1-Methylpiperazine → 5-(4-Methyl-piperazin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester

HRID 334961Notes

Reaction equation

HRID 334961 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CCOCC.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>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 531671-MethylpiperazineHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 16102683N-Boc-5-bromoisoindolineHCID 23676156Sodium t-butoxide

Product 1

HCID 592631315-(4-Methyl-piperazin-1-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl esterYield 46%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent2×HCID 3283Diethyl EtherSolvent

Conditions

Temperature
80 °C

Procedure

5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.97 g, 10 mmol) was azeotropically dried by evaporation from toluene. Tris(dibenzylideneacetone)dipalladium (0) (228 mg, 0.25 mmol), 2-(di-tert-butylphosphino)biphenyl (149 mg, 0.50 mmol) and sodium tert-butoxide (1.34 g, 13.9 mmol) were added and the flask was purged with nitrogen. Toluene (25 mL) then N-methylpiperazine (1.33 mL, 12 mmol) were added and the mixture was heated to 80° C. for 2 hours. After allowing to cool to r.t. the mixture was diluted with ether, filtered through Celite and concentrated to give a residue that was purified by flash chromatography on silica (2M methanolic ammonia/dichloromethane, 1% to 3% gradient). This afforded the title compound as a brown solid (1.45 g, 46%). 1H NMR (MeOH-d4) 7.15 (1H, m), 6.94-6.88 (2H, m), 4.60-4.54 (4H, m), 3.20-3.17 (4H, m), 2.63-2.60 (4H, m), 2.34 (3H, s), 1.52 (9H, s). MS: [M+H]+ 318.

Workup

  1. customthe flask was purged with nitrogen
  2. temperatureto cool to r.t. the mixture
  3. filtrationfiltered through Celite
  4. concentrationconcentrated
  5. customto give a residue that
  6. customwas purified by flash chromatography on silica (2M methanolic ammonia/dichloromethane, 1% to 3% gradient)

Sources & evidence

ORD record
ord-bc6da19b09694a39a02981a81113e391
Source dataset
uspto-grants-2014_11
Patent number
US08883790B2

Reaction notes

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