1-bromo-4-(2-methoxyethoxymethyl)benzene

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

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

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

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

Procedure: 2-(4-bromobenzyloxy) 1-methoxyethane (preparation described in Example 11) (10 g) was added to a stirred mixture of oven dried magnesium (2.74 g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A crystal of iodine was added and the mixture heated until an exothermic reaction commenced. A solution of the remaining 2-(4-bromobenzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml) was added dropwise to maintain the temperature of the reaction mixture at reflux. When the addition was complete the mixture was heated at reflux for a further 20 minutes, allowed to cool and added to trimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10° C., dropwise over 45 minutes whilst maintaining the temperature below -5° C. After stirring for 15 minutes, chilled acetic acid (9.36 g) was added, followed by the dropwise addition of 30% hydrogen peroxide (11.77 ml) in water (11 ml) whilst maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature over a period of 20 minutes and then washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown. The organic layer was dried (MgSO4) and evaporated. The residue was dissolved in ether (100 ml) and extracted into IM aqueous sodium hydroxide (50 ml×3). The aqueous extract was acidified with 2M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated. The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as a colourless oil; NMR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s), 6.7-6.8 (2H, d), 7.1-7.3 (2H, d). the mixture heated until an exothermic reaction to maintain the temperature of the reaction mixture at reflux When the addition was heated at reflux for a further 20 minutes to cool whilst maintaining the temperature below -5° C was added whilst maintaining the temperature below 0° C washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown The organic layer was dried (MgSO4) evaporated The residue was dissolved in ether (100 ml) extracted into IM aqueous sodium hydroxide (50 ml×3) The aqueous extract the mixture was extracted with ethyl acetate (3×50 ml) dried (MgSO4) evaporated The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent

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

Procedure: 2-(4-bromobenzyloxy) 1-methoxyethane (preparation described in Example 11) (10 g) was added to a stirred mixture of oven dried magnesium (2.74 g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A crystal of iodine was added and the mixture heated until an exothermic reaction commenced. A solution of the remaining 2-(4-bromobenzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml) was added dropwise to maintain the temperature of the reaction mixture at reflux. When the addition was complete the mixture was heated at reflux for a further 20 minutes, allowed to cool and added to trimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10° C., dropwise over 45 minutes whilst maintaining the temperature below -5° C. After stirring for 15 minutes, chilled acetic acid (9.36 g) was added, followed by the dropwise addition of 30% hydrogen peroxide (11.77 ml) in water (11 ml) whilst maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature over a period of 20 minutes and then washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown. The organic layer was dried (MgSO4) and evaporated. The residue was dissolved in ether (100 ml) and extracted into IM aqueous sodium hydroxide (50 ml×3). The aqueous extract was acidified with 2M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated. The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as a colourless oil; NMR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s), 6.7-6.8 (2H, d), 7.1-7.3 (2H, d). the mixture heated until an exothermic reaction to maintain the temperature of the reaction mixture at reflux When the addition was heated at reflux for a further 20 minutes to cool whilst maintaining the temperature below -5° C was added whilst maintaining the temperature below 0° C washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown The organic layer was dried (MgSO4) evaporated The residue was dissolved in ether (100 ml) extracted into IM aqueous sodium hydroxide (50 ml×3) The aqueous extract the mixture was extracted with ethyl acetate (3×50 ml) dried (MgSO4) evaporated The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DMF (200 ml) at ambient temperature and under an atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. Solid 4-bromobenzyl bromide (15 g) was added in one portion. The mixture was stirred for 12 hours at ambient temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The ethyl acetate extracts were combined, washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. The residue, an oil, was distilled using a short path distillation apparatus (furnace temperature 125° C./0.05 bar) to give 1-(4-bromobenzyloxy)-2-methoxyethane (9.8 g); NMR (CDCl3): 3.39(3H,s), 3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d). cooled to 5° C for 1 hour at 60° C. cooled extracted with ethyl acetate (3×200 ml) washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml) dried (MgSO4) evaporated The residue, an oil, was distilled a short path distillation apparatus (furnace temperature 125° C./0.05 bar)

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

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

Procedure: To an ice-cooled solution of 4-bromobenzyl bromide (3.00 g) and 2-methoxyethanol (1.04 ml) in tetrahydrofuran (30 ml) was added sodium hydride (60%) (0.58 g) in a stream of nitrogen. The mixture was stirred at this temperature for 15 minutes and at room temperature for further 4 hours. To the mixture was added water (1 ml) under ice-cooling. The reaction mixture was diluted with ethyl acetate and washed successively with water and saturated sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and evaporated to give 1-bromo-4-(2-methoxyethoxymethyl)benzene (3.10 g) as a pale yellow oil. cooling washed successively with water and saturated sodium chloride solution The organic layer was dried over magnesium sulfate filtered evaporated

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

Procedure: 2-(4-bromobenzyloxy) 1-methoxyethane (preparation described in Example 11) (10 g) was added to a stirred mixture of oven dried magnesium (2.74 g) in tetrahydrofuran (20 ml) under an atmosphere of argon. A crystal of iodine was added and the mixture heated until an exothermic reaction commenced. A solution of the remaining 2-(4-bromobenzyloxy)-1-methoxyethane (13.4 g) in tetrahydrofuran (60 ml) was added dropwise to maintain the temperature of the reaction mixture at reflux. When the addition was complete the mixture was heated at reflux for a further 20 minutes, allowed to cool and added to trimethylborate (11.74 g) in tetrahydrofuran (60 ml) under argon at -10° C., dropwise over 45 minutes whilst maintaining the temperature below -5° C. After stirring for 15 minutes, chilled acetic acid (9.36 g) was added, followed by the dropwise addition of 30% hydrogen peroxide (11.77 ml) in water (11 ml) whilst maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature over a period of 20 minutes and then washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown. The organic layer was dried (MgSO4) and evaporated. The residue was dissolved in ether (100 ml) and extracted into IM aqueous sodium hydroxide (50 ml×3). The aqueous extract was acidified with 2M aqueous hydrochloric acid and the mixture was extracted with ethyl acetate (3×50 ml). The ethyl acetate extracts were combined, dried (MgSO4) and evaporated. The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent to give 2-(4-hydroxybenzyloxy)-1-methoxyethane (10.4 g) as a colourless oil; NMR (CDCl3): 3.4 (3H, s), 3.5-3.7 (4H, m), 4.5 (2H, s), 6.7-6.8 (2H, d), 7.1-7.3 (2H, d). the mixture heated until an exothermic reaction to maintain the temperature of the reaction mixture at reflux When the addition was heated at reflux for a further 20 minutes to cool whilst maintaining the temperature below -5° C was added whilst maintaining the temperature below 0° C washed successively with saturated ammonium sulphate containing ferrous ammonium sulphate until the aqueous layer no longer turned brown The organic layer was dried (MgSO4) evaporated The residue was dissolved in ether (100 ml) extracted into IM aqueous sodium hydroxide (50 ml×3) The aqueous extract the mixture was extracted with ethyl acetate (3×50 ml) dried (MgSO4) evaporated The residue was further purified by flash chromatography on silica gel using 10% ethyl acetate in toluene as eluent

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Methoxyethanol (5.0 g) was added to a stirred suspension of sodium hydride (2.64 g of a 60% mineral oil suspension) in DMF (200 ml) at ambient temperature and under an atmosphere of argon. The stirred mixture was heated to 60° C. and then cooled to 5° C. Solid 4-bromobenzyl bromide (15 g) was added in one portion. The mixture was stirred for 12 hours at ambient temperature, then for 1 hour at 60° C. and cooled. The mixture was diluted with iced water (600 ml) and extracted with ethyl acetate (3×200 ml). The ethyl acetate extracts were combined, washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml), dried (MgSO4) and evaporated. The residue, an oil, was distilled using a short path distillation apparatus (furnace temperature 125° C./0.05 bar) to give 1-(4-bromobenzyloxy)-2-methoxyethane (9.8 g); NMR (CDCl3): 3.39(3H,s), 3.51(4H,m), 4.51(2H,s), 7.21(2H,d) and 7.44(2H,d). cooled to 5° C for 1 hour at 60° C. cooled extracted with ethyl acetate (3×200 ml) washed with 2M aqueous hydrochloric acid (100 ml), water (2×100 ml), saturated brine (100 ml) dried (MgSO4) evaporated The residue, an oil, was distilled a short path distillation apparatus (furnace temperature 125° C./0.05 bar)