1-(bromomethyl)-2-phenoxybenzene

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: A 60% suspension of sodium hydride in mineral oil (4.1 g, 101 mmol) was added to a solution of a mixture of (1-(triphenylmethyl)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)-methanol and (3-(triphenylmethyl)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methanol (2.0 g, 5.1 mmol) in THF (8 ml). When the reaction had ceased tetrabutylammonium iodide (0.10 g, 0.25 mmol) and a solution of 2-phenoxybenzyl bromide (1.5 g, 5.6 mmol) in THF (5 ml) were added successively. The reaction mixture was stirred for 16 h. Water (100 ml) was added carefully. The mixture was extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (gradient from 50:50 to 100:0) as eluent, to give 1.21 g of 5-((2-phenoxybenzyloxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((2-phenoxybenzyloxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole. The mixture was extracted with ethyl acetate (3×60 ml) The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) dried over magnesium sulphate The solvent was removed in vacuo The crude product was purified by flash chromatography on silica (90 g)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Phosphorus tribromide (5.5 ml, 57.1 mmol) was added dropwise over a period of 10 min to a solution of 2-phenoxybenzylalcohol (4.08 g, 20.4 mmol) in dioxane (165 ml). The reaction mixture was stirred for 40 min. Another portion of phosphorus tribromide (5.5 ml, 57.1 mmol) was added. The reaction mixture was stirred for 56 hours at room temperature. It was cooled to 0° C. Water (45 ml) was added carefully. The reaction mixture was stirred for 30 min at room temperature. The mixture was extracted with ethyl acetate (100 ml). The ethyl acetate phase was washed with 1 N hydrochloric acid. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous soludtion of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (1:3) as eluent, to give 4.80 g of 2-phenoxybenzyl bromide. The reaction mixture was stirred for 56 hours at room temperature The reaction mixture was stirred for 30 min at room temperature The mixture was extracted with ethyl acetate (100 ml) The ethyl acetate phase was washed with 1 N hydrochloric acid The combined aqueous layers were extracted with ethyl acetate The combined organic layers were washed with a saturated aqueous soludtion of sodium hydrogen carbonate (100 ml) dried over magnesium sulphate The solvent was removed in vacuo The crude product was purified by flash chromatography on silica (90 g)

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

Procedure: Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2 Cl2 /EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%). The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added the aqueous solution extracted with dichloromethane (2×) The organic layers were dried (MgSO4) evaporated purified by chromatography (eluant: CH2 Cl2 /EtOAc/MeOH)

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

Procedure: Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2Cl2 /EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%). The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added the aqueous solution extracted with dichloromethane (2×) The organic layers were dried (MgSO4) evaporated purified by chromatography (eluant: CH2Cl2 /EtOAc/MeOH)

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

Procedure: Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2Cl2 /EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%). The volatile components were removed at reduced pressure, aqueous sodium hydroxide (1N, 20 ml) was added the aqueous solution extracted with dichloromethane (2×) The organic layers were dried (MgSO4) evaporated purified by chromatography (eluant: CH2Cl2 /EtOAc/MeOH)

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

Procedure: Ethylamine (70% solution, 5.2 ml, 80 mmol) was diluted with water (5.2 ml). A solution of 2-bromomethylphenyl phenyl ether (5.0 g, 19.02 mmol) in THF (25 ml) was added dropwise and the reaction stirred at ambient temperature for 2 hours. The volatile components were removed at reduced pressure, aqueous sodium hydroxide (IN, 20 ml) was added and the aqueous solution extracted with dichloromethane (2×). The organic layers were dried (MgSO4), evaporated and purified by chromatography (eluant: CH2Cl2/EtOAc/MeOH) to give N-ethyl-N-(2-(phenoxy)benzyl)amine as a yellow solid (2.2 g, 51%). The volatile components were removed at reduced pressure, aqueous sodium hydroxide (IN, 20 ml) was added the aqueous solution extracted with dichloromethane (2×) The organic layers were dried (MgSO4) evaporated purified by chromatography (eluant: CH2Cl2/EtOAc/MeOH)

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

Procedure: Add 2-Phenoxy-benzoic acid (1 g, 4.67 mmol), in several portions, to a suspension of Lithium aluminium hydride (372 mg, 9.33 mmol) in dry THF (20 ml) at room temperature and stir. After 1 h, add aqueous 1M HCl dropwise carefully, then pour into H2O and extract three times with Et2O. Combine the organic phases, dry over Na2SO4 and concentrate at vacuum to yield pure (2-Phenoxy-phenyl)-methanol as courless oil. Add aqueous concentrated HBr (16 ml) to a solution of (2-Phenoxy-phenyl)-methanol (900 mg, 4.5 mmol) in CH2Cl2 (5 ml) and stir at room temperature. After 1 h. separate the organic phase and wash the aqueous one with CH2Cl2. Combine organic phases, wash with H2, dry over Na2SO4 and concentrate at vacuum to obtain a residue. Purify the residue by column chromatography on silica gel eluting with hexane:CH2Cl2, 2:1 to afford 1-Bromomethyl-2-phenoxy-benzene as colourless oil. 1H-NMR (CDCl3, 200 MHz): δ 7.44-7.01 (m, 8H), 6.84 (d, J=1.2 and 8.0 Hz, 1H), 4.60 (s, 2H). After 1 h. separate the organic phase wash the aqueous one with CH2Cl2 Combine organic phases, wash with H2 dry over Na2SO4 concentrate at vacuum to obtain a residue Purify the residue by column chromatography on silica gel eluting with hexane

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

Procedure: Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(bromomethyl)-2-phenoxybenzene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 418.01 g/mol. Prepared Subsequent purification by preparative HPLC afforded the target compound

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

Procedure: A 60% suspension of sodium hydride in mineral oil (4.1 g, 101 mmol) was added to a solution of a mixture of (1-(triphenylmethyl)-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)-methanol and (3-(triphenylmethyl)-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methanol (2.0 g, 5.1 mmol) in THF (8 ml). When the reaction had ceased tetrabutylammonium iodide (0.10 g, 0.25 mmol) and a solution of 2-phenoxybenzyl bromide (1.5 g, 5.6 mmol) in THF (5 ml) were added successively. The reaction mixture was stirred for 16 h. Water (100 ml) was added carefully. The mixture was extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using ethyl acetate/heptane (gradient from 50:50 to 100:0) as eluent, to give 1.21 g of 5-((2-phenoxybenzyloxy)methyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-((2-phenoxybenzyloxy)methyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole. The mixture was extracted with ethyl acetate (3×60 ml) The combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) dried over magnesium sulphate The solvent was removed in vacuo The crude product was purified by flash chromatography on silica (90 g)