* 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 Medicinal Chemistry, 2006, vol. 49, # 24, p. 7032 - 7043
[2] Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, 1983, vol. 38, # 7, p. 866 - 872
[3] Tetrahedron, 1965, vol. 21, p. 2231 - 2237
2
[ 68-12-2 ]
[ 150-78-7 ]
[ 5312-97-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 2 h; Stage #2: at 0℃; for 2 h; Stage #3: With ammonia; iodine In tetrahydrofuran; hexane; water at 0 - 20℃; for 2 h;
General procedure: n-Butyllithium (1.67 M solution in hexane, 2.9 mL, 4.8 mmol) was added dropwise into a solution of 1,3-dimethoxybenzene (0.55 g, 4.0 mmol) in THF (5 mL) at 0 °C and the mixture was stirred for 2 h at the same temperature. Then, DMF (0.34 mL, 4.4 mmol) was added to the mixture and the obtained mixture was stirred at 0 °C. After 2 h at the same temperature, aq NH3 (8 mL, 120 mmol) and I2 (1.12 g, 4.4 mmol) were added and stirred for 2 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (15 mL) and was extracted with Et2O (3.x.20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide 2,6-dimethoxybenzonitrile in over 80percent purity. The product was purified by a short column chromatography on silica gel (Hexane/EtOAc=3:1) to give pure 2,6-dimethoxybenzonitrile in 91percent yield as a colorless solid.
Stage #1: at 0℃; for 0.5 h; Stage #2: at 100℃; for 10 h; Stage #3: With ammonia; iodine In tetrahydrofuran; water; N,N-dimethyl-formamide at 20℃; for 3 h;
General procedure: To an ice cooled solution of N-methylformanilide (2.2 mmol) was added dropwise diphosphoryl chloride (2.2 mmol). The solution was stirred for 30 min at 0 °C, and then 1,2-dimethoxybenzene (276.3 mg, 2 mmol) in DMF (1.0 mL) was added dropwise. After being stirred for 10 h at 100 °C, I2 (1015.2 mg, 4 mmol), aq NH3 (4 mL, 28-30percent) and THF (1 mL) were added to the reaction mixture. The obtained mixture was stirred for 3 h at rt. After the reaction, the mixture was poured into aq satd Na2SO3 solution and extracted with CHCl3 (3.x.20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The product was purified by flash short column chromatography (Hexane:AcOEt=3:1) to afford 3,4-dimethoxybenzonitrile as a white solid in 92percent yield.
Stage #1: With Bromotrichloromethane; triphenylphosphine In dichloromethane for 0.416667 h; Reflux Stage #2: With triethylamine In dichloromethane for 8 h; Reflux
General procedure: BrCCl3 (940 mg, 4.8 mmol) was added to PPh3 (1.26 g, 4.8 mmol) in dry CH2Cl2 (14 mL). The resulting mixture was stirred at room temperature for 20 min, during which time the solution turned from yellow to red–brownish in colour. Thereafter,3,4-dimethoxybenzaldoxime (4i, 800 mg, 4.4 mmol) was added. The reaction mixture was heated under reflux for 25 min. Then, dry Et3N (485 mg, 4.8 mmol) was added dropwise with a syringe over 1 min. The reaction mixture was heated under reflux for 8 h. Thereafter, it was cooled to room temperature and added to cold water (50 mL). The mixture was extracted with dichloromethane (2 × 30 mL) and chloroform (30 mL). The combined organic phases were dried over anhydrous MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel (CH2Cl2/hexane 4 : 1) to give 3,4-dimethoxybenzonitrile (2q, 665 mg, 92percent) as a colourless solid.
Reference：
[1] Synlett, 2004, # 11, p. 2019 - 2021
[2] Journal of Chemical Research, 2014, vol. 38, # 2, p. 80 - 84
[3] Synthetic Communications, 1998, vol. 28, # 24, p. 4629 - 4637
5
[ 93-02-7 ]
[ 5312-97-0 ]
Reference：
[1] Synthesis, 1989, # 6, p. 451 - 452
[2] Journal of Organic Chemistry, 1985, vol. 50, # 8, p. 1182 - 1186
[3] Synthetic Communications, 1998, vol. 28, # 24, p. 4629 - 4637
[4] Tetrahedron Letters, 2013, vol. 54, # 17, p. 2177 - 2179
[5] Angewandte Chemie - International Edition, 2015, vol. 54, # 14, p. 4241 - 4245
General procedure: BrCCl3 (940 mg, 4.8 mmol) was added to PPh3 (1.26 g, 4.8 mmol) in dry CH2Cl2 (14 mL). The resulting mixture was stirred at room temperature for 20 min, during which time the solution turned from yellow to red-brownish in colour. Thereafter,3,4-dimethoxybenzaldoxime (4i, 800 mg, 4.4 mmol) was added. The reaction mixture was heated under reflux for 25 min. Then, dry Et3N (485 mg, 4.8 mmol) was added dropwise with a syringe over 1 min. The reaction mixture was heated under reflux for 8 h. Thereafter, it was cooled to room temperature and added to cold water (50 mL). The mixture was extracted with dichloromethane (2 × 30 mL) and chloroform (30 mL). The combined organic phases were dried over anhydrous MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel (CH2Cl2/hexane 4 : 1) to give 3,4-dimethoxybenzonitrile (2q, 665 mg, 92%) as a colourless solid.
With N-iodo-succinimide; palladium diacetate; toluene-4-sulfonic acid; In 1,2-dichloro-ethane; at 70℃; for 12h;
<strong>[5312-97-0]2,5-dimethoxybenzonitrile</strong> (0.082 g, 0.5 mmol), Pd(OAc)2 (10 mol%, 0.0056 g, 0.025mmol), NIS (0.124 g, 0.55 mmol), PTSA (0.043 g, 0.25 mmol) and DCE (2 mL) wereadded to a round bottom flask. The reaction mixture was stirred at 70 C for 12 h. Thereaction mixture was dilluted with DCM (15 mL), washed with saturated solution ofNa2S2O3 (15 mL), dried (Na2SO4), subjected to filtration and concentrated under reduced pressure.Purification using flash column chromatography on silica gel (eluting with 8:2 hexanes/ethyl acetate)afforded product 29 (36%, 0.052 g, 0.179 mmol) as a colorless solid.
General procedure: n-Butyllithium (1.67 M solution in hexane, 2.9 mL, 4.8 mmol) was added dropwise into a solution of 1,3-dimethoxybenzene (0.55 g, 4.0 mmol) in THF (5 mL) at 0 C and the mixture was stirred for 2 h at the same temperature. Then, DMF (0.34 mL, 4.4 mmol) was added to the mixture and the obtained mixture was stirred at 0 C. After 2 h at the same temperature, aq NH3 (8 mL, 120 mmol) and I2 (1.12 g, 4.4 mmol) were added and stirred for 2 h at rt. The reaction mixture was quenched with satd aq Na2SO3 (15 mL) and was extracted with Et2O (3×20 mL). The organic layer was washed with brine and dried over Na2SO4 to provide 2,6-dimethoxybenzonitrile in over 80% purity. The product was purified by a short column chromatography on silica gel (Hexane/EtOAc=3:1) to give pure 2,6-dimethoxybenzonitrile in 91% yield as a colorless solid.
General procedure: To an ice cooled solution of N-methylformanilide (2.2 mmol) was added dropwise diphosphoryl chloride (2.2 mmol). The solution was stirred for 30 min at 0 C, and then 1,2-dimethoxybenzene (276.3 mg, 2 mmol) in DMF (1.0 mL) was added dropwise. After being stirred for 10 h at 100 C, I2 (1015.2 mg, 4 mmol), aq NH3 (4 mL, 28-30%) and THF (1 mL) were added to the reaction mixture. The obtained mixture was stirred for 3 h at rt. After the reaction, the mixture was poured into aq satd Na2SO3 solution and extracted with CHCl3 (3×20 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The product was purified by flash short column chromatography (Hexane:AcOEt=3:1) to afford 3,4-dimethoxybenzonitrile as a white solid in 92% yield.
To solution of <strong>[5312-97-0]2,5-dimethoxybenzonitrile</strong> (1.5 g) in dry Et2O (7 mL) was added propyl magnesium chloride (2 M in Et2O, 9.2 mL) and the resulting mixture was heated to 40 C. for 2 h. The mixture was chilled and 4 M HCl (9 mL) was carefully added and it was stirred at ambient temperature for 16 h. The mixture was extracted with EtOAc, the combined organic layers were washed with water, were dried and the volatiles were removed under reduced pressure. The residue was purified by column chromatography (Interchim cartridge 15SiHP/120 g, Cy/EtOAc) to yield the desired compound (57% yield). [0569] LC-MS (Method 1): m/z [M+H]+=209.3 (MW calc.=208.25); Rt=3.5 min
57%
In diethyl ether; at 40℃; for 2h;
Intermediate 42a) To solution of <strong>[5312-97-0]2,5-dimethoxybenzonitrile</strong> (1.5 g) in dry Et20 (7 mL) was added propyl magnesium chloride (2 M in Et20, 9.2 mL) and the resulting mixture was heated to 40 C for 2 h. The mixture was chilled and 4 M HCI (9 mL) was carefully added and it was stirred at ambient temperature for 16 h. The mixture was extracted with EtOAc, the combined organic layers were washed with water, were dried and the volatiles were removed under reduced pressure. The residue was purified by column chromatography (Interchim cartridge 15SiHP / 120 g, Cy / EtOAc) to yield the desired compound (57% yield). LC-MS {Method 1): m/z [M+Hf = 209.3 (MW calc. = 208.25); R, = 3.5 min.
General procedure: Dry HCl (g) was bubbled into a stirred solution of nitrile (10 mmol) in propargyl alcohol (1 equiv.) at 0 C for 10 minutes. The vial was capped and stirred warming to rt overnight (18 h). Air was bubbled through the resulting mixture for 10 minutes. The mixture was then diluted with Et2O (20 mL), and the resulting precipitate was collected by vacuum filtration, and washed with Et2O (20 mL). This salt was suspended in CHCl3 (50 mL), to which saturated NaHCO3 (50 mL) was then added. After mixing, the layers were separated, and the aqueous layer was extracted with an additional amount of CHCl3 (20 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford the imidate.
General procedure: To a solution of anisole 3A (3.0 mmol, 324.4 mg) in THF (3.0 mL) was added n-BuLi (4.5 mmol,1.55 M in hexane, 2.87 mL) at 0 C. The mixture was stirred for 2 h at 0 C under an argon atmosphere. Then, pivalonitrile (9.0 mmol, 748.2 mg) in THF (2.0 mL) was added to the mixture at 0 C and the obtained mixture was stirred for 30 min in the temperature range of 0 C to room temperature. MeOH (2.0 mL) was added to the mixture. Then, I2 (12.0 mmol, 3045.6 mg) and K2CO3 (12.0 mmol, 1658.4 mg) were added to the mixture at room temperature, and the obtained mixture was stirred for 6 h at 70 C. Sat. aq. Na2SO3 solution (20.0 mL) was added to the reaction mixture, and the product was extracted with AcOEt (10.0 mL x 3). The organic layer was dried over Na2SO4. After filtration and removal of the solvent, the residue was purified by silica-gel column chromatography (chloroform: n-hexane 1:1) to give 2-methoxybenzonitrile 2A (315.6 mg, 79%).
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