Toluene → Tert-butyl 4-(4-chloro-3-methoxyphenyl)piperazine-1-carboxylate

HRID 930603Notes

Reaction equation

HRID 930603 reaction equation
C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[O:16][CH3:17].[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:28]2[CH2:27][CH2:26][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:30][CH2:29]2)=[CH:11][C:10]=1[O:16][CH3:17]

Participants

8

Reactant 4

HCID 1140TolueneHCID 143452tert-Butyl piperazine-1-carboxylateHCID 27695675-Bromo-2-chloroanisoleHCID 23676156Sodium t-butoxide

Product 1

HCID 58778031Tert-butyl 4-(4-chloro-3-methoxyphenyl)piperazine-1-carboxylateYield 93%

Reagents, catalysts & solvents 3

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a 3-necked, 5-L Morton flask equipped with a mechanical stirrer, gas adapter, heating mantle and thermometer was added rac-BINAP (4.24 g, 0.005 equiv) and Pd2(dba)3 (3.20 g, 0.0025 equiv). The flask was evacuated, and back-filled with nitrogen. Toluene (100 mL) was added by cannula. The mixture was stirred at room temperature for 15 min to give a purple solution. Toluene (2.0 L) was then added. 2-Chloro-5-bromoanisole (300.3 g, 1.356 mol, 1 equiv) was added in one portion. Boc-piperazine (252.4 g, 1 equiv) was added in one portion. Sodium tert-butoxide (183.0 g, 1.4 equiv) was added in one portion. The flask was evacuated and back-filled with nitrogen. The mixture was then heated to an internal temperature of 60° C. A heterogeneous light-orange slurry was obtained. After 1 h, the mixture becomes a homogeneous brown solution. After an additional 15 h, the mixture was cooled to room temperature. EtOAc (2.0 L) was added to the stirring mixture. The solid was filtered. The filtrate was washed with EtOAc (100 mL). The combined filtrate was washed with 10% aq. K2CO3 solution (1×1 L), water (1×1 L), and dried over MgSO4. The solvent was removed in vacuo to afford the product as an orange solid (410.3 g, 93% yield).

Workup

  1. temperatureheating mantle and thermometer
  2. customThe flask was evacuated
  3. additionback-filled with nitrogen
  4. additionToluene (100 mL) was added by cannula
  5. customto give a purple solution
  6. customThe flask was evacuated
  7. additionback-filled with nitrogen
  8. temperatureThe mixture was then heated to an internal temperature of 60° C
  9. customA heterogeneous light-orange slurry was obtained
  10. waitAfter 1 h
  11. waitAfter an additional 15 h
  12. temperaturethe mixture was cooled to room temperature
  13. filtrationThe solid was filtered
  14. washThe filtrate was washed with EtOAc (100 mL)
  15. washThe combined filtrate was washed with 10% aq. K2CO3 solution (1×1 L), water (1×1 L)
  16. dry with materialdried over MgSO4
  17. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-037de6732c9a4347bb34a644d29b9bfd
Source dataset
uspto-grants-2016_03
Patent number
US09296740B2

Reaction notes

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