* 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.
With pyridine In dichloromethane at 20℃; for 72 h;
λ/-[2-(bis-3-methoxyphenylamino)ethyllacetamide (5c):Cupric acetate (2.1 mmol) and pyridine (0.25 ml) were added to a vigorously stirred solution of 3-methoxyaniline (1 mmol) and 3-methoxyphenylboronic acid (2 mmol) in dry methylene chloride (3.5 ml), under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 72 h (the progress of the reaction was monitored by TLC). λ/-(3-Methoxyphenyl)-3-methoxyaniline (3c) was isolated by direct flash chromatography of the crude reaction mixture following preabsorption on silica gel. Yield (3c): 25percent; EI-MS 229 (M+) [Lit.: Urgaonkar, S.; Verkade, J.G. J. Org. Chem. 2004, 69, 9135-9142].
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere; Schlenk technique Stage #2: With Trimethyl borate In tetrahydrofuran at -78 - 20℃; for 16 h; Inert atmosphere; Schlenk technique
1-bromo-3-methoxybenzene (20 g, 107 mmol) was dissolved in dry THF (200 mL) in a Schlenk tube. The solution was purged with N2 and cooled to -78 ºC. n-Butyllithium (2.5 mol/L, 64.2 mL) was added slowly. A white precipitate was formed during the addition. The mixture was stirred for 1 h at the same temperature and then trimethyl borate (74 mL, 321.0 mmol) was added. The resulting clear solution was slowly warmed to room temperature and stirred for 16 h. Concentrated hydrochloric acid was added until a pH of 3-4 was reached. The reaction mixture was poured into ethyl acetate (200 mL) and the aqueous layer was discarded. The organic layer was washed three times with saturated salt water, dried over anhydrous Na2SO4 and filtered. The solvent was removed and the product was recrystallized from ethyl acetate/petroleum ether (1:10) to afford the title compound (13.8 g, 85 percent). 1H NMR (DMSO-d6, 400 MHz, ppm): δ 8.02 (s, 2H, OH-H), 7.36 (d, J = 4.0 Hz, 2H, Ar-H), 7.25 (t, J= 8.0 Hz, 1H, Ar-H), 6.95 (d, J = 8.0 Hz, 2H, Ar-H), 3.75 (s, 3H, CH3-H); 13C NMR (CDCl3, 100 MHz, ppm): δ 158.55, 128.48, 126.32, 118.98, 115.72, 54.78.
78%
Stage #1: With n-butyllithium In tetrahydrofuran; hexaneInert atmosphere Stage #2: With Trimethyl borate In tetrahydrofuran; hexaneInert atmosphere
General procedure: Under an argon atmosphere a solution of the appropriate bromobenzene (1 equivalent) dissolved in anhydrous THF (approximately 30 mL per mmol bromobenzene) is cooled to -78 °C using a nitrogen-ethanol-bath. A solution of 2.3 equivalents of n-butyllithium in hexane is added drop wise keeping the temperature below -78 °C. After completion the mixture is stirred for one hour at this temperature. Then 1.5 equivalents of trimethyl borate are added slowly and the reaction mixture is stirred at -78 °C for another hour. The cooling bath is then removed, the reaction mixture is stirred until room temperature is reached and quenched with a saturated solution of ammonium chloride. THF and the major part of the water is removed under reduced pressure, the residue is laced with 3M hydrochloric acid until a pH of 3 is reached. After extraction with DCM (3 x) the organic phases are collected, washed with brine, dried over sodium sulphate and filtered. DCM is removed under reduced pressure, the resulting solid is washed first with ice cold water and then with PE and dried.
Reference：
[1] Tetrahedron, 2013, vol. 69, # 19, p. 3934 - 3941
[2] Patent: US6342610, 2002, B2, . Location in patent: Page column 75
[3] European Journal of Medicinal Chemistry, 2017, vol. 126, p. 590 - 603
[4] Journal of Organic Chemistry, 2008, vol. 73, # 11, p. 4212 - 4218
[5] Journal of the American Chemical Society, 2013, vol. 135, # 4, p. 1264 - 1267
[6] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6427 - 6439
5
[ 2398-37-0 ]
[ 121-43-7 ]
[ 10365-98-7 ]
Yield
Reaction Conditions
Operation in experiment
92.1%
With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane
1st Stage 3-Methoxybenzeneboronic Acid 41.3 g (220 mmol) 3-bromoanisole were dissolved in 880 ml tetrahydrofuran and the solution was cooled to -70° C. in a cooling bath (ethanol/dry ice). 160 ml (250 mmol) butyllithium solution (1.6 M in hexane) were added dropwise under nitrogen such that the temperature did not rise above -60° C. After stirring at -70° C. for 1.5 hours, 75 ml (660 mmol) trimethyl borate were also added dropwise such that the temperature did not rise above -60° C. After stirring in the cold for a further hour, the mixture was warmed to 25° C. in the course of two hours, 720 ml hydrochloric acid (1 M) were added and the mixture was stirred at 25° C. for 15 hours. For working up, the mixture was extracted three times with 300 ml ether each time, the organic phases were combined, washed with 100 ml each of water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered and the filtrate was concentrated on a rotary evaporator (500-10 mbar). In this manner, 30.8 g 3-methoxybenzeneboronic acid (92.1percent of theory) were obtained.
80%
Stage #1: With magnesium In tetrahydrofuran; toluene at 60 - 80℃; Inert atmosphere Stage #2: at 0℃; Inert atmosphere Stage #3: With sulfuric acid In tetrahydrofuran; toluene at 20℃; Inert atmosphere
To a mixture of magnesium (2.95 g, 121mmol), THF (35mL), and toluene (35 mL)was added dropwise 3-bromoanisole 2(13.0 mL, 103mmol)with keeping temperature at 60 ºC. The reaction mixture was stirred at 80 ºC for 2hours. Prepared Grignard reagent was slowly dropwise to a toluene solution (20 mL) of trimethyl borate (11.4 mL, 102 mmol) at 0 ºC. The reaction mixture was stirred at 0 ºC for 2 hours, then neutralized with 10percent sulfuric acid, and stirred at r.t. overnight. Organic phase was separated, dried over MgSO4, and evaporated to give 3-methoxyphenylboronic acid (12.36 g, 80percent) as white powder.
Reference：
[1] Patent: US2002/198251, 2002, A1,
[2] Tetrahedron Letters, 2012, vol. 53, # 46, p. 6182 - 6185,4
[3] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 17, p. 2513 - 2523
[4] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1919 - 1922
6
[ 2398-37-0 ]
[ 5419-55-6 ]
[ 10365-98-7 ]
Yield
Reaction Conditions
Operation in experiment
156.1 g
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -70℃; for 1 h; Inert atmosphere Stage #2: at 20℃; for 18 h; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; hexane; water
n-Butyllithium in n-hexane (925.0 mL, 1.59 M) was added dropwise to a mixture of THF (1,000 mL) and 1-bromo-3-methoxybenzene (T-1) (250.0 g, 1.34 mol) at -70° C. under an atmosphere of nitrogen. After the addition had been completed, the reaction mixture was stirred at the same temperature for 1 hour. Triisopropyl borate (300.9 g, 1.60 mol) was added dropwise, and then the mixture was warmed slowly to room temperature. The stirring was continued at room temperature for 18 hours, and the reaction mixture was poured into 6M-hydrochloric acid. The mixture was extracted with ethyl acetate (500 mL) four times, and the organic layer was washed with water. After the organic layer had been dried over anhydrous magnesium sulfate, the organic solvent was distilled off under reduced pressure. The residue was sufficiently washed with heptane to leave colorless solids (156.1 g) of 3-methoxyphenylboronic acid (T-2).
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 23, p. 5612 - 5615
[2] Chemistry - A European Journal, 2017, vol. 23, # 4, p. 935 - 945
[3] Patent: US8394468, 2013, B2, . Location in patent: Page/Page column 52; 53
[4] Organic Letters, 2015, vol. 17, # 2, p. 346 - 349
[5] Journal of Materials Chemistry C, 2015, vol. 3, # 22, p. 5754 - 5763
7
[ 7732-18-5 ]
[ 10365-98-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 25℃; for 2 h;
General procedure: In a flask containing the appropriate potassiumorganotrifluoroborate (0.5 mmol) in distilled water(1 mL) was added montmorillonite K10 (150percent m/m). Themixture was stirred for the time indicated in Scheme 1at room temperature. After this period, the mixture wasextracted with EtOAc (3 × 10 mL) and the organic phasewas washed with water (2 × 15 mL). The organic phasewas dried over anhydrous MgSO4, filtered and the solventwas removed in vacuo to yield the corresponding boronicacids 2a-o.
Reference：
[1] Journal of the Brazilian Chemical Society, 2018, vol. 29, # 9, p. 1777 - 1785
With N-Bromosuccinimide; triphenylphosphine sulfide In dichloromethane at 20℃; for 48 h; Inert atmosphere
Under an argon atmosphere,To a 300 mL 2-diameter eggplant-shaped flask, 3-methoxyphenylboronic acid (12)(9.12 g, 60.0 mmol),Triphenylphosphine sulfide (932 mg, 6.00 mmol),Dichloromethane (200 mL) was added,This was stirred to make a homogeneous solution.In contrast, N-bromosuccinimide (13.0 g, 72.0 mmol) was added,And the mixture was stirred at room temperature for 2 days.To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate to stop the reaction, followed by extraction with dichloromethane (100 mL × 3).The combined organic layer was washed with saturated brine and dried over sodium sulfate.After filtration, concentration under reduced pressure gave a crude product.Purification by silica gel column chromatography (290 g, n-hexane / acetone = 1/1) gave 2-bromo-5-methoxyphenylboronic acid (8b) (8.45 g, 36.6 mmol, yield 61.0 percent) Was obtained.
Reference：
[1] Organic Letters, 2010, vol. 12, # 11, p. 2480 - 2483
[2] Patent: JP2018/30788, 2018, A, . Location in patent: Paragraph 0057
[3] Organic Letters, 2015, vol. 17, # 4, p. 1042 - 1045
1-isopropyl-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; ethanol; water; at 80℃;
Synthesis of 1-isopropyl-3-(3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (BA49); A solution of 3-Methoxyphenylboronic acid (17 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution-of <strong>[862730-04-9]3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine</strong> (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80 C. under an argon atmosphere overnight: After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA49. ESI-MS (M+H)+ m/z calcd 284.1, found 284.0.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; for 1h;Heating / reflux;
[3'-METHOXYBIPHENYL-3-CARBOXYLIC] acid amide. To a stirred mixture 3-bromobenzoic acid amide (0.76 g; 3.8 mmol) and toluene (25 mL), Pd [(PPH3)] 4 (0.180 g; 0.16 mmol), a solution [OF NA2C03] (2.543 g; 24 mmol) in [H20] (10 mL), and one of 3-methoxyphenylboronic acid (1.132 g; 7.45 mmol) in EtOH (10 [ML)] were added. The mixture was refluxed for 1 h under vigorous stirring, cooled, and the acqueous phase extracted with AcOEt. The combined organic layers were dried over [NA2S04] and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1: 1 then 4: 6) and recrystallization gave the desired product (0.64 g) as white solid. Yield 74%. Mp: [138-40 C] (EtOH). MS [(EI)] [: M/Z] 227 (M+, [100%). 1H NMR (CDC13)] : [8] 3.88 (s, 3H); 5.71 (br s, 1H); 6.11 (br s, 1H); 6.94 (m, [1H)] ; 7.18 (m, 2H); 7. [39] (t, [1H)] ; 7. [53] (t, [1H)] ; 7.77 (m, 2H); 8. 05 (t, [1H)] ppm. IR [(NUJOL)] : 3327,3148, 1676,1640, 1613,1584 [CM-1.]
With cesium fluoride;palladium diacetate; In 1,4-dioxane; ethyl acetate;
EXAMPLE 31A 3'-methoxy-6-methyl(1,1'-biphenyl)-3-carbonitrile A mixture of <strong>[21423-81-4]3-chloro-4-methylbenzonitrile</strong> (3.30 g, 20 mmol), 3-methoxyphenylboronic acid (4.56 g, 30 mmol), palladium acetate (89.8 mg, 0.4 mmol), 2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl (0.236 g, 0.6 mmol), and CsF (9.11 g, 60 mmol) in dioxane (60 mL) at room temperature was stirred for 12 hours, and concentrated. The concentrate was dissolved in ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexane to provide 4.38 g (98%) of the desired product. MS (DCI/NH3) m/z 241 (M+NH4)+; 1H NMR (CDCl3) delta7.55-7.52 (m, 2H), 7.38-7.33 (m, 2H), 6.94 (m, 1H), 6.86 (m, 1H), 6.80 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H).
4.38 g (98%)
With cesium fluoride;palladium diacetate; In 1,4-dioxane; ethyl acetate;
EXAMPLE 31A 3'-methoxy-6-methyl(1,1'-biphenyl)-3-carbonitrile A mixture of <strong>[21423-81-4]3-chloro-4-methylbenzonitrile</strong> (3.30 g, 20 mmol), 3-methoxyphenylboronic acid (4.56 g, 30 mmol), palladium acetate (89.8 mg, 0.4 mmol), 2-dicyclohexylphosphanyl-2'-dimethylaminobiphenyl (0.236 g, 0.6 mmol), and CsF (9.11 g, 60 mmol) in dioxane (60 mL) at room temperature was stirred for 12 hours, and concentrated. The concentrate was dissolved in ethyl acetate (10 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4:100 ethyl acetate/hexane to provide 4.38 g (98%) of the desired product. MS (DCI/NH3) m/z 241 (M+NH4)+; 1H NMR (CDCl3) delta 7.55-7.52 (m, 2H), 7.38-7.33 (m, 2H), 6.94 (m, 1H), 6.86 (m, 1H), 6.80 (m, 1H), 3.84 (s, 3H), 2.32 (s, 3H).
(2S)-1-({2-[6-(3-Methoxy-phenyl)-pyridin-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, hydrochloride salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Example 127 (2S)-1-({2-[6-(3-Methoxy-phenyl)-pyridin-2-ylamino]-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Hydrochloride Salt This compound was obtained in analogy to example 36, steps A] to C] starting from 2,6-dibromopyridine, 1,2-diaminoethane, 3-methoxyphenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in THF and precipitated by treatment with HCl in ether yielding a white powder. MS (ISP): 380.5 (MH+).
With methanesulfonic acid; In tetrahydrofuran; ethyl acetate;
Example 131 (2S)-1-({2-[6-(3-Methoxy-phenyl)-pyridin-2-ylamino]-1,1-dimethyl-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Methansolfonic Acid Salt This compound was obtained in analogy to example 36, steps A] to C] starting from 2,6-dibromopyridine, 1,2-diamino-2-methlypropane, 3-methoxyphenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in THF and precipitated by treatment with methanesulfonic acid in ethyl acetate yielding a white powder. MS (ISP): 408.5 (MH+).
(2S)-1-({2-[5-(3-Methoxy-phenyl)-pyridin-2-ylamino]-1,1-dimethyl-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, hydrochloride salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Example 114 (2S)-1-({2-[5-(3-Methoxy-phenyl)-pyridin-2-ylamino]-1,1-dimethyl-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile, Hydrochloride Salt This compound was obtained in analogy to example 36, steps A] to C] starting from 2,5-dibromopyridine, 1,2-diamino-2-methlypropane, 3-methoxyphenylboronic acid and IIA. The residue obtained by flash chromatography was dissolved in THF and precipitated by treatment with HCl in ether yielding a white powder. MS (ISP): 408.5 (MH+).
Example 144 (2S)-1-({2-[5-(3-Methoxy-phenyl)-pyrimidin-2-ylamino]-1,1-dimethyl-ethylamino}-acetyl)-pyrrolidine-2-carbonitrile This compound was obtained in analogy to example 36, steps A] to C] starting from 5-bromo-2-iodopyrimidine, 1,2-diamino-2-methlypropane, 3-methoxyphenylboronic acid and IIA. It was isolated as its free amine, as a slightly yellow foam. MS (ISP): 409.5 (MH+).
A.1.10 Synthesis of S-aryl-thiophene-l-carboxylic acid derivatives; A.1.10.1 3-(3-Methoxy-phenyl)-thiophene-2-carboxylic acid; 3-Bromothiophene-2-carboxylic acid (600 mg; 2.9 mmol) was dissolved in isopropanol (7 ml) / toluene (7 ml), followed by the addition of K2CO3 solution (aq; 2M; 9 ml) and 3- methoxybenzeneboronic acid (440 mg; 2.9 mmol). The reaction mixture was deoxygenized <n="57"/>with N2 (g) for 3 minutes followed by the addition of tetrakis-(triphenylphosine)-palladium and subsequently heated to 800C for 14 h. The mixture was cooled to rt, ether was added and the organic layer was extracted with 2M NaOH-solution. The aq. layer was acidified by the addition of 2M HCl. The product precipitated and was filtered off and dried at high vacuum to give 470 mg of 3-(3-methoxy-phenyl)-thiophene-2-carboxylic acid; LC-MS: tR = 0.94 min; [M-H]+ = 235.27.
With N-Bromosuccinimide; triphenylphosphine sulfide; In dichloromethane; at 20℃; for 48h;Inert atmosphere;
Under an argon atmosphere,To a 300 mL 2-diameter eggplant-shaped flask, 3-methoxyphenylboronic acid (12)(9.12 g, 60.0 mmol),Triphenylphosphine sulfide (932 mg, 6.00 mmol),Dichloromethane (200 mL) was added,This was stirred to make a homogeneous solution.In contrast, N-bromosuccinimide (13.0 g, 72.0 mmol) was added,And the mixture was stirred at room temperature for 2 days.To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate to stop the reaction, followed by extraction with dichloromethane (100 mL × 3).The combined organic layer was washed with saturated brine and dried over sodium sulfate.After filtration, concentration under reduced pressure gave a crude product.Purification by silica gel column chromatography (290 g, n-hexane / acetone = 1/1) gave 2-bromo-5-methoxyphenylboronic acid (8b) (8.45 g, 36.6 mmol, yield 61.0 %) Was obtained.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; for 5h;Inert atmosphere; Reflux;
Step 1: 3-Fluoro-3'-methoxy-4-methyl-biphenyl; A mixture of toluene (22.7 mL) and water (22.7 mL+7.5 ml.) was degassed with nitrogen for 30 min. A mixture of cesium carbonate (3.3 g, 1 .04 mmol), 4-bromo-2-fluoro-1- methyl-benzene (1 .0 g, 5.2 mmol), 3-methoxyphenylboronic acid (0.8g, 5.2 mmol) and tetrakis triphenyl phosphene palladium (0.294 g, 0.26 mmol) was added to the above degassed aq. toluene and the resulting mixture was refluxed for 5 h. After the reaction was completed, it was cooled and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulphate and concentrated. The residue was purified by column chromatography using 10% ethyl acetate in hexane to obtain the title compound (0.85 g, 74%).1H NMR (300 MHz, CDCI3): delta (ppm) = 2.4 (s, 3H), 3.9(s, 3H), 6.9-7.4(m, 7H).
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; at 110℃; for 15h;Inert atmosphere;
Example 1.28; 4-(3-Methoxyphenyl)-N7-phenyl-1H-pyrazolo|3,4-c]pyridine~3,7-diammeStep 1 :[00216] A mixture of <strong>[153463-65-1]3,5-dichloroisonicotinonitrile</strong> (2 g, 11.56 mrnol), 3- methoxyphenylboronic acid (1.932 g, 12.72 mmol), potassium phosphate (4.91 g, 23.12 mmol) and palladium tetrakis(triphenylphosphine) (0.668 g, 0.578 mmol) was pumped and backfilled with nitrogen 3 times. N,N-dimethylacetamide (30 mL) was added. The mixture was again pumped and backfilled with nitrogen 3 times. After heating to 110 C for 15 h, the mixture was diluted with ethyl acetate (300 mL), washed with water (50 mL), brine (50 mL) and dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane-hexanes (1:1) and eluting with 5-30% ethyl acetate in hexanes, gave 3-chloro-5-(3-methoxyphenyl)isonicotinonitrile as white solid (1.20 g, 43% yield). MS (ES+) m/z: 245 (M+H); LC retention time: 3.13 min (analytical HPLC Method A).
With potassium phosphate; catacxium A;palladium diacetate; In toluene; at 100℃; for 3.5h;Inert atmosphere;
A flask charged with a stir bar, <strong>[38180-46-0]3-chloro-2-cyanopyridine</strong> (8.16 g), 3-methoxyphenylboronic acid (13.42 g), K3PO4 (25.00 g), and toluene (100 mL) is sparged with argon for 10 min. Palladium(II) acetate (0.13 g) and n-butyl-di-(1-adamantyl)-phosphine (0.42 g) are added and the resulting mixture is put in a 100 C. hot oil bath and stirred in there for 3.5 h. After cooling to room temperature, ethyl acetate (250 mL) is added and the mixture is washed with 2 M aqueous NaOH solution and brine. The organic phase is dried (Na2SO4) and the solvent is evaporated. The residue is triturated with methanol and dried to give the title compound as a colorless solid. Yield: 12.05 g (97% of theory); LC (method 1): tR=3.32 min; Mass spectrum (ESI+): m/z=211 [M+H]+.
97%
With potassium phosphate;palladium diacetate; catacxium A; In toluene; at 100℃; for 3.5h;Inert atmosphere;
Step 1 : 3-(3-methoxy-phenyl)-pyridine-2-carbonitrile A flask charged with a stir bar, <strong>[38180-46-0]3-chloro-2-cyanopyridine</strong> (8.16 g), 3-methoxyphenylboronic acid (13.42 g), K3P04 (25.00 g), and toluene (100 mL) is sparged with argon for 10 min. Palladium(ll) acetate (0.13 g) and n-butyl-di-(1-adamantyl)-phosphine (0.42 g) are added and the resulting mixture is put in a 100 C hot oil bath and stirred in there for 3.5 h. After cooling to room temperature, ethyl acetate (250 mL) is added and the mixture is washed with 2 M aqueous NaOH solution and brine. The organic phase is dried (Na2S04) and the solvent is evaporated. The residue is triturated with methanol and dried to give the title compound as a colorless solid. Yield: 12.05 g (97% of theory); LC (method 1 ): tR = 3.32 min; Mass spectrum (ESI+): m/z = 21 1 [M+H]+.
97%
With potassium phosphate; n-butyl-di-(1-adamantyl)-phosphine;palladium diacetate; In toluene; at 100℃; for 3.5h;Inert atmosphere;
Step 1 : 3-(3-methoxy-phenyl)-pyridine-2-carbonitrileA flask charged with a stir bar, <strong>[38180-46-0]3-chloro-2-cyanopyridine</strong> (8.16 g), 3-methoxyphenylboronic acid (13.42 g), K3P04 (25.00 g), and toluene (100 ml_) is sparged with argon for 10 min. Palladium(ll) acetate (0.13 g) and n-butyl-di-(1 -adamantyl)-phosphine (0.42 g) are added and the resulting mixture is put in a 100 ^ hot oil bath and stirred in there for 3.5 h. After cooling to room temperature, ethyl acetate (250 ml_) is added and the mixture is washed with 2 M aqueous NaOH solution and brine. The organic phase is dried (Na2S04) and the solvent is evaporated. The residue is triturated with methanol and dried to give the title compound as a colorless solid. Yield: 12.05 g (97% of theory); LC (method 1 ): tR = 3.32 min; Mass spectrum (ESI+): m/z = 21 1 [M+H]+.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In water; N,N-dimethyl-formamide; for 0.25h;Inert atmosphere; Microwave irradiation;
General procedure: A 30-mL screw-cap culture tube was charged with 2-chloro-3-nitropyridine (3.16 mmol), phenyl boronic acid (3.80 mmol, 1.2 equiv), and DMF (10 mL). Pd(PPh3)4 (5% eq) and K2CO3 (0.3 mL of 2 M aqueous solution, 0.60 mmol, 2 equiv) were added to the tube sparged with N2 for 5 min. The reaction mixture was stirred and then irradiated for 15 min at 50 W. The resulting mixture was diluted with ethyl acetate and washed with water and brine, and then was dried over anhydrous Na2SO4. The residue was concentrated with an evaporator, and purified by flash chromatography on silica gel using petroleum ether/ethyl acetate as the eluent, yielded the desired product.
Example 114b 3-amino-3'-methoxy-[1,1'-biphenyl]-2-carbonitrile To a stirred solution of <strong>[77326-62-6]2-amino-6-bromobenzonitrile</strong> (195 mg, 1.0 mmol) and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) was added aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reaction solution was degassed by bubbling N2 for 2 minutes. Palladium tetrakistriphenylphosphine (5% mol) was added to the reaction mixture and the reaction vessel was placed in a microwave reactor and irradiated at 165 C. for 20 minutes. The precipitate was removed by filtration and the filtrate concentrated. The residue was purified by HPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the title compound as an off-white solid (180 mg, 80%). MS 225 (MH+).
80%
In 1,4-dioxane;
Example 114b 3-amino-3'-methoxy-[1,1'-biphenyl]-2-carbonitrile To a stirred solution of <strong>[77326-62-6]2-amino-6-bromobenzonitrile</strong> (195 mg, 1.0 mmol) and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) was added aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reaction solution was degassed by bubbling N2 for 2 minutes. Palladium tetrakistriphenylphosphine (5% mol) was added to the reaction mixture and the reaction vessel was placed in a microwave reactor and irradiated at 165 C. for 20 minutes. The precipitate was removed by filtration and the filtrate concentrated. The residue was purified by HPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the title compound as an off-white solid (180 mg, 80%). MS 225 (MH+).
With copper diacetate; triethylamine; In dichloromethane;
Intermediate 25: 2-Chloro-5-(3-methoxyphenoxy)pyrimidine A mixture of <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (l .Og, 7.66mmol), 3-methoxyphenyl boronic acid (1.16g, 7.66mmol), copper (II) acetate (1.39g, 7.66mmol), triethylamine(5.34mL, 7.66mmol) and powdered 4A molecular sieves in dichloromethane (30mL) was stirred under air for 3 days. A calcium chloride guard tube was used to protect the reaction from moisture. The reaction mixture was diluted with dichloromethane, filtered and washed with water and brine. The organic phase was dried (MgS04), the solvent removed under reduced pressure and the crude product was purified by flash chromatography, using 0-15percent ethyl acetate:hexane as eluent, to provide 2-chloro-5- (3-methoxyphenoxy)-pyrimidine (0.448g, 25percent) as yellow oil.Mass: (ES+) 237 (M+H)+ NMR: deltaEta (CDC13) 3.82 (3H, s), 6.63 (2H, m), 6.81 (IH, br d), 7.33 (IH, t) and 8.39 (2H, s).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In toluene; at 110℃; for 3h;
General procedure: To a argon degassed solution of <strong>[126728-20-9]2,4-dichloropyrido[2,3-d]pyrimidine</strong> 1 (100 mg, 0.5 mmol) in toluene (6 mL) were successively added the desired (het)aryl boronic acid (1.05 equiv), potassium carbonate (1.5 equiv), and Pd(PPh3)4 (29 mg, 0.05 equiv). The reaction mixture was heated at 110 C under vigorous stirring for the desired time. After complete disappearance of 1, water (10 mL) was added. After extraction with CH2Cl2 (3×10 mL), the combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The crude material was purified by column chromatography to afford compounds of type I.
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In ethanol; toluene; at 120℃; for 0.25h;Microwave irradiation;
6-(3-methoxy-phenyl)-pyrazin-2ylamine To a solution of <strong>[33332-28-4]2-amino-6-chloropyrazine</strong> (0.5 g, 3.85 mmol) in a mixture of toluene/ethanol (4:1 , 10 ml), 3-methoxyphenylboronic acid (0.64 g, 4.24 mmol), tetrakis(triphenylphosphino)palladium(0) (0.13 g, 0.11 mmol) and cesium carbonate (2.51 g, 7.71 mmol) are added, degassed briefly and irradiated in microwave at 120°C for 15 minutes. The reaction mixture is passed through celite, washed with dichloromethane, the filterate is concentrated and purified by column using silica gel (60-120) mesh to get the product as yellow solid (0.34 g, 44.15 percent); TLC: Pet ether/Ethylacetate(7/3) Rf - 0.2; 1H NMR: 400 MHz, DMSO-d6: delta [ppm] 8.27 (s, 1 H), 7.83 (s, 1H), 7.57-7.52 (m, 2H), 7.37 (t, J = 7.88 Hz, 1 H), 7.00-6.97 (m, 1 H), 6.51 (br s, 2H), 3.80 (s, 3H); LCMS: Mass found (M+, 202.3) Method: A-0.1 percent TFA in H20, B-0.1 percent TFA in ACN: Flow - 2.0ml/min. Column: XBridge C8 (50 X 4.6 mm, 3.5 pm), +ve mode Rt (min): 2.48 area percent -98.79 (Max), 99.35 (254 nm).
With oxygen; sodium hydroxide; copper dichloride; In methanol; for 8h;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;
<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%).
89%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 120℃; for 1h;Inert atmosphere; Microwave irradiation;
Example 2.2. Preparation of (3- 3-methoxyphenyl)-lH-indazole [00284] iert-Butyl 3-iodo-lH-indazole-l- carboxylate (100 mg, 0.29 mmol) was placed in a suitably sized microwave vial and dissolved in 1,4- dioxane (11.5 ml). 3-Methoxyphenyl boronic 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 turbid orange mixture was sparged thoroughly with nitrogen. An aqueous solution of sodium carbonate (2.0 M, 0.65 ml, 1.31 mmol, 4.5 equiv) was then added. The biphasic mixture was microwaved for 1 hour at a reaction temperature of 120 C. 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 orange oil (58.0 mg, 89%). 1H NMR (300 MHz, CDC13): delta 12.71 (s, 1H), 8.00 (d, J = 8.2, 1H), 7.69 - 7.53 (m, 2H), 7.44 (t, J = 1.9, 1H), 7.31 - 7.22 (m, 1H), 7.17 (dd, J = 4.9, 13.0, 1H), 7.05 (d, J = 8.3, 1H), 7.03 - 6.98 (m, 1H), 3.79 (s, 3H); 13C NMR (75 MHz, CDC13): delta 160.1, 145.4, 141.7, 134.8, 130.0, 126.7, 121.3, 120.9, 120.8, 120.3, 114.2, 113.0, 110.5, 55.3; ESI-MS: m/z 224.
4-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With potassium fluoride; bis(tri-tert-butylphosphine)palladium(0); In 1,4-dioxane; water; at 20 - 150℃; for 0.583333h;Inert atmosphere; Microwave irradiation;
Example 1 4-(3-Methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile A mixture of <strong>[920965-87-3]4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile</strong> (0.1 g, 0.56 mmol), 3-methoxyphenylboronic acid (0.094 g, 0.62 mmol), potassium fluoride (0.098 g, 1.6.9 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.003 g, 0.006 mmol), 1,4-dioxane (6 mL) and water (1 mL) was stirred at room temperature for 5 min under a stream of nitrogen. The stirred reaction mixture was then heated with microwaves at 150 C. for 30 min and cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (2*20 mL), followed by brine (20 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was triturated with dichloromethane, and the residue was dried in vacuo to afford a light yellow solid (0.061 g, 44%), identified as 4-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS (Method B) (m/z) 250 (MH+); tR=1.14. 1H NMR (DMSO-d6, 400 MHz) delta: 12.98 (1H, s, br), 8.52 (1H, s), 8.44-8.43 (1H, d), 7.46-7.42 (1H, m), 7.28-7.27 (1H, d), 7.19-7.16 (2H, m), 7.07-7.04 (1H, m), 3.85 (3H, s).
44%
With potassium fluoride; bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 150℃; for 0.583333h;Inert atmosphere; Microwave irradiation;
A mixture of 4-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonitrile (0.1 g, 0.56 mmol), 3-methoxyphenylboronic acid (0.094 g, 0.62 mmol), potassium fluoride (0.098 g, 1.6.9 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.003 g, 0.006 mmol), 1,4-dioxane (6 mL) and water (1 mL) was stirred at room temperature for 5 min under a stream of nitrogen. The stirred reaction mixture was then heated with microwaves at 150 C for 30 min and cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic phase was separated, washed with water (2x 20 mL), followed by brine (20 mL), dried (MgSC^) and evaporated under reduced pressure. The residue was triturated with dichloromethane, and the residue was dried in vacuo to afford a light yellow solid (0.06 lg, 44%), identified as 4-(3- methoxyphenyl)-lH-pyrrolo[2,3-b]pyridine-3-carbonitrile. LC-MS (Method B) (m/z) 250 (MH+); tR = 1.14. 1H NMR (DMSO-d6, 400 MHz) delta: 12.98 (1 H, s, br), 8.52 (1 H, s), 8.44-8.43 (1 H, d), 7.46-7.42 (1 H, m), 7.28-7.27 (1 H, d), 7.19- 7.16 (2 H, m), 7.07-7.04 (1 H, m), 3.85 (3 H, s).
With potassium fluoride; monophosphine 1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene; palladium diacetate; In water; toluene; at 70℃; for 20h;Inert atmosphere; Sealed tube;
A mixture of <strong>[1837-55-4]3,5-dichloropyridazine</strong> (157 mg), 3-methoxybenzeneboronic acid (157 mg) and KF (147 mg) in toluene (4 mL) and water (1 mL) was degassed with N2. Palladium(II) acetate (11 mg) and Q-phos (42 mg) were added and the mixture was further degassed with N2 and stirred in a sealed tube at 70C for 20 h. The mixture was cooled to rt, diluted with EA, filtered through a glass fibre filter and concentrated under reduced pressure. The crude residue was purified by CC (CombiFlash, EA-Hept 2-8), affording a white solid (127 mg; 58% yield). MSI (ESI, m/z): 221.1 [M+H+]; tR = 0.79 min.
General procedure: A suspension of 3-bromobenzaldehyde (200 mg; commercial) and (3-cyanophenyl)boronic acid neopentyl glycol ester (325 mg; commercial) in toluene/EtOH (2.3 mL; 1 : 1) was treated with sat. aq. Na2C03 (2.3 mL) and degassed by bubbling with nitrogen for 5 min. The suspension was treated with Pd(PPh3)4 (28 mg) and refluxed overnight in a sealed tube. The reaction mixture was allowed to reach rt and diluted with water and EA. The aq. layer was extracted with EA and the combined org. layers were washed with brine, dried over MgS04, filtered and evaporated under reduced pressure. After purification by CC (Hept/EA 2: 1 to 1 : 1), the title compound was obtained as an off-white solid (325 mg; quantitative yield). Starting from 3-methoxyphenylboronic acid (50 mg), 2-bromoisonicotinaldehyde (61 mg), tetrakis-(triphenylphosphine)-palladium (15 mg) and K2C03 (136 mg), and proceeding in analogy to Preparation A, 2-(3-methoxyphenyl)isonicotinaldehyde was obtained. The latter was reacted without purification with (R)-5-(2-aminoethyl)-3-(3-oxo-3,4-dihydro- 2H-benzo[£][l,4]thiazin-6-yl)oxazolidin-2-one (77 mg; prepared according to WO 2009/104147), in analogy to Example 1, affording after purification by prep-HPLC (Method 1), the title compound as a colourless powder (39 mg; 24percent yield).
4-(3-methoxyphenyl)-2-methylisoquinolin-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
17%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; triphenylphosphine; In 1,4-dioxane; water; at 90℃;
A mixture of <strong>[33930-63-1]4-bromo-2-methylisoquinolin-1(2H)-one</strong> (100 mg, 0.42 mmol), and (3-methoxyphenyl)boronic acid (70 mg, 0.46 mmol), PPh3 (66 mg, 0.25 mmol), Na2CO3 (133 mg, 1.26 mmol), and Pd(dppf)Cl2 (62 mg, 0.084 mmol) in dioxane (2.5 mL) and water (0.5 mL) was heated overnight at 90° C. Extractive work up with ethyl acetate followed by preparative TLC (PE:EA=1:1) gave the title compound (18 mg, 0.07 mmol) as a white solid in 17percent yield. 1H NMR (DMSO, 400 MHz): delta 8.30 (d, 1H, J=7.68), 7.68 (t, 1H, J=7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J=7.44), 6.97-7.00 (m, 3H), 3.78 (s, 3H), 3.54 (s, 3H). MS (m/z, relative intensity): 266 (M+, 1).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 165℃; for 0.333333h;Microwave irradiation; Inert atmosphere;
To a stirred solution of <strong>[77326-62-6]2-amino-6-bromobenzonitrile</strong> (195 mg, 1.0 mmol) and (3-methoxyphenyl)boronic acid (300 mg, 2 mmol) in dioxane (2 mL) was added aqueous potassium carbonate (2.0 mmol, 0.7 mL). The reaction solution was degassed by bubbling N2 for 2 minutes. Palladium tetrakistriphenylphosphine (5% mol) was added to the reaction mixture and the reaction vessel was placed in a microwave reactor and irradiated at 165 C. for 20 minutes. The precipitate was removed by filtration and the filtrate concentrated. The residue was purified by HPLC (acetonitrile/water; 10-90% gradient, 25 minutes) to give the title compound as an off-white solid (180 mg, 80%). MS 225 (MH+).
6-(3-methoxyphenyl)-2H,3H,4H-pyrido[3,2-b][1,4]oxazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
32%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere;
A mixture of 6-bromo-2H,3H,4H-pyrido[3,2-£][l,4]oxazin-3-one (1.82 g, 7.95 mmol), 3-methoxyphenylboronic acid (1.45 g, 9.54 mmol), and 2M aqueous Na2C03 solution (12 mL) in anhydrous 1,4-dioxane (80 mL) was degassed with nitrogen for 10 minutes. To the mixture was added bis(cyclopentyldiphenylphosphane) dichloro- palladium iron (294.7 mg, 0.4 mmol), and the resulting mixture was heated at 100C for 3 h. The reaction mixture was allowed to cool to r.t. before being diluted with EtOAc. The suspension was filtered through a pad of Celite, washing with EtOAc. The filtrate was concentrated in vacuo. Purification of the crude residue by column chromatography (0- 40% EtOAc:heptane) gave the title compound (32%). deltaEta (250 MHz, DMSO-de) 11.31 (s, 1H), 7.53 (m, 3H), 7.37 (dd, J 14.3, 8.0 Hz, 2H), 6.95 (m, 1H), 4.67 (s, 2H), 3.80 (s, 3H). Method D HPLC-MS: MH+ mlz 257, RT 1.72 minutes
2-(3-methoxyphenyl)-3-nitropyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 4h;Inert atmosphere;
j0684j A solution of <strong>[2789-25-5]2-chloro-3-nitropyridin-4-amine</strong> (LXVIII) (2 g, 11.52 mmol) and (3-methoxyphenyl) boronic acid (LXXXV) (1.751 g, 11.52 mmol) in 1,4-dioxane (20 mL) was added sodium carbonate (3.66 g, 34.6 mmol) in water (2 mL). The slurry was purged with argon for 1 minute before adding Pd(Ph3P)4 (0.666 g, 0.576 mmol). The reaction was heated at 90°C for 4 h. The reaction was extracted with a mixture of saturated NaHCO3-EtOAc. The product was purified by ISCO (0-50percent EtOAc-hexanes) to yield 2-(3-methoxyphenyl)-3-nitropyridin-4-amine (LXXXVI) as an orange oil (2.6 g, 10.60 mmol, 92.0percent yield). ESIMS found for C12H11N303 mlz 246.1 (M+H).
5-chloro-6-(3-methoxyphenyl)pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
360 mg
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; at 85.0℃; for 16.0h;Inert atmosphere;
A. 5-Chloro-6-(3-methoxyphenyl)pyridazin-3(2H)-one. To a 50-mL round-bottom flask was placed a solution of <strong>[17285-36-8]5,6-dichloro-2,3-dihydropyridazin-3-one</strong> (990 mg, 6.00 mmol) and (3- methoxyphenyl)boronic acid (900 mg, 5.91 mmol) in EtOH (45 mL) and water (9 mL) then Na2C03 (1062 mg, 10.02 mmol) and Pd(PPh3)4 (288 mg, 0.24 mmol) were added under nitrogen. The reaction was stirred for 16 h at 85°C, cooled to rt, and concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtO Ac/petroleum ether (2: 1) affording 360 mg of the title compound as a white solid. Mass Spectrum (LCMS, ESI pos): Calcd. for CiiH10ClN2O2+: 237.0 (M+H); Found: 237.0.
With tetrakis(triphenylphosphine) palladium(0); Aliquat 336; sodium carbonate; In water; toluene; at 100℃; for 4h;Inert atmosphere;
A dried 100-mL two-neck round-bottom flask was charged with methyl-<strong>[17100-65-1]2-bromo-4-methoxybenzoate</strong> (2.0 g, 8.2 mmol), 3- methoxyphenylboronic acid (1.86 g, 12.3 mmol), sodium carbonate (2.60 g, 24.6 mmol), toluene (20 mL) and water (20 mL) under argon atmosphere at room temperature. The resulting mixture was stirred and purged with argon for 10 minutes. Then Pd(PPh3)4 (0.47 g, 0.40 mmol) was added, and the reaction mixture was stirred at 100 C for 4 h. After 4 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), organic layer was washed with water, brine, dried over Na2SO4 and concentrated under vacuum to afford 1.8 g of a crude compound. The crude compound was purified by column chromatography (100-200 silica gel) using 5% EtOAc in petroleum ether to afford a colorless gummy compound (1.56 g, 70%). APCI+ (m/z) Calcd for C16H16O4 ([M+H]+) 273.11. Found 273.09.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene;Inert atmosphere; Reflux;
Toluene (9 mL), ethanol (6 mL) and water (3 mL) were added into the mixture of MU (1,02 g, 5 mmol) 4..bromo-2chloroaniline, (3.methoxyphenyl) boronic acid (0.76 g, 5 mmoi) and potassium carbonate (1.73 g, 12.5 mmol), stirred with nitrogen replacement for three times. Additional replacement with nitrogen was performed for three times after0.3 g of tetraphenyiphenyiphosphine palladium was added. Then the reaction waswarmed up for refiux reaction overnight. The product was filtered and concentrated, then20 mL of dichloromethane and 10 rnL of water were added and stirred for 10 mm. Theliquid was separated and washed with 10 mL of water twice, dried with anhydroussodium sulfate, filtered, concentrated and purified by column chromatography. 0.83 g ofM12 was achieved, with yield of 63%.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; ethanol; at 140℃; for 0.5h;Sealed tube; Microwave irradiation;
General procedure: tert-Butyl 3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 mol%), and 1,4-dioxane: ethanol = 4:1 (5 mL) were added to10 mL vial. The vial was sealed with a crimp cap and placed in a Biotage initiator microwave cavity. After thereaction vial was irradiated at 140 C for 30 min, themicrowave reactor was cooled with air. Product was separatedwith ethyl acetate and saturated aqueous NH4Cl solution.The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated. Products were purifiedby silica gel column chromatography using a hexane: ethylacetate = 4:1.
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; ethanol; at 140℃; for 0.5h;Sealed tube; Microwave irradiation;
General procedure: tert-Butyl 3-bromo 1H-indazole-1-carboxylate (0.5 mmol), Na2CO3(0.5 mmol), boronic acid (1.0 mmol), Pd(PPh3)2Cl2 (1 molpercent), and 1,4-dioxane: ethanol = 4:1 (5 mL) were added to10 mL vial. The vial was sealed with a crimp cap and placed in a Biotage initiator microwave cavity. After thereaction vial was irradiated at 140 C for 30 min, themicrowave reactor was cooled with air. Product was separatedwith ethyl acetate and saturated aqueous NH4Cl solution.The organic layer was dried with anhydrous sodiumsulfate, filtered, and concentrated. Products were purifiedby silica gel column chromatography using a hexane: ethylacetate = 4:1.
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 100℃; for 16h;
General procedure: To a well stirred solution of the respective halide, 1 (1 molar equiv.) in 4:1 ratio of 1,4-dioxane-water (0.6 M) were added boronic acid, 2 (1.2 molar equiv.), K3PO4 (2 molar equiv.) and Pd(dppf)Cl2.DCM (0.05 molar equiv.) sequentially at room temperature and degassed with argon for 5 minutes. The reaction mixture was heated at 100 C for 16 hours. The reaction mixture was cooled to room temperature, poured into ice-cold water and extracted with ethyl acetate. The combined organics was washed with water, brine, dried over sodium sulphate, filtered and concentrated under reduced pressure to give the crude product. This crude product was purified by column chromatography to afford the desired product, 3.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
