Diphenyl Ether → Tolmetin

Participants

Reaction Conditions

Reaction Steps

To a solution of the Grignard reagent prepared from 0.46 g. (20 mmol) of magnesium and 3.4 g. (20 mmol) of 4-bromotoluene in 15 ml. of anhydrous tetrahydrofuran was added under an atmosphere of nitrogen 1.12 g. (6.0 mmol) of the sodium salt of 5-cyano-1-methylpyrrole-2-acetic acid. To the resulting suspension was added 20 g. of diphenyl ether, and the reaction mixture was heated to remove tetrahydrofuran by distillation until the temperature reached 110° C. The reaction mixture was then successively heated under reflux at 110° C. for two hours, cooled, and partitioned between ether and dilute aqueous hydrochloric acid. The ether phase was worked up in the manner described in Example 1 to give 100 mg. (9%) of purple solid that contained mainly 5-cyano-1-methylpyrrole-2-acetic acid by nmr analysis. The aqueous phase was heated in a steam bath for 7 hours and the product was isolated after extraction with methylene chloride to give 1.15 g. (yield: 75%, 83% based on unrecovered cyanoacid) of 1-methyl-5-p-toluoylpyrrole-2-acetic acid as a brown solid.

Provenance & Evidence