反应详情

温度

0 °C

A 2.47 M hexane solution of butyl lithium in an amount of 28.8 mL was added to a solution of 7.83 g of diisopropylamine dissolved in 84 mL of tetrahydrofuran, which was cooled to 0° C. The solution was stirred for 15 minutes, followed by cooling to −62° C. Subsequently, a solution of 12.0 g of ethyl (1R,5R,6R)-6-fluoro-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate dissolved in 40 mL of tetrahydrofuran was added dropwise thereto, while being maintained at −62 to −58° C. One hour later, a solution of 25.3 g of N-phenyl-bis(trifluoromethanesulfonimide) dissolved in 84 mL of tetrahydrofuran was added dropwise thereto over 15 minutes, while maintained at −62 to −60° C. The reaction solution was allowed to naturally warm to room temperature, and was further stirred for one hour. The reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with diethyl ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and was subsequently dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=20:1). Immediately, the produced ethyl (1R,5R,6R)-6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-6-carboxylate was dissolved in 195 mL of N,N-dimethylformamide, and 389 mg of palladium acetate, 910 mg of triphenylphosphine, and 12.5 g of benzyl alcohol were added thereto, followed by addition of 11.7 g of triethylamine. Subsequently, the mixture was stirred under a carbon monoxide atmosphere for 4.5 hours at room temperature. 1M hydrochloric acid was added to the reaction mixture, followed by extractions with diethyl ether twice. The organic layers were combined, and the combined organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, followed by drying over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1 to 1:1), thereby yielding 6.42 g of (1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester.

1. temperatureby cooling to −62° C
2. additionwas added dropwise
3. temperaturewhile being maintained at −62 to −58° C
4. additionwas added dropwise
5. waitover 15 minutes
6. temperaturewhile maintained at −62 to −60° C
7. temperatureto naturally warm to room temperature
8. stirringwas further stirred for one hour
9. customThe reaction was quenched with a saturated aqueous solution of sodium hydrogencarbonate
10. extractionfollowed by extraction with diethyl ether
11. washThe organic layer was washed with water
12. dry with materiala saturated aqueous solution of sodium chloride, and was subsequently dried over anhydrous magnesium sulfate
13. filtrationAfter the desiccant was filtered off
14. concentrationthe filtrate was concentrated under reduced pressure
15. customThe residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=20:1)
16. dissolutionImmediately, the produced ethyl (1R,5R,6R)-6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-6-carboxylate was dissolved in 195 mL of N,N-dimethylformamide
17. addition389 mg of palladium acetate, 910 mg of triphenylphosphine, and 12.5 g of benzyl alcohol were added
18. additionfollowed by addition of 11.7 g of triethylamine
19. stirringSubsequently, the mixture was stirred under a carbon monoxide atmosphere for 4.5 hours at room temperature
20. addition1M hydrochloric acid was added to the reaction mixture
21. extractionfollowed by extractions with diethyl ether twice
22. washthe combined organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate
23. dry with materialby drying over anhydrous magnesium sulfate
24. filtrationAfter the desiccant was filtered off
25. concentrationthe filtrate was concentrated under reduced pressure
26. customThe residue was purified by column chromatography (silica gel: Wako gel C200 (produced by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=10:1 to 1:1)