Hydrochloric Acid → 4-(3,5-Difluorophenyl)cyclohexan-1-one

HRID 1977558Notes

Reaction equation

HRID 1977558 reaction equation
[F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].C1O[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=O)[O:13]C1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]2[CH2:18][CH2:19][C:14](=[O:13])[CH2:15][CH2:16]2)[CH:5]=[C:6]([F:8])[CH:7]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 1363131-Bromo-3,5-difluorobenzeneHCID 5462224MagnesiumHCID 123480741,4-Dioxaspiro[4.5]decan-6-one

Product 1

HCID 177905164-(3,5-Difluorophenyl)cyclohexan-1-oneYield 27.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To Grignard reagent prepared from 3,5-difluorobromobenzene 100 g (518 mmol) and magnesium in dried THF 300 ml at room temperature, a THF (300 ml) solution of cyclohexanedione monoethyleneketal 74.6 g (517 mmol) was added dropwise at room temperature, and the mixture was stirred for 3 hours at room temperature. The reactant was added to one liter of 2N-hydrochloric acid, and the product was extracted with diethylether. The extract was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue, para-toluene sulfonic acid 5 g and toluene 800 ml were added. The mixture was refluxed with heating while removing water formed with Dien-Stark. The reactant was washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon 5 g as a catalyst in ethanol 500 ml. The catalyst was filtered off, the solvent was distilled off under reduced pressure, formic acid 40 g and toluene 300 ml were added to the residue, and the mixture was refluxed for 3 hours. After cooling, water 500 ml was added to the reactant, and the organic layer was fractionated, washed with water, a saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1) to obtain 4-(3,5-difluorophenyl)cyclohexanone 29.4 g (140 mmol). The yield was 27.0% from 3,5-difluorobromobenzene.

Workup

  1. extractionthe product was extracted with diethylether
  2. washThe extract was washed with water
  3. dry with materiala saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate
  4. distillationthe solvent was distilled off under reduced pressure
  5. additionTo the residue, para-toluene sulfonic acid 5 g and toluene 800 ml were added
  6. temperatureThe mixture was refluxed
  7. temperaturewith heating
  8. customwhile removing water
  9. customformed with Dien-Stark
  10. washThe reactant was washed with water
  11. dry with materiala saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate
  12. distillationthe solvent was distilled off under reduced pressure
  13. customThe residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1)
  14. customSuch obtained
  15. custompurified material
  16. filtrationThe catalyst was filtered off
  17. distillationthe solvent was distilled off under reduced pressure, formic acid 40 g and toluene 300 ml
  18. additionwere added to the residue
  19. temperaturethe mixture was refluxed for 3 hours
  20. temperatureAfter cooling
  21. additionwater 500 ml was added to the reactant
  22. washwashed with water
  23. dry with materiala saturated sodium bicarbonate aqueous solution, and then water, and dried over anhydrous magnesium sulfate
  24. distillationthe solvent was distilled off
  25. customThe residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1)

Sources & evidence

ORD record
ord-bd091d586ab14adbb07b20028981fcad
Source dataset
uspto-grants-2001_05
Patent number
US06235355B1

Reaction notes

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