Potassium Carbonate → 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile

HRID 506139Notes

Reaction equation

HRID 506139 reaction equation
[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=3)[C:7]([C:15]#[N:16])=[CH:6]2)[CH2:4][CH2:3][CH2:2]1.C(OB([O-])[O-])(C)C.[Li+].CC([N-]C(C)C)C.[Cl:32][C:33]1[CH:38]=[C:37](I)[CH:36]=[CH:35][C:34]=1[NH2:40].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:40][C:34]1[CH:35]=[CH:36][C:37]([C:6]2[N:5]([CH:1]3[CH2:2][CH2:3][CH2:4]3)[C:13]3[C:8]([C:7]=2[C:15]#[N:16])=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=3)=[CH:38][C:33]=1[Cl:32]

Participants

10

Reactant 5

HCID 11430Potassium CarbonateHCID 2829302-Chloro-4-iodoanilineHCID 2724682Lithium diisopropylamideHCID 594254261-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrileHCID 71368315Isopropylborate

Product 1

HCID 594306152-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrileYield 65.1%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.0 g, 14.1 mmol) and isopropylborate (5 mL, 21.1 mmol) in anhydrous THF (40 mL) at 0° C. was added LDA (16.2 mL, 2.0 M in heptane/THF/ethylbenzene, 32.4 mmol) dropwise. The mixture was stirred at 0° C. for 15 min and then at room temperature for 1 h. After cooling the reaction mixture to 0° C. a solution of 2-chloro-4-iodo-phenylamine (3.9 g, 15.5 mmol) in DMF (40 mL) was added followed by addition of PdCl2(dppf) (0.3 g, 0.4 mmol) and aq. K2CO3 (14 mL, 2.0 M). The mixture was warmed to room temperature and continued to stir overnight. The reaction was diluted with water and then extracted with ethyl acetate. The organic layers was dried, concentrated and triturated with chloroform to provide 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (3.1 g, 64%) as an off-white solid.

Workup

  1. waitat room temperature for 1 h
  2. additionwas added
  3. temperatureThe mixture was warmed to room temperature
  4. stirringto stir overnight
  5. extractionextracted with ethyl acetate
  6. customThe organic layers was dried
  7. concentrationconcentrated
  8. customtriturated with chloroform

Sources & evidence

ORD record
ord-34c1df9741e347c98c4a5600077031b5
Source dataset
uspto-grants-2010_08
Patent number
US07781478B2

Reaction notes

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