Sodium Hydroxide → 4-(3-chloro-4-fluorophenyl)-1H-indole

HRID 982985Notes

Reaction equation

HRID 982985 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:27][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][C:23]=1[F:26]

Participants

7

Reactant 3

HCID 14798Sodium HydroxideHCID 35430654-Bromo-2-chloro-1-fluorobenzeneHCID 113224711H-Indole-4-boronic acid, pinacol ester

Product 1

HCID 225617164-(3-chloro-4-fluorophenyl)-1H-indoleYield 70%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
75 °C

Procedure

To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2) dioxaborolan-2-yl) 1H-indole (3, 3.00 g, 12.34 mmol), and 4-bromo-2-chloro-fluorobenzene (2.58 g, 12.34 mmol) in THF (42 mL)) were added Palladium catalyst Pd(PPh3)4 (0.428 g, 0.37 mmol) and the freshly prepared sodium hydroxide solution (1.50 g, 37.02 mmol in 17 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.11 g (70%) of the product 43-chloro-4-fluoro-phenyl)-1H-indole as a white solid.

Workup

  1. customThe system was degassed
  2. additioncharged with nitrogen
  3. customthe completion of the coupling reaction
  4. temperatureThe mixture was cooled to room temperature
  5. customseparated from water layer
  6. washThe ethyl acetate solution was washed by brine
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customThe crude product was purified by a silica gel column
  10. washeluting with hexanes—EtOAc (9:1)

Sources & evidence

ORD record
ord-060f5f2f801f48b6a49a407c80f2fbb8
Source dataset
uspto-grants-2005_03
Patent number
US06861418B2

Reaction notes

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