Hydrochloric Acid → 4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one

HRID 968876Notes

Reaction equation

HRID 968876 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[CH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[O:23][C:24]([CH:26]=[CH2:27])=[CH2:25].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=3[F:20])[CH2:27][CH2:26][C:24](=[O:23])[CH2:25][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 5546572-(Trimethylsiloxy)-1,3-butadieneHCID 11529749HCID 11529749, compound

Product 1

HCID 104301374-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-oneYield 90%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
130 °C

Procedure

2-[[(4-chlorophenyl)sulfonyl]methyl]-1,4-difluorobenzene (Intermediate 1) (100 g, 0.33 mol) and N,N,N′,N′-tetramethyldiaminomethane (34.2 g, 0.50 mol) were dissolved in dimethyl formamide (1000 mL) at 60° C. Acetic anhydride (68.3 g, 1.00 mol) was added slowly and the reaction mixture was aged for 5 hours. Water (1000 mL) was added dropwise and the resulting slurry was cooled to 5° C. The solids were filtered, and the cake washed sequentially with dimethyl formamide:water (40:60, 200 mL) and water (500 mL). Drying overnight in vacuo at 40° C. under a nitrogen stream furnished 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (98 g, 95%). 1H NMR (CDCl3) 7.64-7.59 (2H, m), 7.43-7.39 (2H, m), 7.27-7.22 (1H, m), 7.08-6.88 (2H, m), 6.88 (1H, s) and 6.09 (1H, s). (ii) A solution of 2-[1-[(4-chlorophenyl)sulfonyl]ethenyl]-1,4-difluorobenzene (100 g, 0.32 mol) in xylenes (500 ml) was azeotropically distilled at 38° C., 20 mmHg, until 300 mL solvent had been removed. 2-Trimethylsilyloxybutadiene (90.4 g, 0.64 mol) was then added under a nitrogen atmosphere and the mixture heated to 130° C. After the reaction was completed, the mixture was distilled in vacuo to remove residual diene, whilst maintaining a constant volume by the addition of xylenes (400 mL). The mixture was cooled to 50° C. and THF (500 mL) and 3M HCl (424 mL, 1.27 mol) were added. After the hydrolysis was complete, the layers were separated. The organic layer was washed with water (300 mL) and then concentrated by atmospheric distillation until 350 mL of solvent had been removed. The solution was allowed to cool until crystallisation started, heptane (600 mL) was added and the resulting mixture cooled to ambient. The solids were filtered and washed sequentially with heptane:xylenes (3:1, 200 ml) and then heptane (200 ml). Drying overnight in vacuo at 40° C. furnished 4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanone (110 g, 90% yield). 1H NMR CDCl3— as for the product obtained via Method (a).

Workup

  1. custom20 mmHg, until 300 mL solvent had been removed
  2. distillationthe mixture was distilled in vacuo
  3. customto remove residual diene
  4. temperaturewhilst maintaining a constant volume
  5. additionby the addition of xylenes (400 mL)
  6. temperatureThe mixture was cooled to 50° C.
  7. customthe layers were separated
  8. washThe organic layer was washed with water (300 mL)
  9. concentrationconcentrated by atmospheric distillation until 350 mL of solvent
  10. customhad been removed
  11. temperatureto cool until crystallisation
  12. additionheptane (600 mL) was added
  13. temperaturethe resulting mixture cooled
  14. filtrationThe solids were filtered
  15. washwashed sequentially with heptane:xylenes (3:1, 200 ml)
  16. customDrying overnight in vacuo at 40° C.

Sources & evidence

ORD record
ord-5bd4ead5b9304ee5ab78459ee64d83af
Source dataset
uspto-grants-2007_12
Patent number
US07304094B2

Reaction notes

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