4-Bromo-2-methoxybenzyl alcohol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 118 mg (0.47) of bis(pinacolato)diboron, 193 mg (1.4 mmol) of dry potassium carbonate, and (4-bromo-2-methoxyphenyl)methanol are dissolved in 1 ml of DMF. Argon is passed through the reaction mixture for 15 minutes, and then 14.2 mg (0.02 mmol) of PdCl2(dppf) are added, and the mixture is heated at 85° C. overnight. Then, 120 mg (0.39 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 1.94 ml of 1N sodium hydroxide solution and a further 14.2 mg (0.02 mmol) of PdCl2(dppf) are added. The mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 60:40:2). The solvent is stripped off under reduced pressure, and final residues of solvent are removed under high vacuum. 5 mg (4% of theory) of the title compound are obtained. The mixture is heated at 85° C. overnight The solvent is removed under reduced pressure The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 60:40:2) are removed under high vacuum

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was added to a mixture of (4-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mol) and imidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the resultant mixture was stirred at ambient temperature for 66 h. The mixture was concentrated to about a third of the original volume then diluted with water and extracted with diethyl ether (×3). The combined organic layer was dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl ether in pentane) to afford the title compound as a colourless oil (1.51 g, 98%). 1H NMR (CDCl3, 400 MHz): 7.34 (dt, J=8.1, 1.05 Hz, 1H); 7.11 (dd, J=8.1, 1.8 Hz, 1H); 6.95 (d, J=1.8 Hz, 1H); 4.69 (d, J=1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08 (m, 6H). The mixture was concentrated to about a third of the original volume then diluted with water extracted with diethyl ether (×3) The combined organic layer was dried over magnesium sulfate filtered evaporated The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl ether in pentane)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was added to a mixture of (4-bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mol) and imidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the resultant mixture was stirred at ambient temperature for 66 h. The mixture was concentrated to about a third of the original volume then diluted with water and extracted with diethyl ether (×3). The combined organic layer was dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl ether in pentane) to afford the title compound as a colourless oil (1.51 g, 98%). 1H NMR (CDCl3, 400 MHz): 7.34 (dt, J=8.1, 1.05 Hz, 1H); 7.11 (dd, J=8.1, 1.8 Hz, 1H); 6.95 (d, J=1.8 Hz, 1H); 4.69 (d, J=1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08 (m, 6H). The mixture was concentrated to about a third of the original volume then diluted with water extracted with diethyl ether (×3) The combined organic layer was dried over magnesium sulfate filtered evaporated The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5% diethyl ether in pentane)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 118 mg (0.47) of bis(pinacolato)diboron, 193 mg (1.4 mmol) of dry potassium carbonate, and (4-bromo-2-methoxyphenyl)methanol are dissolved in 1 ml of DMF. Argon is passed through the reaction mixture for 15 minutes, and then 14.2 mg (0.02 mmol) of PdCl2(dppf) are added, and the mixture is heated at 85° C. overnight. Then, 120 mg (0.39 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 1.94 ml of 1N sodium hydroxide solution and a further 14.2 mg (0.02 mmol) of PdCl2(dppf) are added. The mixture is heated at 85° C. overnight. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 60:40:2). The solvent is stripped off under reduced pressure, and final residues of solvent are removed under high vacuum. 5 mg (4% of theory) of the title compound are obtained. The mixture is heated at 85° C. overnight The solvent is removed under reduced pressure The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 60:40:2) are removed under high vacuum