* 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] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
2
[ 288-32-4 ]
[ 24067-17-2 ]
[ 2301-25-9 ]
Yield
Reaction Conditions
Operation in experiment
76%
With copper(I) sulfide; N,N,N,N,-tetramethylethylenediamine In methanol at 20℃; for 48 h;
General procedure: A 10mL round bottom flask was charged with a magnetic stirring bar, benzimidazole 1 (59mg, 0.5mmol), boronic acid 2 (1.0mmol), Cu2S (4mg, 0.025mmol), and MeOH (2mL), followed with the addition of TMEDA (0.075mL, 0.5mmol). The flask was sealed with a septum, through which was inserted 18-gauche needle. This setup allowed air to go into the reaction and avoid contamination of a mixture. The reaction mixture was stirred from 400 to 600rpm for appropriate time and extracted with EtOAc (2×15mL). Combined organic layers were washed with saturated aqueous solution of ethylenediaminetetraacetic acid disodium salt (15mL), and then dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes – EtOAc) to yield the title product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
75%
With 2-(4-methoxybenzylidene)-N-phenylhydrazinecarbothioamide; copper(II) acetate monohydrate; potassium carbonate In ethanol at 20℃; for 20 h;
General procedure: A mixture of imidazole (1 mmol), phenylboronic acid (2 mmol), K2CO3 (2 mmol), Cu(CH3COO)2H2O (1 mol percent, 1.99 mg) and L1 (1 mol percent, 5.7 mg) in ethanol (5 mL) was stirred at room temperature in a 50 mL oven dried round bottomed flask. After the completion of the reaction (as monitored by TLC), conventional workup of the reaction mixture was done with ethyl acetate (3 × 15 mL) and water (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the solvent was evaporated in a rotary evaporator under reduced pressure to get the crude product. The crude product was purified by column chromatography on silica gel (DCM: Methanol = 9:1) to afford the pure product.
72%
With copper(I) 3-metthylsalicylate; potassium carbonate In methanol at 65℃; for 3 h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
63%
With [CuI2(3,2'-pypzpym)]; oxygen In water; acetonitrile at 60℃; for 24 h; Green chemistry
General procedure: To a solution of 1 (0.02 mmol) in H2O/MeCN (v/v=2/1, 4 mL) was added 1H-imidazole (1.0 mmol) and arylboronic acid (2 mmol)under O2 atmosphere. The mixture was stirred at 60 °C for 24 h. After cooling to ambient temperature, the mixture was partitioned between water and CH2Cl2. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.
Reference：
[1] ChemCatChem, 2016, vol. 8, # 18, p. 2953 - 2960
[2] Chemistry Letters, 2010, vol. 39, # 7, p. 764 - 765
[3] Tetrahedron, 2018, vol. 74, # 5, p. 606 - 617
[4] Bulletin of the Korean Chemical Society, 2017, vol. 38, # 10, p. 1203 - 1208
[5] Synthetic Communications, 2015, vol. 45, # 2, p. 245 - 252
[6] Tetrahedron, 2016, vol. 72, # 44, p. 7014 - 7020
3
[ 1899-24-7 ]
[ 24067-17-2 ]
[ 7147-77-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 19, p. 2681 - 2683
[2] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2481 - 2486
[3] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 11, p. 2621 - 2626
4
[ 24067-17-2 ]
[ 67-68-5 ]
[ 16687-60-8 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 887 - 892
Reference：
[1] Journal of Organic Chemistry, 2005, vol. 70, # 9, p. 3730 - 3733
8
[ 98-80-6 ]
[ 5570-19-4 ]
[ 24067-17-2 ]
Reference：
[1] Synlett, 2005, # 1, p. 127 - 133
[2] Chemistry - A European Journal, 2007, vol. 13, # 22, p. 6452 - 6460
[3] Chemistry - A European Journal, 2007, vol. 13, # 22, p. 6452 - 6460
9
[ 108-24-7 ]
[ 98-80-6 ]
[ 5570-19-4 ]
[ 24067-17-2 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 713
10
[ 24067-17-2 ]
[ 101251-09-6 ]
Reference：
[1] Patent: CN106946920, 2017, A,
11
[ 100-01-6 ]
[ 24067-17-2 ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: With hydrogenchloride; sodium nitrite In methanol; water at 0 - 5℃; for 0.5 h; Stage #2: With tetrahydroxydiboron In methanol; water at 20℃; for 1 h;
General procedure: To a solution of arylamine (0.5 mmol, 1.0 equiv) in MeOH(1.0 mL) was added HCl (0.5 mL, 1.5 mmol, 3.0 equiv), followed by H2O (0.5 ml). This mixture was stirred 2 min,and the NaNO2 solution (0.25 mL) was then added. The NaNO2 solution was prepared by dissolving 35 mg ofNaNO2 in H2O (0.25 mL). This mixture was stirred 30 minat 0–5 °C, followed by HCl (135 mg, 1.5 mmol, 3.0 equivalents) in MeOH (1.0 mL). This mixture was stirred 60min. H2O (10 mL) was added to reaction mixture, then extracted with CH2Cl2 (50 mL, 3×). The combined organic layer was dried over Na2SO4, followed by evaporation to give the products.
Reference：
[1] Synlett, 2014, vol. 25, # 11, p. 1577 - 1584
[2] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
12
[ 13675-18-8 ]
[ 100-01-6 ]
[ 24067-17-2 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
[2] Journal of Organic Chemistry, 2014, vol. 79, # 21, p. 10568 - 10580
13
[ 636-98-6 ]
[ 73183-34-3 ]
[ 24067-17-2 ]
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 32, p. 5515 - 5518
14
[ 586-78-7 ]
[ 24067-17-2 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11667 - 11673
[2] Organic Letters, 2012, vol. 14, # 18, p. 4814 - 4817,4
15
[ 98-80-6 ]
[ 5570-19-4 ]
[ 24067-17-2 ]
Reference：
[1] Synlett, 2005, # 1, p. 127 - 133
[2] Chemistry - A European Journal, 2007, vol. 13, # 22, p. 6452 - 6460
[3] Chemistry - A European Journal, 2007, vol. 13, # 22, p. 6452 - 6460
16
[ 100-00-5 ]
[ 24067-17-2 ]
Reference：
[1] Journal of the American Chemical Society, 2012, vol. 134, # 28, p. 11667 - 11673
17
[ 13675-18-8 ]
[ 456-27-9 ]
[ 24067-17-2 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
18
[ 13675-18-8 ]
[ 586-78-7 ]
[ 24067-17-2 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
19
[ 636-98-6 ]
[ 13675-18-8 ]
[ 24067-17-2 ]
Reference：
[1] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
20
[ 108-24-7 ]
[ 98-80-6 ]
[ 5570-19-4 ]
[ 24067-17-2 ]
Reference：
[1] Journal of the American Chemical Society, 1931, vol. 53, p. 713
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 2.5h;Heating / reflux;
Ethyl 3-(4-nitrophenyl)-1H-indole-2-carboxylate 46 ml of a 1M sodium carbonate solution, 2.23 g of lithium chloride and then 1.1 g of tetrakis(triphenylphosphine)palladium are added successively, under argon and with stirring, to a solution of 5 g of <strong>[91348-45-7]ethyl 3-bromo-1H-indole-2-carboxylate</strong> and 7.8 g of 4-nitrophenylboronic acid in 110 ml of ethanol and 110 ml of toluene. The solution is refluxed for 2 hours 30 minutes and then concentrated under reduced pressure. The precipitate is filtered off and then recrystallized from ethanol, to give 5.1 g of ethyl 3-(4-nitrophenyl)-1H-indole-2-carboxylate, the characteristics of which are as follows: MS (ES+) spectrum: m/z=311 [MH]+ Melting point=218-220 C. (Koefler bench). 1H NMR spectrum (300 MHz, DMSO-d6, delta in ppm): 1.21 (t, J=7.0 Hz, 3H); 4.26 (q, J=7.0 Hz, 2H); 7.14 (broad t, J=8.0 Hz, 1H); 7.37 (broad t, J=8.5 Hz, 1H); from 7.50 to 7.60 (m, 2H); 7.81 (broad d, J=8.0 Hz, 2H); 8.30 (broad d, J=8.5 Hz, 2H); 12.2 (broad m, 1H). IR spectrum (KBr): 3405; 1717; 1510; 1343; 1239; 859 and 757 cm-1
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 100℃; for 3h;
To a 25-mL RB flask, equipped with a condensor, was added tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydro-1(2H)-pyridinecarboxylate (1.0 g), <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (0.71 g), sodium carbonate (0.430 mL of 2M solution), lithium chloride (0.382 g), tetrakis(triphenylphosphine)-palladium(0) (0.173 g) and ethylene glycol dimethyl ether (10 mL). The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100 C. for 3 hrs. After cooling to room temperature, the reaction mixture was diluted with methylene chloride (30 mL) and water (30 mL) and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3×20 mL) and the combined organic extracts were washed with sat NH4Cl (20 mL) and brine (20 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (6:1=hexane:ethyl acetate with 1% NH3) to afford the product (0.55 g, 59.9%) as a yellow oil. The compound is not stable at room temperature and should be used as promptly as practical: 1H NMR (400 MHz, CDCl3) delta 8.20 (d, 2H, J=8.6 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.24 (m, 1H), 4.13 (m, 2H), 3.67 (apparent t, 2H, J=5.5 Hz), 2.55 (m, 2H), 1.49 (s, 9H).
50%
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 85 - 90℃; for 4h;
A solution of 2 M Na2C03 (5.66 mL, .3 mmol) was added to a mixture of 4- nitrophenylboronic acid (0.831 g, 4.98 mmol), ierf-butyl 4- (((trifluoromethyl)sulfonyl)oxy)-5,6-dihydropyridine-1 (2H)-carboxylate (142) (1.50 g, 4.53 mmol), LiCI (0.384 g, 9.06 mmol) and Pd(PPh3)4 (1.308 g, 1.132 mmol) in 1 ,4- dioxane (20 mL). The reaction mixture was stirred at 85 - 90 C for 4 hours. The resulting mixture was dissolved in EtOAc (100 mL) and the organic layer was washed with H20 (50 mL), brine (50 mL) and dried over Na2S04 to yield a dark red oil. The oil was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60 C) to yield the title compound (143) (0.683 g, 50%) as a pale brown solid; 1H NMR (400 MHz, CDCI3) delta 8.24 - 8.16 (m, 2H), 7.55 - 7.47 (m, 2H), 6.23 (s, 1 H), 4.14 - 4.12 (m, 2H), 3.66 (t, J = 5.7 Hz, 2H), 2.55 (bs, 2H), 1 .50 (s, 9H). LCMS Method C: rt 6.39 min; m/z 249 [M-Boc+2H] 205 [M-'Butyl+2H]+.
50%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; lithium chloride; In 1,4-dioxane; at 85 - 90℃; for 4h;
A solution of 2 M Na2C03 (5.66 mL, 1.3 mmol) was added to a mixture of 4- nitrophenyiboronic acid (0.831 g, 4.98 mmol), fe/f -butyl 4- (((trifluoromethyi)sulfonyl)oxy)-5,6-dihydropyridine-1 (2H)-carboxyiate (142) (1.50 g, 4.53 mmol), LiCi (0.384 g, 9.06 mmol) and Pd(PPh3) (1.308 g, 1.132 mmol) in 1 ,4- dioxane (20 mL). The reaction mixture was stirred at 85 - 90 C for 4 hours. The resulting mixture was dissolved in EtOAc (100 mL) and the organic layer was washed with H20 (50 mL), brine (50 mL) and dried over Na2S04 to yield a dark red oil. The oil was purified by column chromatography on silica gel (0-20% EtOAc in petroleum benzine 40-60 C) to yield the title compound {143) (0.683 g, 50%) as a pale brown solid; 1H NMR (400 MHz, CDCI3) delta 8.24 - 8.16 (m, 2H), 7.55 - 7.47 (m, 2H), 6.23 (s, 1 H), 4.14 - 4.12 (m, 2H), 3.66 (t, J = 5.7 Hz, 2H), 2.55 (bs, 2H), 1.50 (s, 9H). LCMS Method C: rt 6.39 min; m/z 249 [M-Boc+2H]+, 205 [M-iButyi+2H]+.
39.1%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; lithium chloride; In 1,4-dioxane; water; at 100℃;Inert atmosphere;
A mixture oftert-butyl 4- ( ( (trifluoromethyl) sulfonyl) oxy) -5, 6-dihydropyridine-1 (2H) -carboxylate (1324 mg, 4.00 mmol) , <strong>[24067-17-2](4-nitrophenyl) boronic acid</strong> (667 mg, 4.00 mmol) , Pd (Ph3P) 4 (231 mg, 0.200 mmol) , Na2CO3 (1271 mg, 11.99 mmol) , LiCl (508 mg, 11.99 mmol) , 1, 4-dioxane (15 mL) and water (6 mL) was degassed and backfilled with N2 three times. The mixture was heated to 100 overnight, and then the solvent was removed under reduced pressure and the residue was dissolved with water (30 mL) , extracted with EtOAc (30 mL × 3) . The combined organic layer was washed with brine (15 mL) , dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography (PE/EtOAc 30/1 to 10/1 ) to afford the tert-butyl 4- (4-nitrophenyl) -5, 6-dihydropyridine-1 (2H) -carboxylate (500 mg, 1.561 mmol, 39.1) . LRMS m/z (M-55) 249.2 found, 249.2 required
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; toluene; at 85℃; for 16h;
Ethyl 4-(4-bromophenyl)-4-oxo-2-(2-phenylethyl)butanoate (4.32 g, 11.1 mmol) and <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (2.22, 13.3 mmol) was added to a dry flask under argon. Toluene (100 mL), dioxane (25 mL), saturated aqueous sodium carbonate (30 mL), and [1,1'-bis(diphenyl phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 453 mg, 0.55 mmol) were added and the mixture was thoroughly degassed. The resulting mixture was then heated at 85 C. for 16 h before it was cooled to rt. Water was added and the mixture was extracted twice with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage flash 75, 5:1 ethyl acetate/hexane) to afford ethyl 4-(4'-nitro-1,1'-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (3.6 g, 75%). HPLC ret. time 3.99 min, 1H NMR (300 MHz, CDCl3) delta 1.29 (t, 3H), 1.85-2.08 (m, 2H), 2.71 (t, 2H), 3.05-3.20 (m, 2H), 3.45-3.52 (m, 1H), 4.20 (q, 2H), 7.18-7.31 (m, 5H), 7.72 (d, 2H), 7.78 (d, 2H), 8.05 (d, 2H), 8.33 (d, 2H).
ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate[ No CAS ]
[ 24067-17-2 ]
[ 791593-86-7 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; toluene; at 85℃; for 16h;
To a 150 mL 3-neck flask fitted with a reflux condenser was added ethyl 4-(4-bromophenyl)-2-(2-methoxyethyl)-4-oxobutanoate (1.06 g, 3.09 mmol) and 4-nitro-phenyl boronic acid (0.62 g, 3.70 mmol) dissolved in toluene (30 mL) and dioxane (8.50 mL), followed by addition of saturated aqueous sodium carbonate solution (8.50 mL). A thin-gauge needle was inserted into the bi-phasic mixture and degassed with argon over 30 minutes, at which point 1,2-bis[(diphenylphosphino) ferrocene] dichloropalladium(II) (0.13 g, 0.15 mmol) was added, followed by an additional 15 minutes of degassing. The reaction mixture was heated at 85 C. for 16 h, and then the resulting dark-colored reaction mixture was allowed to cool, and was diluted with ethyl acetate (75 mL) and saturated aqueous sodium chloride solution (75 mL). The layers were separated, the aqueous layer was extracted twice with ethyl acetate (50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous magnesium sulfate, and filtered in vacuo through 2 cm Celite/2 cm silica. The filtrate was concentrated in vacuo, leaving a dark red-brown oil, that was purified by flash chromatography (4:1 hexane/ethyl acetate, then 3:1 hexane/ethyl acetate, then 2:1 hexane/ethyl acetate) to afford ethyl 2-(2-methoxyethyl)-4-(4'-nitro-1,1'-biphenyl-4-yl)-4-oxobutanoate (1.04 g , 88%). LC-MS ret. time 3.38 min, m/z 385.9 (MH+); 1H NMR (300 MHz, CDCl3) delta 1.27 (t, 3H), 1.80-1.95 (m, 1H), 1.95-2.10 (m, 1H), 3.10-3.25 (m, 2H), 3.40-3.58 (m, 3H), 4.17 (q, 2H), 7.67-7.82 (2d, 4H), 8.10 (d, 2H), 8.33 (d, 2H).
methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentanecarboxylate[ No CAS ]
[ 24067-17-2 ]
[ 791593-90-3 ]
Yield
Reaction Conditions
Operation in experiment
93%
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; toluene; at 85℃; for 16h;
To a 150 mL 3-neck flask fitted with a reflux condenser was added methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentanecarboxylate (1.58 g, 4.64 mmol), 4-nitro phenyl boronic acid (0.93 g, 5.6 mmol), toluene (45 mL), and dioxane (13 mL), followed by the addition of a saturated aqueous sodium carbonate solution (13 mL). The mixture was degassed using argon and 1,2-bis[(diphenylphosphino) ferrocene] dichloropalladium(II) (0.19 g, 0.23 mmol) was added, followed by an additional 15 minutes of degassing, and the deep red reaction mixture was heated to 85 C. for 16 h. The very darkly colored reaction mixture was allowed to cool, and then was diluted with ethyl acetate (100 mL) and saturated aqueous sodium chloride solution (100 mL). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (50 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution (100 mL), dried over anhydrous magnesium sulfate, and filtered under reduced pressure through 2 cm Celite/2 cm silica. The filtrate was concentrated under reduced pressure, leaving a dark red-brown oil, that was purified by flash chromatography (4:1/hexane: ethyl acetate, then 3:1/hexane: ethyl acetate, then 2:1/hexane: ethyl acetate) to afford methyl 1-[2-(4'-nitro-1,1'-biphenyl-4-yl)-2-oxoethyl]cyclopentanecarboxylate (1.65 g, 93%). LC-MS ret. time 3.56 min, m/z 368.0 (MH+); 1HNMR(300 MHz, CDCl3) delta 1.56-1.85 (overlapping signals, 6H), 2.23-2.37 (m, 2H), 3.45 (s, 2H), 3.67 (s, 3H), 7.70 (d, 2H), 7.77 (d, 2H), 8.06 (d, 2H), 8.34 (d, 2H).
methyl 4-[2-(4-bromophenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate[ No CAS ]
[ 24067-17-2 ]
[ 791593-95-8 ]
Yield
Reaction Conditions
Operation in experiment
79%
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; toluene; at 85℃; for 16h;
Methyl 4-[2-(4-bromophenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (820 mg, 2.40 mmol) and 4-nitrophenyl boronic acid (481 mg, 2.88 mmol) were combined in a dry flask under argon. Toluene (20 mL) and dioxane (5 mL) were added, and the resulting solution was degassed for 30 minutes by a flow of argon. The degassing was continued during the addition of saturated aqueous sodium carbonate (6 mL) and [1,1'-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (98 mg, 0.12 mmol). The resulting mixture was then heated at 85 C. for 16 h before it was cooled to rt. Water was added, and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (Biotage Flash 40) using 1:1 ethyl acetate/hexane to afford methyl 4-[2-(4'-nitro-1,1'-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (730 mg, 79%). LC-MS ret. time 3.03; m/z 383.9 (MH+);1H NMR (300 MHz, CDCl3) delta 1.65-1.73 (m, 2H), 2.17-2.21 (m, 2H), 3.37 (s, 2H), 3.68 (s, 3H), 3.71-3.78 (m, 4H), 7.70 (d, 2H), 7.77 (d, 2H), 8.02 (d, 2H), 8.31 (d, 2H).
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; toluene; at 85℃;
A mixture of 4-acetyl-3-methylphenyl trifluoromethanesulfonate (6.90 g, 24.0 mmol), <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (3.80 g, 24 mmol), 2 N aqueous sodium carbonate (88.0 mL), dioxane (88.0 mL), and toluene (296 mL) was purged with argon for 30 minutes before [1,1'-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 1.90 g, 2.30 mmol) was added. The reaction mixture was heated at 85 C. and stirred overnight. The layers were separated and the organic layer was washed with water (2×50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. This material was purified by flash chromatography (7 to 20% ethyl acetate/hexane) to give 1-(3-methyl-4'-nitro-1,1'-biphenyl-4-yl)ethanone as a light yellow solid (6.12 g, 99% yield). GC-MS m/z 255 (M+), ret. time 9.89 min; 1H NMR (CDCl3) delta: 2.61 (s, 3H), 2.62 (s, 3H), 7.49-55 (m, 2H), 7.78 (d, 2H), 7.81 (d, 1H), 8.32 (d, 2H).
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 80℃; for 3h;
(4-Nitrophenyl) boronic acid (1.2 equivalents), tetrakis (TRIPHENYLPHOSPHINE) palladium (0) (0.03 equivalent) and 2. 0M potassium phosphate solution (2.1 equivalents) are added to a solution under nitrogen of methyl 4-BROMOTHIOPHENE-2-CARBOXYLATE in 3.0 ml of degassed DME. The reaction medium is then stirred for 3 hours at 80oC, diluted with ethyl acetate (20 ml), washed with water (2X15 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. Chromatography of the residue on silica gel (98/2 dichloromethane/methanol) allows 1.94 g of the expected product to be isolated. Yield: 78% H NMR (CDC13) 5 (PPM) : 3.92 (s, 3H), 7.75 (d, 2H), 7.82 (s, 1H), 8.12 (s, 1H), 8.30 (d, 2H)
78%
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 3h;
To a solution of <strong>[62224-16-2]methyl 4-bromothiophen-2-carboxylate</strong> and 1.2 equivalents of (4-nitrophenyl) boronic acid in DME were added 2. [1] equivalents of a 2.0 M solution of potassium phosphate and 0.03 equivalent of tetrakis (triphenylphosphie) palladium (0). After stirring at [80XB0;C] for 3 hours the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, filtered over Celite, washed with water, dried over sodium sulfate, and then concentrated under vacuum. The residue was purified on a silica gel column using 9: [1] cyclohexane: ethyl acetate to yield 1.94 g (78%) of the desired compound.
With potassium carbonate;trans-benzyl(chloro)-bis(triphenylphosphine)palladium(II); In 1-methyl-pyrrolidin-2-one; at 110℃; for 48.0h;
2,5-BIS (TRIFLUOROMETHYL) BROMOBENZENE (0.59 G, 2.00 MMOL, 1.00 EQUIV. ), 4- nitrophenylbronic acid (0.334 g, 2. 00 mmol, 1.00 equiv. ), trans- benzyl (chloro) bis (TRIPHENYLPHOSPHINE) PALLADIUM (LL) (0.076 g, 0.10 mmol, 0.05 EQUIV.), K2CO3 1.38 g, 10.00 MMOL, 5.00 equiv. ) and 10 mL dry NMP were charged to a 25 mL round bottom flask. The mixture was thoroughly de- oxygenated by subjecting to vacuum/nitrogen cycle three times, and heated at 110 C for 2 days under nitrogen protection. Usual workup yielded crude product 4'-nitro-2, 5-bis-trifluoromethyl-biphenyl as brown viscous oil (0. 66 g, 1.97 mmol, 99%). H NMR (300 MHz, CDCl3), 6 (ppm): 8.32 (d, J = 8.7 Hz, 2H); 7. 82-8. 00 (m, 2H); 7.52-7. 61 (m, 3H).The crude product made in the last step was dissolved in 10 mL methylene chloride and 10 mL ethanol. Tin (II) CHLORIDE (2.28 g, 12.00 mmol, 6.00 equiv) was added, followed by addition of 1 mL water. After stirring at room temperature for 2 days, the mixture was neutralized with 2 N NAOH solution, and subjected to usual workup to yield crude product 4'-amino-2, 5-bis-trifluoromethyl- biphenyl (0.52 g, 1.70 mmol, 85% crude yield) as brown viscous oil.4'-Amino-2, 5-bis-trifluoromethyl-biphenyl (0.16 g, 0.50 mmol, 1.00 equiv) was dissolved in 10 mL methylene chloride. To the solution was added 2,3- DIFLUOROBENZOYL chloride (0. 088 g, 0.50 mmol, 1.00 equiv), and triethylamine (0.061 g, 0.60 mmol, 1.20 equiv). The mixture was stirred at room temperature for one hour, and loaded to column for flash chromatography. The title compound was isolated as light yellow solid (0.12 g, 0.27 mmol, 54%). 1H NMR (300 MHz, CDCI3), 6 (PPM) : 8. 39 (D, J= 10.5 Hz, 1H) ; 7.75-7. 95 (m, 6H); 7.63 (s, 1H); 7.26-7. 443 (m, 3H); ESMS CALCD. FOR C21H12F8NO (M + H) + : 446.0 ; Found: 446.0
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; toluene; for 3h;Heating / reflux;
To a solution of <strong>[185312-82-7]methyl 4-bromo-2-chlorobenzoate</strong> (0.40 g, 1.6 mmol) and 4- nitrophenylboronic acid (0.67 g, 4.0 mmol) in toluene (8 mL) was added Na2Ctheta3 (1.02 g, 9.62 mmol), l,r-bis(diphenylphosphino)ferrocenepalladium(?) chloride complex with dichloromethane (0.03 g, 0.03 mmol), 1,4-dioxane (4 mL), and water (4 mL). The mixture was heated at reflux for 3 h and then allowed to cool to rt. The mixture was diluted with EtOAc and water, and the organic layer was isolated, dried over MgSO4, and concentrated in vacuo. The material was purified by column chromatography (25% EtOAc in hexanes), yielding 0.275 g (59%) of the title compound. 1H NMR (400 MHz, CD2Cl2) delta 3.98 (s, 3H), 7.58 (d, 2H), 7.68-7.82 (m, 3H), 7.97 (d, IH), 8.33 (d, IH).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃;
Step A: 2-Bromopyridine (650 muL), 4-nitrophenylboronic acid (1.479 g) and palladium tetrakistriphenylphosphine (391.5 mg) were added to a mixture of 40 mL of dimethoxyethane and 10 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 95 C. overnight. The reaction mixture was then cooled to room temperature and diluted with water (200 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 1.40 g of 2-(4-nitrophenyl)pyridine.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 95℃;
2-Bromopyridine (650 uL), 4-nitrophenylboronic acid (1.479 g) and palladium tetrakistriphenylphosphine (391.5 mg) were added to a mixture of 40 mL of dimethoxyethane and 10 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 95 C overnight. The reaction mixture was then cooled to room temperature and diluted with water (~200 mL). The resulting precipitate was collected, washed with water and air-dried. The dried material was purified using silica gel chromatography to give 1.40 g of 2-(4-nitrophenyl)pyridine.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; toluene; for 3h;Heating / reflux;
To a solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (0.95 g, 3.9 mmol) and 4- nitrophenylboronic acid (1.29 g, 7.75 mmol) in toluene (10 mL) was added Na2CO3 (1.85 g, 17.4 mmol), l,r-bis(diphenylphospMno)ferrocenepalladium(IT) chloride complex with dichloromethane (0.06 g, 0.08 mmol), 1,4-dioxane (5 mL), and water (5 mL). The mixture was heated at reflux for 3 h and then allowed to cool to it. The mixture was diluted with EtOAc and water, and the organic layer was isolated, dried over MgSO4, and concentrated in vacuo. The material was purified by column chromatography (25% EtOAc in hexanes), yielding 0.675 g (61%) of the title compound. LC/MS m/z 287.9 (MH+); retention time 3.14 min.
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 2h;
To a mixture of <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (418 mg, 2.50 mmol), trifluoro- methanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh3)4 (433 mg, 0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of 1 ,4-dioxane was added 2.0 M aq Na2CO3 solution (3.13 mL, 6.25 mmol). The resulting mixture was stirred at 80 C for 2 h and then cooled to RT. Treated with 200 mL of EtOAc, the mixture was washed with H2O (2 x 30 mL), brine (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3 % EtOAc/hexane) gave 470 mg (85 %) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): delta 8.19 (d, 2H, J = 9.1 Hz), 7.48 (d, 2H, J - 9.1 Hz), 6.36 (m, IH), 3.39 (m, 2H), 2.91 (t, 2H, J = 5.7 Hz), 2.72 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for CnHi ,NO2S, 222.1 (M+H), found 222.3
85%
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 2h;
To a mixture of <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (418 mg, 2.50 mmol), trifluoro-methanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh3)4 (433 mg, 0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (3.13 mL, 6.25 mmol). The resulting mixture was stirred at 80 C. for 2 h and then cooled to RT. Treated with 200 mL of EtOAc, the mixture was washed with H2O (2×30 mL), brine (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% EtOAc/hexane) gave 470 mg (85%) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): delta 8.19 (d, 2H, J=9.1 Hz), 7.48 (d, 2H, J=9.1 Hz), 6.36 (m, 1H), 3.39 (m, 2H), 2.91 (t, 2H, J=5.7 Hz), 2.72 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C11H11NO2S, 222.1 (M+H), found 222.3.
85%
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 2h;
b) 4-(4-Nitro-phenyl)-3,6-dihydro-2H-thiopyran To a mixture of <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (418 mg, 2.50 mmol), trifluoro-methanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh3)4 (433 mg, 0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (3.13 mL, 6.25 mmol). The resulting mixture was stirred at 80 C. for 2 h and then cooled to RT. Treated with 200 mL of EtOAc, the mixture was washed with H2O (2*30 mL), brine (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% EtOAc/hexane) gave 470 mg (85%) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): delta 8.19 (d, 2H, J=9.1 Hz), 7.48 (d, 2H, J=9.1 Hz), 6.36 (m, 1H), 3.39 (m, 2H), 2.91 (t, 2H, J=5.7 Hz), 2.72 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C11H11NO2S, 222.1 (M+H). found 222.3.
85%
With sodium carbonate; lithium chloride;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 20 - 80℃; for 2h;
To a mixture of <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (418 mg, 2.50 mmol), trifluoro- methanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh3)4 (433 mg, 0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of 1 ,4-dioxane was added 2.0 M aqNa2CO3 solution (3.13 mL. 6.25 mmol). The resulting mixture was stirred at 80 C for 2 h and then cooled to RT. Treated with 200 mL of EtOAc, the mixture was washed with H2O (2 x 30 mL), brine (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3 % EtOAc/hexane) gave 470 mg (85 %) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): delta 8.19 (d, 2H, J = 9.1 Hz), 7.48 (d, 2H, J = 9.1 Hz), 6.36 (m, IH), 3.39 (m, 2H), 2.91 (t, 2H, J = 5.7 Hz), 2.72 (m, 2H). Mass spectrum (ESI5 m/z): Calcd. for CnHnNO2S, 222.1 (M+H), found 222.3.
With potassium carbonate;1,4-diaza-bicyclo[2.2.2]octane; palladium diacetate; In acetone; at 110℃; for 2h;Microwave reactor;
A solution of 4-nitrophenylboronic acid (0.5g, 3 mmol), ethyl 5-bromonicotinate (0.49 g, 2.1 mmol), K2CO3 (1.25 g, 9 mmol), Pd(OAc)2 (67 mg, 0.3 mmol) and diazabicyclooctane (67 mg, 0.6 mmol) in acetone (5 ml) was purged with Ar in a microwave reaction vessel. The mixture was heated at 110C for 2 h via a microwave reactor, cooled to room temperature and diluted with EtOAc and water. Insoluble material was removed by filtration and washed well with additional EtOAc. The EtOAc was separated and washed with brine. Drying and removal of solvent gave a residue that was purified by chromatography, 100% DCM with gradient elution to 5% MeOH in DCM. A solid was obtained and was recrystallized from ethanol to give 320 mg of product as a solid. M/z = 273; NMR: 1.37 (t, J=7.06 Hz, 3H), 4.34 - 4.45 (q, EPO <DP n="64"/>2H), 8.13 (d, J-8.85 Hz, 2H), 8.36 (d, J=8.67 Hz, 2H), 8.60 (t, J=2.07 Hz, IH), 9.17 (d, J=I.70 Hz, IH), 9.26 (d, J=2.26 Hz, IH).
bis(triphenylphosphine)palladium(II) dichloride[ No CAS ]
[ 213744-81-1 ]
[ 24067-17-2 ]
4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydrogencarbonate; In ethanol; cyclohexane; water; toluene;
c) A mixture of <strong>[213744-81-1]4-chloro-5-iodo-7-isopropylpyrrolo[2,3-d]pyrimidine</strong> (0.57 g), 4-nitrophenylboronic acid (0.30 g), bis(triphenylphosphine)palladium (II) chloride (0.126 g), toluene (15 ml), ethanol (2 ml), water (4 ml) and sodium bicarbonate (0.45 g) was heated under nitrogen at 105 C. for 8 hours. The mixture was cooled to ambient temperature and then partitioned between brine (50 ml) and ethyl acetate (50 ml). The aqueous layer was further extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, dried, filtered and evaporated to leave a solid which was purified by flash column chromatography on silica using cyclohexane with increasing amounts of ethyl acetate as the mobile phase to give 4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine.
With sodium hydrogencarbonate; In ethanol; cyclohexane; water; toluene;
c) A mixture of <strong>[213744-81-1]4-chloro-5-iodo-7-isopropylpyrrolo[2,3-d]pyrimidine</strong> (0.57 g), 4-nitrophenylboronic acid (0.30 g), bis(triphenylphosphine)palladium (II) chloride (0.126 g), toluene (15 ml), ethanol (2 ml), water (4 ml) and sodium bicarbonate (0.45 g) was heated under nitrogen at 105C for 8 hours. The mixture was cooled to ambient temperature and then partitioned between brine (50 ml) and ethyl acetate (50 ml). The aqueous layer was further extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, dried, filtered and evaporated to leave a solid which was purified by flash column chromatography on silica using cyclohexane with increasing amounts of ethyl acetate as the mobile phase to give 4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine.
With sodium carbonate;(bis(tricyclohexyl)phosphine)palladium(II) dichloride; In water; acetonitrile; at 150℃; for 0.0833333h;Irradiation;
A mixture of 1 ,1 -dimethylethyl (2S)-([4-chloro-2-([(2,4,6- trimethylphenyl)amino]carbonyl}amino)phenyl]carbonyl}amino)(cyclohexyl)ethanoat e (0.200 g, 0.38 mmol), <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (0.076 g, 0.45 mmol), trans- dichlorobis(tricyclohexylphosphine)palladium(ll) (0.014 g, 0.019 mmol) and 2M aqueous sodium carbonate (0.6 ml_) in 1.5 mL of acetonitrile was heated in a microwave reactor at 150C for 5 minutes. The cooled reaction mixture was diluted with water and ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography on silica gel with hexane/ethyl acetate to give 0.174 g of a yellow solid containing about 85% of desired product.; A mixture of 1 ,1-Dimethylethyl (2S)-([4-chloro-2-([(2,4,6- trimethylphenyl)amino]carbonyl}amino)phenyl]carbonyl}amino)(cyclohexyl)ethanoat e (0.200 g, 0.38 mmol), <strong>[24067-17-2]4-nitrophenylboronic acid</strong> (0.076 g, 0.45 mmol), trans- dichlorobis(tricyclohexylphosphine)palladium(ll) (0.014 g, 0.019 mmol) and 2M aqueous sodium carbonate (0.6 ml_) in 1.5 mL of acetonitrile was heated in a microwave reactor at 15OC for 5 minutes. The cooled reaction mixture was diluted with water and ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography on silica gel with hexane/ethyl acetate to give 0.170 g (73% yield) of desired product as a yellow solid.
With sodium carbonate;polymer-bound tetrakis palladium; In 1,2-dimethoxyethane; ethanol; at 20℃; for 12h;Inert atmosphere;
Example 13. l-(4-(4-amino-l-cyclopentyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3- (3-(trifluoromethyl)phenyl)urea (AD60); [0182] A synthetic strategy for Cmpd AD60 is depicted in Scheme 8 following. Scheme 8[0183] Reagent 3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine) (0.5g; 1.9 mmol; Apsel et al., 2008, Id.) was combined with cyclopentyl iodide (0.24 mL; 2.1 mmol), l .Og K2CO3, in 20 mL DMF and heated to 45 C under argon for 2 hours. The reaction was filtered to remove solid K2CO3, and the filtrate was combined with brine and the organic product was extracted in CH2Cl2 (3x 50 mL). The combined organic layer was concentrated in vacuo and purified by silica gel chromatography (MeOH/Chloroform; 5:95) to afford l-cyclopentyl-3- iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 330.0, calculated 330.0). 4-nitrophenyl boronic acid (190 mg, 1.1 mmol; Sigma-Aldrich), was coupled to 1- cyclopentyl-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-4-amine (150mg, 0.456 mmol) via the Suzuki reaction in 6 mL 1,2 methoxy ethane, 1 mL of saturated sodium carbonate, 1.65 mL EtOH, and 200 mg of polymer-bound tetrakis palladium. The reaction was stirred under argon for 12 hours at room temperature, filtered through Whatman paper to remove palladium, mixed with brine, extracted in chloroform and the product was subsequently purified on silica in EtOAc and concentrated in vacuo. The purified solid l~cyclopentyl-3-(4- nitrophenyl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 325.0, calculated 325.1 ; lOOmg, 0.31 mmol) was combined with Zinc dust (605 mg, 9.25 mmol), 10 mL THF, 0.35 mL HOAc for 12 hours at room temperature under Argon. The reaction was filtered through CeIi te, extracted with EtOAc and concentrated in vacuo to yield 3-(4- aminophenyl)-l -cyclopentyl- lH-pyrazolo [3, 4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 295.0, calculated 295.2). To this reduced product, molar equivalents of3-(trifluoromethyl)phenyl isocyanate (Sigma-Aldrich) were added dropwise in ice-cold CH2C12. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a Cl 8 column in CH3CN/H20/0.1%TFA (1-100% gradient) to yield AD60 l-(4-(4-amino-l -cyclopentyl- IH- pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3-(trifluoromethyl)phenyl)urea (ESI-MS m/z [M+H]+ found 482.2, calculated 482.0).
With sodium carbonate;polymer-bound tetrakis palladium; In 1,2-dimethoxyethane; ethanol; at 20℃; for 12.0h;Inert atmosphere;
Example 9. l-(4-(4-amino-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-3-(3- (trifluoromethyl)phenyl)urea (Cmpd 5); [0174] A synthetic strategy for Cmpd 5 is depicted in Scheme 5 following. Scheme 5[0175] With reference to Scheme 5, 4-nitrophenyl boronic acid (100 mg, 0.330 mmol; Sigma- Aldrich), was coupled to 3-iodo-l-isopropyl-lH-pyrazolo[3,4-d]pyrimidin-4-amine (140mg, 0.8248mmol; Apsel et al., 2008) via the Suzuki reaction in 6 mL 1,2 methoxy ethane, 1 mL of saturated sodium carbonate, 1.65 mL EtOH, and 200 mg of polymer-bound tetrakis Palladium. The reaction was stirred under argon for 12 hours at room temperature, filtered through Whatman paper to remove Palladium, mixed with brine, extracted in chloroform and the product was subsequently purified on silica in EtOAc and concentrated in vacuo. The purified solid l-isopropyl-3-(4-nitrophenyl)-lH-pyrazolo[3,4-
With palladium diacetate; sodium carbonate; triphenylphosphine; In 1,2-dimethoxyethane; water; for 16h;Inert atmosphere; Reflux;
General procedure: To a mixture of 5'-O-tert-butyldimethylsilyl-2',3'-O-isopropylidene-6-iodouridine30 (6, 0.2620 g, 0.50 mmol), arylboronic acid (1.2-4.0 equiv), triphenylphosphine (0.0262 g, 0.10 mmol, 0.2 equiv), and palladium(II) acetate (0.0112 g, 0.05 mmol, 0.1 equiv) in toluene (5 mL) was added 2 M aqueous sodium carbonate solution (0.75 mL, 1.50 mmol, 3 equiv) at room temperature. The reaction system was filled with argon then the reaction mixture was heated at reflux temperature for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure and the residue was partitioned between EtOAc and H2O. The organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to give the product.
With copper(I) sulfide; N,N,N,N,-tetramethylethylenediamine; In methanol; at 20℃; for 48h;
General procedure: A 10mL round bottom flask was charged with a magnetic stirring bar, benzimidazole 1 (59mg, 0.5mmol), boronic acid 2 (1.0mmol), Cu2S (4mg, 0.025mmol), and MeOH (2mL), followed with the addition of TMEDA (0.075mL, 0.5mmol). The flask was sealed with a septum, through which was inserted 18-gauche needle. This setup allowed air to go into the reaction and avoid contamination of a mixture. The reaction mixture was stirred from 400 to 600rpm for appropriate time and extracted with EtOAc (2×15mL). Combined organic layers were washed with saturated aqueous solution of ethylenediaminetetraacetic acid disodium salt (15mL), and then dried over anhydrous Na2SO4. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel, hexanes - EtOAc) to yield the title product, which was characterized by 1H NMR, 13C NMR, HRMS, and melting point (if solid).
75%
With 2-(4-methoxybenzylidene)-N-phenylhydrazinecarbothioamide; copper(II) acetate monohydrate; potassium carbonate; In ethanol; at 20℃; for 20h;
General procedure: A mixture of imidazole (1 mmol), phenylboronic acid (2 mmol), K2CO3 (2 mmol), Cu(CH3COO)2H2O (1 mol %, 1.99 mg) and L1 (1 mol %, 5.7 mg) in ethanol (5 mL) was stirred at room temperature in a 50 mL oven dried round bottomed flask. After the completion of the reaction (as monitored by TLC), conventional workup of the reaction mixture was done with ethyl acetate (3 × 15 mL) and water (10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the solvent was evaporated in a rotary evaporator under reduced pressure to get the crude product. The crude product was purified by column chromatography on silica gel (DCM: Methanol = 9:1) to afford the pure product.
72%
With copper(I) 3-metthylsalicylate; potassium carbonate; In methanol; at 65℃; for 3h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
63%
With [CuI2(3,2'-pypzpym)]; oxygen; In water; acetonitrile; at 60℃; under 760.051 Torr; for 24h;Green chemistry;
General procedure: To a solution of 1 (0.02 mmol) in H2O/MeCN (v/v=2/1, 4 mL) was added 1H-imidazole (1.0 mmol) and arylboronic acid (2 mmol)under O2 atmosphere. The mixture was stirred at 60 C for 24 h. After cooling to ambient temperature, the mixture was partitioned between water and CH2Cl2. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 80℃; for 6h;Inert atmosphere;
Step 1: l-(5-(4-nitrophenyl)pyridin-2-yl)ethanone 80C / 6 h To a stirred solution of l-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in toluene (4 mL) and ethanol (2 mL) was added (4-nitrophenyl)boronic acid (160 mg, 1 mmol), 2M Na2C03 (1.4 mL), and Pd(PPh3)4 (6 mg, 0.005 mmol), the reaction was purged with argon, and then heated at 80C for about 6 h. The reaction mixture was concentrated, diluted with water (50 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2S04 and concentrated under vacuum to obtain crude product. The crude product was purified by flash chromatography (silica gel, 60- 120?) using 10% ethyl acetate in hexane eluent to afford l-(5-(4-nitrophenyl)pyridin- 2-yl)ethanone as off white solid (105 mg, 86% yield). XH NMR (400 MHz, DMSO- d6): ? 9.14 (s, IH), 8.40-8.34 (m, 3H), 8.08 (dd, 3H), 2.67 (s, 3H), LC-MS m/z calcd for [M+H]+ 243.07, found 243.2.
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 120℃;Microwave irradiation;
Compound 296; N-hydroxy-7-(N-(4-(2-methyl-1H-indol-5-yl)phenyl)methylsulfonamido)heptanamide; As shown in reaction scheme 4,6-bromo-2-methyl-1H-indole and 4-nitrophenylboronic acid were subjected to the Suzuki reaction to obtain compound 2, which was then reduced with palladium/activated carbon to obtain compound 3. Then, compound 3 is allowed to react with ethyl 7-bromoheptanoate to obtain compound 4, which was then allowed to react with methanesulfonyl chloride to obtain a compound of formula V-1, after which the compound of formula V-1 (16 mg, 0.035 mmol) was stirred with hydroxylamine and potassium hydroxide for 30 minutes. Then, a 50percent water solution of hydroxylamine was added to the stirred solution until the undissolved solids were dissolved so that the solution became clear. Then, the reaction solution was stirred at mom temperature for 10 hours, and after the completion of the reaction has been confirmed, the reaction product was concentrated under reduced pressure to remove the solvent. The remaining material was extracted using ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized, thus obtaining compound 296 (12 mg, 77.3percent).1H NMR (400 MHz, CD3OD) delta 7.67 (d, J=1.9 Hz, 2H), 7.65 (s, 1H), 7.41 (d, J=6.6 Hz, 2H), 7.30 (d, J=3.5 Hz, 2H), 6.17 (s, 1H), 3.71 (t, J=6.7 Hz, 2H), 2.93 (s, 3H), 2.42 (s, 3H), 2.05 (t, J=7.3 Hz, 2H), 1.57 (m, 4H), 1.31 (m, 4H). MS (ESI) m/z 443 (M++H).
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 120℃;Microwave;
As shown in reaction scheme 4, 6-bromo-2-methyl-1H-indole and 4-nitrophenylboronic acid were subjected to the Suzuki reaction to obtain compound 2, which was then reduced with palladium/activated carbon to obtain compound 3. Then, compound 3 is allowed to react with ethyl 7-bromoheptanoate to obtain compound 4, which was then allowed to react with methanesulfonyl chloride to obtain a compound of formula V-1, after which the compound of formula V-1 (16 mg 0.035 mmol) was stirred with hydroxylamine and potassium hydroxide for 30 minutes. Then, a 50percent water solution of hydroxylamine was added to the stirred solution until the undissolved solids were dissolved so that the solution became clear. Then, the reaction solution was stirred at room temperature for 10 hours, and after the completion of the reaction has been confirmed, the reaction product was concentrated under reduced pressure to remove the solvent. The remaining material was extracted using ethyl acetate, washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized, thus obtaining compound 296 (12 mg, 77.3percent). 1H NMR (400 MHz, CD3OD) delta 7.67 (d, J = 1.9 Hz, 2H), 7.65 (s, 1H), 7.41 (d, J = 6.6 Hz, 2H), 7.30 (d, J = 3.5 Hz, 2H), 6.17 (s, 1H), 3.71 (t, J = 6.7 Hz, 2H), 2.93 (s, 3H), 2.42 (s, 3H), 2.05 (t, J = 7.3 Hz, 2H), 1.57 (m, 4H), 1.31 (m, 4H). MS (ESI) m/z 443 (M+ + H).
With caesium carbonate;palladium diacetate; triphenylphosphine; In N,N-dimethyl-formamide; at 80℃; for 24h;
To a solution of 2-chloropyridine (0.816 g, 7.19 mmol) in nitrogen degassed dry DMF(20 mL) was added 4-nitrophenylboronic acid (1.00 g, 5.99 mmol), Cs2C03 (7.19 g, 24.0 mmol), triphenylphosphine (0.236 g, 0.899 mmol) and Pd(OAc)2 (0.134 g, 0.599 mmol). The reaction mixture was heated at 80 C for 24 hours. The reaction was cooled to room temperature and concentrated to dryness in vacuo. The crude material absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) to give a pale yellow solid. This material (0.365 g) was dissolved in 1 HCI ( 1 .5 mL) and methanol (15 mL) and Pt02 (0.036 g) was added under an atmosphere of nitrogen. The reaction was then subjected to a 40 psi hydrogen atmosphere in a Parr hydrogenator for 24 hours, and then filtered through celite which was washed with EtOAc (3 10 mL) and water (3 0 mL). The combined filtrate was concentrated in vacuo to give the crude material (0.460 g) as a pale brown-pink oily solid. This material was dissolved in anhydrous methanol (20 mL) and treated with triethylamine (0.889 mL, 6.38 mmol) followed by Boc anhydride (0.418 g, 1 ,91 mmol). The reaction was stirred at room temperature for 20 hours, concentrated in vacuo and EtOAc (100 mL) and sat. aq. NaHC03 (50 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (70 mL), the organics were combined and washed with water (50 mL), brine (50 mL), dried (MgS0 ), filtered and concentrated in vacuo to give a yellow solid. The crude product was purified by silica gel chromatography (Biotage Isolera, 12 g Si cartridge, 0- 00% EtOAc in petroleum benzine 40-60 C), to give the title compound (136) (0.122 g, 8% yieid over 3 steps) as a white solid; 1H NMR (400 MHz, oyDMSO) delta 6.85 - 6.78 (m, 2H), 6.57 - 6.51 (m, 2H), 5.14 (d, J = 3.7 Hz, 1 H), 4.98 - 4.89 (m, 2H), 3.85 (d, J = 13.0 Hz, 1 H), 2.70 - 2.57 (m, 1 H), 2.19 (d, J = 13.9 Hz, 1 H), 1.73 - 1.61 (m, 1 H), 1 ,57 - 1.44 (m, 2H), 1.44 - 1.27 (m, 11 H). LCMS Method C: rt 4.94 min; m/z 177.3 [M-Boc+2H]+.
With palladium diacetate; caesium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 80℃; for 24h;Inert atmosphere;
To a solution of 2-chloropyridine (0.816 g, 7.19 mmol) in nitrogen degassed dry DMF (20 mL) was added 4-nitrophenyiboronic acid (1.00 g, 5.99 mmol), Cs2C03 (7.19 g, 24.0 mmol), triphenylphosphine (0.236 g, 0.899 mmol) and Pd(OAc)2 (0.134 g, 0.599 mmol). The reaction mixture was heated at 80 C for 24 hours. The reaction was cooled to room temperature and concentrated to dryness in vacuo. The crude material absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60 C) to give a pale yellow solid.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
General procedure: To a solution of 2,7-dibromonaphthalene (300 mg, 1.05 mmol) in1,4-dioxane (10 mL) were added 4-nitrophenylboronic acid (381 mg, 2.28 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol), and aq. Cs2CO3 (2 M, 2 mL), and the reaction mixture was stirred overnight at reflux under Ar. Then, the reaction mixture was diluted with water (30 mL), and the product was extracted with chloroform (100 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography [hexane/chloroform (2:1)] to give 2,7-bis(4-nitrophenyl)naphthalene 3a (326 mg, 0.879 mmol, 84%) as a yellow solid
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water;Inert atmosphere; Reflux;
To a solution of <strong>[58556-75-5]2,7-dibromonaphthalene</strong> (300 mg, 1.05 mmol) in1,4-dioxane (10 mL) were added 4-nitrophenylboronic acid (381 mg, 2.28 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol), and aq. Cs2CO3 (2 M, 2 mL), and the reaction mixture was stirred overnight at reflux under Ar. Then, the reaction mixture was diluted with water (30 mL), and the product was extracted with chloroform (100 mL × 3). The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography [hexane/chloroform (2:1)] to give 2,7-bis(4-nitrophenyl)naphthalene 3a (326 mg, 0.879 mmol, 84%) as a yellow solid.
With oxygen; sodium hydroxide; copper dichloride; In methanol; for 30h;Reflux;
General procedure: A mixture of 1.6 mmol of C-nitro-NH-azole (1a-e), 2.6 mmol of arylboronic acid (2a-n), 1.6 mmol of sodium hydroxide, 0.2 mmol of CuCl2 and methanol (15 mL) was refluxed while air was bubbled through the reaction mixture. After completion of the reaction, determined on the basis of TLC analysis, the solvent was removed under reduced pressure using a rotary evaporator. The obtained crude product was purified by silica gel column chromatography with 5:95 v/v MeOH/CHCl3 as an eluent to give corresponding N-aryl-C-nitroazole. The product was crystallized from methanol/water.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 0.0833333h;Microwave irradiation; Inert atmosphere;
General procedure: 4-Iodo-1-methyl-1H-pyrazole 1 (101 mg, 0.5 mmol) and phenylboronic 2 (59 mg, 0.5 mmol) were dissolved in DME (3 mL) and H2O (1.2 mL) in a microwave vial under a nitrogen atmosphere. Pd(PPh3)4 (2 mmol%, 11.6 mg) and Cs2CO3 (407.3 mg, 1.25 mmol) were added, and the reaction mixture was irradiated in a microwave apparatus at 90 C for 5-12 min. After the reaction mixture was cooled to ambient temperature, the product was concentrated, and the crude mixture was purified by silica gel column chromatography using petroleum ether/acetone as eluent to give the title compound.
ethyl 2-(3-(4-nitrophenyl)oxetan-3-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium hydroxide; In 1,4-dioxane; water; for 18h;
Potassium hydroxide solution (1.5 M, 38.9 mL) was added to a solution of cyclooctadiene rhodium chloride dimer (2.33 mmol) in dry dioxane and stirred for 1 minute, followed by the addition of 4-nitrophenyl boronic acid (117 mmol) and <strong>[922500-91-2]ethyl 2-(oxetan-3-ylidene)acetate</strong> (Intermediate 1, 58.5 mmol). The entire reaction mixture was stirred for 18 hours. Reaction mixture was partitioned between ether and brine. The organic layer was concentrated and purified (silica gel column, EtOAc/ petroleum ether as eluent) to obtain the title compound. Yield: 90%; JH NMR (300 MHz, CDCI3): delta 8.25-8.22 (d, J=8.7 Hz, 2H), 7.41-7.38 (d, J=8.7Hz, 2H), 5.03-5.01 (d, J = 6.0 Hz 2H), 4.92-4.90 (d, J =6.0 Hz, 2H), 4.05-4.00 (q, 2H), 3.21 (s, 2H), 1.18- 1.13 (t, 3H).
tert-butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-nitrophenyl)azetidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; potassium carbonate; In tetrahydrofuran; 1,4-dioxane; water; at 100℃; for 0.0833333h;Microwave irradiation;
Aqueous K2CO3 solution (1.5 M, 62.2 mmol) was added to a solution of cyclooctadiene rhodium chloride dimer (1.03 mmol) in 1,4-dioxane (20 mL) and stirred for 5 minutes, followed by the addition of (4-nitrophenyl)boronic acid (20.72 mmol) and teri-butyl 3-(2- ethoxy-2-oxoethylidene)azetidine-l-carboxylate (Intermediate 8, 62.2 mmol) in THF (10 mL) successively. The reaction mixture was irradiated with microwave (300 W) at 100 C for 5 minutes, then diluted with water and extracted using EtOAc. The organic layer was dried over sodium sulfate, filtered, concentrated and purified (silica gel column, EtOAc/ petroleum ether) to obtain the title compound. Yield: 26%; JH NMR (300 MHz, CDCI3): delta 7.42-7.32 (m, 4H), 4.29-4.22 (m, 4H), 4.05-4.01 (q, J=8.7 Hz, 2H), 3.05 (s, 2H), 1.59 (s, 9H), 1.17-1.14 (t, J=9 Hz, 3H); MS: 387 (M+Na).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 110℃; for 12h;
General procedure: [1,1?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42mg, 0.05mmol) and patassium carbonate solution (2M, 100muL) were added to a solution of bromide 23a (187mg, 1.00mmol) and 4-nitrophenylboronic acid (249mg, 1.50mmol) in dioxane (5mL). The mixture was refluxed at 110C for 12h before concentrated to dryness. The resulted brown residue was purified via column chromatography (SiO2, 100:1, CH2Cl2: acetone) to afford desired product as a yellow amorphous solid (134mg, 59%). Compound 24a was prepared following the general procedure B to afford a yellow amorphous solid (134mg, 59%).
44%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 110℃; for 12h;Reflux;
2-methoxy-4'-nitro-[1,1'-biphenyl]-4-ol (24f): [1,1?-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.05 mmol) and potassium carbonate solution (2M, 100 muL) were added to a solution of bromide (23f, 1.00 mmol) and 4-nitrophenylboronic acid (1.50 mmol) in dioxane (5 mL). The mixture was refluxed at 110 oC for 12 hours before concentrated to dryness. The resulted brown residue was purified via column chromatography (SiO2, 100:1, CH2Cl2:acetone) to afford desired product as a yellow amorphous solid (44%). 1H NMR (500 MHz, chloroform-d) delta 8.23 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.2 Hz, 1H), 6.62- 6.45 (m, 2H), 4.96 (s, 1H, OH), 3.82 (s, 3H). 13C NMR (126 MHz, CDCl3) delta 157.18, 156.88, 145.60, 144.69, 130.92, 129.41, 122.65, 120.40, 107.07, 98.88, 55.01. HRMS (ESI+) m/z: [M + H+] calcd for C13H12NO4: 246.0766; found 246.0769.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 110℃; for 12h;Reflux;
2-chloro-4'-nitro-[1,1'-biphenyl]-4-ol (24d): [1,1?-Bis(diphenylphosphino)ferrocene] dichloropalladium(II) (0.05 mmol) and potassium carbonate solution (2M, 100 muL) were added to a solution of bromide (23d, 1.00 mmol) and 4-nitrophenylboronic acid (1.50 mmol) in dioxane (5 mL). The mixture was refluxed at 110 oC for 12 hours before concentrated to dryness. The resulted brown residue was purified via column chromatography (SiO2, 100:1, CH2Cl2:acetone) to afford desired product as a yellow amorphous solid (74%). 1H NMR (500 MHz, chloroform-d) delta 8.25- 8.14 (m, 2H), 7.58- 7.43 (m, 2H), 7.11 (dt, J = 8.4, 1.8 Hz, 1H), 6.92 (t, J = 2.4 Hz, 1H), 6.80- 6.71 (m, 1H). 13C NMR (126 MHz, CDCl3) delta 158.21, 146.82, 146.34, 132.64, 131.88, 130.64, 129.48, 123.32, 117.12, 114.74. HRMS (ESI-) m/z [M+K]+ calcd for C12H8ClNO3 288.0214, found 288.2896
44%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 110℃; for 12h;
General procedure: [1,1?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42mg, 0.05mmol) and patassium carbonate solution (2M, 100muL) were added to a solution of bromide 23a (187mg, 1.00mmol) and 4-nitrophenylboronic acid (249mg, 1.50mmol) in dioxane (5mL). The mixture was refluxed at 110C for 12h before concentrated to dryness. The resulted brown residue was purified via column chromatography (SiO2, 100:1, CH2Cl2: acetone) to afford desired product as a yellow amorphous solid (134mg, 59%). Compound 24a was prepared following the general procedure B to afford a yellow amorphous solid (134mg, 59%).
With dipotassium peroxodisulfate; silver nitrate; trifluoroacetic acid; In dichloromethane; water; at 20℃; for 27h;Inert atmosphere;
To a solution of pyridine (323 muL, 4.0 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (308 muL, 4.0 mmol) followed by 4-nitrophenylboronic acid (51) (2.0 g, 12.0 mmol). Water (12 mL) was then added, followed by silver(I) nitrate (0.14 g, 0.8 mmol) in water (8 mL). Potassium persulfate (3.2 g, 12.0 mmol) was then added and the solution was stirred vigorously at room temperature and monitored by thin-layer chromatography analysis of the organic layer. After 3 hours, a second addition of solid silver(I) nitrate (0.14 g, 0.8 mmol) and potassium persulfate (3.2 g, 12.0 mmol) was added. After stirring for 24 h, the reaction was diluted with dichloromethane (70 mL) and washed with aqueous sodium hyrdoxide (2 M; 50 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL), the organic extracts were combined, dried (MgSO4), filtered, and evaporatedin vacuo. Purification by flash chromatography on silica eluting with hexane-ethyl acetate (1:1) gave compound52(0.22 g, 27%) as a yellow solid; mp 131-133 C (lit mp 131-132 C);numax/cm-11583, 1516, 1435, 1347, 856;deltaH(500 MHz, CDCl3) 8.75 (1 H, d,J4.5 Hz), 8.32 (2 H, d,J8.5 Hz), 8.18 (2 H, d,J8.5 Hz), 7.84-7.81 (2 H, m), 7.34 (1 H, m);deltaC(125 MHz, CDCl3) 155.0, 150.3, 148.3, 145.4, 137.3, 127.8, 124.3, 123.7, 121.4;m/z(ESI) 154 ([M - NO2]+, 100).4-(Pyridin-2-yl)aniline (53)[64,65]
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 1h;Microwave irradiation; Inert atmosphere;
<strong>[57876-69-4]2-chloro-3-methylquinoline</strong> (1 .00 g, 5.65 mmol), (4-nitrophenyl)boronic acid (1 .20 g, 7.22 mmol), and Pd(PPh3)2C12 catalyst (19.7 mg) was added to DME (16 mL)in a microwave vial. 2M aqueous potassium carbonate was added (4 mL) added, vial capped and then mix degassed with nitrogen before being irradiated in the microwave at 120C for 1 hour. The reaction mixture was partitioned between ethyl acetate and sat. aqueous sodium bicarbonate solution. Organic phase was washed with water, dried (Mg504) and concentrated to give a light tan solid, which was purified by flash chromatography on silica gel (40g), eluting with a gradient of 20-50% EtOAc in hexane to give a light-cream solid (1.32 g, 88%).
With copper(I) 3-metthylsalicylate; potassium carbonate; In methanol; at 65℃; for 3h;
General procedure: A dry flask was charged with the nitrogen containing heterocycles (1 mmol), aryl boronic acids (2.2 mmol), potassium carbonate (2 mmol) andCuMeSal (0.015 mmol)then anhydrous methanol (10 ml) was added. The reaction mixture was stirred at 65 oC, open to air, for 3 h (5 h in case of indole and benzimidazole), cooled to room temperature, filtered, and the precipitate was washed with methanol (2 ml), the filtrate was concentrated under vacuum, then stirred with ice water (30 ml) and extracted with ethyl acetate (3 × 50 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography or recrystallization as indicated with each compound.
6-(4-nitrophenyl)-3,4-dihydronaphthalen-2(1H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; for 4h;Inert atmosphere; Reflux;
6-(4-nitrophenyl)-3,4-dihydronaphthalen-2(1 H)-one (40A) j0469] Pd(PPh3)4 (0.0736 g, 0.06 mmol) was added to a solution of <strong>[4133-35-1]6-bromo-2-tetralone</strong> (1.5 g, 6.66 mmol) in SOmE of 1,4 dioxane-H20 (3:1) mixture under argon atmosphere, followed by cesium carbonate (6.49 g, 19.99 mmol) and 4-nitrophenyl boronic acid (1.32 g, 7.99 mmol). The reaction mixture was degassed for 5 mm. The reaction mixture was refluxed for 4 h and solvent removed under reduced pressure. The residue partitioned between ethyl acetate and watet The separated organic layer was dried over sodium sulphate, filtered and removed under reduced pressure. The product was purified by flash chromatography using 18% ethyl acetate in hexane to afford title compound (0.9 g, 50%) as solid. ?H NMR (300 MHz, CDC13): oe 8.31 (d, J=9.0 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.5 (m, 2H), 7.27 (s, 1H), 3.66 (s, 2H), 3.16 (t, J=6.9 Hz, 2H), 2.61 (t, J=6.9 Hz, 2H).
With copper(l) iodide; sulfur; sodium t-butanolate; at 60 - 80℃; for 10h;
General procedure: A one-necked flask was charged with CuI (30 mg, 0.15 mmol), NaOt-Bu (376 mg, 4.0 mmol), S8 (47 mg, 1.5 mmol), phenolic ester (1 mmol), arylboronic acid (1.1 mmol), and PEG200 (2 mL). The mixture was magnetically stirred and heated at 60-80 C for the appropriate reaction time (Table 2). After completion of the reaction, the reaction mixture was cooled to r.t. H2O (4 mL) was added and the product was extracted with EtOAc (3 × 4 mL) and dried (anhyd Na2SO4). Evaporation of the solvent and purification by column chromatography on silicagel (n-hexane/EtOAc) gave the desired unsymmetrical diaryl sulfides in 74-95% yields.
With copper diacetate; ethylenediamine; sodium t-butanolate; In toluene; at 100℃; for 6.0h;
General procedure: CuI (10mol%) and EDA (10mol%) were added to a mixtureof O-alkyl carbamate (1mmol), NaOtBu (1.5mmol) and aryl halide (1mmol) in 2mL toluene and the mixture wasstirred for the appropriate time, which was determined byTLC monitoring, at 100C. After completion of the reaction,the catalyst was removed by filtration and 20mL H2Owas added to the filtrate. The resultant mixture was extractedwith CHCl3.Then the organic phase was washed with water(2 × 10mL) and dried over anhydrous Na2SO4.After evaporationof CHCl3under reduced pressure, the correspondingcrude product was purified by flash chromatography to givethe desired pure cross-coupling product in good to excellentyield. In the case of using arylboronic acids as couplingpartners, Cu(OAc)2 was employed instead of CuI.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In methanol; water; toluene;Inert atmosphere;
General procedure: <strong>[405224-23-9]5-bromo-2-chloronicotinonitrile</strong> (5, 2.16 g, 10 mmol), aromatic boronic acid (10 mmol), (PPh3)2PdCl2 (175 mg, 0.25 mmol), Na2CO3 (2.12 g, 20 mmol) were dissolved in a mixed solvent (22 mL, toluene: ethanol: water = 10: 10: 2). Nitrogen gas was bubbled through the reaction mixture for 5 min, and then the mixture was heated to 60C under inert atmosphere for 6 h. The mixture was filtered and the filtrate was concentrated under vacuum. The crude product was extracted with ethyl acetate and the organic layer was concentrated, then the solid was washed with ethyl acetate and petroleum ether to give compounds 6.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃;Inert atmosphere;
To a mixture of <strong>[767-68-0]4-bromo-benzothiazole</strong> (500 mg, 2.3 mmol), 4- nitrophenylboronic acid (576 mg, 3.45 mmol) and K2C03 (952.2 mg, 6.9 mmol) in dioxane/H20 (20 mL/1 0 mL) was added Pd(PPh3)4 (132 mg, 0.115 mmol). The mixture was stirred at 95 C under N2 overnight. The mixture was concentrated. The residue was purified with flash to give 4-(4-nitro- phenyl)-benzothiazole (288 mg, yield 49%) as a yellow solid. ?H NIVIR (300 MHz, DMSO-d6): oe = 9.51 (s, 1H), 8.38-8.30 (m, 3H), 8.17 (d, J= 8.7 Hz, 2H), 7.79 (d, J= 7.5 Hz, 1H), 7.651 (t, J=7.5Hz, 1H). MS: m/z 257.0 (M+H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃;
To a solution of <strong>[858629-06-8]5-fluoro-3-iodo-1H-indazole</strong> (2.0 g, 7.6 mmol) in dioxane (40 mL) and H20 (10 mL) was added 4-nitrophenylboronic acid (1.89 g, 11.4 mmol) and K2C03 (2.09 g, 15.2 mmol), Pd(dppf)C12 (555.56 mg, 0.76 mmol), the mixture was stirred at 80 C overnight. The reaction was monitored by TLC. After completion, the mixture was filtered, the filtrate was concentrated in vacuum to give a residue, which was purified by a silica gel column (PE/EA = 3/1) to afford 5-fluoro-3-(4-nitro-phenyl)-1H-indazole (1.87 g, yield: 95.4%) as a yellow solid. ?HNIVIR (400 IVIHz, DMSO-d6): oe = 14.06 (s, 1H), 8.41-8.28 (m, 4H), 7.99 (dd,J 7.2, 2.0 Hz, 1H), 7.73 (dd, J 4.4, 4.8 Hz, 1H), 7.41-7.33 (m, 1H)
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; water; toluene; at 80℃; for 12h;Inert atmosphere;
A mixture of 4-nitrophenyl)boronic acid (23.00 g, 137.78 mmol, 1.00 eq.), 2-bromothiazole (25.54 g, 155.69 mmol, 14.03 mL, 1.13 eq.), Na2C03 (36.51 g, 344.45 mmol, 2.50 eq.) and Pd(dppf)Cl2.CH2Cl2 (6.75 g, 8.27 mmol, 0.06 eq.) in Tol. (250.00 mL)/H20 (100.00 mL)/dioxane (250.00 mL) was degassed and purged with N2 for 3 times. The mixture was stirred at 80C for 12 hrs under N2 atmosphere and LCMS showed the reaction was complete. The mixture was concentrated and the residue was purified by column chromatography (Petroleum ethenEthyl acetate=50: l to 5: 1) to give 2-(4-nitrophenyl)thiazole (14.00 g, 67.89 mmol, 56.00% yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) delta = 8.35 - 8.29 (m, 2H), 8.21 - 8.12 (m, 2H), 7.99 (d, J = 3.2 Hz, 1H), 7.50 (d, J = 3.2 Hz, 1H).
General procedure: In a oven-dried flask and under nitrogen flow, benzenediazonium o-benzenedisulfonimide (1a, 161mg, 0.5mmol) was added to a suspension of 4-methoxyphenylboronic acid (3a, 91mg, 0.6mmol), [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold(I) (2:1) toluene adduct (39mg, 0.025mmol, 5mol%), Cs2CO3 (325mg, 1mmol) in THF (5mL). The resulting mixture was stirred at room temperature for 2h; the completion of the reaction was confirmed by the absence of azo coupling with 2-naphthol. Then, the reaction mixture was poured into diethyl ether/water (100mL, 1:1). The aqueous layer was separated and extracted with diethyl ether (50mL). The combined organic extracts were washed with water (50mL), dried with Na2SO4 and evaporated under reduced pressure. GC-MS analyses of the crude residue showed 4-methoxybiphenyl (4a), MS (EI): m/z 184 (M+) as the major product, besides traces of biphenyl, MS (EI): m/z 154 (M+), 4,4'-dimethoxybiphenyl, MS (EI): m/z 214 (M+), N-phenyl-o-benzenedisulfonimide, MS (EI): m/z 295 (M+). The crude residue was purified on a short column, eluting with petroleum ether/diethyl ether (9:1). The only isolated product was the title compound (4a, 81mg, 88% yield).
With palladium diacetate; potassium carbonate; triphenylphosphine; In water; N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; Microwave irradiation; Sealed tube;
<strong>[16870-28-3]2-hydroxy-4-iodobenzoic acid</strong> (50 mg, 0.189 mmol), 4-nitrobenzeneboronic acid (38 mg, 0.227 mmol), PPh3 (7.4 mg, 0.028 mmol), K2CO3 (91.4 mg, 0.662 mmol), Pd(AcO)2 (2.12 mg, 0.0095 mmol), 1:1 DMF: H2O (2 ml) were used. In this case, prior to chromatographic purification, the residue from evaporating the filtrate was resuspended in acetonitrile. The precipitate was separated from the liquid phase and the latter was discarded. The solid was then purified by flash chromatography (elution with AcOEt: CH3CN:H2O:CH3OH 70:10:5:5 mixture). Compound 101 was obtained as a yellowish solid. Yield after purification: 69.5 % (34 mg). 1H NMR (500 MHz, methanol-d4) delta 8.31 (d, J = 8.9 Hz, 2H), 7.96 (d, J = 7.94 Hz, 1H), 7.87 (d, J = 8.9 Hz, 2H), 7.17-7.13 (m, 2H). 13C NMR (126 MHz, methanol-d4) delta 175.2 (CO), 163.1 (C), 148.7 (C), 148.2 (C), 144.5 (C), 132.4 (CH), 129.1 (2CH), 124.9 (2CH), 119.5 (C), 118.1 (CH), 116.1 (CH). HRMS (TOF, ES-): Calculated for C13HsNO5: (M-H)-: m/z 258.0402. 258.0411 found (deviation 3.5 ppm). m.p. (C) > 300
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