1,4-Difluorobenzene → HCID 12788467, compound

HRID 1855902Notes

Reaction equation

HRID 1855902 reaction equation
[H-].[Na+].C(O)(=O)C(O)=O.[CH3:9][N:10]1[CH2:15][CH2:14][C@@H:13]([O:16][C:17]2[CH:22]=[CH:21][C:20](C(F)(F)F)=[CH:19][CH:18]=2)[C@H:12]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:11]1.[F:33]C1C=CC(F)=CC=1>CN(C=O)C>[F:33][C:20]1[CH:21]=[CH:22][C:17]([O:16][C@@H:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][C@H:12]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:18][CH:19]=1

Participants

5

Reactant 3

HCID 108921,4-DifluorobenzeneHCID 24758Sodium hydride2×HCID 12788391HCID 12788391, compound

Product 1

HCID 12788467HCID 12788467, compound

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
90 °C

Procedure

A mixture of 0.6 g of sodium hydride, 3.83 g of sodium hydride, 3.83 g of trans-1-methyl-3-phenyl-4-piperidinol of Example 1 and 30 ml of anhydrous DMF is heated to 90° C. for 1.5 hours, then cooled to room temperature. A solution of 2.85 g of p-difluorobenzene in 20 ml of DMF is added all at once; the mixture is stirred at 70°-80° C. under nitrogen for 48 hours. The mixture is cooled and partitioned between ether and saturated aqueous NaCl solution. The aqueous phase is extracted with ether, and the combined ether extracts are washed with water and saturated aqueous NaCl solution and then concentrated in vacuo to an oil. This material is dissolved in 200 ml of dichloromethane, and the solution is extracted with 2 N HCl solution. The dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and concentrated in vacuo to afford an oil which crystallizes upon standing. This material is chromatographed on silica gel, using acetone and then 25% methanol/acetone as solvent to obtain trans-4-(4-fluorophenoxy)-1-methyl-3-phenylpiperidine, m.p. s 67°, 69.5°-71.5° C.

Workup

  1. temperaturecooled to room temperature
  2. temperatureThe mixture is cooled
  3. custompartitioned between ether and saturated aqueous NaCl solution
  4. extractionThe aqueous phase is extracted with ether
  5. washthe combined ether extracts are washed with water and saturated aqueous NaCl solution
  6. concentrationconcentrated in vacuo to an oil
  7. dissolutionThis material is dissolved in 200 ml of dichloromethane
  8. extractionthe solution is extracted with 2 N HCl solution
  9. washThe dichloromethane phase is successively washed with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution
  10. dry with materialdried over anhydrous Na2SO4
  11. concentrationconcentrated in vacuo
  12. customto afford an oil which
  13. customcrystallizes
  14. customThis material is chromatographed on silica gel

Sources & evidence

ORD record
ord-fed2d22b6ed94c9eb56b977fd5a9d379
Source dataset
uspto-grants-1980_08
Patent number
US04216218

Reaction notes

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