1-bromo-2-(dimethoxymethyl)benzene

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred and cooled (-78° C.) mixture of 50 parts of 1-bromo-2-(dimethoxymethyl)benzene and 245 parts of 1,1'-oxybisethane were added dropwise 59 parts of a 1-butyllithium solution 2.5M in hexane. Upon complete addition, stirring was continued for 10 minutes at room temperature. A solution of 23.1 parts of 3-pyridinecarboxaldehyde in 42 parts of 1,1'-oxybisethane was added dropwise to the reaction mixture. Upon completion, the mixture was allowed to reach room temperature. The mixture was taken up in ice water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 56 parts (99.9%) of α-[2-(dimethoxymethyl)phenyl]-3-pyridinemethanol as a residue (intermediate 1). cooled Upon complete addition stirring to reach room temperature the product was extracted with 1,1'-oxybisethane The extract was dried filtered evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-bromobenzaldehyde (451.9 g, 2.44 mol), trimethyl orthoformate (324 g, 3.05 mol) and concentrated hydrochloric acid (4.0 ml, 0.05 mol) in methanol (2 L) was refluxed for four hours. The volatile components were evaporated on the rotary evaporator and the residue dried over anhydrous potassium carbonate, filtered, and distilled (66°-72° C. at 0.1-0.2 mm) to give 474.1 g (84%) of the 2-Bromobenzaldehyde Dimethyl Acetal compound as a colorless oil. 'H NMR (CDCl3): 3.35 (s, 6, OCH3), 5.50 (s, 1, CH), 7.5 (m, 4, Ar--H). The volatile components were evaporated on the rotary evaporator the residue dried over anhydrous potassium carbonate filtered distilled (66°-72° C. at 0.1-0.2 mm)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-bromobenzaldehyde (451.9 g, 2.44 mol), trimethyl orthoformate (324 g, 3.05 mol) and concentrated hydrochloric acid (4.0 ml, 0.05 mol) in methanol (2 L) was refluxed for four hours. The volatile components were evaporated on the rotary evaporator and the residue dried over anhydrous potassium carbonate, filtered, and distilled (66°-72° C. at 0.1-0.2 mm) to give 474.1 g (84%) of the 2-Bromobenzaldehyde Dimethyl Acetal compound as a colorless oil. 'H NMR (CDCl3): 3.35 (s, 6, OCH3), 5.50 (s, 1, CH), 7.5 (m, 4, Ar--H). The volatile components were evaporated on the rotary evaporator the residue dried over anhydrous potassium carbonate filtered distilled (66°-72° C. at 0.1-0.2 mm)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL round bottom flask equipped with a reflux condenser were added 2-bromobenzaldehyde (102.5 g, 0.554 mol, Aldrich), trimethyl orthoformate (64.9 mL, 0.594 mol, Aldrich), 10-camphor sulfonic acid (1.25 g, 5.40 mmol, Aldrich), and methanol (100 mL). The reaction was heated at reflux for 14 hrs and concentrated in vacuo. The residue was taken up in 500 mL of ether, washed with 200 mL each of sat. aqueous sodium bicarbonate, water, and sat. aqueous NaCl, dryed over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was distilled through a 27 cm Vigrew column (b.p. 78-82° C./1.2 mmHg), affording a clear colorless oil (120.8 g, 94%). 1H-NMR (300 MHz, CDCl3) δ3.37 (s, 6H), 5.54 (s, 1H), 7.18 (dt, 1H, J=1.7, 8.1 Hz), 7.31 (dt, 1H, J=1.2, 7.5 Hz), 7.54 (dd, 1H, J=1.2, 8.1 Hz), 7.59 (dd, 1H, J=1.7, 7.5 Hz). Mass spectrum (EI+) m/e 230, 232 (M+), 199, 201 (bp). To a 500 mL round bottom flask equipped with a reflux condenser The reaction was heated at reflux for 14 hrs concentrated in vacuo washed with 200 mL each of sat. aqueous sodium bicarbonate, water, and sat. aqueous NaCl filtered concentrated in vacuo The crude product was distilled through a 27 cm Vigrew column (b.p. 78-82° C./1.2 mmHg)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 500 mL round bottom flask equipped with a reflux condenser were added 2-bromobenzaldehyde (102.5 g, 0.554 mol, Aldrich), trimethyl orthoformate (64.9 mL, 0.594 mol, Aldrich), 10-camphor sulfonic acid (1.25 g, 5.40 mmol, Aldrich), and methanol (100 mL). The reaction was heated at reflux for 14 hrs and concentrated in vacuo. The residue was taken up in 500 mL of ether, washed with 200 mL each of sat. aqueous sodium bicarbonate, water, and sat. aqueous NaCl, dryed over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was distilled through a 27 cm Vigrew column (b.p. 78-82° C./1.2 mmHg), affording a clear colorless oil (120.8 g, 94%). 1H-NMR (300 MHz, CDCl3) δ3.37 (s, 6H), 5.54 (s, 1H), 7.18 (dt, 1H, J=1.7, 8.1 Hz), 7.31 (dt, 1H, J=1.2, 7.5 Hz), 7.54 (dd, 1H, J=1.2, 8.1 Hz), 7.59 (dd, 1H, J=1.7, 7.5 Hz). Mass spectrum (EI+) m/e 230, 232 (M+), 199, 201 (bp). To a 500 mL round bottom flask equipped with a reflux condenser The reaction was heated at reflux for 14 hrs concentrated in vacuo washed with 200 mL each of sat. aqueous sodium bicarbonate, water, and sat. aqueous NaCl filtered concentrated in vacuo The crude product was distilled through a 27 cm Vigrew column (b.p. 78-82° C./1.2 mmHg)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: BuLi (1.55 M in hexane, 14.7 mL, 22.7 mmol) was added to a sol. of 1-bromo-2-(dimethoxymethyl)benzene (5.00 g, 21.6 mmol) in Et2O (50 mL). The mixture was stirred for 30 min at −78 ° C. and MgBr2.Et2O (5.87 g, 22.7 mmol) was added. The mixture was allowed to warm up to 0° C. over 15 min and CuI (420 mg, 2.16 mmol) was added. The mixture was stirred at 0° C. for 5 min and allyl bromide (1.92 mL, 22.7 mmol) was added. The mixture was stirred overnight while warming up to rt. Aq. 1M HCl (1 mL) was added and the mixture was diluted with Et2O, and washed with aq. 1M HCl (1×). The org. Extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was dissolved in acetone (20 mL) and water (10 mL), and TosOH (cat. amount) was added. The mixture was stirred for 5 h at rt, and the solvents were partially removed under reduced pressure. The residue was diluted with Et2O, and washed with aq. 1M HCl (1×), and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (Et2O/petroleum ether 1:49→24:1) yielded 2-allylbenzaldehyde (1.06 g, 34%). This compound was transformed into the title compound following typical procedure J with cyclopropylamine. to warm up to 0° C. over 15 min The mixture was stirred at 0° C. for 5 min The mixture was stirred overnight while warming up to rt washed with aq. 1M HCl (1×) Extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure The residue was dissolved in acetone (20 mL) water (10 mL), and TosOH (cat. amount) was added The mixture was stirred for 5 h at rt the solvents were partially removed under reduced pressure The residue was diluted with Et2O washed with aq. 1M HCl (1×), and aq. sat. NaHCO3 (1×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (Et2O/petroleum ether 1:49→24:1)

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: BuLi (1.55 M in hexane, 14.7 mL, 22.7 mmol) was added to a sol. of 1-bromo-2-(dimethoxymethyl)benzene (5.00 g, 21.6 mmol) in Et2O (50 mL). The mixture was stirred for 30 min at −78 ° C. and MgBr2.Et2O (5.87 g, 22.7 mmol) was added. The mixture was allowed to warm up to 0° C. over 15 min and CuI (420 mg, 2.16 mmol) was added. The mixture was stirred at 0° C. for 5 min and allyl bromide (1.92 mL, 22.7 mmol) was added. The mixture was stirred overnight while warming up to rt. Aq. 1M HCl (1 mL) was added and the mixture was diluted with Et2O, and washed with aq. 1M HCl (1×). The org. Extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The residue was dissolved in acetone (20 mL) and water (10 mL), and TosOH (cat. amount) was added. The mixture was stirred for 5 h at rt, and the solvents were partially removed under reduced pressure. The residue was diluted with Et2O, and washed with aq. 1M HCl (1×), and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (Et2O/petroleum ether 1:49→24:1) yielded 2-allylbenzaldehyde (1.06 g, 34%). This compound was transformed into the title compound following typical procedure J with cyclopropylamine. to warm up to 0° C. over 15 min The mixture was stirred at 0° C. for 5 min The mixture was stirred overnight while warming up to rt washed with aq. 1M HCl (1×) Extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure The residue was dissolved in acetone (20 mL) water (10 mL), and TosOH (cat. amount) was added The mixture was stirred for 5 h at rt the solvents were partially removed under reduced pressure The residue was diluted with Et2O washed with aq. 1M HCl (1×), and aq. sat. NaHCO3 (1×) extracts were dried over MgSO4 filtered the solvents were removed under reduced pressure Purification of the residue by FC (Et2O/petroleum ether 1:49→24:1)

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred and cooled (-78° C.) mixture of 50 parts of 1-bromo-2-(dimethoxymethyl)benzene and 245 parts of 1,1'-oxybisethane were added dropwise 59 parts of a 1-butyllithium solution 2.5M in hexane. Upon complete addition, stirring was continued for 10 minutes at room temperature. A solution of 23.1 parts of 3-pyridinecarboxaldehyde in 42 parts of 1,1'-oxybisethane was added dropwise to the reaction mixture. Upon completion, the mixture was allowed to reach room temperature. The mixture was taken up in ice water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 56 parts (99.9%) of α-[2-(dimethoxymethyl)phenyl]-3-pyridinemethanol as a residue (intermediate 1). cooled Upon complete addition stirring to reach room temperature the product was extracted with 1,1'-oxybisethane The extract was dried filtered evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-bromobenzaldehyde dimethylacetal and 3,4-dimethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3,4-dimethoxy-α-hydroxybenzyl)benzaldehyde dimethylacetal is obtained as pale yellow syrup.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a stirred and cooled (-78° C.) mixture of 50 parts of 1-bromo-2-(dimethoxymethyl)benzene and 245 parts of 1,1'-oxybisethane were added dropwise 59 parts of a 1-butyllithium solution 2.5M in hexane. Upon complete addition, stirring was continued for 10 minutes at room temperature. A solution of 23.1 parts of 3-pyridinecarboxaldehyde in 42 parts of 1,1'-oxybisethane was added dropwise to the reaction mixture. Upon completion, the mixture was allowed to reach room temperature. The mixture was taken up in ice water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated, yielding 56 parts (99.9%) of α-[2-(dimethoxymethyl)phenyl]-3-pyridinemethanol as a residue (intermediate 1). cooled Upon complete addition stirring to reach room temperature the product was extracted with 1,1'-oxybisethane The extract was dried filtered evaporated