Ethyl Acetate → methyl 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylate

HRID 1054669Notes

Reaction equation

HRID 1054669 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([O:14][CH3:15])=[O:13].[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(O)C.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].O>[C:16]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][C:10]=2[Cl:11])[NH:7][CH:6]=[C:5]3[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:17]=1

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 1512531,1'-Biphenyl-4-yl-boronic acidHCID 86698569methyl 5-bromo-6-chloro-1H-indole-3-carboxylate

Product 1

HCID 86698673methyl 5-(biphenyl-4-yl)-6-chloro-1H-indole-3-carboxylateYield 35%

Reagents, catalysts & solvents 4

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

A mixture of methyl 5-bromo-6-chloro-1H-indole-3-carboxylate (150 mg, 0.52 mmol), 4-biphenylboronic acid (113 mg, 0.57 mmol) and 2M aqueous potassium carbonate (2M, 1.04 mL, 2.08 mmol) in toluene (3.0 mL) and ethanol (1.0 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg, 0.026 mmol) and heated at 110° C. for 2 h in a sealed reaction vessel, which caused the reaction to appear burnt orange. The reaction mixture was cooled to room temperature and poured into ethyl acetate and water. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was then dissolved in ethyl acetate and methanol then silica gel was added. The solvent was removed and the crude material adsorbed onto silica gel was added to a column of silica gel and eluted with ethyl acetate/heptanes (1:4 to 1:1) to give the desired product as a tan solid 61 mg (35% yield). MS (ES+) 362.5 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.53 (br. s., 1 H), 8.17 (s, 1H), 7.94 (d, J=2.15 Hz, 1H), 7.61-7.72 (m, 4H), 7.57 (d, J=6.05 Hz, 2H), 7.45 (t, J=7.61 Hz, 2H), 7.31-7.40 (m, 1H), 3.89 (s, 3H).

Workup

  1. customwas degassed with nitrogen for 10 minutes
  2. customthe reaction
  3. temperatureThe reaction mixture was cooled to room temperature
  4. customThe layers were separated
  5. extractionthe aqueous layer was back-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. dissolutionThe material was then dissolved in ethyl acetate
  11. additionmethanol then silica gel was added
  12. customThe solvent was removed
  13. additionwas added to a column of silica gel
  14. washeluted with ethyl acetate/heptanes (1:4 to 1:1)

Sources & evidence

ORD record
ord-12ba269a7ce74677897e8116ef1e478a
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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