Dimethylformamide → 4-(4-Fluorophenyl)-4-hydroxycyclohexan-1-one

HRID 1658648Notes

Reaction equation

HRID 1658648 reaction equation
C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([OH:16])([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.CN(C)C=O.[H-].[Na+].CI>C1C=CC=CC=1>[OH:16][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 6328Methyl iodide2×HCID 24758Sodium hydrideHCID 86733586HCID 86733586, compound

Product 1

HCID 223953644-(4-Fluorophenyl)-4-hydroxycyclohexan-1-oneYield 49%

Reagents, catalysts & solvents 1

HCID 241BenzeneSolvent

Procedure

To a solution of 21.65 g. (0.085 mole) of 4-hydroxy-4-(p-fluorophenyl)cyclohexanone dimethyl ketal (prepared as in Example 25) in 80 ml. of dimethylformamide and 320 ml. of benzene, 3.56 g. of 57% sodium hydride is added. Following about 1 hour of stirring at room temperature, 35 ml. of methyl iodide is added and the mixture heated at reflux. After about 4 hours of heating an additional 10 ml. of methyl iodide is added. At the end of about 18 hours of heating, the suspension, after cooling, is washed with water and brine. The organic layer is evaporated to dryness and the gum remaining dissolved in 400 ml. of acetone, then 40 ml. of 2.5N hydrochloric acid added. At the end of about 4 hours, most of the solvent is removed under vacuum. The residue is extracted with ether and the organic layer washed with aqueous sodium bicarbonate solution and brine and then evaporated to dryness. The residual gum is chromatographed on a 2 l. column of Florisil (synthetic magnesium silicate), with elution by 2 l. of Skellysolve B, 2 l. of 95% Skellysolve B:5% acetone and 4 l. of 70% Skellysolve B:30% acetone. Crystalline fractions of first the product, then 6.87 g. (49%) of 4-hydroxy-4-(p-fluorophenyl)-cyclohexanone, melting at 108° to 114° C., are obtained. The product is recrystallized from petroleum ether to give 7.76 g. (41%) of 4-methoxy-4-(p-fluorophenyl)cyclohexanone, melting at 60° to 69° C. The analytical sample melts at 68° to 70° C.

Workup

  1. temperaturethe mixture heated
  2. temperatureat reflux
  3. temperatureAfter about 4 hours of heating an additional 10 ml
  4. temperatureAt the end of about 18 hours of heating
  5. temperaturethe suspension, after cooling
  6. washis washed with water and brine
  7. customThe organic layer is evaporated to dryness
  8. dissolutionthe gum remaining dissolved in 400 ml
  9. additionof 2.5N hydrochloric acid added
  10. customAt the end of about 4 hours, most of the solvent is removed under vacuum
  11. extractionThe residue is extracted with ether
  12. washthe organic layer washed with aqueous sodium bicarbonate solution and brine
  13. customevaporated to dryness
  14. customThe residual gum is chromatographed on a 2 l
  15. washcolumn of Florisil (synthetic magnesium silicate), with elution by 2 l

Sources & evidence

ORD record
ord-fff484632e114a788948ee16e07f0c4f
Source dataset
uspto-grants-1976_06
Patent number
US03965180

Reaction notes

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