Cesium carbonate → (1-{4-[6-(4-methyl-piperazin-1-yl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester

HRID 1037203Notes

Reaction equation

HRID 1037203 reaction equation
[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]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.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CO.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]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 634876Binap, (A+-)-2×HCID 67067709{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester

Product 1

HCID 67067974(1-{4-[6-(4-methyl-piperazin-1-yl)-4-oxo-2-phenyl-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl esterYield 27%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
150 °C

Procedure

{1-[4-(6-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (55 mg, 0.1 mmol), 1-methylpiperazine (13 μL, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol), (S)-BINAP (9 mg, 0.015 mmol) and cesium carbonate (46 mg, 0.14 mmol) were suspended in toluene (1.0 mL) in a microwave vial. The vial was sealed, evacuated and flushed twice with nitrogen. The mixture was heated in a microwave at 150° C. for 30 min. Further tris(dibenzylideneacetone)dipalladium(0) (5 mg, 0.005 mmol) and (S)-BINAP (9 mg, 0.015 mmol) were added to the vial and the mixture heated conventionally at 110° C. for 24 hours. The mixture was cooled to RT, dissolved in methanol and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before eluting with 2M ammonia in methanol solution. The eluent was collected and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 3%-4% 2M ammonia in methanol/DCM) to afford the title compound as a yellow oil (15 mg, 27%). LCMS (Method B): RT=3.74 min, M+H+=566.

Workup

  1. customThe vial was sealed
  2. customevacuated
  3. customflushed twice with nitrogen
  4. temperatureheated conventionally at 110° C. for 24 hours
  5. temperatureThe mixture was cooled to RT
  6. washThe cartridge was washed repeatedly with methanol
  7. washbefore eluting with 2M ammonia in methanol solution
  8. customThe eluent was collected
  9. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-1aff722743a34b91a3a15dd2f6231582
Source dataset
uspto-grants-2013_10
Patent number
US08546376B2

Reaction notes

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