Reaction #2175427

Reaction equation

1-Butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene

hydrochloric acid

trimethyl borate

sec-Butyllithium

→

1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorophenol

Yield 78.2%

Solvents

THF

THF

Ethyl acetate

n-hexane

cyclohexane

Conditions

Workup

1. 1
   workup.ADDITION23.0 ml) was added dropwise
2. 2
   workup.WAITin the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture
3. 3
   Otherto come to 25° C
4. 4
   workup.ADDITIONThen, the reaction mixture was poured into a vessel
5. 5
   workup.ADDITIONmixed with them
6. 6
   Otherto separate into organic and aqueous phases
7. 7
   Extractionthe extraction
8. 8
   WashThe combined organic phase was washed successively with water
9. 9
   Dryinga saturated aqueous solution of sodium hydrogencarbonate and salt water, and dried over anhydrous magnesium sulfate
10. 10
    workup.DISTILLATIONThen, the solvent was distilled off under reduced pressure
11. 11
    OtherThe residue and acetic acid (50 ml) were put in a reaction vessel under an atmosphere of nitrogen
12. 12
    workup.ADDITION1.0 g) was added in the temperature range of 25° C. to 30° C.
13. 13
    workup.WAITthe stirring was continued for another 2 hours
14. 14
    workup.ADDITIONThen, the reaction mixture was poured into a vessel
15. 15
    workup.ADDITIONcontaining an aqueous solution of sodium hydrogensulfite (100 ml) and ethyl acetate (200 ml)
16. 16
    workup.ADDITIONmixed with them
17. 17
    Otherhad separated into organic and aqueous phases
18. 18
    Extractionthe extraction
19. 19
    WashThe combined organic phase was washed successively with water and salt water
20. 20
    Dryingdried over anhydrous magnesium sulfate
21. 21
    workup.DISTILLATIONThen, the solvent was distilled off

Procedure

1-Butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorobenzene (s-20) (7.2 g) and THF (200 ml) were put in a reaction vessel under an atmosphere of nitrogen and cooled to −74° C. sec-Butyllithium (a 1.00 M solution in n-hexane and cyclohexane; 23.0 ml) was added dropwise thereto in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, trimethyl borate (2.0 g) in a THF (30 ml) solution was added dropwise thereto in the temperature range of −74° C. to −65° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. Then, the reaction mixture was poured into a vessel containing 1 N hydrochloric acid (100 ml) and ice-water (200 ml), and mixed with them. Ethyl acetate (200 ml) was added and the mixture was allowed to separate into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and salt water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue and acetic acid (50 ml) were put in a reaction vessel under an atmosphere of nitrogen, and hydrogen peroxide (a 31% aqueous solution; 1.0 g) was added in the temperature range of 25° C. to 30° C., and then the stirring was continued for another 2 hours. Then, the reaction mixture was poured into a vessel containing an aqueous solution of sodium hydrogensulfite (100 ml) and ethyl acetate (200 ml), and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction was carried out. The combined organic phase was washed successively with water and salt water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to give 1-butoxy-4-(4-(2,3-difluorophenyl)cyclohex-1-enyl)-2,3-difluorophenol (s-21) (5.9 g). The yield based on the compound (s-20) was 78.6%.

Source