Ethyl Acetoacetate → 4-Chloro-7-iodo-2,6-dimethylquinoline

Participants

Reaction Conditions

Reaction Steps

A suspension of 3-iodo-4-methylaniline (50.0 g, 215 mmol), ethyl acetoacetate (30.7 g, 236 mmol), and toluene-4-sulfonic acid monohydrate (430 mg, 2.15 mmol) was refluxed for 2 h in cyclohexane (100 mL), allowing the water formed to collect in a Dean-Stark trap, then after cooling insoluble material was removed by filtration and the filtrate evaporated. The residue was dissolved in Dowtherm® A (25 mL) and added dropwise to hot (ca. 250° C.) Dowtherm® A. After 15 min the reaction mixture was allowed to reach room temperature, then heptane (150 mL) was added and the precipitate collected by filtration. This material was triturated in ethyl acetate to afford a 1:1 mixture of 7-iodo-2,6-methyl-1H-quinolin-4-one and 5-iodo-2,6-dimethyl-1H-quinolin-4-one (46.4 g), which was treated with phosphorus oxide chloride (130 mL) and N,N-dimethylformamide (0.6 mL). The solution obtained was stirred at 50° C. for 20 min, then carefully poured upon ice and brought to pH 7 with 25% aq. ammonium hydroxide solution. After extraction with ethyl acetate, the organic layer was washed with brine, dried (MgSO4), and evaporated. Recrystallization of the product mixture thus produced (4-chloro-7-iodo-2,6-dimethyl-quinoline and 4-chloro-5-iodo-2,6-dimethyl-quinoline) in hexane/ethyl acetate 9:1 (150 mL) afforded the title compound (7.55 g, 11%). Light brown solid, ISP-MS: m/e=318.1 ([M+H]+).

Provenance & Evidence