Ethyl Acetate → methyl 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylate

HRID 338328Notes

Reaction equation

HRID 338328 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].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1OC.[C:28](=[O:31])([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>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([O:31][CH3:28])=[CH:18][C:17]=1[F:16]

Participants

9

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 27821943-Fluoro-4-methoxyphenylboronic acidHCID 86698569methyl 5-bromo-6-chloro-1H-indole-3-carboxylate

Product 1

HCID 86698675methyl 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylateYield 32%

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), (3-fluoro-4-methoxyphenyl)boronic acid (93 mg, 0.55 mmol) and aqueous 2M 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 then treated with [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20.0 mg, 0.026 mmol). The reaction mixture was then heated at 110° C. for 2 h in a sealed reaction vessel, which caused the reaction mixture to appear burnt orange. The cooled reaction mixture was 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/heptane (1:4 to 1:1) to provide the desired product (55 mg, 32% yield) as a tan solid. MS (ES+) 334.5 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 12.07 (br. s., 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 7.26 (t, J=8.69 Hz, 1H), 6.90 (dd, J=11.91, 2.15 Hz, 1H), 6.85 (dd, J=8.49, 2.24 Hz, 1H), 3.80 (s, 3H), 3.76 (s, 3H).

Workup

  1. customwas degassed with nitrogen for 10 minutes
  2. customThe cooled reaction mixture
  3. customThe layers were separated
  4. extractionthe aqueous layer was back-extracted with ethyl acetate
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. dissolutionThe material was then dissolved in ethyl acetate
  10. additionmethanol then silica gel was added
  11. customThe solvent was removed
  12. additionwas added to a column of silica gel
  13. washeluted with ethyl acetate/heptane (1:4 to 1:1)

Sources & evidence

ORD record
ord-37d0179883d94a63bf75edf192d6fa91
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

Loading…