Methyl Nicotinate → Methyl 4-(3-ethoxy-3-oxopropyl)nicotinate

Participants

Reaction Conditions

Reaction Steps

Under an argon gas atmosphere, a mixture of zinc (21.0 g, 321 mmol) and 1,2-dibromoethane (1.40 mL, 16.2 mmol) in tetrahydrofuran (105 mL) was stirred at 80° C. for 20 min. After cooling to room temperature, chlorotrimethylsilane (400 μL, 3.13 mmol) was added at room temperature, and the mixture was stirred for 30 min. A solution of ethyl 3-iodopropanoate (60.0 g, 263 mmol) in tetrahydrofuran (53 mL) was added dropwise to the mixture at room temperature, and the mixture was stirred at 40° C. for 3 hr. A solution of copper(I) cyanide (19.2 g, 214 mmol) and lithium chloride (18.3 g, 432 mmol) in tetrahydrofuran (50 mL) was added dropwise to the mixture at 0° C., and the mixture was stirred for 30 min. This mixture was added dropwise at −78° C. under an argon gas atmosphere to a mixture obtained by stirring a solution of ethyl chlorocarbonate (19.4 mL, 203 mmol) and methyl nicotinate (27.8 g, 203 mmol) in tetrahydrofuran (105 mL) at 0° C. for 30 min, and the mixture was stirred for 12 hr while heating to room temperature. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Xylene (105 mL) and sulfur (20.0 g, 624 mmol) were added to the residue, and the mixture was stirred at 140° C. for 12 hr. After cooling to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (20.5 g, yield 43%).

Provenance & Evidence