Reacción #1753062

Ecuación de reacción

N-phenyl-bis(trifluoromethanesulfonimide)

(1R,5R,6R)-6-fluoro-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate ethyl ester

hexamethyldisilazane

diethyl ether

n-butyl lithium hexane

→

(1R,5R,6R)-6-fluorobicyclo[3.1.0]hex-2-en-2,6-dicarboxylic acid diethyl ester

Disolventes

tetrahydrofuran

tetrahydrofuran

tetrahydrofuran

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturawhile being maintained at −63° C. to −54° C
2. 2
   workup.ADDITIONwas added dropwise
3. 3
   Temperaturawhile being maintained at −63° C. to −52° C
4. 4
   workup.ADDITIONwas added an hour later 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-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-en-6-carboxylate 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 2.66M n-butyl lithium hexane solution was added dropwise to 700 mL of a tetrahydrofuran solution containing 137 mL of hexamethyldisilazane, and the mixture was stirred for 1 hour while being maintained at −63° C. to −54° C. 340 mL of a tetrahydrofuran solution containing 101 g of (1R,5R,6R)-6-fluoro-2-oxo-bicyclo[3.1.0]hexane-6-carboxylate ethyl ester was added dropwise thereto while being maintained at −63° C. to −52° C. 700 mL of a tetrahydrofuran solution containing 213 g of N-phenyl-bis(trifluoromethanesulfonimide) was added an 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-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-en-6-carboxylate 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, 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-fluorobicyclo[3.1.0]hex-2-en-2,6-dicarboxylic acid diethyl ester.

Fuente