2-氯-4-氟-3-甲氧基苯甲醛

反应条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a mixture of 2-Chloro-4-fluoro-3-methoxybenzaldehyde (17.6 g, 93.3 mmol) and malonic acid (18.6 g, 179 mmol) was added pyridine (60 mL) followed by piperidine (1.6 mL, 19 mmol). The mixture was heated in a 90° C. oil bath giving a clear yellow solution. After 220 minutes, the hot solution was poured into 500 mL of ice cold 2.5N HCl with stirring. The resulting solid was isolated by filtration, washing thoroughly with water. Drying under vacuum gave (2E)-3-(2-chloro-4-fluoro-3-methoxyphenyl)acrylic acid as a yellow solid. giving a clear yellow solution The resulting solid was isolated by filtration washing thoroughly with water Drying under vacuum

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of N,N,N′-trimethylethylenediamine (20.3 mL, 156 mmol) in 75 mL of THF was cooled to −50° C. and a 2.5M solution of n-butyllithium in hexanes (62.5 mL, 156 mmol) was added dropwise with stirring during 15 minutes, keeping the internal temperature below −35° C. The temperature was maintained at 40° C. for 30 minutes, and then the reaction mixture was cooled to −70° C. A solution of 4-fluoro-3-methoxybenzaldehyde (24.09 g, 156.3 mmol) in 75 mL of THF was added dropwise during 15 minutes, keeping the reaction temperature below −50° C. When the addition was complete, the reaction was allowed to warm to −40° C. and held there for 25 minutes. The reaction was then re-cooled to −70° C. and a 2.5M solution of n-butyllithium in hexanes (62.5 mL, 156 mmol) was added dropwise. When the addition was complete, the reaction was allowed to warm to −20° C. and kept at that temperature overnight (12 hours). The reaction mixture was then cooled to −30° C. and the cold solution was added via cannula during 30 minutes to a room temperature solution of hexachloroethane (111 g, 469 mmol) in 200 mL of THF. After stirring at room temperature for 4 hours, the reaction mixture was poured into 500 mL of ice cold 4N HCl. Most of the THF was removed by rotary evaporation under reduced pressure and the residual mixture was extracted twice with 1:1 ethyl ether/hexanes. The organic layers were combined and washed successively with 1N NaOH, 1N HCl, water, and brine. After drying over sodium sulfate, removal of the solvent under vacuum gave a yellow solid. Flash chromatography on silica gel eluting with hexanes/dichloroethane (2:1 to 1:1) gave 2-chloro-4-fluoro-3-methoxybenzaldehyde as a white solid. the internal temperature below −35° C the reaction mixture was cooled to −70° C the reaction temperature below −50° C When the addition to warm to −40° C. held there for 25 minutes The reaction was then re-cooled to −70° C. When the addition to warm to −20° C. kept at that temperature overnight (12 hours) The reaction mixture was then cooled to −30° C. After stirring at room temperature for 4 hours Most of the THF was removed by rotary evaporation under reduced pressure the residual mixture was extracted twice with 1:1 ethyl ether/hexanes washed successively with 1N NaOH, 1N HCl, water, and brine After drying over sodium sulfate, removal of the solvent under vacuum gave a yellow solid