3,4,5-Trimethoxyaniline → 4-(6,6-Dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)benzonitrile

HRID 900463Notes

Reaction equation

HRID 900463 reaction equation
CC(C)([O-])C.[Na+].Br[C:8]1[CH:15]=[C:14]([N:16]2[C:24]3[CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20](=[O:27])[C:19]=3[C:18]([CH3:28])=[N:17]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:25][C:22]1([CH3:26])[CH2:23][C:24]2[N:16]([C:14]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([NH:34][C:33]4[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=4)[CH:15]=3)[N:17]=[C:18]([CH3:28])[C:19]=2[C:20](=[O:27])[CH2:21]1

Participants

8

Reactant 3

HCID 322853,4,5-TrimethoxyanilineHCID 118541702-Bromo-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzonitrileHCID 23676156Sodium t-butoxide

Product 1

HCID 669528904-(6,6-Dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)benzonitrileYield 246.6%

Reagents, catalysts & solvents 4

HCID 167845palladium(II) acetateCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
120 °C

Procedure

Sodium tert-butoxide (269 mg, 2.80 mmol, 2.0 equiv) was added to a stirred solution/suspension of 2-bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (500 mg, 1.40 mmol, 1.0 eq.), 3,4,5-trimethoxyaniline (513 mg, 2.80 mmol, 2.0 eq.), palladium (II) acetate (16 mg, 0.07 mmol, 0.05 eq.), and 1,1′-bis(diphenylphosphino)ferrocene (78 mg, 0.14 mmol, 0.10 eq.) in 3.75 mL of toluene. The reaction vial was capped, and the reaction mixture was heated 20 minutes at 120° C. under microwave irradiation. The individual reaction mixtures were diluted with ethyl acetate, combined, and partitioned with water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage System (SiO2, hexanes-ethyl acetate) to afford 4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzonitrile (1.59 g, 82%) as a tan solid: LC/MS (m/z): [M+H]+ 461.9.

Workup

  1. customThe reaction vial was capped
  2. customThe individual reaction mixtures
  3. custompartitioned with water
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted with ethyl acetate
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customThe residue was purified on a Biotage System (SiO2, hexanes-ethyl acetate)

Sources & evidence

ORD record
ord-8eb62365680d45d4be964ed8957d82b7
Source dataset
uspto-grants-2008_04
Patent number
US07358370B2

Reaction notes

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