4-ethoxyphenol

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: To a solution of 4-ethoxyphenol (511 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 2 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(4-ethoxyphenyl) -2-hydroxy-2-methylpropionamide as an off-white solid (536 mg, 2.40 mmol, 64.8% yield).: mp 146-148° C. 1H NMR (400 MHz, CDCl3) δ 8.59 (br s, 1H, N--H), 7.45 (dd, 2H, Ar--H, J=9.0, 2.2 Hz), 6.84 (dd, 2H, Ar--H, J=9.0, 2.2 Hz), 4.00 (q, 2H, CH2 -CH3, J=7.1 Hz), 2.73 (br s, 1H, O--H), 1.53 (s, 6H, C(CH3)2), 1.39 (t, 3H, CH2 -CH3, J=7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 174.0, 155.7, 130.6, 74.0, 63.7, 27.9, 14.8; IR (KBr pellet) 1604, 1647 (amide C=O stretches), 3256 (NH stretch), 3281 (OH stretch); MS (CI/CH4) 224; the resulting mixture was stirred at reflux for 16 h The resulting mixture was stirred at 150° C. for 72 h The reaction was cooled to room temp. partitioned between water (50 mL) and EtOAc (100 mL) The aqueous layer was extracted with EtOAc (100 mL) the combined organics washed with water (2×50 mL) dried (Na2SO4) concentrated to about 2 g of material The brown oil was chromatographed on silica (200 mL, 4 cm diam. column) eluting with 3:7 EtOAc/hexane

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

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

Procedure: Then, 5.10 g of 4-bromo-2-trifluoromethyl-1-benzyloxybenzene, 2.34 g of p-ethoxyphenol, 2.13 g of potassium carbonate, 100 mg of copper and 200 mg of cuprous chloride were charged into a reaction vessel, and stirred at 130° C. to 140° C. for 5 hours. The reaction solution was cooled to room temperature, poured into ice-water and then acidified by adding 10% hydrochloric acid. The solution was extracted twice with 100 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.50 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)-1-benzyloxybenzene (yield, 41%). The solution was extracted twice with 100 ml of diethyl ether washed with water dried over anhydrous magnesium sulfate concentrated to give a crude product

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

Procedure: Then, 5.10 g of 4-bromo-2-trifluoromethyl-1-benzyloxybenzene, 2.34 g of p-ethoxyphenol, 2.13 g of potassium carbonate, 100 mg of copper and 200 mg of cuprous chloride were charged into a reaction vessel, and stirred at 130° C. to 140° C. for 5 hours. The reaction solution was cooled to room temperature, poured into ice-water and then acidified by adding 10% hydrochloric acid. The solution was extracted twice with 100 ml of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 2.50 g of 2-trifluoromethyl-4-(4-ethoxyphenoxy)-1-benzyloxybenzene (yield, 41%). The solution was extracted twice with 100 ml of diethyl ether washed with water dried over anhydrous magnesium sulfate concentrated to give a crude product

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

Procedure: A mixture of 10 g of 4-bromo-2-isopropylphenyl benzyl ether, 4.7 g of 4-ethoxyphenol, 4.7 g of potassium carbonate, 0.30 g of copper powder, 0.30 g of cuprous iodide and 30 ml of pyridine was stirred at 130° C. to 140° C. for 24 hours. The reaction solution was cooled to room temperature, poured into ice-water and then acidified by adding 10% hydrochloric acid. The solution was extracted with 100 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 4.4 g of 4-(4-ethoxyphenoxy)-2-isopropylphenyl benzyl ether (yield, 37%). The solution was extracted with 100 ml of diethyl ether washed in turn with 10% hydrochloric acid an aqueous 10% sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate concentrated

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

Procedure: A mixture of 10 g of 4-bromo-2-isopropylphenyl benzyl ether, 4.7 g of 4-ethoxyphenol, 4.7 g of potassium carbonate, 0.30 g of copper powder, 0.30 g of cuprous iodide and 30 ml of pyridine was stirred at 130° C. to 140° C. for 24 hours. The reaction solution was cooled to room temperature, poured into ice-water and then acidified by adding 10% hydrochloric acid. The solution was extracted with 100 ml of diethyl ether, washed in turn with 10% hydrochloric acid, an aqueous 10% sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 4.4 g of 4-(4-ethoxyphenoxy)-2-isopropylphenyl benzyl ether (yield, 37%). The solution was extracted with 100 ml of diethyl ether washed in turn with 10% hydrochloric acid an aqueous 10% sodium hydroxide solution and a saturated saline solution, dried over anhydrous magnesium sulfate concentrated

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

Procedure: A mixture of 520 mg of trans-4-(4-pentenyl)cyclohexanecarboxylic acid, 439.4 mg of p-ethoxyphenol, 765.5 mg of dicyclohexylcarbodiimide and 45 mg of 4-(dimethylamino)pyridine were dissolved in 80 ml of methylene chloride and the solution was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave an 0.7 g (83%) of trans-4-(4-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 3 ml of methanol there were finally obtained 455 mg of product in the form of colourless crystals; m.p. (C-N) 32.7° C., cl.p. (N-I) 57.5° C. the precipitated urea was filtered off the filtrate was concentrated the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water The aqueous phases were back-extracted twice with hexane The organic phases were dried over magnesium sulphate evaporated

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

Procedure: A mixture of 520 mg of trans-4-(4-pentenyl)cyclohexanecarboxylic acid, 439.4 mg of p-ethoxyphenol, 765.5 mg of dicyclohexylcarbodiimide and 45 mg of 4-(dimethylamino)pyridine were dissolved in 80 ml of methylene chloride and the solution was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was diluted with diethyl ether, the precipitated urea was filtered off and the filtrate was concentrated. The residue was taken up in hexane and the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water. The aqueous phases were back-extracted twice with hexane. The organic phases were dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting residue on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave an 0.7 g (83%) of trans-4-(4-pentenyl)cyclohexanecarboxylic acid p-ethoxyphenyl ester. After recrystallization from 3 ml of methanol there were finally obtained 455 mg of product in the form of colourless crystals; m.p. (C-N) 32.7° C., cl.p. (N-I) 57.5° C. the precipitated urea was filtered off the filtrate was concentrated the solution was washed with dilute hydrochloric acid, sodium hydrogen carbonate solution and water The aqueous phases were back-extracted twice with hexane The organic phases were dried over magnesium sulphate evaporated

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

Procedure: 4-Ethoxyphenol (0.25 g, 1.81 mmol), anhydrous potassium carbonate (0.50 g, 3.62 mmol) and epichlorohydrin (0.57 ml, 7.24 mmol) were added to acetone (4.52 ml) and the resulting heterogeneous solution was refluxed for 16 hrs. The mixture was cooled to room temperature, filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The resulting oil was dissolved in toluene (20 mL), washed sequentially with water (15 mL), 5% aqueous NaOH (20 mL) and water again (20 mL). The organic layer was dried with MgSO4 and concentrated under reduced pressure to yield 0.292 g (83%) of 2-((4-ethoxyphenoxy)methyl)oxirane as a white solid (mp=41° C.). 1H NMR (400 MHz, CDCl3) δ 6.91-6.77 (m, 4H), 4.17 (dd, J=11.0, 3.2, 1H), 3.98 (q, J=7.0, 2H), 3.91 (dd, J=11.0, 5.6, 1H), 3.34 (m, 1H), 2.90 (dd, J=4.9, 4.1, 1H), 2.75 (dd, J=5.0, 2.7, 1H), 1.39 (t, J=6.98, 3H). 13C NMR (75 MHz, CDCl3) δ 153.72, 152.78, 115.90, 115.90, 115.59, 115.59, 69.71, 64.18, 50.49, 44.98, 15.15. HRMS (m/z): [MNa]+ calc. for C11H14O3Na+, 217.08. found 217.0826. the resulting heterogeneous solution was refluxed for 16 hrs filtered through a pad of celite the filtrate was concentrated under reduced pressure The resulting oil was dissolved in toluene (20 mL) washed sequentially with water (15 mL), 5% aqueous NaOH (20 mL) and water again (20 mL) The organic layer was dried with MgSO4 concentrated under reduced pressure

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

Procedure: Analogously to Example 1, 6.16 g of 2-pentyl-1,2,3,4-tetrahydronaphthalene-6-carboxylic acid are converted into the acid chloride and this is reacted with 3.45 g of p-ethoxyphenol in 15 ml of absolute pyridine. There are obtained 8.9 g of crude p-ethoxyphenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthoate which, for purification, is chromatographed on 230 g of silica gel. Elution with toluene/hexane (1:1) and toluene/hexane (7:3) yields 8.8 g of substance which are recrystallized from acetone/hexane up to constant melting point and clearing point and dried in a high vacuum (0.01 mbar). There are obtained colorless crystals of p-ethoxy-phenyl 2-pentyl-1,2,3,4-tetrahydro-6-naphthalene; m.p. 95.4°-96.2° C., cl.p. 119.0°-119.4° C.