Piperazine → (3aR,6aR)-5-Methyl-1-(4-piperazin-1-yl-phenyl)-octahydro-pyrrolo[3,4-b]pyrrole

HRID 12972Notes

Reaction equation

HRID 12972 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>O.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].C1(C)C=CC=CC=1>[CH3:16][N:14]1[CH2:13][C@@H:10]2[C@@H:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:3][CH:4]=3)[CH2:12][CH2:11]2)[CH2:15]1

Participants

8

Reactant 4

HCID 4837PiperazineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 44221503(3aR,6aR)-1-(4-Bromophenyl)-5-methyloctahydropyrrolo[3,4-b]pyrrole

Product 1

HCID 68497954(3aR,6aR)-5-Methyl-1-(4-piperazin-1-yl-phenyl)-octahydro-pyrrolo[3,4-b]pyrrole

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
140 °C

Procedure

The product of Example 72B (200 mg, 0.71 mmole), piperazine (200 mg, 2.33 mmole), tris(dibenzylideneacetone)dipalladium (20 mg, 0.022 mmole), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (28 mg, 0.045 mmole), sodium tert-butoxide (140 mg, 1.46 mmole) and 7 ml of toluene were mixed under N2 in a Emrys process vial. The vial was sealed heated in the microwave for 15 minutes at 140° C. using the Emrys Creator. The mixture was diluted with water and extracted with dichloromethane (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (10% methanol and 1% ammonium hydroxide in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 6.84-6.94 (m, 2H) 6.53-6.60 (m, 2H) 4.00-4.07 (m, 1H) 3.44-3.51(m, 1H) 3.11-3.20 (m, 1H) 2.99-3.09 (m, 9H) 2.88-2.96 (m, 1H) 2.68 (dd, J=9.66, 2.54 Hz, 1H) 2.48-2.59 (m, 2H), 2.31(s, 3H) 2.09-2.19 (m, 1H) 1.89 (m, 1H). MS-(M+H)+=287.

Workup

  1. customThe vial was sealed
  2. extractionextracted with dichloromethane (4×)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give the crude product which
  8. customwas purified by column chromatography (10% methanol and 1% ammonium hydroxide in dichloromethane)

Sources & evidence

ORD record
ord-5096d94f2d7c4e03973ee5d92679950c
Source dataset
uspto-grants-2010_06
Patent number
US07728031B2

Reaction notes

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