Hydrochloric Acid → 3-(benzofuran-3-yl)-4-(5-bromo-1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dione

HRID 222457Notes

Reaction equation

HRID 222457 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)N[CH:6]=[CH:5]2.[H-].[Na+].CI.Cl.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[CH:20]2.[C:27](Cl)(=[O:31])[C:28](Cl)=O.C1C[O:36]CC1.CC[O-].[Na+].CCO.C[N:46]([CH:48]=[O:49])[CH3:47]>CCOCC>[O:31]1[C:27]2[CH:28]=[CH:2][CH:10]=[CH:9][C:8]=2[C:4]([C:5]2[C:47](=[O:36])[NH:46][C:48](=[O:49])[C:6]=2[C:20]2[C:19]3[C:23](=[CH:24][CH:25]=[C:17]([Br:16])[CH:18]=3)[N:22]([CH3:26])[CH:21]=2)=[CH:3]1

Participants

12

Reactant 10

HCID 313Hydrochloric AcidHCID 702EthanolHCID 6228DimethylformamideHCID 6328Methyl iodideHCID 8028TetrahydrofuranHCID 24758Sodium hydrideHCID 249055-BromoindoleHCID 65578Oxalyl chlorideHCID 2857575-Bromo-1-methyl-1H-indoleHCID 2723922Sodium ethoxide

Product 1

HCID 167414753-(benzofuran-3-yl)-4-(5-bromo-1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dioneYield 86%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

To a solution of 5-bromo-indole (3.30 g, 11.73 mmol) in dry DMF (15 mL) cooled with an ice bath was added NaH (55% suspension in mineral oil, 1.02 g, 23.46 mmol), followed by methyl iodide (2.50 g, 17.60 mmol) after which the reaction mixture was allowed to warm to room temperature. After 6 h the reaction mixture was poured into ice-water; 1N HCl was added to adjust the pH to about 4, and the solution was extracted with ethyl acetate. The ethyl acetate extract was washed with water and brine, then dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was filtered through silica gel (ethyl acetate:hexane; 1:4). The product, 5-bromo-1-methyl-1H-indole, was subjected to further reaction without additional purification. To a solution of 5-bromo-1-methyl-1H-indole in Et2O (20 mL) cooled to 0° C. a 2.0 M solution of oxalyl chloride in THF (17.0 mL, 34.0 mmol) was added dropwise. The reaction was then stirred for 0.5 h at 0° C. and allowed to warm to room temperature and stirred overnight. It was then cooled to −60° C. and a 21% solution of NaOEt in EtOH (13.50 mL, 45.70 mmol) was added, after which the reaction mixture was allowed to warm to room temperature. The reaction was quenched by the addition of water and diluted with ethyl acetate. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography (ethyl acetate:hexane; 1:3) to give a product (2.92 g, 86%).

Workup

  1. extractionthe solution was extracted with ethyl acetate
  2. extractionThe ethyl acetate extract
  3. washwas washed with water and brine
  4. dry with materialdried over anhydrous Na2SO4
  5. concentrationconcentrated in vacuo
  6. filtrationThe residue was filtered through silica gel (ethyl acetate:hexane; 1:4)
  7. customThe product, 5-bromo-1-methyl-1H-indole, was subjected to further reaction without additional purification
  8. additionwas added dropwise
  9. temperatureto warm to room temperature
  10. stirringstirred overnight
  11. temperatureIt was then cooled to −60° C.
  12. temperatureto warm to room temperature
  13. customThe reaction was quenched by the addition of water
  14. additiondiluted with ethyl acetate
  15. customThe organic layer was separated
  16. dry with materialdried over anhydrous Na2SO4
  17. concentrationconcentrated
  18. customThe residue was purified by column chromatography (ethyl acetate:hexane; 1:3)

Sources & evidence

ORD record
ord-d6b5bab1902d44f6b8352b7452fb9047
Source dataset
uspto-grants-2012_06
Patent number
US08207216B2

Reaction notes

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