Reaction #607441

Reaction equation

3′,5′-difluoroacetophenone

acetaldehyde

→

title compound

Yield 40.0%

(−)-(S)-1-(3,5-difluorophenyl)ethanol

Yield 40.0%

Solvents

THF

Conditions

Workup

1. 1
   Temperaturecooled to −27° C. to −25° C.
2. 2
   TemperatureThe reaction was maintained at this temperature for 17 h
3. 3
   Otherto reach room temperature
4. 4
   OtherThe solvent was then removed in vacuo
5. 5
   Otherthe resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL)
6. 6
   ExtractionThe aqueous phase was extracted again with TBME (20 mL)
7. 7
   WashThe organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL)
8. 8
   Dryingdried over anhydrous Na2SO4
9. 9
   Filtrationfiltered
10. 10
    OtherThe solvent was removed in vacuo
11. 11
    Otherto give a residue, which
12. 12
    Otherwas purified by two subsequent column chromatographic steps

Procedure

To a stirred solution of (−)-DIP-Cl ((−)-diisopinocampheylboron chloride) (2.67 g, 8.33 mmol, 1.3 eq) in THF (20 mL) kept under inert atmosphere (Ar) and cooled to −27° C. to −25° C., 3′,5′-difluoroacetophenone (1.00 g, 6.40 mmol) was added drop wise over 2 min. The reaction was maintained at this temperature for 17 h. The reaction mixture was then treated with acetaldehyde (0.44 mL, 7.69 mmol, 1.2 eq). Thereafter, the temperature was allowed to reach room temperature and the reaction mixture was stirred at for 7 h. The solvent was then removed in vacuo and the resulting residue was partitioned between water (10 mL) and TBME (tert-butyl-methyl ether) (20 mL). The aqueous phase was extracted again with TBME (20 mL). The organic layer was washed with an aqueous 2 N NaOH solution (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and filtered. The solvent was removed in vacuo to give a residue, which was purified by two subsequent column chromatographic steps: First by normal phase chromatography (silica gel, heptane/ethyl acetate, v/v=1/0-9/1) followed by a reversed phase chromatography (90 C18-silica gel, acetonitrile for the second one). This gave the title compound (0.40 g, 40%) as a colorless oil with a specific rotation of [α]25D=−26.66 (c=1.054 g/100 mL, CH2Cl2, 589 nm).

Source