Pinacolone → 1-(4-Chlorophenyl)-3,3-dimethylbutan-2-one

HRID 605585Notes

Reaction equation

HRID 605585 reaction equation
CC(C)([O-])C.[Na+].Br[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:10]=1

Participants

7

Reactant 4

HCID 6416PinacoloneHCID 7806p-BromochlorobenzeneHCID 25517Ammonium ChlorideHCID 23676156Sodium t-butoxide

Product 1

HCID 101045691-(4-Chlorophenyl)-3,3-dimethylbutan-2-one

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent3×

Conditions

Temperature
25 °C

Procedure

(a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, is charged with 100.0 g of sodium t-butoxide and 300 mL of dry toluene. The mixture is stirred at 23-27° C. and added to a solution of 1.48 g of palladium acetate and 125.0 g of 4-bromochlorobenzene in 850 mL of dry toluene. The mixture is heated to a temperature at 95-100° C. using a heating mantle temperature set at about 95-125° C. over a period of 40 minutes. A solution of 98.1 g of pinacolone in 300 mL of toluene is added over a period of 45 minutes to 1 hour while maintaining the internal temperature at 95-100° C. The mixture is stirred for an additional 9 hours, then cooled to an internal temperature at 23-25° C. over a period of 30 minutes. Six hundred (600) g of 15% ammonium chloride solution is added over a period of 10 minutes while maintaining the internal temperature at 20-27° C. The mixture is stirred, the organic layer separated, and washed with 600 mL of saturated sodium chloride solution. The organic layer is charged into a 5 L, 4-necked, round-bottomed flask equipped with a mechanical stirrer, digital thermometer, addition funnel, heating mantle and a condenser with nitrogen inlet-outlet, and a solution of 150.0 g of L-cysteine in 900 mL of water is added. The mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes to achieve reflux, then stirred for an additional 5 hours. After cooling, the aqueous layer is removed, and the organic layer filtered over a Buchner funnel containing a pad of 20.0 g of Celite. After washing the Celite pad with 200 mL of toluene, and saving the filtrate, to the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water. The mixture is heated to an internal temperature at 78-82° C. White solids formed gradually. The triphasic mixture is stirred at this temperature for an additional 5 hours, then cooled, and the organic layer is separated. The organic layer is filtered over a pad of 20.0 g of Celite and the pad is washed with 200 mL of toluene. The combined filtrates is washed again with 400 mL of saturated NaCl solution. The organic layer is filtered and concentrated to collect about 800 mL of solvent to afford about 1.0 L of crude 1-(4-chlorophenyl)-3,3-dimethyl-2-butanone in toluene, which is used directly in the next step, theoretical Yield: 137.6 g (Pd 2 ppm).

Workup

  1. custom(a′) A 5 L, 4-necked, round-bottomed flask, equipped with a mechanical stirrer
  2. additiondigital thermometer, addition funnel
  3. temperatureheating mantle and a condenser with nitrogen inlet-outlet
  4. temperatureThe mixture is heated to a temperature at 95-100° C.
  5. temperaturewhile maintaining the internal temperature at 95-100° C
  6. stirringThe mixture is stirred for an additional 9 hours
  7. temperaturecooled to an internal temperature at 23-25° C. over a period of 30 minutes
  8. temperaturewhile maintaining the internal temperature at 20-27° C
  9. stirringThe mixture is stirred
  10. customthe organic layer separated
  11. washwashed with 600 mL of saturated sodium chloride solution
  12. additionThe organic layer is charged into a 5 L
  13. custom4-necked, round-bottomed flask equipped with a mechanical stirrer
  14. additiondigital thermometer, addition funnel
  15. temperatureheating mantle and a condenser with nitrogen inlet-outlet
  16. additiona solution of 150.0 g of L-cysteine in 900 mL of water is added
  17. temperatureThe mixture is heated to an internal temperature at 84-90° C. over a period of 40 minutes
  18. temperatureto achieve reflux
  19. stirringstirred for an additional 5 hours
  20. temperatureAfter cooling
  21. customthe aqueous layer is removed
  22. filtrationthe organic layer filtered over a Buchner funnel
  23. additioncontaining a pad of 20.0 g of Celite
  24. washAfter washing the Celite pad with 200 mL of toluene
  25. additionto the filtrate is added a solution of 75.0 g of L-cysteine and 2.5 g of sodium thiosulfate pentahydrate in 600 mL of water
  26. temperatureThe mixture is heated to an internal temperature at 78-82° C
  27. customWhite solids formed gradually
  28. stirringThe triphasic mixture is stirred at this temperature for an additional 5 hours
  29. temperaturecooled
  30. customthe organic layer is separated
  31. filtrationThe organic layer is filtered over a pad of 20.0 g of Celite
  32. washthe pad is washed with 200 mL of toluene
  33. washThe combined filtrates is washed again with 400 mL of saturated NaCl solution
  34. filtrationThe organic layer is filtered
  35. concentrationconcentrated
  36. customto collect about 800 mL of solvent

Sources & evidence

ORD record
ord-09556b37873942aa9f8090257b31eb6c
Source dataset
uspto-grants-2011_03
Patent number
US07915264B2

Reaction notes

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