Diphenyl Ether → Tolmetin

Participants

Reaction Conditions

Reaction Steps

To a solution of the Grignard reagent prepared from 0.71 g. (31 mmol) of magnesium and 5.3 g. (31 mmol) of 4-bromotoluene in 20 ml. of anhydrous tetrahydrofuran was added under an atmosphere of nitrogen a solution of 0.98 g. (6.0 mmol) of 5-cyano-1-methylpyrrole-2-acetic acid in 5 ml. of tetrahydrofuran. After the resulting yellow suspension was heated to the boiling point, 20 g. of diphenyl ether was added, and tetrahydrofuran was distilled from the reaction mixture until the temperature reached 110° C. The reaction mixture was then heated under reflux (110° C.) for 1.5 hours. During this time, the color of the suspension changed from yellow to dark orange. The reaction mixture was cooled and partitioned between ether and dilute aqueous hydrochloric acid. The ether phase was extracted with five percent aqueous sodium hydroxide solution, which was then acidified and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and concentrated to give 30 mg. of purple liquid which contained only a trace of starting cyanoacid by nmr analysis. The aqueous phase was heated in a steam bath for four hours, and the resulting suspension was cooled and extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate and concentrated to give 1.33 g. (86% yield) of 1-methyl-5-p-toluoyl-pyrrole-2-acetic acid as a brown solid.

Provenance & Evidence