Iodine → 4-(2-Methoxyethyl)benzoic acid

Participants

Reaction Steps

To a 3-necked 50 mL flask fitted with two septa and a nitrogen balloon was added 800 mg (20 mmol) of 60% NaH dispersed in mineral oil. The oil was removed by washing and decanting with hexanes (3×5 mL), using a pipette and keeping a positive pressure of N2 over the flask. Next, 5 mL of THF was added, the suspension was cooled with an ice bath, then a solution of 2.01 g (10.0 mmol) of 4-bromophenethanol in 5 mL of THF was added via cannula. The ice bath was removed, and the mixture was stirred for 10 min, then 700 mL (11 mmol) of iodomethane was added. The mixture was stirred at ambient temperature for 1 h, then 1 mL of H2O was added to quench the excess NaH. The reaction was poured into 50 mL of H2O, then extracted with diethyl ether (3×20 mL). The combined ether layers were back extracted with brine (1×20 mL), dried over MgSO4, filtered, and concentrated to 2.08 g (97%) of a colorless oil. To a solution of 1.03 g (4.78 mmol) of the above 4-(2-methoxy)ethylbromobenzene in 10 mL of THF was added 400 mg of magnesium turnings, and a crystal of I2. The mixture was heated to reflux under N2 for 5 min, then cooled to ambient temperature. The Grignard reagent was transferred via syringe to a 50 mL 3-necked flask under N2. A balloon of C02 was opened over the reaction, and the red color quickly faded to yellow. After stirring for 1 h at ambient temperature, the reaction was concentrated in vacuo. The residue was taken up in 20 mL of H2O and acidified with 12M HCl to pH=1, then extracted with diethyl ether (3×10 mL). The combined ether layers were back extracted with 2M NaOH (3×5 mL), then the combined NaOH layers were extracted with diethyl ether (2×5 mL). The basic layers were treated with 12M HCl until pH=1, then the product was extracted with ethyl acetate (2×5 mL). The combined ethyl acetate layers were back extracted with brine (1×5 mL), dried over MgSO4, filtered, and concentrated to 427 mg (50%) of 4-(2-methoxy)ethylbenzoic acid as a yellow solid. The yellow impurity did not interfere with any subsequent reactions.

Provenance & Evidence