* 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 potassium carbonate In acetonitrile at 25℃; for 6 h;
A mixture of 3-bromo-4-hydroxybenzonitrile (5.0 g, 25.3 mmol), potassium carbonate (7.0 g, 50.1 mmol) and iodomethane (3.9 g, 2,7.8 mmol) in acetonitriie (20 ml) was stirred at 25°C for 6 hours. TLC showed the reaction was complete. The mixture was paititioned between etliyl acetate (100 mi) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted 30percent ethyl acetate in hexane) to afford 3-bromo-4-methoxybenzonitrile (4.8 g, 22.6 mmol, yield 89percent).
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1925 - 1934
14
[ 108-24-7 ]
[ 117572-79-9 ]
Reference：
[1] Journal of the Chemical Society, 1924, vol. 125, p. 1062
15
[ 108-24-7 ]
[ 117572-79-9 ]
Reference：
[1] Journal of the Chemical Society, 1924, vol. 125, p. 1062
16
[ 5419-55-6 ]
[ 117572-79-9 ]
[ 612833-37-1 ]
Yield
Reaction Conditions
Operation in experiment
79%
With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h;
3-Bromo-4-methoxybenzonitrile (7.7 g, 36 mmol) and 481 triisopropyl borate (14 g, 73 mmol)were dissolved by adding 20 tetrahydrofuran (150 mL), and 2.5 mol/L 27 n-butyllithium (hexanesolution, 22 mL, 55 mmol) was slowly added over 20 min at −78° C. After stirring at −78° C. for 2 hr, to thereaction mixture was added 7percent 482 phosphoric acid (100 mL), and the mixture was heated to roomtemperature. The reaction mixture was partitioned, to the organic layer was added 12 dichloromethane,and the mixture was extracted with 5percent aqueous sodium hydroxide solution (200 mL). The aqueous layer waswashed with diethyl ether, adjusted to pH2.5 with 85percent phosphoric acid and the insoluble material wascollected by filtration. The obtained solid was washed with water, and dried to give the 483 titlecompound ( 5.1 g , 29 mmol, 79percent). MS (ESI) m/z 178 (M+H)+ 1H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 2H), 7.86-7.78 (m, 2H), 7.13 (d, J=11.6 Hz, 1H), 3.85 (s, 3H).
79%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2 h; Stage #2: With phosphoric acid In tetrahydrofuran; hexane at 20℃;
To 3-Bromo-4-methoxybenzonitrile (7.7 g, 36 mmol) and triisopropyl borate (14 g, 73 mmol) was added tetrahydrofuran (150 mL) for dissolution, and 2.5 mol/L n-butyllithium (hexane solution, 22 mL, 55 mmol) was gradually added over 20 min at - 78°C. After stirring at -78°C for 2 hr, 7percent phosphoric acid (100 mL) was added to the reaction mixture and the mixture was heated to room temperature. The reaction mixture was partitioned, dichloromethane was added to the organic layer, and the mixture was extracted with 5percent aqueous sodium hydroxide solution (200 mL). The aqueous layer was washed with diethyl ether, adjusted to pH 2.5 by adding 85percent phosphoric acid and insoluble material was collected by filtration. The obtained solid was washed with water and dried to give the title compound (5.1 g, 29 mmol, 79percent). MS (ESI) m/z 178 (M+H)+1H NMR (300 MHz, DMSO-d6) δ 8.03 (s, 2H), 7.86 - 7.78 (m, 2H), 7.13 (d, J = 11.6 Hz, 1H), 3.85 (s, 3H).
Stage #1: With n-butyllithium; Triisopropyl borate In tetrahydrofuran; hexane at -78℃; for 1.33333 h; Cooling with acetone-dry ice Stage #2: With phosphoric acid In tetrahydrofuran; hexane; water at -78 - 20℃; Cooling with acetone-dry ice
To a 5-L, 3-neck flask fitted with an addition funnel and mechanical stirrer was added 3-bromo-4-methoxybenzonitrile (Lancaster; 159.0 g; 750 mmol), anhydrous THF (3.0 L), and triisopropylborate (345 mL; 282 g; 1.50 mol). The solution was cooled to-78 °C in a dry ice/acetone bath then a solution of 2.44 M n-butyllithium in hexane (461 mL; 1.12 mol) was added over a 20-minute period. After the addition was complete, the reaction mixture was stirred at-78 °C for 1 hour. The reaction mixture was quenched with 7percent aqueous phosphoric acid (2 L) and the reaction mixture was allowed to warm to room temperature. Stirring was stopped and the reaction mixture was allowed to stand overnight. The layers were separated, the aqueous phase discarded, and the organic phase was diluted with dichloromethane (2 L) and the organic phase was extracted with 5percent aqueous sodium hydroxide (2x1.7 L). The aqueous phase was washed with MTBE (1.5 L) then acidified to pH = 2.5 with 85percent aqueous phosphoric acid, resulting in the formation of a white precipitate. The precipitate was filtered and washed with water to give 2-methoxy-5-cyanophenylboronic acid (104 g, 78percent) as a white solid .
With sodium azide; triethylamine hydrobromide; In toluene;Heating / reflux;
In Scheme 36, the <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> 7 is converted to the tetrazole and alkylated to compounds 9 and 10 using reaction conditions described for intermediates 2,3, and 4 in Scheme 35. Intermediate 9 is carbonylated in the presence of a suitable coupling reagent such as a palladium catalyst, including bis (triphenylphosphinyl) chloride, palladium acetate, or palladium tetrakis triphenylphosphine, in the presence of a base such as a tertiary organic amine, including triethylamine or diisopropylethylamine, in a protic solvent such as methanol and under an atmosphere of carbon monoxide whose pressure and temperature may require as high as 500 psi and [100 XB0;C.] Compound 11 can then be converted to a variety of amides 13 utilizing the experimental conditions previously described in Scheme 35.
With potassium carbonate; In acetonitrile; at 25℃; for 6h;
A mixture of 3-bromo-4-hydroxybenzonitrile (5.0 g, 25.3 mmol), potassium carbonate (7.0 g, 50.1 mmol) and iodomethane (3.9 g, 2,7.8 mmol) in acetonitriie (20 ml) was stirred at 25C for 6 hours. TLC showed the reaction was complete. The mixture was paititioned between etliyl acetate (100 mi) and water (30 ml). The organic layer was collected, washed with brine (20 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted 30% ethyl acetate in hexane) to afford 3-bromo-4-methoxybenzonitrile (4.8 g, 22.6 mmol, yield 89%).
In DMF (N,N-dimethyl-formamide); at 20℃; for 3 - 12h;
The tetrazole of the present example was prepared by dissolving 4-hydroxy-3-bromo-4-hydroxy-benzonitrile in DMF and adding methyl iodide and stirring at RT for 3-12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water and brine. The resulting organic phase was then dried over Na2SO4 and concentrated in vacuo to yield the 3-bromo4-methoxy-benzonitrile. This compound then was used to form the corresponding tetrazole via the method described in Example 3.
To a 5-L, 3-neck flask fitted with an addition funnel and mechanical stirrer was added <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (Lancaster; 159.0 g; 750 mmol), anhydrous THF (3.0 L), and triisopropylborate (345 mL; 282 g; 1.50 mol). The solution was cooled to-78 C in a dry ice/acetone bath then a solution of 2.44 M n-butyllithium in hexane (461 mL; 1.12 mol) was added over a 20-minute period. After the addition was complete, the reaction mixture was stirred at-78 C for 1 hour. The reaction mixture was quenched with 7% aqueous phosphoric acid (2 L) and the reaction mixture was allowed to warm to room temperature. Stirring was stopped and the reaction mixture was allowed to stand overnight. The layers were separated, the aqueous phase discarded, and the organic phase was diluted with dichloromethane (2 L) and the organic phase was extracted with 5% aqueous sodium hydroxide (2x1.7 L). The aqueous phase was washed with MTBE (1.5 L) then acidified to pH = 2.5 with 85% aqueous phosphoric acid, resulting in the formation of a white precipitate. The precipitate was filtered and washed with water to give 2-methoxy-5-cyanophenylboronic acid (104 g, 78%) as a white solid .
(1S,2R)-4-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)benzeneboronic acid[ No CAS ]
[ 117572-79-9 ]
[ 497-19-8 ]
(1S,2R)-4'-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-6-methoxybiphenyl-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
tetrakis(triphenylphosphine)palladium (0); In ethanol; dichloromethane; toluene;
EXAMPLE 52 (1S,2R)-4'-(2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy)-6-methoxybiphenyl-3-carbonitrile Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.20 g, Example 33), <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (0.20 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.03 g) in toluene (5 ml) and ethanol (2 ml), with heating at 90 C. for 4 hours. After work up, the residue was purified by normal-phase HPLC eluding with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.17 g). MS(APCI) 389/390 (M+H)+ 1H-NMR(CDCl3); 8.52(1H, s); 8.46(1H, d); 7.60(1H, d); 7.56(2H, m); 7.40(2H, d); 7.23(1H, dd); 7.00(1H, d); 6.93(2H, d); 4.39(1H, m); 3.87(4H, m); 2.95(1H, m); 2.74(1H, m); 2.29(1H, br.s); 1.86(2H, m); 1.32(3H, d).
bis(acetonitrile) Pd(II) chloride(53 mg, 0.206 mmol)[ No CAS ]
[ 117572-79-9 ]
[ 177-11-7 ]
[ 6163-58-2 ]
1-(5-cyano-2-methoxyphenyl)-4-piperidone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium hexamethyldisilazane; In tetrahydrofuran; 1,4-dioxane; hexane; ethyl acetate; toluene;
EXAMPLE 5A 1-(5-cyano-2-methoxyphenyl)-4-piperidone 1,4-Dioxa-8-azaspiro[4.5]decane (1.47 g, 10.28 mmol), sodium bis(trimethylsilyl)amide (1 N in THF, 12 ml), and PdCl2(p(o-tolyl)3)2 [2 mol % catalyst prepared from bis(acetonitrile) Pd(II) chloride(53 mg, 0.206 mmol) and tri(o-tolyl)phosphine (125 mg, 0.52 mmol)] were added to a solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (1.82 g, 8.58 mmol) in toluene (40 ml). The reaction was stirred for 5 hours at 100 C. The reaction was concentrated in vacuo, diluted with water, and extracted with methylene chloride. The organic extract was concentrated in vacuo, and the residue purified by chromatography on silica gel using hexane/ethyl acetate (80/20) as the eluent to give 1-(5-cyano-2-methoxyphenyl)-4-piperidone ethylene ketal (900 mg, 38%). This ketal was dissolved in dioxane (15 ml) and HCl (6 N, 2.2 ml) and stirred at 100 C. for 2 h. The solution was cooled, quenched with saturated aqueous NaHCO3. The mixture was extracted with methylene chloride, concentrated in vacuo, and purified by chromatography on silica gel using hexane/ethyl acetate (80/20) as the eluent to give 1-(5-cyano-2-methoxyphenyl)-4-piperidone (125 mg, 19%).
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; under 3102.97 Torr; for 4h;
Example 26A Methyl 5-cyano-2-methoxybenzoate A mixture of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (20 g, 94 mmol), PdCl2(dppf)CH2Cl2 (2 g) and Et3N (25 mL, 179 mmol) in methanol (200 mL) were shaken under a 60 psi atmosphere of CO at 100 C. for 4 h. The mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (SiO2, 50% hexanes in EtOAc) to provide the title compound (16.7 g, 87 mmol, 93% yield). MS (DCI/NH3) m/z 192 (M+H)+.
93%
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; at 100℃; under 3102.97 Torr; for 4h;
Example 25A methyl 5-cyano-2-methoxybenzoate Commercially available 3-Bromo-4-methoxybenzonitrile (10 g, 47 mmol, Aldrich) in MeOH (100 mL) was treated with triethylamine (9.1 g, 12.5 mL, 90 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.0 g) in methylene chloride. The mixture was heated at 100 C. under CO at 60 psi for 4 hrs, filtered, and concentrated. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-50% EtOAc in hexanes) to afford 8.2 g (93%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-D) delta ppm 3.92 (s, 3H) 3.98 (s, 3H) 7.06 (d, J=8.54 Hz, 1H) 7.76 (dd, J=8.54, 2.14 Hz, 1H) 8.10 (d, J=2.14 Hz, 1H).
93%
With triethylamine;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; at 100℃; under 3102.97 Torr; for 4h;
Example 26; N-[(5Z)-4-butyl-2-tert-butylisothiazol-5(2H)-ylidene]-5-cyano-2-methoxybenzamide; Example 26A; methyl 5-cyano-2-methoxybenzoate; 3-Bromo-4-methoxybenzonitrile (10 g, 47 mmol) in MeOH (100 mL) was treated with triethyamine (9.1 g, 12.5 mL, 90 mmol) and PdCl2(dppf)CH2Cl2 (1.0 g). The mixture was heated at 100 0C under CO at 60 psi for 4 hrs, then filtered and the filtrate concentrated. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-50% Hexane in ethyl acetate) to afford 8.2 g (93 %) of the title compound. 1H NMR (500 MHz, CDCl3) delta ppm 3.92 (s, 3 H) 3.98 (s, 3 H) 7.06 (d, J=8.54 Hz, 1 H) 7.76 (dd, J=8.54, 2.14 Hz, 1 H) 8.10 (d, J=2.14 Hz, 1 H).
93%
With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 100℃; under 3102.97 Torr; for 4h;
Example 26 A; methyl 5-cyano-2-methoxybenzoate; 3-Bromo-4-methoxybenzonitrile (10 g, 47 mmol) in MeOH (100 mL) was treated with triethyamine (9.1 g, 12.5 mL, 90 mmol) and PdCl2(dppf)CH2Cl2 (1.0 g). The mixture was heated at 100 0C under CO at 60 psi for 4 hrs, then filtered and the filtrate concentrated. The residue was purified by column chromatography using an Analogix Intelliflash280 (SiO2, 0-50% Hexane in ethyl acetate) to afford 8.2 g (93 %) of the title compound. 1H NMR (500 MHz, CDCl3) delta ppm 3.92 (s, 3 H) 3.98 (s, 3 H) 7.06 (d, J=8.54 Hz, 1 H) 7.76 (dd, J=8.54, 2.14 Hz, 1 H) 8.10 (d, J=2.14 Hz, 1 H).
22%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; at 100℃; under 3102.97 Torr; for 4h;
A solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (32, 1 g, 4.72 mmol), triethylamine(954 mg, 9.43 mmol) and Pd(dppf)Cl2 (150 mg, 0.205 mmol) inMeOH (20 mL) was stirred at 100 C under CO atmosphere (60 psi)for 4 h. The reaction mixture was then cooled down, concentratedunder reduced pressure and the resulting crude material was purifiedby column chromatography on silica gel (PE/EtOAc =100/0-80/20) The title compound (200 mg, 22%) was obtained as awhite solid. 1H NMR (400 MHz, CDCl3): delta 8.11 (d, J = 2.0 Hz, 1H), 7.76(dd, J = 2.0, 8.5 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 3.98 (s, 3H), 3.92 (s,3H). MS m/z 192 [M+H]+.
Example 76 [3-Bromo-4-(methyloxy)phenyl]methyl}amine <strong>[117572-79-9]3-Bromo-4-(methyloxy)benzonitrile</strong> (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. The mixture was then heated to 50 C. for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3* with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3* with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound.
With borane-THF; In tetrahydrofuran; for 240h;Reflux;
Example 76 [3-Bromo-4-(methyloxy)phenyl]methyl}amine <strong>[117572-79-9]3-Bromo-4-(methyloxy)benzonitrile</strong> (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. The mixture was then heated to 50 C. for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3* with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3* with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound.
Example 91 [3-Bromo-4-(methyloxy)phenyl]methyl}amine <strong>[117572-79-9]3-Bromo-4-(methyloxy)benzonitrile</strong> (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux. The additional 1.5 M borane in THF (30 mL, 45 mmols) and reflux continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total of ten days to drive the reaction to completion. The reaction was worked up by the cautious addition of ethanol followed by 1N HCl until the pH was 2. This mixture was then heated to 50 C. for 4 h. The solvents were pumped off, and the residue partitioned between EtOAc and water. The aqueous phase was washed 3* with EtOAc and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3* with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give the title compound. LC-MS m/z 198.7 (M-NH2), 0.99 min (ret time).
Example 76 [3-Bromo-4-(methyloxy)phenyl] methyl} amine<strong>[117572-79-9]3-Bromo-4-(methyloxy)benzonitrile</strong> (2.12 g, 10 mmol), THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) were combined and stirred under argon at reflux, Then additional 1.5 M borane in THF (30 mL, 45 mmols) was added and refluxing was continued. THF (30 mL), and 1.5 M borane in THF (30 mL, 45 mmols) was again added and the mixture refluxed for a total often days to drive the reaction to completion. Reaction worked up by the cautious addition of ethanol followed by IN HCl until the pH was 2. The mixture was then heated to 50 0C for 4 h. The solvents were pumped off and the residue partitioned between EtOAc and water. The aqueous phase was washed 3X with EtOAc, and adjusted to pH 10 by the addition of 2.5 N NaOH. The aqueous phase was extracted 3X with EtOAc. The combined organic phases were dried over anhydrous Na2SOzI, filtered and evaporated to give the title compound.
With lithium chloride;bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 135℃; for 0.5h;Microwave irradiation;
3-ethyl-4-methoxybenzonitrile (12-2)To a solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (12-1, 0.3 g, 1.42 mmol) in DMF (14 mL) was added tetraethyltin (0.56 mL, 2.83 mmol), bis(tri-t-butylphosphine) palladium(O) (0.072 g, 0.141 mmol), and lithium chloride (0.18 g, 4.24 mmol) and the system was heated to 135 C for 30 minutes in a microwave reactor. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to yield the desired product (12-2) as a clear oil. ESI+ MS [M+H]+ Ci0Hi iNO: 162.1 found, 162.2 required.
With lithium chloride;bis(tri-t-butylphosphine)palladium(0); In N,N-dimethyl-formamide; at 135℃; for 0.5h;Microwave irradiation;
3-ethyl-4-methoxybenzonitrile (6-2)To a solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (6-1, 0.3 g, 1.42 mmol) in DMF (14 mL) was added tetraethyltin (0.56 mL, 2.83 mmol), bis(tri-t-butylphosphine) palladium(0) (0.072 g, 0.141 mmol), and lithium chloride (0.18 g, 4.24 mmol) and the system was heated to 135 C. for 30 minutes in a microwave reactor. The mixture was partitioned between saturated NaHCO3 and EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica gel (0 to 10% EtOAc in hexanes) to yield the desired product (6-2) as a clear oil. ESI+MS [M+H]+C10H11NO: 162.1 found, 162.2 required.
With potassium phosphate; tricyclohexylphosphine;palladium diacetate; In water; toluene; at 80℃; for 19h;
3-cvclopropyl-4-methoxybenzonitrile (8-2)A mixture of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (8-1., 5.0g, 23.6 mmol, 1.0 eq), aqueous potassium phosphate tribasic (65.0 ml, 1.27 M, 3.5 eq), cyclopropylboronic acid (10.1 g, 1 18 mmol, 5.0 eq), Pd(OAc)2 (0.539 g, 2.36 mmol, 0.1 eq) and tricyclohexylphosphine (0.661 g, 2.36 mmol, 0.1 eq) was stirred in degassed toluene (103 ml) and heated to 80 C for three hours. An additional amount of cyclopropylboronic acid (1.Og, 1.16 mmol, 0.5 eq) was added and the solution was further heated for 16 hours at 8O0C to complete the reaction. The reaction mixture was cooled and partitioned between brine and EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated to give an orange oil. The oil was purified by normal phase column chromatography (0 to 10% EtOAc in hexanes) to afford the product (8-2) as a yellow oil. 1H NMR (CDCl3) ? 7.44 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J= 2.0 Hz), 6.86 (d, 1H, J= 8.4 Hz), 3.92 (s, 3H), 2.13 (m, 1H), 0.97 (m, 2H), 0.65 (m, 2H).
With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 80℃; for 19h;
3-cyclopropyl-4-methoxybenzonitrile (2-2)A mixture of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (2-1, 5.0 g, 23.6 mmol, 1.0 eq), aqueous potassium phosphate tribasic (65.0 ml, 1.27 M, 3.5 eq), cyclopropylboronic acid (10.1 g, 118 mmol, 5.0 eq), Pd(OAc)2 (0.539 g, 2.36 mmol, 0.1 eq) and tricyclohexylphosphine (0.661 g, 2.36 mmol, 0.1 eq) was stirred in degassed toluene (103 ml) and heated to 80 C. for three hours. An additional amount of cyclopropylboronic acid (1.0 g, 1.16 mmol, 0.5 eq) was added and the solution was further heated for 16 hours at 80 C. to complete the reaction. The reaction mixture was cooled and partitioned between brine and EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated to give an orange oil. The oil was purified by normal phase column chromatography (0 to 10% EtOAc in hexanes) to afford the product (2-2) as a yellow oil. 1H NMR (CDCl3) delta 7.44 (dd, 1H, J=8.4, 2.0 Hz), 7.09 (d, 1H, J=2.0 Hz), 6.86 (d, 1H, J=8.4 Hz), 3.92 (s, 3H), 2.13 (m, 1H), 0.97 (m, 2H), 0.65 (m, 2H).
With potassium phosphate;palladium diacetate; tricyclohexylphosphine; In water; toluene; at 80℃; for 19h;
3-cvclopropyl-4-methoxybenzonitrile (5-2)A mixture of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (5J., 5.Og, 23.6 mmol, 1.0 eq), aqueous potassium phosphate tribasic (65.0 ml, 1.27 M, 3.5 eq), cyclopropylboronic acid (10.1 g, 118 mmol, 5.0 eq), Pd(OAc)2 (0.539 g, 2.36 mmol, 0.1 eq) and tricyclohexylphosphine (0.661 g, 2.36 mmol, 0.1 eq) was stirred in degassed toluene (103 ml) and heated to 800C for three hours. An additional amount of cyclopropylboronic acid (1.Og, 1.16 mmol, 0.5 eq) was added and the solution was further heated for 16 hours at 800C to complete the reaction. The reaction mixture was cooled and partitioned between brine and EtOAc. The organic phase was dried over sodium sulfate, filtered and concentrated to give an orange oil. The oil was purified by normal phase column chromatography (0 to 10% EtOAc in hexanes) to afford the product (5^2) as a yellow oil. 1H NMR (CDCl3) delta 7.44 (dd, IH, J=8.4, 2.0 Hz), 7.09 (d, IH, J= 2.0 Hz), 6.86 (d, IH, J= 8.4 Hz), 3.92 (s, 3H), 2.13 (m, IH), 0.97 (m, 2H), 0.65 (m, 2H).
Example 57i (3-Bromo-4-methoxyphenyl)(cyclopropyl)methanimine 3-Bromo-4-methoxybenzonitrile (2.00 g, 9.43 mmol) and copper(I) bromide (0.068 g, 0.47 mmol) were dissolved in THF (15.0 mL) under argon and then heated to 40 0C.Cyclopropylmagnesium bromide (0.5 M in THF) (20.75 mL, 10.38 mmol) was added. The resulting mixture was stirred at 40 0C for 3 h, then additional cyclopropylmagnesium bromide (0.5 M in THF) (9.43 mL, 4.72 mmol) was added and the resulting mixture was stirred at 40 C for 2 h. The reaction was quenched by addition of ammonium acetate (1.091 g, 14.15 mmol) in methanol (30.0 mL). The mixture was partitioned between water and dichloromethane (twice). The organic layers were collected and concentrated in vacuo to give crude (3-bromo-4-methoxyphenyl)(cyclopropyl)methanimine (2.57 g,quantitative yield) That was used as such in the next step: MS (APCI+) m/z 254, 256 [M+H]+.
<strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (5.22 g, 24.62 mmol) was added to rapidly stirring fuming nitric acid (10 ml, 201 mmol) at 00C. The ice bath was removed and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with ethyl acetate and water, and then the organic layer was washed with water and brine, dried ( sodium sulfate), filtered, and concentrated in vacuo to afford the title compound, which was carried on without further purification.
-tert-butyl 1-(5-cvano-2-methoxyphenyl)hvdrazine-1 ,2-dicarboxylate To a stirred solution of 5 g (23.58 mmol) <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> in 100 ml THF, a solution of 21.77 ml (1.3 M, 28.3 mmol) isopropyl magnesium chloride. LiCI in THF was added drop wise under Ar at -78C. The reaction mixture was allowed to warm up at RT and after 3 hours, 5.43 g (23.58 mmol) di-tertbutyl azodicarboxylate was added and the reaction mixture was stirred for 3 hours at RT. The reaction mixture was diluted with saturated NH4CI, then extracted twice with EtOAc. The organic layers were combined and washed with saturated NaHC03, dried over Na2S04 and evaporated. The crude product was purified by chromatography (silicagel, hexane, EtOAc 95:5 to 70:30) to afford 5.49 g (15.11 mmol, 64.1 % yield) of the title compound as yellow solid. TLC: Rf = 0.55 (hexane/EtOAc 1 : 1). LCMS: (M-H) = 362.2; tR = 1.16 min (LC-MS 1). 1 H NMR (400 MHz, DMSO-d6) delta ppm 9.61 (s, 1 H) 7.75 (dd, 1 H) 7.60 (s, 1 H) 7.23 (d, 1 H) 3.86 (s, 3H) 1.41-1.29 (m, 18H).
5.5 g
Isopropylmagnesium chloride-lithium chloride complex (1 .3 M in THF, 21.8 mL, 28.3 mmol) was added dropwise to a cold (-78C) solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (5 g, 23.6 mmol) in THF (100 mL), under argon. The reaction mixture was allowed to warm to rt. Di- tertbutyl azodicarboxylate (5.43 g, 23.58 mmol) was added. The reaction mixture was stirred for 3 h at rt, diluted with a saturated aqueous solution of ammonium chloride (175 mL), and extracted with EtOAc. The organic layers were combined, washed with a saturated solution of sodium bicarbonate, dried (Na2S04), and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc, 95:5? 7:3) to provide 5.5 g of the title compound. tR: 1.16 min (LC-MS 4); ESI-MS: 362.2 [M-H]"(LC-MS 4); Rf= 0.55(hexane/EtOAc, 1 :1 ).
With palladium diacetate; XPhos; In toluene; tert-butyl alcohol; at 90℃; for 16h;Reflux; Inert atmosphere;
Example 194-[4- (4-fluoro-2-methoxyphenyl)piperazin- I -yI]-1 -phenyl- I H-pyrazolo[ 3,4- d ] pyri midi ne To a so[ution of 300 mg (1.07 mmo[) of intermediate 8A) and 250 mg (1.18 mmo[) 3-bromo-4-methoxybenzonitri[e in a mixture of 6 mL to[uene and 6 mL tert.-butano[24.0 mg (0.11 mmo[) Pa[[adium(II)acetate and 51.0 mg (0.11 mmo[) Xphos were added and the reaction mixture was heated to ref[ux under an N2-atmosphere for 7 hours and at 90CC for 16 hours. After coo[ing to rt the mixture was fi[tered and to the fi[trate water and ethy[ acetate were added. After separation of the phases thewater-phase was extracted again with ethy[ acetate. The combined organic phases were washed with brine and dried with sodium su[fate. After fi[tration and evaporation in vacuo the resu[ting raw materia[ was purified twice with a Biotage Chromatography system (10 g snap co[umn, hexane p[us 0 to 100% ethy[ acetate, then ethy[ acetate p[us 0 to 100% methano[). The given materia[ (94 mg) was stirred inether, then dried and gave the desired materia[: 50 mg (11% yie[d, 95% purity).1H-NMR (300 MHz, DMSO d6) 6 (ppm) = 3.16 (d, 4H), 3.89 (5, 3H), 4.06 - 4.13 (m, 4H),7.13 (d, 1H), 7.28 (d, 1H), 7.30 - 7.36 (m, 1H), 7.45 - 7.57 (m, 3H), 8.11 - 8.17 (m,2H), 8.39 (5, 1H), 8.62 (5, 1H).
With sodium azide; ammonium cerium (IV) nitrate; In N,N-dimethyl-formamide; at 110℃; for 6h;Inert atmosphere; Green chemistry;
General procedure: sodiumazide (1.5 mmol) was added to a magnetically stirred solution of nitrile 1a(1 mmol) in anhydrous DMF and the CAN (10 mmol %) was added. The reactionmixture was constantly stirred for another 6 h at 110 C under nitrogenatmosphere. After the completion of reaction as seen by TLC, the reactionmixture was brought to room temperature and the solvent was evaporatedunder vacuum. The crude thus obtained, was dissolved in ethyl acetate (20 mL)and solution was washed with acidified water (4 M HCl, 15 mL) twice.Separated organic layer was washed with brine solution dried overanhydrous Na2SO4, and solvent was removed under high vacuum to obtaintetrazole 1b as a white crystalline solid in 97% yield.
93%
With sodium azide; silver; In N,N-dimethyl-formamide; at 120℃; for 8h;
General procedure: Briefly, AgNPs (20 mol%) was added to the reaction mixture ofthe solution of benzonitrile (0.206 g, 2 mmol) in DMF (3 ml) andsodium azide (0.195 g, 3 mmol) with stirring for 8 h at 120C. Thereaction was monitored by TLC and solvent removed in vacuoon completion of reaction. The crude product was then dilutedby ice cooled water and centrifuged. The pH of the solution wasadjusted to 2-3 by addition of 6 N HCl and extracted with ethyl-acetate. The resultant organic layer was separated and aqueous layer was extracted again with ethylacetate (3 × 20 mL). The com-bined organic layer was concentrated in vacuo to yield the crudewhite crystalline solid 5-phenyltetrazole in 82-93% yield. The crudetetrazole was then recrystallized by mixture of solvents (50% ethylacetate in hexane) and subsequently characterized by1HNMR,13CNMR, IR and crystallography.
80%
With sodium azide; lead(II) chloride; In N,N-dimethyl-formamide; at 120℃; for 10h;Inert atmosphere;
General procedure: Benzonitrile (103 mg, 1 mmol) and sodium azide (97.5 mg, 1.5 mmol) were dissolved in 2 ml of dry DMF in a 25 ml round bottom flask. PbCl2 (27.8 mg, 0.1 mmol, 10 mol %) was added to the reaction mixture and stirred at 120 C for 8 h under nitrogen. After completion of the reaction (as monitored by TLC), the reaction mixture was cooled to room temperature and 10 ml of ice water was added followed by addition of 3 N HCl until the reaction mixture became strongly acidic (pH 2-3). The reaction mixture was extracted three times with 20 ml ethyl acetate. The organic layer was washed with brine solution and dried over anhydrous sodium sulfate, and was evaporated under reduced pressure to give a white solid product of 5-phenyl 1H-tetrazole with 81% yield.
78%
With sodium azide; silver nitrate; In N,N-dimethyl-formamide; at 20 - 120℃; for 5h;
General procedure: Sodiumazide (0.378 g, 0.046 mmol) was added to a solution of AgNO3 (5 mg, 10 mmol)in DMF (5 ml) and reaction mixture was stirred for 5 min, to this stirredsolution benzonitrile 1a (0.4 ml, 0.033 mmol) was added dropwise over theperiod of 1 min at room temperature and stirring continued for 10 min at thesame temperature and then heated at 120 C for 5 h. After consumption of 1a,the reaction mixture was cooled to room temperature and chilled by addingcrushed ice into the reaction mixture followed by addition of 2 N HCl tillreaction mixture reached the pH 2. The reaction mixture was then extractedwith ethyl acetate. The organic layer was dried with anhydrous Na2SO4, andconcentrated to obtain tetrazole 2a in 83% yield as an off white solid (268 mg).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 14h;Inert atmosphere; Sealed tube;
Example 46 2-[Ethyl-(4-fluoro-benzenesulfonyl)-amino]-N-(6-methoxy-4'-trifluoromethyl-biphenyl-3- ylmethyl)-acetamide A solution of 4,4,5,5-tetramethyl-2-(4-trifluoromethyl-phenyl)-[l,3,2]dioxaborolane(1.00 g, 3.68 mmol), <strong>[117572-79-9]3-bromo-4-methoxy-benzonitrile</strong> (0.78 g, 3.68 mmol) and potassium carbonate (0.51 g, 3.68 mmol) in DMF (5 mL) at 25C was purged with nitrogen gas and evacuated three times. The solution was then treated with teira 3s(triphenylphosphine)palladium(0) (212 mg, 184 muiotaetaomicron) and then sealed and heated to 120C for 14 h. The reaction mixture was cooled to 25 C, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 6-methoxy- 4'-trifluoromethyl-biphenyl-3-carbonitrile (0.80 g, 79%) as a white solid.
4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In dimethyl sulfoxide; at 100℃; for 3h;Inert atmosphere;
Step 12.1 : 4-Methoxy-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile To a solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (3 g, 14.15 mmol), bis(pinacolato)diboron (7.2 g, 28.4 mmol) and potassium acetate (4.2 g, 42.8 mmol) in DMSO (50 ml), PdCI2(dppf)-CH2Cl2 adduct (1.15 g, 1.408 mmol) were added under argon and the mixture was degassed and stirred at 100 C for 3 hour. The reaction mixture was quenched with saturated NaHC03 and extracted with EtOAc. The organic phase was dried (Na2S04), filtered and concentrated to dryness. The crude product was purified by chromatography (Silicagel, heptane, EtOAc). The pure fractions were recombined and concentrated under reduced pressure to give 3.46 g (13.09 mmol, 92% yield) of the title compound as a colourless oil. 1 H-NMR (d6-DMSO, 400.13 MHz) delta ppm 7.92 (d, 1 H) 7.80 (s, 1 H) 7.14 (d, 1 H) 3.82 (s, 3H) 1.26 (s, 12H).
68%
With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); potassium acetate; In 1,4-dioxane; dimethyl sulfoxide; at 20℃; for 2h;Inert atmosphere; Reflux;
To a stirred solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (5.0 g, 23.6 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.0 g, 35.4 mmol), and potassium acetate (6.9 g, 70.1 mmol) in dioxane (50 ml)-dimethyl sulfoxide (1 ml) was added 1,1-bis(diphenylphosphino)ferrocene palladium(II)dichloride (1.7 g, 2.3 mmol) at room temperature under nitrogen atmosphere; the mixture was degassed with nitrogen three times. The resulting mixture was refluxed for 2 hours. TLC showed the reaction was complete. The cooled reaction mixture was partitioned between ethyl acetate (100 mi) and water (80 ml). The organic layer was collected, and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layers were washed with brine (40 ml x 2), dried over anhydrous sodium, sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash chromatography (eluted with 10-33 % ethyl acetate in hexane) to afford 4-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (4.2 g, 16.2 mmol, yield 68%) as white solid. LC_MS: (ES+): m/z 260.0 [M+H]+
To a solution of <strong>[117572-79-9]3-bromo-4-methoxybenzonitrile</strong> (1 g, 4.72 mmol) in 10 mL of ethane- 1,2- diamine was added sulfur (0.121 g, 3.77 mmol) and the mixture was heated at 1 10C overnight. The mixture was cooled, quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine (25 mL each), dried over sodium sulfate, filtered, and concentrated to afford the title compound. LCMS: 257 (M+2)+.
tert-butyl 3-(4-(5-(1-(tert-butoxycarbonyl)-4,5-dihydro-1H-imidazol-2-yl)-2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)piperidine-1-carboxylate[ No CAS ]
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;
General procedure: Intermediate 23-bromo-4- isobutoxy benzonitrile nitrile (method a) preparation ofFor 100 ml to single-mouth bottle 5.0g (0.025mol) 3-bromo-4-hydroxy-benzonitrile (intermediate 1), 6.8g (0.05mol) bromo isobutane, 6.9g (0.05mol) potassium carbonate and water-free 25mLDMF, reaction under 80 C 3h, the response finishes, filtering, with a small amount of DMF (5 ml × 2) washing, collect filtrate, reducing pressure and evaporating about 1/3 solvent, the residue is dissolved in ethyl acetate is dissolved, two times washing with water, saturated salt water wash once, overnight drying by anhydrous sodium sulfate, concentrated to dry, to obtain light yellow oily 6.1g, yield: 96.0%, directly used for the next reaction.
77
[ 117572-79-9 ]
[ 57260-71-6 ]
tert-butyl 4-(5-cyano-2-methoxyphenyl)piperazine-1-carboxylate[ No CAS ]
With n-butyllithium; In tetrahydrofuran; hexane; at -78℃; for 2h;
3-Bromo-4-methoxybenzonitrile (7.7 g, 36 mmol) and 481 triisopropyl borate (14 g, 73 mmol)were dissolved by adding 20 tetrahydrofuran (150 mL), and 2.5 mol/L 27 n-butyllithium (hexanesolution, 22 mL, 55 mmol) was slowly added over 20 min at -78 C. After stirring at -78 C. for 2 hr, to thereaction mixture was added 7% 482 phosphoric acid (100 mL), and the mixture was heated to roomtemperature. The reaction mixture was partitioned, to the organic layer was added 12 dichloromethane,and the mixture was extracted with 5% aqueous sodium hydroxide solution (200 mL). The aqueous layer waswashed with diethyl ether, adjusted to pH2.5 with 85% phosphoric acid and the insoluble material wascollected by filtration. The obtained solid was washed with water, and dried to give the 483 titlecompound ( 5.1 g , 29 mmol, 79%). MS (ESI) m/z 178 (M+H)+ 1H NMR (300 MHz, DMSO-d6) delta 8.03 (s, 2H), 7.86-7.78 (m, 2H), 7.13 (d, J=11.6 Hz, 1H), 3.85 (s, 3H).
79%
To 3-Bromo-4-methoxybenzonitrile (7.7 g, 36 mmol) and triisopropyl borate (14 g, 73 mmol) was added tetrahydrofuran (150 mL) for dissolution, and 2.5 mol/L n-butyllithium (hexane solution, 22 mL, 55 mmol) was gradually added over 20 min at - 78C. After stirring at -78C for 2 hr, 7% phosphoric acid (100 mL) was added to the reaction mixture and the mixture was heated to room temperature. The reaction mixture was partitioned, dichloromethane was added to the organic layer, and the mixture was extracted with 5% aqueous sodium hydroxide solution (200 mL). The aqueous layer was washed with diethyl ether, adjusted to pH 2.5 by adding 85% phosphoric acid and insoluble material was collected by filtration. The obtained solid was washed with water and dried to give the title compound (5.1 g, 29 mmol, 79%). MS (ESI) m/z 178 (M+H)+ 1H NMR (300 MHz, DMSO-d6) delta 8.03 (s, 2H), 7.86 - 7.78 (m, 2H), 7.13 (d, J = 11.6 Hz, 1H), 3.85 (s, 3H).
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