical Society, 1926, p. 2908
[7] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 15, p. 1727
17
[ 91-56-5 ]
[ 15733-89-8 ]
Reference：
[1] Helvetica Chimica Acta, 1957, vol. 40, p. 499
[2] Archiv der Pharmazie (Weinheim, Germany), 1899, vol. 237, p. 687
18
[ 91-56-5 ]
[ 5467-57-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4629 - 4635
19
[ 91-56-5 ]
[ 60434-13-1 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 42, p. 7372 - 7386
20
[ 91-56-5 ]
[ 20870-79-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7349 - 7353
[2] Letters in Organic Chemistry, 2011, vol. 8, # 7, p. 526 - 530
[3] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7440 - 7443
[4] Archiv der Pharmazie, 2015, vol. 348, # 10, p. 715 - 729
21
[ 91-56-5 ]
[ 4692-98-2 ]
Yield
Reaction Conditions
Operation in experiment
77%
With N-Bromosuccinimide In acetonitrile at 20℃; for 528 h;
The reaction was carried out in a round-bottom flask fittedwith a magnetic stirrer bar and a rubber septum with aneedle as vent. To a solution of 1.00 g isatin (3, 6.8 mmol)in 95 cm3 acetonitrile, a solution of 6.05 g NBS (34 mmol)in 40 cm3 acetonitrile was added at temperature 0 C. Nextreaction was continued for 22 days at ambient temperature,with access to air. The separated solid was collected byfiltration and washed with acetonitrile (2 9 10 cm3). Thepure product was obtained as a yellow solid in 77 percent yield.
Reference：
[1] Chemische Berichte, 1914, vol. 47, p. 358
23
[ 91-56-5 ]
[ 6943-17-5 ]
Reference：
[1] Patent: CN106146410, 2016, A,
24
[ 91-56-5 ]
[ 611-09-6 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 0℃; for 1 h;
A solution of NaNO3 (5.78 g, 0.068 mol) in concentrated H2SO4 (100 mL) was added drop wise, with stirring, to a solution of isatin 3h (10.0 g, 0.068 mol) in concentrated H2S04 (120 mL) for a period of 1 h at 0 °C. Then the reaction mixture was poured into ice water (750 mL), the precipitate was collected by filtration and washed with water to give 22a. Yield 11. 88 g, 91percent.
90%
at 5℃; for 3 h;
A mixture of compound 10 (10g, 0.068mol) and 100ml of H2SO4 (98percent) was iced to 5°C, then Sodium nitrate(6g, 0.071mol) was added slowly to ensure the temperature was low 5°C. The mixture was continued to stir 3h after the sodium acetate added. The mixture was poured to ice water and the yellow solid precipitate. The precipitate was filtered out and dried to get 11.75g of yellow solid with a yield of 90percent. m.p.254~257°C; IR (KBr): 3334.61, 3095.36, 1770.03, 1751.21, 1619.29, 1533.45, 1470.52, 1336.55, 903.33, 852.46 cm-1; UV-VIS (CH3OH), λ/nm: 210, 321nm; 1H NMR (400 MHz, CDCl3): δ 10.74(s, 1H), 8.25(d, 1H), 7.97(s, 1H), 7.69(d, 1H); ESI-MS for C8H4N2O4 [M+H]+: calcd:193.13, found:193.08; Anal. Calcd for C8H4N2O4: C, 50.01; H, 2.10; N, 14.58. Found: C, 50.05; H, 2.06; N, 14.56.
87.6%
at -4 - 20℃; for 0.666667 h;
Weigh isatin5.00g (33.98mmol), potassium nitrate 3.44g (33.98mmol), in which case stirredslowly 15mL dissolved in 20mL, concentrated sulfuric acid, respectively, andthen at 0 ~ -4 , the isatin concentrated sulfuric acidsolution was slowly added dropwise a solution of potassium nitrate inconcentrated sulfuric acid, after the addition was complete stirring wascontinued for 30min, and then stirred at room temperature 10min, TLC thereaction was complete, the mixture was poured into ice-water, stirred for30min, suction filtered to give a yellow solid, dried under vacuum oven to givethe desired product 5-nitro-indole-dione 5.72g, yield 87.6percent.
83.4%
at -5 - 0℃;
-5 conditions,5.9 g of isatin (II) were weighed in batches dissolved in 26 mL of cold concentrated sulfuric acid,A mixture of 2 mL of fuming nitric acid and 3 mL of concentrated sulfuric acid was slowly added dropwise,And the reaction temperature was controlled around 0 ° C,After completion of the reaction, the reaction was continued for 3 hours.After completion of the reaction, the mixture was poured into a beaker containing 100 g of crushed ice,Filtration, ice water washing to neutral,The filter cake was dried to yield 6.4 g of the orange-red product (III) in 83.4percent yield,
65%
at 60℃; for 1 h;
The 5-nitroisatin (1) was prepared according to the reported literature refPreviewPlaceHolder[25]. Briefly, in a mixture of 50 g (35 mL, 0.50 mol) of conc. nitric acid and 74 g (40 mL, 0.75 mol) conc. sulfuric acid, isatin (48.50 g, 0.33 mol) was added slowly with frequent shaking in 500 mL round bottomed flask. Then the mixture was cooled by immersing the flask in crushed ice cold water. After adding all isatin, flask was fitted with reflux condenser and the mixture was heated on water bath maintaining the temperature at 60 °C for 1 h to obtain the desired compound 5-nitroisatin (1). Then the entire content was then transferred into a beaker containing 500 mL cold water, stirred in order to wash out as much acid from the desired product. When compound 1 settled completely to the bottom, the upper acid layer was removed from the mixture. Then the bottom layer was transferred to the separating funnel and shaked vigorously with about 50 mL of water. Then the residual layer was collected, dried with anhydrous calcium chloride and finally filtered to obtain the pure compound (1). Yield 65percent, Mp 230 °C; IR (KBr) cm-1: 3342 (NHstr), 2996 (ArCHstr), 1732 (CO, Isatin), 1570 (ArNO2, NO asym); 1348 (ArNO2, NO sym); 1H NMR (400 MHz, CDCl3, δ ppm): 7.02-7.94 (m, 3H, ArH), 8.92 (s, 1H, NH-Isatin); MS (EI) m/z 192 [M+]; Anal. Calcd for C8H4N2O4: C, 50.01; H, 2.10; N, 14.58. Found: C, 49.91; H, 2.12; N, 14.62.
62%
at 60℃; Cooling with ice
Compound indoline-2, 3-dione (48.5 g, 0.33 mol) was added into a mixture of 50 g (35 mL, 0.5 mol) of conc. nitric acid and 74 g (40 mL, 0.75 mol) conc. sulfuric acid with frequent shaking in 500-mL round bottomed flask, keeping the mixture cool by immersing the flask in ice cold water. After adding all indoline-2, 3-dione, flask was fitted with reflux condenser and the mixture was heated on water bath maintaining the temperature at 60 °C for 1 h to obtain the desired compound 5-nitroindoline-2, 3-dione (1). Content was then poured into a beaker containing 500 mL cold water, stirred in order to wash out as much acid from the desired compound. When compound (1) completely settled to the bottom, the upper acid liquor was completely poured off from the mixture. Then the residual liquid was transferred to the separating funnel and shaked vigorously with about 50 mL of water. Bottom layer was collected, dried with anhydrous calcium chloride and finally filtered to obtain the pure compound (1). Yield 62percent, mp 230 °C. IR (KBr) cm-1: 3306 (NHstr.), 3015 (Ar-CHstr.), 1725 (CO, Isatin), 1563 (NOstr.-sym.), 1325 (NOstr.-asym.), 1H NMR (CDCl3) δ (ppm): 7.12-7.89 (m, 3H, Ar-H), 9.53 (s, 1H, NH-Isatin); 13C NMR (DMSO-d6) δ (ppm): 107.34, 114.46, 127.24, 129.83, 144.24, 152.73, 160.26, 178.45.
47%
at 0 - 20℃; for 2.5 h;
The solution of isatin (52.09 g, 0.352 mol) in 520 mL of concentrated sulfuric acid was cooled down by ice bath to 0 0C. The potassium nitrate (35.55 g, 0.352 mol) was added portionwise over 2 hours maintaining the temperature between 0-5 0C. After complete addition the mixture was stirred at room temperature for 0.5 hour and poured into 1500 g of ice. The yellow precipitate was collected by vacuum filtration, washed with cold water and dried on air to give 32.16 g (47 percent yield) 5-nitro-isatin. mp (exp) = 243 0C (mp [5] = 251 0C). Spectrum NMR 1 (DMSO-d6, δ, ppm, J, Hz): 7.09 (d, 1H, J = 8.6); 8.2 (d, 1H, J = 2.3), 8.44 (dd,1H, J = 8.54, J = 2.5); 11.67 (s,1H).
Reference：
[1] Patent: WO2005/41954, 2005, A1, . Location in patent: Page/Page column 31; Figure 3A
[2] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 11, p. 2589 - 2593
[3] Patent: CN103554008, 2016, B, . Location in patent: Paragraph 0053-0054
[4] Journal of Pharmaceutical Sciences, 1984, vol. 73, # 3, p. 407 - 408
[5] Patent: CN106146410, 2016, A, . Location in patent: Paragraph 0023; 0024
[6] Journal of Organic Chemistry USSR (English Translation), 1990, vol. 26, # 6, p. 1146 - 1148[7] Zhurnal Organicheskoi Khimii, 1990, vol. 26, # 6, p. 1327 - 1330
[8] Archiv der Pharmazie, 2015, vol. 348, # 10, p. 715 - 729
[9] Journal of Chemical Research - Part S, 1999, # 10, p. 632 - 633
[10] European Journal of Medicinal Chemistry, 2011, vol. 46, # 12, p. 6057 - 6065
[11] Archives of Pharmacal Research, 2013, vol. 36, # 4, p. 411 - 422
[12] European Journal of Medicinal Chemistry, 2011, vol. 46, # 6, p. 2236 - 2242
[13] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 2, p. 931 - 938
[14] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3787 - 3793
[15] Chemische Berichte, 1907, vol. 40, p. 2512
[16] Chemische Berichte, 1879, vol. 12, p. 1312[17] Chemische Berichte, 1883, vol. 16, p. 1478
[18] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 520
[19] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2002, vol. 41, # 3, p. 668 - 672
[20] Chinese Chemical Letters, 2012, vol. 23, # 5, p. 541 - 544
[21] Chemical Biology and Drug Design, 2012, vol. 80, # 4, p. 524 - 532
[22] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 10, p. 420
25
[ 2243-35-8 ]
[ 91-56-5 ]
[ 485-89-2 ]
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 22, p. 8874 - 8877
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 1, p. 40 - 64
[3] Patent: US2749347, 1953, ,
[4] Journal of Pharmacology and Experimental Therapeutics, 1949, vol. 95, p. 185,186
[5] Patent: US2749347, 1953, ,
1-(quinolin-8-ylmethyl)indoline-2,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
NaH (0.135g, 3.38 mmol, 60percent) was washed with hexane (7 mL) and suspended in dry DMF (4 mL). To this suspension, isatin (0.33 g, 2.25 mmol) was added slowly over a period of 10 minutes in small portions and the sides of the reaction container were rinsed with 1.5 mL of DMF to wash in all of the isatin that stuck on the sides. After stirring for 20 minutes 8- (bromomethyl)quinoline (0.5 g, 2.25 mmol) was added. The reaction was stirred at room temperature for 3 h. TLC indicated completion of the reaction. Crushed ice was added over the solution and the precipitated solid was filtered, washed with excess water and dried under high vacuum overnight. The crude compound was dissolved in EtOAc by boiling to which a small amount of hexane was added. The solution was left for crystallization at room temperature for 4 h. The crystallized compound was filtered, washed with 50percent EtOAc/hexane, dried under suction and then under high vacuum overnight. Yield: 0.29g (45percent). ? NMR (400 MHz, CDC13) delta 9.01 (d, J = 4.2 Hz, 1H), 8.21 (d, J = 8.3Hz, 1H), 7.80 (d, J = 8.2Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.60 (d, J = 7.4 Hz, 1H), 7.78 - 7.51 (m, 2H), 7.42 (t, J = 7.8 Hz, 1H), 7.02 - 7.07 (m, 2H) & 5.70 (s, 2H).
Reference Example 16 Synthesis of 2-(4'-trifluoromethoxyphenyl)quinoline-4-carboxylic Acid The above-mentioned compound (2.27 g) was formed from 1.47 g of isatin and 4.08 g of 4-trifluoromethoxyacetophenone in the same manner as in Reference Example 1. 1 H-NMR(DMSO-d6), delta: 7.55(d, 2H), 7.72(t, 1H), 7.87(t, 1H), 8.19(d, 1H), 8.41(d, 2H), 8.49(s, 1H), 8.68(d, 1H)
3-(3-Oxopiperazin-1-ylmethyl)-2-(4-trifluoromethylphenyl)quinoline-4-carboxylic Acid ((S)-1-cyclohexylethyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 45 3-(3-Oxopiperazin-1-ylmethyl)-2-(4-trifluoromethylphenyl)quinoline-4-carboxylic Acid ((S)-1-cyclohexylethyl)-amide The compound was prepared following the procedure of Example 26 starting from 1-(4-trifluoromethylphenyl)-propan-1-one (CAS [711-33-1]) and isatin (CAS [91-56-5]) according to Description 23-25).
5mmol of Phen-NH2, 5.5mmol of indoline-2,3-dione and 0.1mmol of 4-methylbenzenesulfonic acid were added into 25mL of ethanol and heated to reflux overnight. After cooling, the solution was poured into 300mL of cold water. The crude product was collected and recrystalized in ethanol to yield IPP as gray powder. 1H NMR (300Hz, CDCl3, 25°C): delta 10.13 (d, 1H, J=8.5Hz), 9.24 (d,1H, J=2.5Hz), 9.17 (d, 1H, J=2.0Hz), 9.09 (d, 1H, J=5.5Hz), 8.55 (d, 1H, J=5.5Hz), 7.60?7.64 (m, 2H), 7.55 (d, 1H, J=8.5Hz), 7.34 (m, 2H). Anal. Calcd for C20H11N5: C, 74.76; H, 3.45; N, 21.79. Found: C, 74.67, H, 3.60; N, 21.68.
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).
To a solution of isatin (100 mg, 0.68 mmol) in ethanol (2 mL) was added l -(6- methoxypyridin-3-yl)efhanone (1 12 mg, 0.74 mmol), followed by diethylamine (77 mu, 0.74 mmol). The mixture was stirred at room temperature for 2 hours then concentrated under reduced pressure. The resulting alcohol intermediate was triturated in diethyl ether with sonication, filtered and the resulting white solid was used without further purification
With 3-chloro-benzenecarboperoxoic acid; trifluoroacetic acid; for 8h;Inert atmosphere; Reflux;
General procedure Typical free radical procedure a mixture of 2,6-diaminopyrimidin-4(3H)-one (2.0 mmol), isatin (1.0 mmol), TFA (0.5 mmol), and mCPBA (1.0 mmol) in refluxing DCE (5 ml) was stirred for 8 h (TLC). After completion of reaction, the reaction mixture was filtered and the precipitate washed with water and then with EtOH to afford the pure product 7 as a white powder (0.31 g, 40%). The filtrate was evaporated in vacuo and washed the with 10 ml water and extracted with EtOAc (2*20 ml). The organic layer was dried over sodium sulfate (anhyd) and concentrated under pressure to obtain crude substance, which was subjected to flash chromatography (EtOAc/hexane 60:40) to obtain compound 10, 8, and 9 at 24, 40 min, 84 min in 1-2%, 8% and 14% whereas the mixture of compound 11 and 12 was found to be contained in the fractions between 5 and 18 min. The fractions of 5-18 min was collected, concentrated, and subjected to flash chromatography (EtOAc/hexane 40:60) to obtain 11 and 12 in 19% and 11% at 20 and 32 min.
4.2.10 (R)-3-(4-Amino-2-(methylthio)-6-oxo-1,6-dihydropyrimid in-5-yl)-3-hydroxyindolin-2-one (6) A solution of isatin (1.0 mmol) and pyrimidine (5, 1.0 mmol) in dioxane/water (4:1.0 ml) was stirred along with gradual addition of Cu(OTf)2 (0.1 mmol) and CuSO4 (1.1 mmol) at -10 C. After 2.5 h the solid precipitated was filtered, washed and dried under vacuum the obtained solid (244 mg, 0.8 mmol) was treated with 8-hydroxyquinoline (0.8 mmol) in dioxane:
5H-[1,2,5]oxadiazolo[3′,4′:5,6]pyrazino[2,3-b]indole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With acetic acid; for 15h;Reflux;
a. PREPARATION OF 5H-[1,2,5]OXADIAZOLO[3 ',4' :5,6]PYRAZINO[2,3- BJINDOLE (COMPOUND 27) [00295] To a solution of isatin (0.20 g, 1.36 mmol) in glacial acid (5 mL) was added 1,2,5- oxadiazole-3,4-diamine (0.14 g, 1.36 mmol). The resulting mixture was heated to gentle reflux for 15 h and then poured into ice water. The resulting precipitate was filtered and washed with water to afford 27 as red solid (0.05 g, 17% yield). Ti NMR (300 MHz, d6- DMSO) delta ppm 12.35 (brs, IH), 8.19 (d, J = 7.8 Hz, IH), 7.73 (t, J= 7.5 Hz, IH), 7.39 (d, J = 8.1 Hz, IH), 7.32 (t, J= 7.2 Hz, IH); 1 C NMR (75 MHz, c/'-DMSO) delta ppm 153.96, 152.62, 152.50, 151.93, 148.81, 136.37, 125.33, 123.11, 118.86, 113.38; HRMS (ESI) Calcd for C10H5N5O (M - H) 210.0416, found 210.0427.
6-fluoro-2-(2-(2-oxoindolin-3-ylidene)hydrazino)benzothiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
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.
General procedure: To a stirred solution of compound 3 (0.3g, 2.04mmol) in ethanol (2mL), equivalent substituted acetophenone was added. The reaction stirred at room temperature for 2-24h, the precipitate was formed. After filtration and washing with water, the crude product was used next step without purification. Then the crude product was dissolved in ethanol solution (10mL), concentrated hydrochloric acid (1mL) was added. The mixture was stirred at 60C for 2h. Then the mixture was poured into ice water, the precipitate was formed. After filtration and washing with water, the crude product was purified by silica gel chromatography using hexane and ethyl acetate gradient to obtain desired products 5a-5r.
2-(4,6-bis(3-methoxyphenyl)-1,3,5-triazin-2-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With potassium phosphate; copper(l) iodide; at 20℃; for 5h;
The specific steps are as follows: adding ruthenium (44.1 mg, 0.3 mmol), m-methoxybenzimid hydrochloride to the pressure tube.(167.9 mg, 0.9 mmol), CuI (5.7 mg, 0.03 mmol) and potassium phosphate (381.6 mg, 1.8 mmol),After adding 3 mL of acetonitrile, the reaction was stirred under magnetic stirring for 5 hours at room temperature, and the reaction mixture was extracted with dichloromethane.After drying over sodium sulfate, the solvent is evaporated under reduced pressure to give a crude product. methylene chloride / petroleum ether = 1:20 (V/V) as eluentThe column was separated and purified to obtain the desired product. The product was a yellow solid with a yield of 52percent.
2-(4,6-dicyclopropyl-1,3,5-triazin-2-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 20℃; for 5h;
The specific steps are as follows: adding blush (44.1 mg, 0.3 mmol) to the pressure tube, cyclopropyl-substituted hydrazine hydrochloride (108.5 mg,0.9 mmol), CuI (5.7 mg, 0.03 mmol) and potassium phosphate (381.6 mg, 1.8 mmol), added to 3 mL of DMSO, magnetic at room temperatureAfter stirring for 5 hours, the reaction mixture was extracted with methylene chloride.After that, the solvent is distilled off under reduced pressure to obtain a crude product, and the crude product is subjected to column separation using dichloromethane/petroleum ether = 1:20 (V/V) as eluent.Purification is the desired product, the product is a yellow solid with a yield of 34percent.
Isatin (1.0 mol) and KOH (1.0 mol) weredissolved into a sufficient amount of water and filtered. Thefiltrate and 1.0 mol KOH were added into chloroacetone(2.0 mol), and hydrochloric acid was added dropwise toadjust to pH = 7, and the solution was then filtered. Yield95% and m.p. 225C. IR peaks (KBr, cm-1): 3433(vs),3125(w), 3043(w), 2869(w), 2499 (m), 2040(m), 1621(m),1553 (s), 1500 (m), 1462(m), 1410(m), 1242(vs), 1160(m),1014(w), 906(m), and 686(s); HRMS m/z (ESI) calcd forC11H9NO3 ([M+H]+) 203.0582, found 203.0548; 1H NMR(400 MHz, DMSO) delta 9.15 (s, 1H), 7.93 (d, J = 8.2 Hz 1H),7.64 (t, J = 7.7 Hz, 1H), 7.60-7.52 (m, 3H), 2.70 (s, 3H).The melting points of isatin and HMCA are in reasonableagreement with those reported in the literature.9
95%
With potassium hydroxide; In water;
isatin (147 g, 1.0 mol) and KOH (56g, 1.0 mol) were dissolved into a sufficient amount of waterand filtered. The filtrate and KOH (56 g, 1.0 mol) wereadded into chloroacetone (184 g, 2.0 mol), and hydrochloricacid was added dropwise to adjust pH = 7, then filtered.Yield: 193 g (95%); m.p. 225 C. IR peaks (KBr, cm-1):3433(vs), 3125(w), 3043(w), 2869(w), 2499 (m), 2040(m),1621(m), 1553 (s), 1500 (m), 1462(m), 1410(m), 1242(vs),1160(m), 1014(w), 906(m) and 686(s); HRMS m/z (ESI)calcd for C11H9NO3 ([M+H]+) 203.0582, found 203.0548;1H NMR (400MHz, DMSO) delta 9.15 (s, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.60-7.52 (m, 1H), 2.70(s, 3H).
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