Reaction #1973901

Reaction equation

4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone

ammonium chloride

3-Butoxy-1,2-difluorobenzene

sec-Butyllithium

→

4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol

Yield 99.6%

Solvents

THF

ethyl acetate

THF

Conditions

Workup

1. 1
   workup.ADDITIONwas added dropwise in the temperature range of −74° C. to −70° C.
2. 2
   Otherto come to 25° C
3. 3
   workup.ADDITIONmixed with them
4. 4
   Otherhad separated into two phases of organic and aqueous phases
5. 5
   Extractionthe extraction into an organic phase
6. 6
   OtherThe resulting organic phase was separated
7. 7
   Washwashed successively with water
8. 8
   Dryinga saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate
9. 9
   workup.DISTILLATIONThe solvent was then distilled off under reduced pressure

Procedure

3-Butoxy-1,2-difluorobenzene (7) (10.0 g) and THF (200 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. sec-Butyllithium (1.00 M, in n-hexane and cyclohexane solution; 64.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Successively, 4-(1,4-dioxaspiro[4.5]decan-8-yl)-cyclohexanone (21) (12.8 g) in THF (50 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., while the mixture was allowed to come to 25° C. The reaction mixture was poured into a 3%-aqueous solution of ammonium chloride (100 ml) and ethyl acetate (100 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-(4-butoxy-2,3-difluorophenyl)-cyclohexanol (22) (22.7 g). The resulting compound (22) was a pale yellow oil.

Source