Cyclohexane → 1-(5-Chloropyridin-2-yl)ethan-1-one

Participants

Reaction Conditions

Reaction Steps

A two liter 4 neck flask was equipped with a stirrer, a thermometer and a 250 mL addition funnel. The reaction setup was flushed with nitrogen overnight. A 1.3 M cyclohexane solution of sec-butyllithium (222 mL, 0.289 mol) was charged to the addition funnel with a cannula. 2-Bromo-5-chloropyridine (57.72 g, MW=192.4, 0.30 mol) and 600 mL of ethyl ether were charged to the flask and then cooled in an acetone/dry ice bath. The temperature of the resultant slurry was -76° C. The sec-butyllithium was added dropwise at a rate to maintain the temperature at -74° C. or lower. The addition took 1.5 hours. When the addition was complete the addition funnel was rinsed with 20 mL of ethyl ether, then charged with 30.7 mL of N,N-dimethylacetamide (MW=87.12, d=0.937, 0.330 mol) and 30 mL of ethyl ether. Ten minutes after the completion of the sec-butyllithium addition, the N,N-dimethylacetamide solution was added dropwise to the reaction mixture, again maintaining the temperature at -74° C. or less. This addition took about 40 minutes. The reaction mixture was held at -76° C. for one hour after the N,N-dimethylacetamide addition was complete, then the bath was removed and the temperature allowed to warm to -30° C. At this temperature the cold bath was replaced and the reaction was quenched with 200 mL of 3 N HCl. The reaction mixture was allowed to warm to room temperature and held overnight. The phases were separated, the ethyl ether phase washed with water and saturated brine and then dried over anhydrous MgSO4. The ethyl ether was stripped, the crude product dissolved in methylene chloride and then treated with one weight equivalent of silica gel. The resulting slurry was filtered through Celite and stripped. The product was recrystallized from hexane to give 29.35 g of 2-acetyl-5-chloropyridine (65% yield based on sec-butyllithium, the limiting reagent).

Provenance & Evidence