Diethyl Ether → 4-Methoxy-3-methylbenzenebutanoic acid

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Reaction Steps

[2-(1,3-Dioxolan-2-yl) ethyl]triphenylphosphonium bromide (28.2 9, 63.8 mmol) was suspended in tetrahydrofuran (100 mL) and a solution of potassium t-butoxide (7.15 9, 63.8 mmol) in tetrahydrofuran (100 mL) was added thereto under nitrogen atmosphere over 30 minutes, followed by stirring of the mixture under ice-cooling for 30 minutes. A solution of 4-methoxy-3-methylbenzaldehyde (8.2 mL, 60.6 mmol) in tetrahydrofuran (100 mL) was added thereto over 20 minutes and the mixture was stirred under ice-cooling for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture to stop the reaction and ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate, 15:1-10:1) to obtain a crude product (14.9 9). 10% Palladium-carbon (5.00 9, 50% moisture) was added to a solution of the obtained crude product (14.9 g) in ethanol (100 mL) and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the palladium-carbon in the reaction mixture was Celite-filtered, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 10:1) to obtain [1-(1,3-dioxolan-2-yl)-3-(4-methoxy-3-methylphenyl)]propane (12.8 g, yield: 85%). A 3N aqueous hydrochloric acid solution was added dropwise to a solution of the obtained [1-(1,3-dioxolan-2-yl)-3-(4-methoxy-3-methylphenyl)]propane (12.8 g, 54.0 mmol) in THF (200 mL) and the mixture was stirred for 2 hours. Water (400 mL) and ethyl acetate (300 mL) were added to the reaction mixture to separate it. The thus obtained organic phase was separated, washed with water and a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 4-(3-methyl-4-methoxyphenyl)butanaldehyde (8.42 g, 81%). An aqueous solution (50 mL) of sulfamic acid (7.8 9, 0.08 mol) and an aqueous solution (50 mL) of sodium chlorite (9.2 g, 0.10 mol) were added to a solution of 4-(3-methyl-4-methoxyphenyl)butanaldehyde (8.42 9, 43.8 mmol) in dioxane (100 mL) under ice-cooling and the mixture was stirred at room temperature for 1 hour. Ethyl ether (200 mL) was added to the reaction mixture to separate it. After the pH of the aqueous phase was brought to 3 to 4 by 1N hydrochloric acid, ethyl acetate was added thereto to separate it. The thus obtained organic phase was separated, washed with a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 4-(3-methyl-4-methoxyphenyl)butyric acid (5.38 g, yield: 60%).

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