Reacción #217679

Ecuación de reacción

N-phenyl-bis(trifluoromethanesulfonimide)

diethyl ether

n-butyllithiumhexane

hexamethyldisilazane

(1R,5R,6R)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester

→

(1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid diethyl ester

Disolventes

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturamaintained at −63° C. to −54° C
2. 2
   Temperaturaat a temperature maintained at −63° C. to −52° C
3. 3
   Otro1 hour
4. 4
   Otrolater at 63° C. to −45° C
5. 5
   workup.STIRRINGfurther stirred for 2.5 hours
6. 6
   Lavadowashed three times with a saturated aqueous solution of sodium hydrogen carbonate
7. 7
   Secadowith a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate
8. 8
   FiltraciónAfter the desiccant was filtered off
9. 9
   Concentraciónthe filtrate was concentrated under reduced pressure
10. 10
    Otrothe residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:1 to 20:1 to 5:1)
11. 11
    workup.DISSOLUTIONThe obtained 175 g of (1R,5R,6R)-6-fluoro-2-trifluoromethanesulfonyloxybicyclo[3.1.0]hex-2-ene-6-carboxylic acid ethyl ester was dissolved in 875 mL of N,N-dimethylformamide
12. 12
    workup.ADDITION875 mL of ethanol, and after 95.1 mL of diisopropylethylamine, 8.65 g of triphenylphosphine and 3.70 g of palladium acetate were added
13. 13
    workup.STIRRINGthe mixture was stirred for 5.5 hours at room temperature, under a carbon monoxide atmosphere
14. 14
    workup.ADDITION1N hydrochloric acid was added
15. 15
    Extracciónthe reaction solution was extracted six times with diethyl ether
16. 16
    Lavadowashed four times with a saturated aqueous solution of sodium hydrogen carbonate
17. 17
    Secadowith a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate
18. 18
    FiltraciónAfter the desiccant was filtered off
19. 19
    Concentraciónthe filtrate was concentrated under reduced pressure
20. 20
    Otrothe residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:1 to 20:1 to 10:1)

Procedimiento

245 mL of a solution of 2.66 M n-butyllithiumhexane was added dropwise to 700 mL of a solution of tetrahydrofuran containing 137 mL of hexamethyldisilazane and stirred for 1 hour at a temperature maintained at −63° C. to −54° C. 340 mL of a solution of tetrahydrofuran containing 101 g of (1R,5R,6R)-6-fluoro-2-oxobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester was added dropwise thereto at a temperature maintained at −63° C. to −52° C. 700 mL of a solution of tetrahydrofuran containing 213 g of N-phenyl-bis(trifluoromethanesulfonimide) was added thereto 1 hour later at 63° C. to −45° C. The reaction solution was warmed naturally to room temperature and further stirred for 2.5 hours. The reaction solution was diluted with diethyl ether, washed three times with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:1 to 20:1 to 5:1). The obtained 175 g of (1R,5R,6R)-6-fluoro-2-trifluoromethanesulfonyloxybicyclo[3.1.0]hex-2-ene-6-carboxylic acid ethyl ester was dissolved in 875 mL of N,N-dimethylformamide and 875 mL of ethanol, and after 95.1 mL of diisopropylethylamine, 8.65 g of triphenylphosphine and 3.70 g of palladium acetate were added thereto, the mixture was stirred for 5.5 hours at room temperature, under a carbon monoxide atmosphere. 1N hydrochloric acid was added thereto, and the reaction solution was extracted six times with diethyl ether. The organic layers were combined, washed four times with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:1 to 20:1 to 10:1), thereby yielding 92.6 g of (1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylic acid diethyl ester.

Fuente