2-benzyl-4-chlorophenol

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

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

Procedure: A suspension containing 21.87 g of 2-benzyl-4-chlorophenol, 27.76 g of 1-chloro-2,3-epoxypropane and 27.64 g of potassium carbonate in 200 ml of butanone is refluxed for 12 hours. The inorganic salts formed are filtered off and drained. The solvent and excess 1-chloro-2,3-epoxypropane are evaporated off under vacuum and the residue is distilled at between 160° C. and 180° C. under 0.01 mm of mercury. is refluxed for 12 hours The inorganic salts formed are filtered off The solvent and excess 1-chloro-2,3-epoxypropane are evaporated off under vacuum the residue is distilled at between 160° C. and 180° C. under 0.01 mm of mercury

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A German patent, Ger.Offen 2,547,030 (1977), disclosed the preparation of o-benzyl toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product-containing 49.9% o-benzylphenol. A German Patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by alkylation of p-substituted phenols with benzylalcohol in the presence of Na-Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na-Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A German patent, Ger.Offen 2,547,0310 (1977), disclosed the preparation of o-benzyl-toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, Jpn. Kokai Tokkyo Koho JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product containing 49.9% o-benzylphenol. A German patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by benzylation of p-substituted phenols with benzylalcohol in the presence of Na—Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na—Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol. to give a product

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

Procedure: 2-Benzyl-4-chlorophenol (43.7 parts) is propoxylated with propylene oxide (12.6 parts) using sodium hydroxide (0.2 part) as catalyst at 145° C. in a manner similar to that used in Example 10 to give 1-(2-benzyl-4-chlorophenoxy)propan-2-ol (16.3 parts) at 145° C.

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

Procedure: 2-Benzyl-4-chlorophenol (43.7 parts) is propoxylated with propylene oxide (12.6 parts) using sodium hydroxide (0.2 part) as catalyst at 145° C. in a manner similar to that used in Example 10 to give 1-(2-benzyl-4-chlorophenoxy)propan-2-ol (16.3 parts) at 145° C.

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Powdered K2CO3 (2.07 g, 15.0 mmol) is added to a stirred solution of 2-benzyl-4-chlorophenol (2.19 g, 10.0 mmol) and 1,3-dibromopropane (3.05 mL, 30.0 mmol) in anhydrous DMF (20 mL) at ambient temperature under nitrogen; The mixture is heated at 80° C. for 1 hour. At ambient temperature, EtOAc (100 mL) and water (150 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% EtOAc in hexane) to give 2.45 g (7.21 mmol, 72% yield) of the title compound as a white solid. EIMS: m/z 338 (M+, 35Cl, 79Br), 340 (M+, 37Cl, 37Br or 35Cl, 81Br), 342 (M+, 37Cl, 81Br). The organic layer is separated dried over MgSO4 filtered concentrated The crude product is chromatographed on silica (gradient 0-2% EtOAc in hexane)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Powdered K2CO3 (2.07 g, 15.0 mmol) is added to a stirred solution of 2-benzyl-4-chlorophenol (2.19 g, 10.0 mmol) and 1,3-dibromopropane (3.05 mL, 30.0 mmol) in anhydrous DMF (20 mL) at ambient temperature under nitrogen; The mixture is heated at 80° C. for 1 hour. At ambient temperature, EtOAc (100 mL) and water (150 mL) are added to the mixture. The organic layer is separated, dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% EtOAc in hexane) to give 2.45 g (7.21 mmol, 72% yield) of the title compound as a white solid. EIMS: m/z 338 (M+, 35Cl, 79Br), 340 (M+, 37Cl, 37Br or 35Cl, 81Br), 342 (M+, 37Cl, 81Br). The organic layer is separated dried over MgSO4 filtered concentrated The crude product is chromatographed on silica (gradient 0-2% EtOAc in hexane)

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

Procedure: 5 g of 2-benzyl-4-chlorophenol, 2.6 ml of chloroacetone, 1.38 g of potassium carbonate and 0.34 g of potassium iodide are dissolved in 50 ml of acetone and boiled under reflux for 20 h. After cooling, the precipitate is filtered, concentrated by evaporation, the residue dissolved in ethyl acetate, the solution washed three times with a 1 n sodium hydroxide solution, then with saturated sodium chloride solution, dried with magnesium sulphate and concentrated by evaporation under vacuum. After recrystallisation from diethylether, 1-(2-benzyl-4-chlorophenoxy)-propan-2-one is obtained as a white powder with a melting point of 65-6° C. under reflux for 20 h After cooling the precipitate is filtered concentrated by evaporation the residue dissolved in ethyl acetate the solution washed three times with a 1 n sodium hydroxide solution with saturated sodium chloride solution, dried with magnesium sulphate concentrated by evaporation under vacuum After recrystallisation from diethylether

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

Procedure: A solution of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester (0.1 g, 0.3 mmol), 2-benzyl-4-chloro-phenol (69 mg, 0.32 mmol), copper(I) chloride (14 mg, 0.14 mmol), 2,2,6,6-tetramethyl-3,5-heptanedione (0.01 mL, 0.07 mmol), and cesium carbonate (113 mg, 0.35 mmol) in NMP (3 mL) is heated to 120° C. The reaction is stirred overnight and cooled to rt. The reaction is then quenched with 1N aqueous HCl and extracted with ethyl ether. The organic is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude ester intermediate. The intermediate is treated with 5N NaOH (0.4 mL, 2.2 mmol) in MeOH (5 mL) and heated to reflux. The reaction is stirred at reflux for 2 hours and then cooled. The reaction is quenched with 1N aqueous HCl to obtain pH=4. The aqueous layer is extracted with ethyl ether. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed to afford the crude product. The crude is purified by prep HPLC to afford 63 mg (47%) of desired product. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H25ClO4 472, found 473 and 475 (M+1 and M+3, 100%). The reaction is then quenched with 1N aqueous HCl extracted with ethyl ether The organic is washed with brine dried over sodium sulfate filtered The solvent is removed to afford the crude ester intermediate heated to reflux The reaction is stirred at reflux for 2 hours cooled The reaction is quenched with 1N aqueous HCl to obtain pH=4 The aqueous layer is extracted with ethyl ether The organic layer is washed with brine dried over sodium sulfate filtered The solvent is removed to afford the crude product The crude is purified by prep HPLC

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A German patent, Ger.Offen 2,547,030 (1977), disclosed the preparation of o-benzyl toluenes by the reaction of o-methylbenzyl halides with substituted benzenes in the presence of Al-silicate. The 2-CH3C6H4CH2Cl was stirred with toluene and Al-silicate (25% Al2O3) at 110° C. to give 81% 2-methylbenzyltoluene. According to a Japanese patent, JP 59,186,937 (1984), o-benzylphenol was prepared by the liquid phase reaction of benzyl alcohol with phenol in the presence of γ-Al2O3. For example 7.5 g γ-Al2O3 was added to a mixture of 32.5 g benzyl alcohol and 47 g phenol at 190° C. under stirring to give a product-containing 49.9% o-benzylphenol. A German Patent, Ger. Offen DE 3,700,917 (1988), disclosed the preparation of p-substituted o-benzylphenols by alkylation of p-substituted phenols with benzylalcohol in the presence of Na—Y type zeolite. A mixture of 0.5 mole 4-ClC6H4OH, 0.1 mole C6H5CH2OH and 0.6 g of Na—Y type zeolite was heated at 200° C. for 3 hrs to give 25.4% 2-benzyl-4-chlorophenol.