* 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] Organic Letters, 2018, vol. 20, # 8, p. 2273 - 2277
[2] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 19, p. 2681 - 2683
[3] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2481 - 2486
3
[ 1679-18-1 ]
[ 67-68-5 ]
[ 16687-61-9 ]
Reference：
[1] Journal of Organic Chemistry, 2017, vol. 82, # 2, p. 887 - 892
4
[ 1679-18-1 ]
[ 6011-14-9 ]
[ 140-53-4 ]
Reference：
[1] Angewandte Chemie - International Edition, 2014, vol. 53, # 39, p. 10510 - 10514[2] Angew. Chem., 2014, vol. 126, # 39, p. 10678 - 10682,5
5
[ 464192-28-7 ]
[ 1679-18-1 ]
[ 721920-84-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7216 - 7221
6
[ 1679-18-1 ]
[ 26905-02-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 10, p. 1731 - 1735
7
[ 1298131-29-9 ]
[ 1679-18-1 ]
[ 20026-96-4 ]
[ 1298131-49-3 ]
Reference：
[1] Chemical Communications, 2011, vol. 47, # 14, p. 4282 - 4284
8
[ 108-43-0 ]
[ 1679-18-1 ]
[ 6842-62-2 ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper diacetate; triethylamine In dichloromethane at 0℃; for 6 h; Molecular sieve
General procedure: To a solution ofphenol (1a-j) (1.0 mmol) and phenylboronicacid (2-5) (2mmol) in dry CH2Cl2 (5 ml) were added powdered activated4 Å molecular sieves (1.0 g), catalyst Cu(OAc)2 (1.0 mmol)and Et3N (5 mmol). The mixture was cooled to 0 °C and stirred for 6hours under air atmosphere. The reaction was quenched with an excess of n-hexane and precipitated catalyst andmolecular sieves were separated by filtration. The filtrate was evaporatedunder vacuum and the residue was purified by flash chromatography to affordpure product (6a-p).
Reference：
[1] Advanced Synthesis and Catalysis, 2009, vol. 351, # 10, p. 1567 - 1574
10
[ 1679-18-1 ]
[ 583-53-9 ]
[ 21711-56-8 ]
Yield
Reaction Conditions
Operation in experiment
19.5 g
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene at 100℃; for 5 h; Inert atmosphere
Under a nitrogen stream1,2-dibromobenzene (20.0 g, 84.78 mmol),4-chlorophenyl boronic acid (30.49 g, 194.99 mmol), Pd (PPh3) 4 (4.89 g, 4.24 mmol) and K2CO3 (28.10 g, 203.33 mmol) were mixed with 150 ml of toluene, 150 ml of H2O and 150 ml of ethanol And the mixture was stirred at 100 degree For 5 hours. After completion of the reaction, the mixture was extracted with methylene chloride, concentrated under reduced pressure, and 19.5 g of a-1 was obtained by column chromatography.
19.5 g
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); DavePhos In ethanol; water; toluene at 100℃; for 5 h; Inert atmosphere
Under a stream of nitrogen 1,2dibromobenzene(20.0 g, 84.78 mmol), 4chlorophenylboronic acid (30.49 g, 194.99 mmol),Pd (PPh3) 4 (4.89 g, 4.24 mmol), K2CO3 (28.10 g, 203.33 mmol) in a 150 ml Toluene, 150ml of H2O, the solvent put into a150ml of ethanol are mixed and stirred at 100 ° C for 5 hours. After completion of the reaction, and extracted with methylenechloride and concentrated under reduced pressure to give the a-1 19.5 g purified by column chromatography
Reference：
[1] Patent: KR2015/103949, 2015, A, . Location in patent: Paragraph 0055-0057
[2] Patent: KR2016/104607, 2016, A, . Location in patent: Paragraph 0055-0057
11
[ 589-87-7 ]
[ 1679-18-1 ]
[ 23055-77-8 ]
Reference：
[1] Catalysis Communications, 2015, vol. 69, p. 11 - 15
[2] Patent: WO2006/120859, 2006, A1, . Location in patent: Page/Page column 44; 54
[3] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2744 - 2748
12
[ 1679-18-1 ]
[ 14752-66-0 ]
Reference：
[1] Chemical Communications, 2016, vol. 52, # 14, p. 2980 - 2983
13
[ 583-55-1 ]
[ 1679-18-1 ]
[ 179526-95-5 ]
Yield
Reaction Conditions
Operation in experiment
90%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water for 4 h; Heating
To a solution of 1-bromo-2-iodobenzene (30 g, 106 mmol) and (4-chlorophenyl) boronic acid (16.9 g, 108.6 mmol) in dioxaneAfter the addition, a 2M potassium carbonate aqueous solution (100 ml) was added, and tetrakis triphenylphosphinopalladium (2.45 g, 2 molpercent) was addedAnd the mixture was heated and stirred for 4 hours. After the temperature was lowered to room temperature and the reaction was terminated, a potassium carbonate solutionAnd then layer separation was performed. After removal of the solvent, the product was subjected to column chromatography with hexane to obtain Compound A1, a white solid (25.3 g, 90percent)
Reference：
[1] Patent: KR2017/41159, 2017, A, . Location in patent: Paragraph 0274-0276
[2] Organic Letters, 2015, vol. 17, # 2, p. 386 - 389
[3] Organic Letters, 2013, vol. 15, # 24, p. 6186 - 6189
[4] Advanced Synthesis and Catalysis, 2018, vol. 360, # 16, p. 3049 - 3054
[5] Chemical Communications, 2014, vol. 50, # 17, p. 2193 - 2195
[6] Chemical Communications, 2014, vol. 50, # 36, p. 4686 - 4689
[7] Beilstein Journal of Organic Chemistry, 2014, vol. 10, p. 1220 - 1227
[8] Angewandte Chemie - International Edition, 2016, vol. 55, # 21, p. 6319 - 6323[9] Angew. Chem., 2016, vol. 128, # 21, p. 6427 - 6431,5
[10] Angewandte Chemie - International Edition, 2017, vol. 56, # 4, p. 1125 - 1129[11] Angew. Chem., 2017, vol. 129, p. 1145 - 1149,5
14
[ 1679-18-1 ]
[ 583-53-9 ]
[ 179526-95-5 ]
Yield
Reaction Conditions
Operation in experiment
71%
With sodium carbonate In water; tolueneInert atmosphere; Reflux
Sodium carbonate (19.8 g, 186.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.90 mmol) were added to a solution of 1,2-dibromobenzene (12.8 ml, 105.98 mmol) and 4-chlorophenylboronic acid (14.1 g, 90.08 mmol) in toluene (170 ml) and water (80 ml). The mixture was purged with nitrogen and heated at reflux overnight. The reaction mixture was allowed to cool to room temperature, and partitioned between saturated aq. NH4Cl and ethyl acetate (500 ml). The organic layer was dried over MgSO4, filtered and the volatiles were evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO, 330 g silica gel column, eluting with 100percent hexanes) to give the title product (17.0 g, yield: 71percent).1H NMR (400 MHz, DMSO-d6) δ ppm 7.34 (td, 1H) 7.37-7.45 (m, 3H) 7.45-7.50 (m, 1H) 7.50-7.56 (m, 2H) 7.75 (d, 1H).GC-MS: 268 [M]
Reference：
[1] Patent: US2012/35134, 2012, A1, . Location in patent: Page/Page column 7; 34
[2] Patent: US5739166, 1998, A,
15
[ 31928-44-6 ]
[ 1679-18-1 ]
[ 179526-95-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2015, vol. 54, # 35, p. 10276 - 10279[2] Angew. Chem., 2015, vol. 127, # 35, p. 10414 - 10418,5
Stage #1: at 40℃; for 2 h; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran; 1,4-dioxane; hexane; water at 40℃; for 2 h;
To a 10 mL reaction tube equipped with a magnet was added 0.4 mg (0.8 mmol) of 4-chlorophenylboronic acid, 0.4 mL (0.8 mmol) of trimethylsilyl diazomethane (2 M n-hexane solution), 1 mL of toluene was added to the system, The stopper was stoppered and reacted on an electromagnetic heating stirrer at 40 ° C for 2 hours.Followed by addition of 71 mg (0.6 mmol) of pinacol (dissolved in 1 mL of 1,4-dioxane), 0.3 mL of tetrabutylammonium fluoride (1 M tetrahydrofuran solution) and 200 uL of water at 40 ° C, To continue for 2 hours.After completion of the reaction, the organic solvent was removed by a rotary evaporator and purified by column chromatography4-chlorobenzyl boronic acid pinacol ester, its structure is as follows:The compound was a colorless liquid in a yield of 85percent with the following NMR data:
Reference：
[1] Patent: CN105884808, 2016, A, . Location in patent: Paragraph 0076; 0077; 0078; 0079; 0080; 0081
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In Dimethyl ether; waterReflux
General procedure: Procedure: 5-bromo-1 H-pyrrolo[2,3-b]pyridine (2 g, 10.2 mmol, 1.0 eq.) , K2C03(2.8 g, 20.3 mmol, 2 eq.) and (4-chlorphenyl)boronic acid (1.8 g, 1 1.2 mmol, 1.1 eq.) was suspended in DME/H20 (30 ml, 4:1 ) and degassed with argon. Pd(PPh3)4(587 mg,508 μηηοΙ, 0.05 eq.) was added and the reaction mixture was heated under reflux until complete consumption of the starting material. The resulting solution was passed through a Celite pad, diluted with EtOAc and washed with water. The combined organic layers were dried over Na2S04and the solvent was evaporated under reduced pressure. The crude product was purified via flash chromatography (Si02, nHex/EtOAc 6:4).Yield: 2.23 g, 9.4 mmol, 92percent (white solid).TLC: PE/EtOAc 1 :11H NMR (DMSO-de,200 MHz, ppm): δ 1 1.76 (s, 1 H), 8.51 (d, J = 2.1 Hz, 1 H), 8.20 (d, J = 1 .9 Hz, 1 H), 7.72 (d, J = 8.5 Hz, 2H), 7.57 - 7.43 (m, 3H), 6.50 (dd, J = 3.2, 1.7 Hz, 1 H).;13C NMR (DMSO-d6, 50 Hz, ppm): δ 148.2, 141 .4, 138.0, 131.7, 128.9, 128.6, 127.1 , 126.9, 126.1 , 1 19.7, 100.2.
76%
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In 1,2-dimethoxyethane at 130℃; for 0.5 h; Inert atmosphere; Microwave irradiation
5-Bromo-7-azaindole (6e) (1.0 g, 5.0 mmol) and (4-chlorophenyl)boronic acid (6f) (954 mg, 6.2 mmol) were dissolved in 1,2-dimethoxyethane (28 mL). A solution of potassium carbonate (844 mg, 6.2 mmol) in water (8.0 mL) was then added. The resulting mixture was purged with argon for 5 min, followed by addition of bis(triphenylphosphine)dichloropalladium(II) (356 mg, 0.5 mmol). The reaction mixture was then reacted at 130 °C for 30 min under microwave irradiation. The volatiles were then removed under reduced pressure and the crude residue diluted with water (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layer was dried over sodium sulphate, filtered, and the resulting filtrate evaporated in vacuo to give a crude solid that was purified using flash column chromatography to afford compound 6b (875 mg, 76percent) as a light-brown crystalline solid.
4.2 g
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 85 - 90℃; for 3 h;
A 250 ml round bottom flask fitted with a mechanical stirrer, reflux condenser, thermometer socket was charged 5-bromoazaindole (10gm) of Formula VII, 4- chlorophenyl boronic acid (7.1gm) of Formula VIII in 1,4-dioxane (lOOmi) at room temperature and stirred for I 0mm. To the reaction mass aqueous potassium carbonate(10.5gm dissolved in 40m1 water), Pd(PPh3)4 was charged and heated to 85°C to 90°C for 3hr. After completion of the reaction cooled the temperature to 55°C to 60°C and separated organic and aqueous layers and followed by cooling the organic layer to 0°C to 5°C and stirred for lhr to precipitate solid compound. The precipitated solid was isolated by filtration, washed with n-heptane (30m1) to get crude compound.Yield: 7.2 gmPurity by HPLC: 94.8percentFormula A by HPLC: 0:1percentPurification of Formula IX:A 250 ml round bottom flask fitted with a mechanical stirrer, reflux condenser, thermometer socket was charged above obtained crude product (7.2gm) and tetrahydrofuran (1 lOmi) at room temperature and heated to 65°C for 1 1w, then distilled the tetrahydrofuran till the reaction mass volume 3 5-40 ml in the flask. Then the reaction mass temperature was cooled to room temperature and followed by 0°C to 5°C and allowed to stir for 1 hr. The precipitated solid was isolated by filtration, washed with n5 heptane (15m1) to get cream color solid. Same purification was repeated once again toobtaine pure compound of Formula IX.Yield: 4.2 gmPurity by HPLC: 99.9percentFormula A by HPLC: 0.02percent
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 24 h; Inert atmosphere; Reflux
Round bottom flask was charged with 9-Phenyl-9H-carbazole-3-boronic acid 15g (52.25mmol), 4-chloro-Phenylboronicacid8.98g (57.47mmol) and the mixture of toluene (174ml) and the mixture was then dissolved in 21.66g of potassium carbonate (156.74 mmol) was added to a stirred aqueous solution of dissolved 87ml. Followed by adding thereto tetrakis triphenylphosphine palladium 1.20g (1.04mmol) was stirred and refluxed for 24 hours under a nitrogen atmosphere. After the end of the reaction the extract was concentrated to dryness and extracted with ethyl acetate and filtered through a magnesium sulfate, and the filtrate under reduced pressure. The product n- hexane / dichloromethane (6: 4 by volume) was purified by a silica gel column chromatography to give the intermediate (I) as 16.13g (85percent yield).
85%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 24 h; Inert atmosphere; Reflux
Round bottom flask was charged with 9-Phenyl-9H-carbazole-3-boronic acid 15g (52.25mmol), 4-chloro-Phenylboronicacid 8.98g dissolved in an aqueous solution of potassium carbonate 21.66g (156.74mmol) was dissolved was added to (57.47mmol) in toluene (174ml) into theIt was added to 87ml and stirred. Here tetrakistriphenylphosphine palladium was added to 1.20g (1.04mmol) of nitrogen atmosphere It was stirred under reflux for 24 hours under a group. After completion of the reaction, magnesium sulfate, the extract was then extracted with ethyl acetateIt was dried, filtered and concentrated under reduced pressure to the filtrate. Silica gel with: a product n- hexane / dichloromethane (volume ratio 4 6)The desired compound was purified by column chromatography of the intermediate (I) to give a 16.13g (85percent yield).
Reference：
[1] Patent: KR2016/12846, 2016, A, . Location in patent: Paragraph 0207; 0208; 0209
[2] Patent: KR2016/22081, 2016, A, . Location in patent: Paragraph 0454; 0455; 0456; 0457
24
[ 57486-69-8 ]
[ 1679-18-1 ]
[ 1329489-84-0 ]
Reference：
[1] Chemistry - An Asian Journal, 2011, vol. 6, # 8, p. 2040 - 2047
With pyridine; copper diacetate; In dichloromethane; at 20℃; for 50h;Molecular sieve;
(R)-l-(4-Chlorophenyl)-piperazine-2-carboxylic acid methyl esterR-4N-Boc-piperazine 2-carboxylic acid methyl ester (4.0gms, 16.4mmol) and 4- chlorophenylboronic acid (5.0gms, 32.8mmol) are mixed in dichloromethane (5OmI) . followed by addition of cupric acetate (3.0gms, 16.4mmol), 4 A molecular sieves (1 gm) and pyridine (3.28ml, 32.8mmol). The mixture is stirred at room temperature for 50 hr. The reaction mixture is concentrated directly in vacuo, diluted with ethyl acetate, and filtered through Celite. The organic filtrate is concentrated and the remaining residue is purified over silica gel column chromatography eluting with hexane and ethyl acetate to give 860 mg as a <n="85"/>white solid.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 18h;
A mixture of ethyl 6-chloroimidazo [1,2-b] pyridazine-2-carboxylate (2.26 g), 4-chlorophenyl boronic acid (1.88 g), tetrakis(triphenylphosphine)palladium (0) (578 mg), 2 M sodium carbonate aqueous solution (10 mL) and 1,2-dimethoxyethane (60 mL) was stirred for 18 hours at 80C. Water was added to the reaction solution, which was then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by basic silica gel column chromatography and recrystallized from ethyl acetate-hexane to obtain ethyl 6-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (1.57 g) as colorless crystals. 1H-NMR (300MHz, CDCl3); delta 1.46 (3H, t, J=7.2Hz), 4.50 (2H, q, J=7.2Hz), 7.52 (2H, d, J=8.7Hz), 7.54 (1H, d, J=9.6Hz), 7.92 (2H, d, J=8.7Hz), 8.08 (1H, dd, J=0.6, 8.7Hz), 8.55 (1H, s)
With sodium carbonate; In ethanol; water; toluene; at 60 - 75℃; for 40h;
Example 10: (2S)-2-F 3-(4-CHLOROPHENYL) PYRIDIN-2-YL] THIO} (PHENYL . METHYLLMORPHOLINE fumarate CI/CI / N Ph Ph H S NJ S \\N t°fPh 1 C ? P N"N" Ph H Fumarate salt I) To bis (benzonitrile) palladium (II) dichloride (0.054 g, 0.14 mmole) and 1,4- bis (diphenylphosphine) butane (0.091 g, 0.21 mmole) is added dry toluene (6 ml), under nitrogen, and the mixture stirred for half an hour. To this is added 3-bromo-2- fluoropyridine (0.50 g, 2.83 mmole) in ethanol (1.4 ml) followed by a solution of 4- chlorophenylboronic acid (0.887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueous solution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture is heated at 60°C for 24 hours, then at 75°C for a further 16 hours. The organic layer is loaded directly onto a 40 g Redisep Si02 column and components isolated by automated flash chromatography (ISCO System, 0-30 percent ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 3- (4-chlorophenyl)-2- fluoropyridine as a white solid (0.323 g, 55 percent). LCMS 6 min gradient method, Rt = 4.0 min, (M+H+) = 208
55%
With sodium carbonate;bis(benzonitrile)palladium(II) dichloride; 1,4-di(diphenylphosphino)-butane; In ethanol; water; toluene; at 60 - 75℃; for 40.5h;
To bis (benzonitrile) palladium (II) dichloride (0.054 g, 0.14 mmole) and 1,4- bis (diphenylphosphine) butane (0.091 g, 0.21 mmole) is added dry toluene (6 ml), under nitrogen, and the mixture stirred for half an hour. To this is added 3-bromo-2- fluoropyridine (0. 50 g, 2.83 mmole) in ethanol (1.4 ml) followed by a solution of 4- chlorophenylboronic acid (0. 887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueous solution of sodium carbonate (1 M, 2.83 ml, 2.83 mmole). The mixture is heated at 60°C for 24 hours, then at 75°C for a further 16 hours. The organic layer is loaded directly onto a 40 g Redisep SIO2 column and components isolated by automated flash chromatography (ISCO System, 0-30 percent ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 3- (4-CHLOROPHENYL)-2-FLUOROPYRIDINE as a white solid (0. 323 g, 55 percent). LCMS 6 min gradient method, Rt = 4.0 min, (M+EFF) = 208
55%
With sodium carbonate; 1,4-di(diphenylphosphino)-butane;bis(benzonitrile)palladium(II) dichloride; In ethanol; water; toluene; at 60 - 75℃; for 40.5h;
To bis (benzonitrile) palladium (II) dichloride (0.054 g, 0.14 mmole) and 1,4- bis (diphenylphosphine) butane (0.091 g, 0.21 mmole) is added dry toluene (6 ml), under nitrogen, and the mixture stirred for half an hour. To this is added 3-bromo-2- fluoropyridine (0.50 g, 2.83 mmole) in ethanol (1.4 ml) followed by a solution of 4- chlorophenylboronic acid (0. 887 g, 5.67 mmole) in ethanol (2.4 ml). To this is added an aqueous solution of sodium carbonate (1 M, 2. 83 ml, 2.83 mmole). The mixture is heated at 60°C for 24 hours, then at 75°C for a further 16 hours. The organic layer is loaded directly onto a 40 g Redisep SiO2 column and components isolated by automated flash chromatography (ISCO System, 0-30 percent ethyl acetate in cyclohexane gradient elution over 40 minutes). This gave 3- (4-chlorophenyl)-2-fluoropyridine as a white solid (0.323 g, 55 percent). LCMS 6 min gradient method, Rt = 4.0 min, (M+H+) = 208
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 100℃; for 16h;
To a mixture of <strong>[41933-33-9]2-benzyl-4,5-dichloropyridazin-3(2H)-one</strong> (30.6 g, 120 mmol), prepared as described in Example 244A, 4-chlorophenyl boronic acid (20.6 g, 132 mmol) and tetrakis(triphenylphosphine)palladium (5 g, 4.3 mmol) in toluene (300 mL) under an atmosphere of argon, and was added an aqueous Na2CO3 solution (2M, 66 mL, 132 mmol). The reaction mixture was stirred at 100 C. under argon for 16 h. The reaction was then allowed to cool to RT and was subsequently poured into water (200 mL). The resulting mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained thick syrup was dissolved in MeOH (100 mL) and the resulting solution kept at 0 C. until white solid precipitated. The solid was collected by filtration, washed with hexanes, and then triturated with EtOAc-hexanes to give the title compound, 2-benzyl-5-chloro-4-(4-chlorophenyl)pyridazin-3(2H)-one (12 g, 30%) as a white powder. LC/MS (method A, general procedure): RT=3.81 min, (M+H)+=331.
Preparation 55 To a suspension of <strong>[89488-29-9]2-bromo-4-methoxypyridine</strong> (1.21 g), 4-chlorophenylboronic acid (1.21 g) and tetrakis(triphenylphosphine)-palladium (372 mg) in 1,2-dimethoxyethane (20 ml) was added 2M aqueous solution of sodium carbonate (7.74 ml). The mixture was stirred at 80 C. for 12 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. 2-Propanol was added to the residue. The precipitate was collected by filtration and dried under reduced pressure to give 4-(4-methoxypyridin-2-yl)-chlorobenzene (1.03 g). 1H-NMR (CDCl3): delta3.91(3H,s), 6.78(1H,dd,J=5.7 Hz,2.4 Hz), 7.19(1H,d,J=2.4 Hz), 7.42(2H,d,J=8.6 Hz), 7.90(2H,d,J=8.0 Hz), 8.51(1H,d,J=5.7 Hz)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 0.833333h;
Preparation 18 2-(4-Chlorophenyl)-5-methoxypyrimidine 4-Chlorobenzeneboronic acid (7.25 g, 46.35 mmol) was added to a stirred solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (6.70 g, 46.35 mmol) in 1,4-dioxane (66 mL) and water (33 mL). Potassium carbonate (6.41 g, 46.35 mmol) and tetrakis(triphenylphosphine) palladium(0) (2.68 g, 46.35 mmol) were added and the resulting mixture was stirred at 100° C. for 50 minutes. The mixture was partitioned between diethyl ether (350 mL) and aqueous sodium hydroxide solution (1M, 200 mL). The aqueous layer was re-extracted with diethyl ether (2*100 mL). The combined organic extracts were dried over sodium sulphate, filtered through a plug of silica and concentrated under reduced pressure to afford the title compound, after trituration with diethyl ether (100 mL), as a white solid in 39.6percent yield, 4.05 g. LRMS ES m/z 221 [MH]+
Method N:Synthesis of (S)-l-(4-Chloro-phenyl)-6-oxo-piperidine-2-carboxylic acid (3-tert-butgammal- isoxazol-5-yl)-amide (Example 131):Step 1: Synthesis of (S)-l-(4-Chloro-phenyl)-6-oxo-piperidine-2-carboxylic acidTo a stirred suspension of (S)-l-(4-chloro-phenyl)-6-oxo-piperidine-2-carboxylic acid (1.368g, 9.558mmol) in 1,2-dichloroethane (35 rnL) l,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (3.ImL, 20.854mmol) is added at room temperature. After 10 min di-mu-hydroxy- bis[N,N,N',N'-tetramethylenediamine)-copper (II) chloride (Cu-TMEDA) (1.614g, 3.476mmol) is added to the clear solution. The mixture is stirred for 10 min and A- chlorophenylboronic acid (1.495g, 9.558mmol) is added. After 20 h solvent is evaporated in vacuo, the concentrate taken up in saturated sodium bicarbonate solution (15OmL) and the aqueous layer is washed with ethyl acetate (3XlOOmL). The aqueous layer is treated with 1 N hydrochloric acid to pH 2 and extracted with ethyl acetate (3XlOOmL). Combined organic extracts washed with brine (2X50mL), dried over anhydrous sodium sulfate and solvent removed in vacuo to give the title compound as an off-white solid, m/z 254 [M+H+] .
Methyl 2-bromoisonicotinate (3.39 g, 15.69 mmol), 4-chlorophenylboronic acid (3.68 g, 23.54 mmol), potassium carbonate (3.25 g, 23.54 mmol) and PdCl2 (dppf) (0.341 g, 0.47 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100 C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield an orange solid. The solid was dissolved in MTBE, then HCl (4 M in dioxane) was added to give crude methyl 2-(4-chlorophenyl)isonicotinate hydrochloride (4.3 g). MS m/z 248 (M+H)+
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 80℃; for 1.33333h;
Intermediate 2 (33.0 mg, 0.10 mmol) was mixed with 80% aqueous dimethoxyethane (1 mL), 4-chlorophenylboronic acid (23.0 mg, 0.15 mmol) and K2CO3 (35.0 mg, 0.25 mmol). Tetrakis-(triphenylphosphine)palladium(0) (6.00 mg, 0.005 mmol) was added and the mixture was stirred at 80 C for 80 min. After cooling, water (0.8 mL) and EtOAc (8 mL) were added. The mixture was centrifuged and the organic layer was separated. Flash chromatography (1 :3 EtO Ac/toluene) gave the title compound (21 mg, 64%). HRMS (ESI+) calcd for Ci8H17ClN202 328.0979, found 328.0980.
64%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 80℃; for 1.33333h;
Intermediate 2 (33.0 mg, 0.10 mmol) was mixed with 80% aqueous dimethoxyethane (1 mL), 4-chlorophenylboronic acid (23.0 mg, 0.15 mmol) and K2CO3 (35.0 mg, 0.25 mmol). Tetrakis-(triphenylphosphine)palladium(0) (6.00 mg, 0.005 mmol) was added and the mixture was stirred at 80 C. for 80 min. After cooling, water (0.8 mL) and EtOAc (8 mL) were added. The mixture was centrifuged and the organic layer was separated. Flash chromatography (1:3 EtOAc/toluene) gave the title compound (21 mg, 64%). HRMS (ESI+) calcd for C is H17ClN2O2 328.0979, found 328.0980.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 20℃; for 18.0h;
A solution of 2.2 g 2,4-chloro-5-fluoropyridine, 2.28 g 4-chlorophenylboronic acid and 0.6 g tetrakistriphenylphosphinpalladium in 30 mL tetrahydrofuran was added 30 mL of a 10% a solution of potassium carbonate in water and the mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed water, 10% aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of heptane:dichloromethane=9:1 to 1:1 (only starting spot was removed) The product fractions were collected and evaporated. The residue was subjected to kugelrohr distillation at 0.03 mBar and 110 C. to yield 1.72 g of the title compound as colorless oil which solidified into white crystals, MS 241 and 243 (M+H)+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 20℃; for 18.0h;
Example lOd6-Chloro-2-(4-chloro-phenyl)-3-fluoro-pyridineA solution of 2.2g 2,4-chloro-5-fluoropyridine, 2.28g 4-chlorophenylboronic acid and 0.6 g tetrakistriphenylphosphine palladium in 30 ml tetrahydrofuran was added 30 ml of a 10% a solution of potassium carbonate in water and the mixture was stirred at ambient temperature for 18h. The reaction mixture was diluted with ethyl acetate and water. The phases were separated and the organic phase was washed water, 10% aqueous citric acid, 10% aqueous sodium bicarbonate and brine, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of heptane : dichloromethane = 9 : 1 to 1 : 1 (only startspot was removed) The product fractions were collected and evaporated. The residue was subjected to Kugelrohr distillation at 0.03 mbar and 110 C to yield 1.72 g of the title compound as colorless oil which solidified into white crystals. MS (EI) (M+H): 241 and 243:
5-amino-4-(4-chlorophenyl)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With bis-triphenylphosphine-palladium(II) chloride; N-iodo-succinimide; sodium hydrogencarbonate; In ethanol; water; at 80℃; for 18h;Inert atmosphere;
General procedure: Phenylpyrazole (0.2 mmol), arylboronic acid (0.4 mmol), NIS (0.2 mmol), [Pd] (10 mol%), NaHCO3 (0.4 mmol) and C2H5OH:H2O (3:1, 10 mL), were added to a Schlenk tube. Then the tube was charged with N2 and the reaction mixture was stirred at 80 C for 18 h. After the completion of the reaction, as monitored by TLC, the mixture was cooled and filtrated. The filtrate was extracted with ethyl acetate and washed with brine. Then the combined organic extracts were dried over Na2SO4, concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford the desired products.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 80℃; for 6h;Inert atmosphere;
General procedure: A 1,4-dioxane solution (3 mL) of 1, arylboronic acid (1.2 equiv), aqueous K2CO3 (2.0 M, 1.0 mL) and Pd(PPh3)4 (3 mol percent) was heated at 80 °C for 6 h under argon atmosphere. After cooling to 20 °C, H2O was added and the reaction mixture was extracted with CH2Cl2 (3×25 mL). The organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtOAc).#10;
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 120℃; for 8h;Inert atmosphere;
General procedure: A 1,4-dioxane solution (3 mL) of 1, arylboronic acid (2.2 equiv), aqueous K2CO3 (2.0 M, 1.0 mL) and Pd(PPh3)4 (6 mol percent) was heated at 120 °C for 8 h under argon atmosphere. After cooling to 20 °C, H2O was added and the reaction mixture was extracted with CH2Cl2 (3×25 mL). The organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, heptane/EtAOc).#10;
2-(3-(4-chlorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper diacetate; triethylamine; at 20℃;
Example 105A 2-(3-(4-chlorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.23 g), copper(II) acetate (0.19 g), triethylamine (0.218 g) and 4-chlorophenylboronic acid (0.237 g) were stirred at room temperature overnight. The solid was filtered off, and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (Varian, Superflash SF25-40 g column), eluting with 0-25% ethyl acetate/hexane, to provide the title compound.
With pyridine; copper diacetate; In dichloromethane; at 20℃; for 72h;Molecular sieve;
Step 3 4-(4-Chloro-phenyl)-piperazine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 4-Chloro phenyl boronic acid (2.0 equiv, 3.68 mmol) and <strong>[129799-15-1]piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester</strong> (1.0 equiv, 1.84 mmol) were dissolved in dichloromethane followed by the addition of copper acetate (1.0 equiv), 4 A molecular sieves and pyridine (2.0 equiv). The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, filtered through celite and concentrated. The crude product was purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (20%). ESI-MS m/z: 354 (M+1), UV retention time: 2.88 min.
General procedure: Arylboronic acid (0.5 mmol), KF (1.0 mmol) were added to a Schlenk tube. The tube was charged with nitrogen and then DCE (2 mL) and benzyl esters (0.75 mmol) were added. The mixture was stirred at 70 C for 10-24 h. After the mixture was cooled down to room temperature, solvent was removed to give a crude product, which was purified by column chromatography on silica gel, eluted with petroleum ether or petroleum ether:ethyl acetate 30:1 to afford the product. In some cases, the reaction was carried out at 100 C with LiOtBu as the base, as indicated in Scheme 4.
70%
With potassium fluoride; at 70℃; for 11h;Sealed tube;
To a 10 mL reaction tube containing a magnet was added (4-chlorophenyl) boronic acid (78 mg, 0.5 mmol)Potassium fluoride (58 mg, 1.0 mmol).Dichloroethane (2 mL)And benzyl methanesulfonate (140 mg, 0.75 mmol).Stuffed rubber stopper,The reaction was conducted on a 70 C electromagnetic stirrer for about 11 hours.After the reaction,Cool to room temperature,The organic solvent is removed using a rotary evaporator,And purified by column chromatography to give 1-benzyl-4-chlorobenzene (71 mg, 70%).The compound is a colorless oily liquid,
methyl 2-(4-chlorophenyl)pyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In methanol; at 100℃; for 0.166667h;Microwave irradiation;
A mixture of commercially available <strong>[26156-48-9]methyl 2-bromoisonicotinate</strong> (3.0 g, 13.9 mmol), commercially available (4-chlorophenyl)-boronic acid (2.61 g, 16.7 mmol), potassium carbonate (2.30 g, 16.7 mmol) and PdCl2(dppf) (340 mg, 417 mupiiotaomicron) in methanol (27 ml) was heated at 100C for 10 min in a microwave reactor. The reaction mixture was filtered and purified by flash chromatography on silica gel [heptane/ethyl acetate 4: 1] to yield methyl 2-(4-chlorophenyl)- pyridine-4-carboxylate (3.16 g, 92%) as a white solid, MS (ISP) m/z = 248.1 [(M+H)+], mp 74C.
92%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In methanol; at 100℃; for 0.166667h;Microwave irradiation;
A mixture of commercially available <strong>[26156-48-9]methyl 2-bromoisonicotinate</strong> (3.0 g, 13.9 mmol), commercially available (4-chlorophenyl)-boronic acid (2.61 g, 16.7 mmol), potassium carbonate (2.30 g, 16.7 mmol) and PdC12(dppf) (340 mg, 417 tmol) in methanol (27 ml) was heated at 100C for 10 mm in a microwave reactor. The reaction mixture was filtered and purified by flash chromatography on silica gel [heptane/ethyl acetate 4:11 to yield methyl 2-(4-chlorophenyl)- pyridine-4-carboxylate (3.16 g, 92 %) as a white solid, MS (ISP) mlz = 248.1 [(M+H)j, mp 74 C.
92%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In methanol; at 100℃; for 0.166667h;Microwave irradiation;
A mixture of commercially available <strong>[26156-48-9]methyl 2-bromoisonicotinate</strong> (3.0 g, 13.9 mmol), commercially available (4-chlorophenyl)-boronic acid (2.61 g, 16.7 mmol), potassium carbonate (2.30 g, 16.7 mmol) and PdCl2(dppf) (340 mg, 417 mupiiotaomicron) in methanol (27 ml) was heated at 100 C for 10 min in a microwave reactor. The reaction mixture was filtered and purified by flash chromatography on silica gel [heptane/ethyl acetate 4: 1] to yield methyl 2-(4- chlorophenyl)-pyridine-4-carboxylate (3.16 g, 92 %) as a white solid, MS (ISP) m/z = 248.1 [(M+H)+], mp 74 C.
6-(4-chlorophenyl)-5-methylpyridine-2,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 16.0h;Inert atmosphere;
5-Bromo-6-methylpyridine-2,3-diamine (50 mg, 0.25 mmol), 4-chlorophenylboronicacid (45 mg, 0.29 mmol), and cesium carbonate (240 mg, 0.74 mmol) were suspendedin dioxane/water (4:1; v/v) (1.25 ml) and this mixture was degassed (3 x vacuumnitrogen cycles). [1,1 ?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1)dichloromethane complex was added and the mixture degassed again (3 x vacuum30 nitrogen cycles). The resulting reaction mixture was stirred at 110 00 for 16 h. Then, the mixture was allowed to cool and it was worked-up adding chloroform and washing with water and brine. The organic phase was dried and evaporated under reduced pressure to afford a residue of 93 mg. This crude material was purified by flash chromatography (methanol-dichloromethane gradient, 0:100 rising to 10:90) to give 46mg (0.20 mmol, 80percent yield) of the title compound as a solid. Purity 95percent.1H NMR (400 MHz, CHLOROFORM-d) oe ppm 7.35 (d, 2H, J = 8.3 Hz), 7.20 (d, 2H, J =8.3 Hz), 6.78 (s, 1 H), 4.30 (br.s, 2H), 3.23 (br.s, 2H), 2.28 (s, 3H)UPLC/MS (3mm) retention time 1.08 mm.LRMS: m/z 234 (M+1, ixCI).
With C20H29Cl2N5O2Pd; potassium carbonate; In ethanol; at 78 - 83℃; for 2.5h;
General procedure: A 15 mL screw-top glass tube was loaded with 4 mL of 96% ethanol, 226 mg (1 mmol) of 1-bromo-2,4-dichlorobenzene, 172 mg (1.1 mmol) of 4-chlorophenylboronic acid, and 207 mg (1.5 mmol) of anhydrous K2CO3. The tube was put in an oil bath heated to 78C. The reaction mixture was stirred during 3 min, and then 0.7 mg (0.0012 mmol) of acyclic diaminocarbene complex of palladium 7 in 0.5 mL of ethanol was added. The tube was tightly screwed and stirred during 2.5 h at 83C. The mixture was then cooled to ambient, 10 mL of water was added, and the reaction product was extracted with a 2 : 1 hexane-dichloromethane mixture (320 mL), the organic layer was dried over anhydrous Na2SO4, the solvent was evaporated, and the residue was weighed and analyzed by 1H NMR and GLC.
(2) 9.67 g (0.03 mol) of 9- (2-bromophenyl) carbazole,Chlorophenylboronic acid(0.081mol) of 5.01g (0.032mol) potassium carbonate and 100mL of solvent (toluene: EtOH: H2O = 10: 2: 1) were placed in a reactor, stirred and replaced with nitrogen for 30min. Pd2 (dba) 3 0.055 g, X-phos 0.029g, heated to reflux, 4h, TLC no raw material, add water and finallyThe reaction was stopped and the aqueous layer was separated. The organic layer was filtered to remove the catalyst through silica gel. The solvent was distilled off under reduced pressure, the mixture was cooled to 15 ° C and suction-filtered. The residue was vacuum-dried to obtain 9.76 g of a solid9- (4'-Chlorobiphenyl-2-yl) carbazole 92percent yield.
72%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; for 6h;Reflux; Inert atmosphere;
Under a nitrogen atmosphere,In a 1 L round bottom flask,The compound 9- (2-bromophenyl) -9H-carbazole(20.0 g, 62.31 mmol),(4-chlorophenyl) boronic acid(10.21 g, 65.42 mmol)After completely dissolved in 360ml of tetrahydrofuran,2M potassium carbonate aqueous solution (180 ml) was added,After tetrakis-(triphenylphosphine) palladium (2.16 g, 1.87 mmol) was added,The mixture was heated and stirred for 6 hours. The temperature is reduced to room temperature,The water layer is removed,After drying over anhydrous magnesium sulfate,Concentrated under reduced pressure,Tetrahydrofuran was used240ml for recrystallization,Compound D (15.79 g, 72percent) was prepared.
With potassium phosphate; palladium diacetate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; at 50℃; for 14h;Sealed tube; Inert atmosphere;
General procedure: The desired amount of substrate, boronic acid (3 equiv), base (3equiv), Pd(OAc)2 (2.5 molpercent) and ligand (5 molpercent) were weighed out as solids, the vial was sealed and purged with argon, then solvent was added and the vial was purged again. The reactions were run for 14 h at the specified temperature. The crude material was filtered through a pad of Celite and washed three times with CHCl3. The solvent was removed under reduced pressure, an internal standard was added and the reaction was analysed by 1H NMR spectroscopy. For purification, the analysed mixture was concentrated, the product extracted with Et2O and filtered through anhydrous MgSO4 and further purified by flash column chromatography.
2-phenyl-4,6-bis(p-chlorophenyl)pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; acetonitrile; for 2h;Reflux;
PPMCl (5.63 g, 25 mmol), 4-chlorophenylboronic acid (8.6 g, 55 mmol), 1 M aqueous solution of sodium carbonate (Na 2 CO 3) (13.3 ml, 125 mmol) was added to a 500 ml four-necked flask equipped with a reflux condenser and a thermometer, ,350 ml of acetonitrile, and 125 ml of water,Nitrogen bubbling was carried out for 1 hour.Thereafter, PdCl 2 (PPh 3) 2 (700 mg, 1.25 mmol) was added and the reaction was carried out under reflux. The reaction solution was a yellow clear solution. After 2 hours, disappearance of the raw material SMPMCl was confirmed by TLC, and the reaction was terminated.After suction filtration and washing with methanol, the filtrate was dissolved in 200 ml of chloroform. Washed with 100 ml of water × 3 times, 150 ml of brine × 1 time and concentrated by evaporation. Also, the catalyst was removed by silica gel column chromatography (silica gel; filled with 400 cc (height up to 7 cm)) using a column tube having a diameter of 8 cm. For injection solvent and developing solvent, chloroform was used. After purification, 8.3 g (yield 88percent) of a white solid was obtained. The product was identified by 1 H-NMR and MS.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 110℃;Inert atmosphere;
Under nitrogen, one equivalent (eq)Compound A, 2 equivalents of compound B, 0.002 equivalents of Pd(PPh3)4, 2 equivalents of K2CO3 (aq), and THF were introduced into a round-bottomed flask in one go and under reflux,The resultant was stirred at 110 °C.The reaction solution is cooled to room temperature.And then separating the organic layer,Vacuum dried and purified using column chromatography.
With pyridine; oxygen; copper diacetate; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: To a solution of <strong>[461-89-2]6-azauracil</strong> (100 mg, 0.88 mmol) inDMF (10.0 mL) was added base (1.76 mmol) and Cu(OAc) 2(159 mg, 0.88 mmol) at room temperature. The resulting reationmixture was degassed with oxygen for 10 min and then addedarylboronic acids (0.96 mmol) at room temperature and stirredat appropriate temperature (Table-1) under oxygen atmosphere.The reaction mixture was diluted with water (15 mL) andextracted with dichloromethane (3 × 15 mL). The organic layerwashed with H 2 O (15 mL), brine solution (15 mL), dried overNa 2 SO 4 and concentrated. The obtained crude product waspurified by column chromatography (0 to 10 % CH 3 OH/CH 2 Cl 2 )to afford the title compounds.
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