Reaction #2329018

Reaction equation

2-chloro-4-fluorobenzonitrile

trans 1,3-cyclohexanediol

NaH

→

title compound

Yield 9.2%

(1R,3R)-2-Chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile

Yield 9.2%

Solvents

THF

THF

Conditions

Workup

1. 1
   Temperaturecooled in an ice/acetone bath
2. 2
   OtherThe cold bath was removed
3. 3
   workup.STIRRINGto stir at room temperature overnight
4. 4
   OtherThe reaction was quenched with approximately 10 mL 5% citric acid
5. 5
   Otherthe THF was removed by rotovap
6. 6
   workup.ADDITIONEthyl acetate was added
7. 7
   Otherthe layers were separated
8. 8
   ExtractionThe aqueous layer was extracted twice more with ethyl acetate
9. 9
   WashThe combined organic layers were washed twice with brine
10. 10
    Dryingdried over magnesium sulfate
11. 11
    Filtrationfiltered
12. 12
    OtherThe resulting product was triturated with hexane
13. 13
    Otherthe hexane decanted off
14. 14
    OtherThe crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate)
15. 15
    Otherthe solvent removed
16. 16
    OtherThe results of two such runs

Procedure

A commercial mixture of cis/trans 1,3-cyclohexanediol (7.77 g, 66.9 mmol) was dissolved in 50 mL anhydrous THF (tetrahydrofuran), under a nitrogen atmosphere, and cooled in an ice/acetone bath. NaH (60% suspension in oil, 2.69 g, 6.725 mmol) was then added and the solution stirred approximately 10 min. Then a solution of 2-chloro-4-fluorobenzonitrile (1.06 gms, 6.79 mmol)(in 20 mL anhydrous THF was added in a slow, steady stream (not dropwise). The cold bath was removed, and allowed to stir at room temperature overnight. The reaction was quenched with approximately 10 mL 5% citric acid and the THF was removed by rotovap. off. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the organic layers were combined. The combined organic layers were washed twice with brine, then dried over magnesium sulfate, filtered and rotovapped. The resulting product was triturated with hexane, and the hexane decanted off. The crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate), and the desired fractions were combined, and the solvent removed. The results of two such runs were combined, and submitted for preparative reverse phase HPLC. The title compound (0.1575 g) was returned. HNMR (CDCl3, ppm) 7.5 (1H, d, J=8.8 Hz), 6.96 (1H, s), 6.82 (1H, d, J=8.8 Hz), 4.8-4.6 (1H, m), 4.2-4.1 (1H, m), 2.1-1.4 (9H, m).

Source