* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 2013, vol. 135, # 29, p. 10638 - 10641
2
[ 768-35-4 ]
[ 40503-87-5 ]
Reference：
[1] Patent: WO2017/135306, 2017, A1,
3
[ 1073-06-9 ]
[ 768-35-4 ]
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[1] Organic Letters, 2011, vol. 13, # 17, p. 4479 - 4481
[2] Organic Letters, 2014, vol. 16, # 5, p. 1494 - 1497
[3] Journal of Organometallic Chemistry, 2000, vol. 598, # 1, p. 127 - 135
[4] Angewandte Chemie - International Edition, 2008, vol. 47, # 6, p. 1115 - 1118
[5] Journal of Nanoscience and Nanotechnology, 2010, vol. 10, # 8, p. 5153 - 5160
[6] Journal of the American Chemical Society, 2013, vol. 135, # 4, p. 1264 - 1267
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[ 121-43-7 ]
[ 1073-06-9 ]
[ 768-35-4 ]
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[1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 17, p. 2513 - 2523
[2] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922
5
[ 625-98-9 ]
[ 768-35-4 ]
Reference：
[1] Patent: US2002/161230, 2002, A1,
6
[ 372-19-0 ]
[ 13675-18-8 ]
[ 768-35-4 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
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[ 13675-18-8 ]
[ 1073-06-9 ]
[ 768-35-4 ]
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[1] Journal of the American Chemical Society, 2016, vol. 138, # 9, p. 2985 - 2988
[2] Organic Process Research and Development, 2017, vol. 21, # 11, p. 1859 - 1863
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[ 13675-18-8 ]
[ 1996-38-9 ]
[ 768-35-4 ]
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[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
Reference：
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[3] , Gmelin Handbook: B: B-Verb.13, 4.7.2.4, page 203 - 209,
11
[ 372-19-0 ]
[ 768-35-4 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
12
[ 380893-73-2 ]
[ 768-35-4 ]
[ 380894-77-9 ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium carbonate In 2-methylpropyl acetate; water at 70 - 80℃; for 3 h;
Example 1; Preparation of [5-(3-Fluoro-phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl ester; To a reaction vessel was charged (100 g, 0.29 mol) of phosphonate compound 139 (where R9 is ethyl- for all occurrences), 5percent Pd/C 50percent wet (5.0 g), 3-fluorophenylboronic acid (61 g; 0.44 mol) and sodium carbonate (100 g; 0.94 mol). 600 ml of iso-butyl acetate was charged and the mixture agitated. 400 ml of water was charged, and the agitated mixture was heated to 70-80° C. for at least 3 h at which time an HPLC assay indicated complete reaction. Upon completion, the reaction mixture was cooled to 25° C. and filtered to remove the Pd/C catalyst. The catalyst cake was washed with 200 ml iso-butyl acetate (combined with the filtrate/batch) and 100 ml water (waste). 25percent sodium hydroxide solution was used to adjust batch to pH 11-13. During the process the reaction mixture was maintained at a temperature of from 20° C. to 30° C. The organic layer was separated and washed with 500 ml water with agitation. A 25percent sodium hydroxide solution was used to adjust the pH of the batch to a pH value of from pH 11 to pH13. Throughout the was the temperature was maintained at a value of from about 20° C. to about 30° C. After washing the layers were separated and the organic layer was washed with 300 ml of 2percent sodium chloride solution with 10-15 minutes with agitation. The layers were separated and an HPLC assay of the organic layer indicated impurities were reduced to a desirable level. Darco (10 g) was added to the organic layer. The resultant slurry was agitated for 1 hour, and then filtered to remove the de-coloring agent. The filter cake was washed with 200 ml iso-butyl acetate (combined with the filtrate/batch) and the batch was concentrated under reduced pressure to about 200 ml at from 40° C. to 50° C., then cooled to a temperature of from 15° C. to 25° C. Heptanes (1000 ml) were charged into the cold concentrate over 2.5-3 hr, maintaining the temperature at from about 15° C. to 25° C. The mixture was cooled to a temperature of from -15° C. to -5° C. over 3 hr and agitated at the same temperature for 1 hr. The crystalline solid was filtered, washed with 200 ml heptanes, and dried overnight under vacuum at a temperature of from about 25° C. to 35° C. to provide 70.37 g (75percent). Mp 61-63° C. 1H NMR (CDCl3) δ 1.3 (t, J=7.05 Hz, 6H), 3.47 (d, J=22.02 Hz, 2H), 4.12 (q, J=7.08 Hz, 4H), 7.10 (ddd, J=8.42, 2.55, 0.88, Hz, 1H), 7.28 (ddd, J=9.85, 2.36, 1.80 Hz, 1 H), 7.36 (dt, J=7.86, 1.27, Hz, 1H), 7.46 (m, 1H), 7.83 (ddd, J=8.1, 2.2, 0.32 Hz, 1H), 8.76 (d, J=2.38, 1H).
With potassium carbonate In ethanol; water; toluene at 120℃; for 22 h;
The Step 1 compound (6.2 g, 25.7 mmol), 3-fluorobenzeneboronic acid (4.3 g, 30.7 mmol), K2CO3 (10.7 g, 77.4 mmol) and Pd(PPh3)4 (297 mg, 0.26 mmol) were introduced into a 250 mL round-bottomed flask, to which was added a solvent mixture of toluene/ethanol/water (4/2/1) (60 mL). The mixture was heated to 120°C for 22 h. After the mixture was cooled to room temperature, water was added. The mixture was extracted with ethyl acetate, dried over MgSO4 and filtered. The filtrate was distilled under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (4.3 g, Yield 97percent). [773] 1H-NMR (300 MHz, CDCl3) δ 2.62 (s, 3H), 7.04-7.47 (m, 5H), 7.76 (dd, J = 8.1Hz, 2.4Hz, 1H), 8.72 (d, J = 2.1Hz, 1H).
Reference：
[1] Patent: JP2005/82526, 2005, A, . Location in patent: Page/Page column 25
16
[ 464192-28-7 ]
[ 768-35-4 ]
[ 914348-84-8 ]
Yield
Reaction Conditions
Operation in experiment
54%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; water; toluene at 120℃; for 4 h; Inert atmosphere
Step 1 : 2-(3-fluorophenyl)thiazole-5-carbaldehyde: To a solution of 2-bromothiazole-5-carbaldehyde (0.6 g , 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. a2C03. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120°C for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera® One chromatography (using 6percent ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54percent yield); XH NMR (400 MHz, DMSO-d6): ? 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]+ 208.02, found 208.0.
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In water; N,N-dimethyl-formamide at 180℃; for 1 h; Microwave irradiation; Inert atmosphere
To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 niL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes → 7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83percent> yield) as a yellow-white solid. ESIMS found for CnH9FN2 mlz 189.1 (M+H).
83%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In water; N,N-dimethyl-formamide at 180℃; for 1 h; Microwave irradiation; Inert atmosphere; Sealed tube
To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180°C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes → 7:3 EtOAc:hexanes) to afford the 5-(3- fluorophenyl)pyridin-3 -amine (LIII) (0.360 g, 1.92 mmol, 83percent yield) as a yellow -white solid. ESIMS found for CnH9FN2 mlz 189.1 (M+H).
With sodium carbonate;5%-palladium/activated carbon; In 2-methylpropyl acetate; water; at 70 - 80℃; for 3h;
Example 1; Preparation of [5-(3-Fluoro-phenyl)-pyridin-2-ylmethyl]-phosphonic acid diethyl ester; To a reaction vessel was charged (100 g, 0.29 mol) of phosphonate compound 139 (where R9 is ethyl- for all occurrences), 5% Pd/C 50% wet (5.0 g), 3-fluorophenylboronic acid (61 g; 0.44 mol) and sodium carbonate (100 g; 0.94 mol). 600 ml of iso-butyl acetate was charged and the mixture agitated. 400 ml of water was charged, and the agitated mixture was heated to 70-80 C. for at least 3 h at which time an HPLC assay indicated complete reaction. Upon completion, the reaction mixture was cooled to 25 C. and filtered to remove the Pd/C catalyst. The catalyst cake was washed with 200 ml iso-butyl acetate (combined with the filtrate/batch) and 100 ml water (waste). 25% sodium hydroxide solution was used to adjust batch to pH 11-13. During the process the reaction mixture was maintained at a temperature of from 20 C. to 30 C. The organic layer was separated and washed with 500 ml water with agitation. A 25% sodium hydroxide solution was used to adjust the pH of the batch to a pH value of from pH 11 to pH13. Throughout the was the temperature was maintained at a value of from about 20 C. to about 30 C. After washing the layers were separated and the organic layer was washed with 300 ml of 2% sodium chloride solution with 10-15 minutes with agitation. The layers were separated and an HPLC assay of the organic layer indicated impurities were reduced to a desirable level. Darco (10 g) was added to the organic layer. The resultant slurry was agitated for 1 hour, and then filtered to remove the de-coloring agent. The filter cake was washed with 200 ml iso-butyl acetate (combined with the filtrate/batch) and the batch was concentrated under reduced pressure to about 200 ml at from 40 C. to 50 C., then cooled to a temperature of from 15 C. to 25 C. Heptanes (1000 ml) were charged into the cold concentrate over 2.5-3 hr, maintaining the temperature at from about 15 C. to 25 C. The mixture was cooled to a temperature of from -15 C. to -5 C. over 3 hr and agitated at the same temperature for 1 hr. The crystalline solid was filtered, washed with 200 ml heptanes, and dried overnight under vacuum at a temperature of from about 25 C. to 35 C. to provide 70.37 g (75%). Mp 61-63 C. 1H NMR (CDCl3) delta 1.3 (t, J=7.05 Hz, 6H), 3.47 (d, J=22.02 Hz, 2H), 4.12 (q, J=7.08 Hz, 4H), 7.10 (ddd, J=8.42, 2.55, 0.88, Hz, 1H), 7.28 (ddd, J=9.85, 2.36, 1.80 Hz, 1 H), 7.36 (dt, J=7.86, 1.27, Hz, 1H), 7.46 (m, 1H), 7.83 (ddd, J=8.1, 2.2, 0.32 Hz, 1H), 8.76 (d, J=2.38, 1H).
With potassium carbonate; triphenylphosphine;tris-(dibenzylideneacetone)dipalladium(0); bis(dibenzylideneacetone)-palladium(0); In DMF (N,N-dimethyl-formamide); water; toluene; at 100℃; for 4h;
To a stirred solution of 6-amino-8-bromo-1, 7-naphthyridine (0.5 g) in a mixture of toluene (2.5 ml), DMF (4 ml) and aqueous KZCOS (0.68 g in 2 ml water) is added bis (dibenzylideneacetone) palladium (51 mg), triphenylphosphine (47 mg) and 3- fluorophenylboronic acid (0.33 g). The mixture is stirred for 4 hours at 100C. The mixture is diluted with ethyl acetate, then filtered through a CeliteTM filter. The ethyl acetate solution is washed with 2 N NAOH and water, dried over magnesium sulphate, then concentrated to afford the title compound. MS: APCI 240.0 MH+.
4-(3'-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
sodium carbonate; tetrakis(triphenylphosphine)palladium (0); In toluene;
Step (a) Preparation of 4-(3'-Fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester In a manner similar to Example 12, Step (b), (3-fluoro-phenyl)boronic acid (0.7698 g, 0.005502 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluding with chloroform (18*125 mL), 1.221 g of 4-(3'-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 99-101 C.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110℃; for 4h;
6-(3-Fluorophenyl)pyrazin-2-amine To a stirred solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (2.0 g, 15.43 mmol) in a mixture of toluene (90 ml.) and ethanol (8.5 ml_) was added 3-fluorophenyl boronic acid (2.60 g, 18.51 mmol) and a 2M aqueous solution of sodium carbonate (16.2 mL, 32.40 mmol). The mixture was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (0.713 g, 0.617 mmol) was added. The mixture was subjected again to three cycles of evacuation-backfilling with argon the flask was capped and placed in a 11O0C oil bath. After 4h, the mixture was cooled, partitioned between dichloromethane and water the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (33percent ethyl acetate in hexanes to 50percent ethyl acetate in hexanes). Concentration in vaccuo of the product-rich fractions provided the titled compound (2.79 g, 95percent) as a yellowish solid (2.79 g, 95percent). delta 1H-NMR (CDCI3): 8.38 (s, 1 H), 7.95 (s, 1H), 7.60 (m, 2H), 7.40 (m, 1 H), 4.65 (s, 2H).
With sodium hydroxide;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 24.0h;Heating / reflux;
Example 6; 8-(3-fluorophenyl)H-imidazo[1,5-a]pyridine8-bromo-H-imidazo[1,5-a]pyridine (0.1 g, 0.5 mmol, 1 eq) was dissolved in 10 mL of DME and kept under an argon atmosphere. To that solution [Pd(PPh3)4] (0.025 mmol, 0.05 eq), 3-fluorophenyl boronic acid (0.105 g, 0.75 mmol, 1.5 eq) and an aqueous NaOH solution (0.2M, 5 mL) were added under stirring. The resulting mixture was refluxed for 24 h. After cooling, the mixture was diluted with water and the aqueous layer was extracted with CHCl3. The organic layers were dried (Na2SO4), filtered and evaporated under reduced pressure. Semi-preparative HPLC-chromatography afforded the pure product.Yield: 0.026 g (24%), 1H-NMR, 500 MHz, CDCl3: delta 6.98-7.04 (m, 2H); 7.18-7.22 (m, 1H); 7.29-7.32 (m, 1H); 7.40-7.42 (m, 1H); 7.48-7.52 (m, 1H); 7.74 (s, 1H); 8.16 (d, 1H); 9.05 (s, 1H), MS: m/z 213.2 [M+H]+; HPLC: Method [B], (214 nm), rt: 4.54 min (94.5%)
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In Solmix A-11; water; toluene; for 3h;Inert atmosphere; Reflux;
[Example 1] Synthesis of 4-[difluoro(3,4,5-trifluorophenoxy)methyl]-4'''-n-pentyl-2',2'',3,5-tetrafluoro-1,1',4',1'',4'',1'''-quarterphenyl (No. 1-4-5) [Synthesis of the Compound (T-2)] <strong>[51554-95-1]1-Bromo-4-pentylbenzene</strong> (T-1; 50.0g), 3-fluorophenylboronic acid (31.4 g), potassium carbonate (91.2 g), Pd(Ph3P)2Cl2 (4.63 g), toluene (150 ml), Solmix A-11 (150 ml), and water (150 ml) were added to a reaction vessel under a nitrogen atmosphere, and heated under reflux for 3 hours. The reaction mixture was cooled to 25 °C, and then poured into water (500 ml) and toluene (500 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from Solmix A-11 and dried, whereby 45.2 g of 3-fluoro-4'-pentylbiphenyl (T-2) was obtained. The yield based on the compound (T-1) was 85percent.
STEP 2. Methyl 5-CHLORO-2- (3-FLUOROBENZYL) benzoate; A mixture of methyl 2- (BROMOMETHYL)-5-CHLOROBENZOATE (step 1,300 mg, 1.14 mmol) and tetrakis (triphenylphosphine) palladium (0) (132 mg, 0.11 mmol) in 1,2- dimethoxyethane (6 mL) was stirred at 50 C under nitrogen for 30 min. Then 3- fluorophenylboronic acid (191 mg, 1.37 mmol) and 2 M sodium carbonate solution (2.28 mL, 4.55 mmol) was added, and the resulting mixture was heated at 90 C under nitrogen for 16 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated sodium hydrogen carbonate aqueous (30 mL), and brine (30 ML). The organic layer was dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by TLC [hexane/ethyl acetate (8: 1) ] to give 107 mg (34%) of the title compound as colorless oil : H-NMR (CDC13) 8 7.91 (1H, d, J = 2.4 Hz), 7.41 (1H, dd, J = 8. 4,2. 4 Hz), 7.26-7. 14 (2H, m), 6.91-6. 79 (3H, m), 4.34 (2H, s), 3.84 (3H, s).
3-(3-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Tert-butyl 3-bromo-5l6-dihydro-[1 l2,4]tria2thetalo[4l3-a]pyrazine-7(8H)- carboxylate (202) (0.12 g, 0.4 mmol), m-fluorophenylboronic acid (70 mg, 0.5 mmol), Pd(PPh3)2CI2 (20 mg), K2CO3 (110 mg, 0.8 mmol) were mixed in a microwave reaction vial. The vial was capped and air was removed by vacuum through a needle, and back-filled with nitrogen (3 times). CH3CN (3 mL) and water (0.6 mL) was introduced via syringe. The mixture was then heated to 90 C for 10 h then diluted with ethyl acetate, washed with brine, dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography to give compound 203 which was treated with 4 N HCl in dioxane at r.t. for 2 h to give the HCl salt.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 150℃; for 0.333333h;sealed tube; Microwave irradiation;
EXAMPLE 23c 6-(3-fluorophenyl)imidazo[1,2-a]pyrimidine The compound can be prepared in the following way: 400 mg of <strong>[865156-68-9]6-bromoimidazo[1,2-a]pyrimidine</strong> (commercially available product), 345 mg of 3-fluorophenylboronic acid, 69 mg of tetrakis(triphenylphosphine)palladium, 2 ml of a 2M aqueous sodium carbonate solution and 8 ml of dimethylformamide are charged to a sealed glass tube. The medium is heated at 150 C. for 20 minutes using microwave radiation. After returning to a temperature in the vicinity of 20 C., the medium is filtered through a bed of Clarcel Flo M and rinsing is carried out with 2 times 2 ml of dimethylformamide and then 2 times 5 ml of methanol. The filtrate is concentrated to dryness by evaporation under reduced pressure. The solid isolated is suspended in 80 ml of distilled water, stirred, filtered off, washed with distilled water, superficially freed from the washing medium and dried under reduced pressure. 430 mg of 6-(3-fluorophenyl)imidazo[1,2-a]pyrimidine are thus obtained in the form of a light brown solid. MS: method A; [M+H]+ m/z=214; Tr=0.38 min. 1H NMR (400 MHz, d6-DMSO) delta ppm 7.28 (td, J=8.5, 2.6 Hz, 1H) 7.51-7.66 (m, 2H) 7.69 (dt, J=10.5, 2.0 Hz, 1H) 7.78 (d, J=1.5 Hz, 1H) 7.92 (d, J=1.5 Hz, 1H) 8.93 (d, J=2.7 Hz, 1H) 9.38 (d, J=2.7 Hz, 1H).
With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 80℃; for 14.5h;Inert atmosphere;Product distribution / selectivity;
A solution of <strong>[67754-03-4]methyl 2,5-dichloronicotinate</strong> (8.2 g, 40 mmol), (3- fluorophenyl)boronic acid (6.1 g, 44 mmol), and potassium carbonate (12 g, 86 mmol) in water (71 mL) and 1,4-dioxane (190 mL) was degassed with nitrogen (10 minutes). The reaction mixture was treated with bis(triphenylphosphine)palladium(II) chloride (3.1 g, 4.4 mmol), degassed with nitrogen (10 minutes), and heated at 80 C for 14.5 hours. The reaction mixture was diluted with ethyl acetate and water and filtered over celite. The aqueous layer was separated and re-extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0-80%) gave the desired product (8.7 g, 83%). LCMS calculated forC13H10CIFNO2 (M+H)+: m/z = 266.0; found: 265.8
With pyridine;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper diacetate; In dichloromethane; at 20℃;molecular sieves 4A;
Example 30l-(3-Fluorophenyl)-N-((2'-methvH2,4'-bipyridm^carboxamide (89)Compound 89[0231] Step 1: A mixture of methyl 2-oxo-l,2-dihydropyridine-4-carboxylate 89-1 (153 mg, 1.00 mmol), (3-fluorophenyl)boronic acid 6-6 (280 mg, 2.00 mmol), Cu(OAc)2 (36 mg, 0.2 mmol), molecular sieves (4 A, activated, 200 mg), pyridine (162 mu, 2.0 mmol) and TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy, free radical, 172 mg, 1.1 mmol) in DCM (2.0 mL) was stirred at room temperature under dry air. The mixture was then filtered through celite (washed with ethyl acetate); and the filtrate was washed with 5% ammonia solution, dried with Na2S04 and concentrated with rotavap. The residue was subjected to silica gel column chromatography with 1:3 ethyl acetate/DCM as eluent to give methyl l-(3-fluorophenyl)-2-oxo-l,2- dihydropyridine-4-carboxylate as a solid 89-2.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 18h;Inert atmosphere;
3-Fluorobenzeneboronic acid (405 mg, 2.89 mmol) and <strong>[13631-21-5]4-<strong>[13631-21-5]bromo-3-chlorophenol</strong></strong> (500 mg, 2.41 mmol) were dissolved in dioxane (15 mL) and water (3 mL) and the solution degassed. Tetrakis(triphenylphosphine) palladium (0) (278 mg, 0.24 mmol) was added followed by caesium carbonate (2.36 g, 7.23 mmol) and the reaction was stirred at 80 C. under nitrogen for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% ethyl acetate in heptane) to afford the title compound (509 mg, 95%) as a colourless oil.1HNMR (400 MHz, CDCl3): delta 6.80 (d, 1H), 7.00 (s, 1H), 7.06 (dd, 1H), 7.12 (dd, 1H), 7.18 (m, 2H), 7.36 (dd, 1H).LCMS Rt=3.02 minutes MS m/z 221 [M-H]
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 22h;
The Step 1 compound (6.2 g, 25.7 mmol), 3-fluorobenzeneboronic acid (4.3 g, 30.7 mmol), K2CO3 (10.7 g, 77.4 mmol) and Pd(PPh3)4 (297 mg, 0.26 mmol) were introduced into a 250 mL round-bottomed flask, to which was added a solvent mixture of toluene/ethanol/water (4/2/1) (60 mL). The mixture was heated to 120C for 22 h. After the mixture was cooled to room temperature, water was added. The mixture was extracted with ethyl acetate, dried over MgSO4 and filtered. The filtrate was distilled under reduced pressure and purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to give the title compound (4.3 g, Yield 97%). [773] 1H-NMR (300 MHz, CDCl3) delta 2.62 (s, 3H), 7.04-7.47 (m, 5H), 7.76 (dd, J = 8.1Hz, 2.4Hz, 1H), 8.72 (d, J = 2.1Hz, 1H).
With N-ethyl-N,N-diisopropylamine;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130℃; for 0.333333h;Microwave irradiation;
INTERMEDIATE 38 - PREPARATION of methyl 5-(3-fluorobenzyl)picolinate. A mixture of 3-fluorophenylboronic acid (0.319 g; 2.28 mmol), methyl 5- (bromomethyl)picolinate (0.350 g; 0.230 mmol), tetrakis-(triphenylphosphine)-palladium(0) (0.175; 0.152 mmol) and N,N diisopropylethylamine (0.524 g; 3.04 mmol) in dimethoxyethane (9 mL) and water (3 mL) was irradiated in a microwave oven at 130°C for 20 minutes. The resulting solution was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 1 to 10 percent ethyl acetate in dichlomethane) to afford 0.149 g (40percent) of the title compound as a yellow oil.ESI/APCI(+): 246 (M+H), 268(M+Na).
40%
With tetrakis(triphenylphosphine) palladium(0); N-ethyl-N,N-diisopropylamine; In 1,2-dimethoxyethane; water; at 130℃; for 0.333333h;Microwave irradiation;
A mixture of 3-fluorophenylboronic acid (0.319 g; 2.28 mmol), <strong>[55876-84-1]methyl 5-(bromomethyl)picolinate</strong> (0.350 g; 0.230 mmol), tetrakis-(triphenylphosphine)-palladium(0) (0.175; 0.152 mmol) and N,N diisopropylethylamine (0.524 g; 3.04 mmol) in dimethoxyethane (9 mL) and water (3 mL) was irradiated in a microwave oven at 130° C. for 20 minutes. The resulting solution was partitioned between water and ethyl acetate. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 1 to 10percent ethyl acetate in dichlomethane) to afford 0.149 g (40percent) of the title compound as a yellow oil. [0625] ESI/APCI(+): 246 (M+H), 268 (M+Na).
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;
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 180.0℃; for 1.0h;Microwave irradiation; Inert atmosphere;
To a microwave vial was added <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 niL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes ? 7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83%> yield) as a yellow-white solid. ESIMS found for CnH9FN2 mlz 189.1 (M+H).
83%
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In water; N,N-dimethyl-formamide; at 180.0℃; for 1.0h;Microwave irradiation; Inert atmosphere; Sealed tube;
To a microwave vial was added <strong>[13535-01-8]3-amino-5-bromopyridine</strong> (LII) (0.400 g, 2.31 mmol), 3 -fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes ? 7:3 EtOAc:hexanes) to afford the 5-(3- fluorophenyl)pyridin-3 -amine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow -white solid. ESIMS found for CnH9FN2 mlz 189.1 (M+H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; N,N-dimethyl-formamide; at 100℃;Inert atmosphere;
To a solution of 3 -fluorophenyl boronic acid (0.7 g, 5.0 mmol, 1.0 eq), 3-bromo-5-fiuoro- benzoic acid (1 g, 4.6 mmol, 1.1 eq) and Na2C03 (1.45g, 13.7 mmol, 3 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and H20 (5 mL) under N2 was added Pd(PPh3)4 (200 mg, 0.17 mmol, 0.05 eq). The mixture was stirred at 100C overnight then cooled to room temperature. Water and ethyl acetate were added and the reaction was filtered through Celite and the aqueous layer was extracted with EtOAc. The organic extract was discarded and the aqueous layer was acidified to pH 4-5 by addition of 1M HCl and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried ( a2S04), filtered and evaporated in vacuo to give the title compound as a white solid (970 mg, 90 %).LC-MS : m z 233.0 [M-H]~ 1H NMR (400 MHz, MeOD/CDCl3) ? 7.62 (t, J = 1.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 7.10 - 6.97 (m, 3H), 6.93 - 6.87 (m, 1H), 6.72 - 6.64 (m, 1H)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In N,N-dimethyl-formamide; at 95℃;Inert atmosphere;
To a solution of 3-bromo-6-fiuoro-2-methylbenzoic acid (1.35 g, 5.8 mmol, 1.0 eq) and 3 -fluorophenyl boronic acid (970 mg, 6.9 mmol, 1.2 eq) in DMF (25 mL) under N2 were addedNa2C03 (2.45 g, 23.1 mmol, 4 eq) and Pd(PPh3)4 (0.33 g, 0.29 mmol, 0.05 eq). The reaction was heated at 95 C overnight, then the reaction acidified by addition of 4M HC1 to a final pH of 4. The reaction mixture was filtered through celite and extracted with EtOAc. The organic extract was washed with brine, dried (Na2S04), filtered and evaporated in vacuo to give the title compound (680 mg, 48%). This material was used without further purification.LC-MS: m/z 247.0 [M-H]~
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; N,N-dimethyl-formamide; at 100℃; for 4h;Inert atmosphere;
To a solution of <strong>[79669-49-1]5-bromo-2-methyl-benzoic acid</strong> (1 g, 5.12 mmol, 1.0 eq) and (3- fluorophenyl)boronic acid (720 mg, 4.65 mmol, 1.1 eq) in a mixture of EtOH (5 mL), DMF (20 mL) and H20 (5 mL) were added Na2C03 (1.98g, 18.68 mmol, 4 eq) and Pd(PPh3)4 (270 mg, 0.23 mmol, 0.05 eq). The mixture was heated at 100C under N2 for 4h and the reaction quenched by addition of 1M HCl. The aqueous phase was extracted with EtOAc and the combined organic extracts washed with brine, dried (Na2SC>4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ethenEtOAc, 20: 1 to 1 : 1) to give the title compound as a white solid (780 mg, 68 %).LC-MS: m z 229.0 [M-H]" 1H NMR (400 MHz, DMSO-d6) ? 13.01 (br s, 1H), 8.08 (d, J= 1.9 Hz, 1H), 7.78 (dd, J = 7.9, 1.9 Hz, 1H), 7.56 - 7.47 (m, 3H), 7.41 (d, J= 8.0 Hz, 1H), 7.25 - 7.16 (m, 1H), 2.55 (s, 3H)
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 120℃; for 4h;Inert atmosphere;
Step 1 : 2-(3-fluorophenyl)thiazole-5-carbaldehyde: To a solution of <strong>[464192-28-7]2-bromothiazole-5-carbaldehyde</strong> (0.6 g , 3.125 mmol) in toluene (2 mL) and ethanol (1 mL) was added 4-fluorophenyl boronic acid (0.524 g, 3.75 mmol), 2 M solution of aq. a2C03. The reaction mixture degassed with argon, tetrakis (0.180 g, 0.156 mmol) was added, the reaction mixture was again degassed with argon for 10 min, and heated to 120C for 4 h. The reaction mixture was evaporated under vacuum to remove ethanol, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL) and dried over sodium sulphate, filtered and evaporated under reduced pressure to obtain crude product. The crude product was purified by Biotage Isolera One chromatography (using 6% ethyl acetate and hexane) to give 2-(3-fluorophenyl)thiazole-5-carbaldehyde (0.350 g, 54% yield); XH NMR (400 MHz, DMSO-d6): ? 8.78 (s, 1H), 7.90 (dd, 2H), 7.61 (q, 1H); 7.44 (t, 1H); LC-MS m/z calcd for [M+H]+ 208.02, found 208.0.
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 90℃;
A solution of PdCl2(dppf)-CH2Cl2 adduct (0.065 g, 0.080 mmol), l-bromo-4-iodo- 2-methoxybenzene (CombiBlocks, 0.250 g, 0.799 mmol), 3-fluorophenylboronic acid (0.123 g, 0.879 mmol) and potassium phosphate (0.848 g, 3.99 mmol) in dioxane (2.130 ml)/water (1.065 ml) was heated to 90 C overnight. The reaction was diluted with DCM and separated from the aqueous via phase separator (Radleys Discovery Technologies). After concentration in vacuo, the material was purified via MPLC (12-g Redi Sep Gold), eluting with 0-100% ethyl acetate in heptanes to yield, after concentration, 4-bromo-3 '-fluoro-3 -methoxy- 1,1'- biphenyl as an orange oil, which was used without further purification.
With oxygen; sodium hydroxide; copper dichloride; In methanol; for 11h;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); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Microwave irradiation;
General procedure: <strong>[290368-00-2]ter<strong>[290368-00-2]t-butyl 3-iodo-1H-indazole-1-carboxylate</strong></strong> (S2, 100 mg, 0.29 mmol) was placed in a microwave vial and dissolved in 1,4-dioxane (11.5 mL). 3-Methoxyphenylboronic acid (88 mg, 0.58 mmol, 2.0 equiv) and tetrakis(triphenylphosphine)palladium (20 mg, 0.017 mmol, 0.06 equiv) were added, and the resulting mixture was sparged thoroughly with nitrogen. An aqueous solution of sodium carbonate (2.0 M, 0.65 mL, 1.3 mmol, 4.5 equiv) was then added. The biphasic mixture was microwaved for 1 hour at a reaction temperature of 120 C. After cooling to room temperature, the reaction was diluted with ethyl acetate (2 mL), and then filtered through a celite pad with additional ethyl acetate. The filtrate was concentrated under reduced pressure to give an oil. The crude material was purified by column chromatography over silica gel (hexanes/ethyl acetate: 100/0 to 30/70) to give the title compound as an oil (58.0 mg, 89%).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃;
To a solution of 6-bromo-3,4-dihydro-2H-chromen-4-one (1.5 g, 6.6 mmol), 3- fluorophenylboronic acid (1.39 g, 9.9 mmol) and sodium carbonate (2.1 g, 19.8 mmol) indioxane (20 mL) and water (1 mL) was added Pd(PPh3)4 (382 mg, 0.3 mmol) at rt. The solution was heated at 100 o C overnight. The reaction was filtered, concentrated, and purified by silica gel chromatography (PE/EtOAc/DCM = 10:1:2) to give 1.4 g (88%) of the title compound as a white solid. 1H NMR (300 MHz, CDCh): 8 2.86 (2H, t, J = 6.6Hz), 4.60 (2H, t, J= 6.6 Hz), 7.11-7.14 (1H, m), 7.18 (1H, d, J= 1.5 Hz), 7.23-7.29 (2H, m), 7.32-7.45 (2H, m), 7.98 (1H, d, J = 8.1 Hz).
With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,3-dioxane; water; at 90℃; for 2.0h;
To a 25 mL round bottom flask, were added <strong>[178876-83-0]methyl 6-amino-3-bromopicolinate</strong> (1 g, 0.0043 mol), 3-fluorophenylboronic acid (0.72 g, 0.0052 mol), potassium carbonate (1.52 g, 0.011 mol), 1,4-dioxane (20 mL) and water (4 mL). The reaction mixture was degassed with nitrogen for 5 min. To the same flask, bis(triphenylphosphine)palladium(II) dichloride (0.14 g, 0.00022 mol) was added. The reaction mixture was again degassed with nitrogen for 5 min. The reaction mixture was stirred at 90 C for 2 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by flash column chromatography using 20 - 40 % ethyl acetate in hexane to obtain the title compound [0.6 g, 57 %]. FontWeight="Bold" FontSize="10" H NMR (CDC13, 400 MHz): delta 7.68-7.63 (m, 1H), 7.48 (d, = 8.8 Hz, 1H), 7.36-7.31 (m, 1H), 7.05-6.97 (m, 2H), 6.67 (d, = Hz, 1H), 4.79 (brs, 2H), 3.72 (s, 3H); LC-MS: 247.1 [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In tetrahydrofuran; water; at 60℃; for 3.5h;Inert atmosphere;
[10121] (6-1) In a nitrogen atmosphere, a solution prepared by mixing 50.00 g of 4-propylbromobenzene, 0.87 g of tetrakis-triphenylphosphine palladium, 60 mE of an aqueous potassium carbonate solution (2 mol/E), and 150 mE of THF was heated to 60° C., and 35.14 g of 3-fluorophenylboronic acid was added to the solution over 20 minutes. After the resultant mixture was stirred at 60° C. for 3 hours, the mixture was allowed to cool, and an organic layer was separated by adding hexane. The organic layer was washed with saturated brine and dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure. As a result of purification by silica gel column chromatography, 44.32 g of 3-fluoro-1 -(4-propylphenyl)benzene was produced.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In toluene; at 80℃;Schlenk technique; Inert atmosphere; Sealed tube;
Step 1. 5-(3-Fluorophenyl)benzofuran-3(2H)-one Cesium carbonate (612 mg, 1.88 mmol) was added to a solution of <strong>[54450-20-3]5-bromobenzofuran-3(2H)-one</strong> (200 mg, 0.939 mmol), (3-fluorophenyl)boronic acid (263 mg, 1.88 mmol) and toluene (20 mL) in a 50 mL Schlenk tube. A nitrogen atmosphere was established by evacuating and refilling with nitrogen (3*), then tetrakis(triphenylphosphine)palladium (0) (11 mg, 0.01 mmol) was added to the reaction. The flask was sealed and heated in a 80 C. oil bath overnight. The resulting mixture was cooled to room temperature. The reaction was then diluted with ethyl acetate and filtered through celite. Ethyl acetate (30 mL) was used to wash the flask and the combined organic filtrate was concentrated. The resulting crude residue was purified on a Teledyne-Isco Combiflash machine (40 g column, hexanes?100% ethyl acetate/hexanes, gradient), to afford 212 mg (99%) of 5-(3-fluorophenyl)benzofuran-3(2H)-one.
With 1,1'-bis-(diphenylphosphino)ferrocene; tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; toluene; for 12h;Reflux;
General procedure: A mixture of 2-chloro-4-(trifluoromethyl)-benzonitrile (1.00 mmol), appropriate boronic acid (1.20 mmol)were dissolved in toluene/dioxane:2 N Na2CO3 (2:1:1) solution(6 ml). Tetrakis(triphenyl-phosphine)palladium(0) (0.10 mmol)and 1,10-Ferrocenediyl-bis(diphenylphosphine) (0.20 mmol) wasadded to the mixture and it was refluxed for 12 h. After cooleddown to ambient temperature, the reaction was filtered over celiteand extracted with EtOAc twice. The combined organic extractswere dried over MgSO4, filtered, and concentrated in vacuo. Theresidue was purified by flash column chromatography on silicagel using EtOAc/hexanes (1:10) eluant condition. (R-B(OH)2 =1-pentenyl boronic acid for 53, 1-cyclohexenylboronicacid for 54).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 85℃;Inert atmosphere;
A 100-mL recovery flask containing <strong>[89488-29-9]2-bromo-4-methoxypyridine</strong> (1.446 g, 7.69 mmol, purchased from Combi-Blocks, Inc.), 3-fluorophenylboronic acid (2.152 g, 15.38 mmol, purchased from Oakwood Products, Inc.), and 1,1'-bis(diphenylphosphino)ferrocene palladium(11)dichloride dichloromethane adduct (0.314 g, 0.385 mmol) was flushed with N2 and subsequently charged with dioxane (29 mL) and 1.9 M Na2CO3 in H2O (10 mL). The black-red mixture was stirred at 85 C. overnight. The next morning, after cooling to rt, the dark red mixture was diluted with H2O and extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a black oil. Column chromatography (50 g Snap Ultra column, 10-100% EtOAc/hept) afforded 2-(3-fluorophenyl)-4-methoxypyridine (2.25 g, >99% yield) as a viscous yellow oil. m/z (ESI) 204.2 (M+H)+.
2-(3-fluorophenyl)-3-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVII) (2.0 g, 11.5 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (LXVIII) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34 mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), 0 (10 mL) and EtOH (4 mL) was stirred at 75°C for 15 h under nitrogen atmosphere. Then the reaction mixture was washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (PE:EtOAc = 1 : 1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXIX) (1.91 g, 8.2 mmol, 71.2percent yield) as a yellow solid.E SIMS found for C11H8FN3O2 m/z 234.2 (M+H).
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; at 75℃; for 15h;Inert atmosphere;
j0667j A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVIII) (2.0 g, 11.5 mmol,1.0 eq), (3-fluorophenyl)boronic acid (LXIX) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), H20(10 mL) and EtOH (4 mL) was stirred at 75°C for 15 h under nitrogen atmosphere. Then the reactionmixture was washed with brine (30 mL) and dried over anhydrous Na2504, filtered andconcentrated in vacuo, the resultant residue was purified by chromatography on silica gel(PE:EtOAc = 1:1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXX) (1.91 g, 8.2 mmol,71.2percent yield) as a yellow solid. ESIMS found for C11H8FN302 m/z 234.2 (M+H).
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXXXI) (2.0 g, 11.5 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (DOOM) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34 mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), H2O (10 mL) and EtOH (4 mL) was stirred at 75° C. for 15 h under nitrogen atmosphere. Then the reaction mixture was washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (PE:EtOAc=1:1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXXXIII) (1.91 g, 8.2 mmol, 71.2percent yield) as a yellow solid. ESIMS found for C11H8FN3O2 m/z 234.2 (M+H).
71.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 75℃; for 15h;Inert atmosphere;
Step 1 A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVI) (2.0 g, 11.5 mmol, 1.0 eq), (3-fluorophenyl)boronic acid (LXVII) (1.93 g, 13.8 mmol, 1.2 eq), Pd(PPh3)4 (0.40 g, 0.34 mmol, 0.03 eq), Na2CO3 (2.44 g, 23.05 mmol, 2.0 eq) in a mixed solvent of toluene (20 mL), H2O (10 mL) and EtOH (4 mL) was stirred at 75° C. for 15 h under nitrogen atmosphere. Then the reaction mixture was washed with brine (30 mL) and dried over anhydrous Na2SO4, filtered and concentrated in vacuo, the resultant residue was purified by chromatography on silica gel (PE:EtOAc=1:1) to afford 2-(3-fluorophenyl)-3-nitropyridin-4-amine (LXVIII) (1.91 g, 8.2 mmol, 71.2percent yield) as a yellow solid. ESIMS found for C11H8FN3O2 m/z 234.2 (M+H).
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; for 3h;Reflux;
dding reaction bottle 0.1mol compound 1-a, 0 . 12mol between fluorophenylboronic acid (reactant), 0.3mol sodium carbonate (reactant), 80 ml toluene (solvent), 60 ml ethanol (solvent), 60 ml water (solvent), pass under the protection of nitrogen, adding 0.4g four (triphenylphosphine) palladium (catalyst), stirring and heating to reflux reaction 3 hours; cooling down to room temperature, liquid, with 50 ml toluene (solvent) extracting the aqueous phase, the organic phase with water to neutral, solvent evaporation to dryness of the organic phase, the material is dissolved in 100 ml toluene, the decoloring by silica gel column, eluting with toluene (solvent), collecting the eluant and drying solvent, with 3 times volume after dissolving petroleum ether at -20 C freezing re-crystallization, filtration, to obtain white crystal 3-b, the yield is 90%, gas-phase chromatographic purity of 99.5%.
3-bromo-1-(3-fluorophenyl)-1,2,4-triazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
38%
With pyridine; copper diacetate; In dichloromethane; at 20℃; for 72h;
<strong>[7343-33-1]3-bromo-1H-1,2,4-triazole</strong> (9.6 g, 64.9 mmol), pyridine (10.5 mL, 129.8 mmol), copper (II) acetate (17.7 g, 97.3 mmol) and (3-fluorophenyl) boronic acid (11.4 g, 81.1 mmol) were mixed in DCM (200 mL) and the reaction was stined at room temperature for 3 days. The solid was filtered off and the filtrate was washed with water several times. The organic layer was dried, concentrated and purified on silica gel to afford 6.3 g of desired product JW-2c in 38percent yield. ?H NMR (400 MHz, CDC13) oe 8.45 (s, 1H), 7.54 - 7.47 (m, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.20 - 7.04 (m, 1H) ppm. ESI-MS m/z calc. 240.96509, found 242.27 (M+1)+; Retention time:0.75 minutes.
tert-butyl 4-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;
j0696j To a solution of tert-butyl 4-bromo-1H-pyrrolo[2,3-bjpyridine-1-carboxylate (XCII) (1.5 g, 5.1 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (XCIII) (1.07 g, 7.65 mmol, 1.1 eq) in a mixture solvent of dioxane (18 mL) and water (6 mL) was added K3P04 (2.11 g, 15.3mmol, 2.5 eq). The suspension was purged with nitrogen (x 3) followed by addition of Pd(dppf)C12 (373 mg, 0.51 mmol, 0.1 eq). The reaction was stirred at 60C for 5 h. The suspension was poured into water(10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. Then the crude product was purified by column chromatography on silica gel to afford tert-butyl 4-(3- fluorophenyl)-1H-pyrrolo[2,3-bjpyridine-1-carboxylate (XCIV) as a white solid (1.37 g, 4.39 mmol, 86.0% yield). ?HNMR(CDC13, 400 MHz) ppm 1.69 (s, 9H), 6.68 (d, J=4Hz, 1H), 7.17 (dt, J=2Hz, J8.4Hz, 1H), 7.25 (d, J4.8Hz, 1H), 7.35 (d, J12Hz, 1H), 7.41 - 7.53 (m, 2H), 7.70 (d, J=4Hz, 1H), 8.57 (d, J4.8Hz, 1H); ESIMS found for C,8H,7FN202 mlz 313.1 (M+H).
86%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;
To a solution of fert-butyl 4-bromo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (LXXV) (1.5 g, 5.1 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (LXXVI) (1.07 g, 7.65 mmol, 1.1 eq) in a mixture solvent of dioxane (18 mL) and water (6 mL) was added K3PO4 (2.11 g, 15.3 mmol, 2.5 eq). The suspension was purged with nitrogen (x 3) followed by addition of Pd(dppf)Cl2 (373 mg, 0.51 mmol, 0.1 eq). The reaction was stirred at 60C for 5 h. The suspension was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2S04 and concentrated under reduced pressure. Then the crude product was purified by column chromatography on silica gel to afford fert-butyl 4-(3-fluorophenyl)-lH-pyrrolo[2,3-b]pyridine- l-carboxylate (XLXXVII) as a white solid (1.37 g, 4.39 mmol, 86.0% yield). NMR (CDC13, 400 MHz) delta ppm 1.69 (s, 9H), 6.68 (d, J=4Hz, 1H), 7.17 (dt, J=2Hz, J=8.4Hz, 1H), 7.25 (d, J=4.8Hz, 1H), 7.35 (d, J=12Hz, 1H), 7.41 - 7.53 (m, 2H), 7.70 (d, J=4Hz, 1H), 8.57 (d, J=4.8Hz, 1H); ESIMS found for C18H17FN2O2 mlz 313.1 (M+H).
86%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;
Step 2 [0677] To a solution of fert-butyl 4-bromo-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (LXXV) (1.5 g, 5.1 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (LXXVI) (1.07 g, 7.65 mmol, 1.1 eq) in a mixture solvent of dioxane (18 mL) and water (6 mL) was added K3PO4 (2.11 g, 15.3 mmol, 2.5 eq). The suspension was purged with nitrogen (x 3) followed by addition of Pd(dppf)Cl2 (373 mg, 0.51 mmol, 0.1 eq). The reaction was stirred at 60C for 5 h. The suspension was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2SC>4 and concentrated under reduced pressure. Then the crude product was purified by column chromatography on silica gel to afford fert-butyl 4-(3-fluorophenyl)-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (XLXXVII) as a white solid (1.37 g, 4.39 mmol, 86.0% yield). NMR (CDC13, 400 MHz) delta ppm 1.69 (s, 9H), 6.68 (d, J=4Hz, 1H), 7.17 (dt, J=2Hz, J=8.4Hz, 1H), 7.25 (d, J=4.8Hz, 1H), 7.35 (d, J=12Hz, 1H), 7.41 - 7.53 (m, 2H), 7.70 (d, J=4Hz, 1H), 8.57 (d, J=4.8Hz, 1H); ESIMS found for C18H17FN2O2 mlz 313.1 (M+H).
86%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 60℃; for 5h;Inert atmosphere;
To a solution of fert-butyl 4-bromo-lH-pyrrolo[2,3-b]pyridine- l-carboxylate (LXXV) (1.5 g, 5.1 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (LXXVI) (1.07 g, 7.65 mmol, 1.1 eq) in a mixture solvent of dioxane (18 mL) and water (6 mL) was added K3PO4 (2.11 g, 15.3 mmol, 2.5 eq). The suspension was purged with nitrogen (x 3) followed by addition of Pd(dppf)Cl2 (373 mg, 0.51 mmol, 0.1 eq). The reaction was stirred at 60C for 5 h. The suspension was poured into water (10 mL) and extracted with EtOAc ( 10 mL x 3). The combined organic layer was washed with brine (5 mL), dried over Na2S04 and concentrated under reduced pressure. Then the crude product was purified by column chromatography on silica gel to afford fert-butyl 4-(3-fluorophenyl)-lH-pyrrolo[2,3-b]pyridine- l-carboxylate (XLXXVII) as a white solid (1.37 g, 4.39 mmol, 86.0% yield). NMR (CDC13, 400 MHz) delta ppm 1.69 (s, 9H), 6.68 (d, J=4Hz, 1H), 7.17 (dt, J=2Hz, J=8.4Hz, 1H), 7.25 (d, J=4.8Hz, 1H), 7.35 (d, J=12Hz, 1H), 7.41 - 7.53 (m, 2H), 7.70 (d, J=4Hz, 1H), 8.57 (d, J=4.8Hz, 1H); ESIMS found for C18H17FN2O2 mlz 313.1 (M+H).
4-(3-fluorophenyl)-1H-pyrrolo[3,2-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 25 - 100℃; for 2h;Inert atmosphere;
To a solution of 4-chloro-lH-pyrrolo[3,2-c]pyridine (LXXIX) (13.3 g, 87.2 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (LXXX) (1.59 g, 113.3 mmol, 1.3 eq) in a solution of dioxane (80 mL) and water (27 mL) was added K3PO4 (46.3 g, 218 mmol, 2.5 eq) in one portion at 25C under N2. Then Pd(dppf)Cl2 (5.1 g, 6.97 mmol, 0.08 eq) was added under N2 atmosphere. The yellow solution was heated to 90-100C and stirred for 2 h. The reaction was added into water (500 mL), and the resultant solution was extracted with EtOAc (300 mL x 3). The organic layers were washed with brine (200 mL), dried over Na2S04 and concentrated to give a residue. The residue was purified by chromatography on silica gel to give 4-(3-fluorophenyl)-lH-pyrrolo[3,2- c]pyridine (LXXXI) as a red solid (10.9 g, 51.4 mmol, 58.9% yield). NMR (DMSO-£, 400 MHz) delta ppm 6.80 (s, IH), 7.24 - 7.33 (m, IH), 7.42 (d, J=6Hz, IH), 7.52 - 7.63 (m, 2H), 7.76 (d, J=8Hz, IH), 7.87 (d, J=7.6Hz, IH), 8.28 (d, J=5.6Hz, IH), 11.71 (brs, IH); ESIMS found for C13H9FN2 mlz 213.1 (M+H).
58.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 90 - 100℃; for 2h;Inert atmosphere;
To a solution of 4-chloro-lH-pyrrolo[3,2-c]pyridine (LXXIX) (13.3 g, 87.2 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (LXXX) (1.59 g, 113.3 mmol, 1.3 eq) in a solution of dioxane (80 mL) and water (27 mL) was added K3PO4 (46.3 g, 218 mmol, 2.5 eq) in one portion at 25C under N2. Then Pd(dppf)Cl2 (5.1 g, 6.97 mmol, 0.08 eq) was added under N2 atmosphere. The yellow solution was heated to 90-100C and stirred for 2 h. The reaction was added into water (500 mL), and the resultant solution was extracted with EtOAc (300 mL x 3). The organic layers were washed with brine (200 mL), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by chromatography on silica gel to give 4-(3-fluorophenyl)- lH-pyrrolo[3,2-c]pyridine (LXXXI) as a red solid (10.9 g, 51.4 mmol, 58.9% yield). NMR (DMSO-£, 400 MHz) delta ppm 6.80 (s, 1H), 7.24 - 7.33 (m, 1H), 7.42 (d, J=6Hz, 1H), 7.52 - 7.63 (m, 2H), 7.76 (d, J=8Hz, 1H), 7.87 (d, J=7.6Hz, 1H), 8.28 (d, J=5.6Hz, 1H), 11.71 (brs, 1H); ESIMS found for Ci3H9FN2 mlz 213.1 (M+H).
58.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 25 - 100℃; for 2h;Inert atmosphere;
To a solution of 4-chloro-lH-pyrrolo[3,2-c]pyridine (XCVI) (13.3 g, 87.2 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (XCVII) (1.59 g, 113.3 mmol, 1.3 eq) in a solution of dioxane (80 mL) and water (27 mL) was added K3PO4 (46.3 g, 218 mmol, 2.5 eq) in one portion at 25C under N2. Then Pd(dppf)Cl2 (5.1 g, 6.97 mmol, 0.08 eq) was added under N2 atmosphere. The yellow solution was heated to 90-100C and stirred for 2 h. The reaction was added into water (500 mL), and the resultant solution was extracted with EtOAc (300 mL x 3). The organic layers were washed with brine (200 mL), dried over Na2S04 and concentrated to give a residue. The residue was purified by chromatography on silica gel to give 4-(3-fluorophenyl)-lH-pyrrolo[3,2- c]pyridine (XCVIII) as a red solid (10.9 g, 51.4 mmol, 58.9% yield). NMR (DMSO-£, 400 MHz) delta ppm 6.80 (s, IH), 7.24 - 7.33 (m, IH), 7.42 (d, J=6Hz, IH), 7.52 - 7.63 (m, 2H), 7.76 (d, J=8Hz, IH), 7.87 (d, J=7.6Hz, IH), 8.28 (d, J=5.6Hz, IH), 11.71 (brs, IH); ESIMS found for C13H9FN2 mlz 213.1 (M+H).
58.9%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In 1,4-dioxane; water; at 25 - 100℃; for 2h;Inert atmosphere;
Step 1 [0680] To a solution of 4-chloro-lH-pyrrolo[3,2-c]pyridine (LXXIX) (13.3 g, 87.2 mmol, 1.0 eq) and (3-fluorophenyl)boronic acid (LXXX) (1.59 g, 113.3 mmol, 1.3 eq) in a solution of dioxane (80 mL) and water (27 mL) was added K3PO4 (46.3 g, 218 mmol, 2.5 eq) in one portion at 25C under N2. Then Pd(dppf)Cl2 (5.1 g, 6.97 mmol, 0.08 eq) was added under N2 atmosphere. The yellow solution was heated to 90-100C and stirred for 2 h. The reaction was added into water (500 mL), and the resultant solution was extracted with EtOAc (300 mL x 3). The organic layers were washed with brine (200 mL), dried over Na2SC>4 and concentrated to give a residue. The residue was purified by chromatography on silica gel to give 4-(3-fluorophenyl)- lH-pyrrolo[3,2-c]pyridine (LXXXI) as a red solid (10.9 g, 51.4 mmol, 58.9% yield). NMR (DMSO-£, 400 MHz) delta ppm 6.80 (s, 1H), 7.24 - 7.33 (m, 1H), 7.42 (d, J=6Hz, 1H), 7.52 - 7.63 (m, 2H), 7.76 (d, J=8Hz, 1H), 7.87 (d, J=7.6Hz, 1H), 8.28 (d, J=5.6Hz, 1H), 1 1.71 (brs, 1H); ESIMS found for C13H9FN2 mlz 213.1 (M+H).
3,3”-difluoro-[1,1’:3’,1”-terphenyl]-5’-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃;
The mixture of <strong>[626-41-5]3,5-dibromophenol</strong> (500 mg, 1.99 mmol), (3-fluorophenyl)boronic acid (834 mg, 5.96 mmol), K2C03 (824mg, 5.96mmol) in a mixture of 1,4-dioxane, H20 solution (20/5 mL) was degassed and Pd(PPh3)4 (115 mg, 0.10 mmol) was added. The reaction mixture was heated at 100 °C overnight and it was extracted with EtOAc and washed with brine and concentrated. Then it was purified by column chromatography on silica gel (0-30percent ethyl acetate/hexanes) to give the product (472 mg, 84percent yield) as a white solid. ?H NMR (300 MHz, CDC13) 7.36-7.18 (m, 7H),7.06-6.95 (m, 4H), 5.03 (s, 1H).
2-(3'-fluoro-[1,1'-biphenyl]-4-yl)ethan-1-amine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
General procedure: A mixture of N-boc-2-(4-bromophenyl)ethylamine, the desiredarylboronic acid (a-m) (1.2 equiv), tetrakis(triphenylphosphine)-palladium(0) (0.04 equiv), Na2CO3 (5 equiv) in degassed toluene/H2O (5/2) was refluxed for 18 h. The reaction mixture was filteredthrough Celite and concentrated in vacuo. The resulting residuewas dissolved in in EtOAc (200 mL), washed with H2O (200 mL 2) and brine (200 mL). The organic layer was dried with anhydrousNa2SO4 and concentrated in vacuo. The residue was purified by columnchromatography on SiO2. Using Method E, 13 (1.00?g, 3.3?mmol), 3-fluorophenylboronic acid (0.56?g, 4.0?mmol), tetrakis(triphenylphosphine)palladium(0) (0.15?g, 0.1?mmol), Na2CO3 (1.77?g, 16.7?mmol) in toluene/H2O (33?ml/13.3?ml), followed by 4.0?M HCl in dioxane (2.50?ml, 10.0?mmol) gave 14d as a white solid (0.52?g, 62%); Rf?=?0.00 (EtOAc 9: acetone 1): 1H NMR (DMSO-d6, 400?MHz) delta 2.98-3.09 (m, NH3CH2CH2), 7.17-7.52 (m, 6 ArH), 7.68 (d, J?=?8.0?Hz, 2 ArH), 8.34 (s, NH3); 13C NMR (DMSO-d6, 100?MHz) delta 33.0 (NCH2CH2), 113.6 (d, JC-F?=?21.8?Hz), 114.5 (d, JC-F?=?20.9?Hz), 123.0 (d, JC-F?=?2.4?Hz), 127.4, 129.8, 131.3 (d, JC-F?=?8.5?Hz), 137.6 (d, JC-F?=?2.1?Hz), 137.9, 142.8 (d, JC-F?=?7.7?Hz), 163.2 (d, JC-F?=?241.7?Hz) (12 ArC).
4-(3-fluorophenyl)-3,5-dimethyl-1H-pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 85 - 110℃; for 23h;Sealed tube;
4-iodo-3,5-dimethyl-1 H-pyrazole (231 mg, 1.04 mmol), boronic acid (281 mg, 2.01 mmol), sodium carbonate (551 mg, 5.20 mmol), dioxane (5.2 ml) and water (1.3 ml) were charged to a screw-cap type tube. The mixture was degassed for 10 min andPd(PPh3)4(60 mg, 0.05 mmol) was added. The tube was sealed and the mixture was heated to 85 C. After 1 h there was no reaction. After 16h the ratio of iodopyrazole: product was 1 :6. The mixture was heated to 1 10 C. After 6h there was no iodopyrazole starting material remaining, so the mixture was cooled to rt, diluted with water and EtOAc. The phases were separated and the aqueous phase was washed with brine. Si02 was added to the organic phase and it was concentrated to dryness. The crude on silica was purified on Isco using a gradient of hexanes to EtOAc. Afforded 144 mg (0.76 mmol, 73%) of product as a colorless oil.
6-chloro-5-(3-fluorophenyl)pyrazin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 20h;Inert atmosphere;
In a pressure tube were mixed <strong>[173253-42-4]2-amino-5-bromo-6-chloropyrazine</strong> (2.00 g, 9.60 mmol), 3-fluor-ophenylboronic acid (1.48 g, 10.55 mmol), sodium carbonate (2.03 g, 19.19 mmol) in a 4:1 mixture of 1 ,4-dioxane : water (25 mL). The reaction mixture was sparged with argon and Pd(PPh3)4 (0.22 g, 0.20 mmol) was then added. The mixture was sparged with argon shortly and the vessel was sealed and the reaction mixture was heated at 10000 for 20h. After that time the reaction mixture was cooled down to r.t. filtered through Celite pad diluted with AcOEt, or-ganic layer was washed with NaHCO3, brine and dried over Na2SO4. Then the mixture was concentrated under reduced pressure. The obtained residue was purified by flash chromatography on silica eluting with hexane : EtOAc (1:0 - 1:1) to lead to the title product as a light yellow solid(1 .82 g, 85%). ESI-MS: 224.00 [M+H].
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 7h;Inert atmosphere; Reflux; Large scale;
Compound 2: A flask charged with compound 1 (2818 g, 10.71 mol), (3- fluorophenyl)boronic acid (1574 g, 11.25 mol), and Na2C03 (1135.1 g, 10.71 mol, 1 equiv) was evacuated and refilled with Ar for three times. Deionized water (5.6 L), DME (14 L) and Pd(PPh3)4 (123.8 g, 0.107 mol) were added sequentially. The resulting mixture was degassed and refilled with Ar for three times and then refluxed for 7 h. The suspension was filtered through Celite (500 g) plug. The filtrate was a two-phase mixture. The organic phase was separated. The aqueous phase was extracted with EtOAc (10 L). The combined organic extracts was dried over Na2S04 (3 kg), filtered and concentrated. Half of the crude product was purified by column chromatography (silica gel, eluting with 20% CH2Cl2 in hexanes) to give compound 2 (1040 g, 70% yield) as a white solid.
With potassium carbonate; palladium dichloride; In water; at 25℃;
General procedure: A mixture of arylboronic acids 3a-n (5.5 mmol, 1.1 equiv.), dierent substituted 2-(4-bromophenyl)acetonitriles 4a-c (5.0 mmol, 1.0 equiv.), PdCl2 (0.025 mmol, 0.005 equiv.), K2CO3 (17.5 mmol, 3.5 equiv.),PEG400 15 mL, and H2O 15 mL were added to a 100-mL round-bottom flask, and stirred at roomtemperature for the desired time until complete consumption of starting material as judged by TLC.Then, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered,and removed by evaporation under reduced pressure to aord the crude products, which were furtherpurified by column chromatography on silica gel eluting with EtOAc/petroleum ether to 5a-p aswhite solid.
methyl 3-amino-6-chloro-5-(3-fluorophenyl)pyrazine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
47.3%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 70℃; for 3h;Inert atmosphere;
To a stirred mixture of methyl 3-amino-5, 6-dichloropyrazine-2-carboxylate (1.5 g, 6.756 mmol, 1 equiv) and (3-fluorophenyl) boronic acid (0.95 g, 6.790 mmol, 1.00 equiv) in 1, 4-dioxane (100 mL) and H 2O (5mL) were added Cs 2CO 3 (6.60 g, 0.020 mmol, 3 equiv) and Pd (dppf) Cl 2 (0.74 g, 0.001 mmol, 0.15 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 70 C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with CH 2Cl 2 (1x30 mL) . The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH 2Cl 2 /EtOAc (4: 1) to afford methyl 3-amino-6-chloro-5- (3-fluorophenyl) pyrazine-2-carboxylate (900 mg, 47.30%) as a yellow solid. LCMS: m/z (ESI) , [M+H] + = 282.0. 1H-NMR (300 MHz, Chloroform-d) delta 4.03 (3H, s) , 7.22 (1H , m) , 7.41-7.59 (2H , m) , 7.65 (1H , ddd) .
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