Sulfuric Acid → methyl 6-bromo-5-iodo-1H-indole-3-carboxylate

HRID 338385Notes

Reaction equation

HRID 338385 reaction equation
[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].[Br:15]Br.S(=O)(=O)(O)O>C(O)(=O)C.CO.CO.ClCCl>[Br:15][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][NH:7]2)=[CH:3][C:2]=1[I:1]

Participants

7

Reactant 3

HCID 1118Sulfuric AcidHCID 24408BromineHCID 53408147methyl 5-iodo-1H-indole-3-carboxylate2×

Product 1

HCID 86698727methyl 6-bromo-5-iodo-1H-indole-3-carboxylate

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolvent2×HCID 887MethanolSolventHCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
70 °C

Procedure

To a suspension of methyl 5-iodo-1H-indole-3-carboxylate (1.20 g, 3.09 mmol) in acetic acid (30 ml) was added a solution of bromine (0.15 ml, 2.9 mmol) in acetic acid (5 ml). Reaction was heated to reflux and stirred for 3 hours. The reaction was then cooled and poured onto ice water, then partitioned between water and dichloromethane. The aqueous layer was extracted with 10% MeOH/DCM (2×100 mL). The organics were combined, washed with brine, and dried over sodium sulfate, filtered and concentrated to give a dark red semi solid. The residue was taken up in methanol (30 ml). Concentrated sulfuric acid (0.5 ml) was added and mixture was heated to 70° C. for 2 days. The reaction was cooled then concentrated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The layers were separated and organic washed with brine, dried over sodium sulfate, filtered and concentrated to give a reddish solid. The residue was dissolved in methanol/dichloromethane and adsorbed onto silica gel and purified by silica gel chromatography (50 g, 20-100% ethyl acetate/heptane). The major peak was isolated to afford a mixture of the title compound and methyl 5-iodo-1H-indole-3-carboxylate confirmed as a brown solid (260 mg) that was taken forward without further purification.

Workup

  1. customReaction
  2. temperaturewas heated
  3. temperatureto reflux
  4. temperatureThe reaction was then cooled
  5. additionpoured onto ice water
  6. custompartitioned between water and dichloromethane
  7. extractionThe aqueous layer was extracted with 10% MeOH/DCM (2×100 mL)
  8. washwashed with brine
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto give a dark red semi solid
  13. temperatureThe reaction was cooled
  14. concentrationthen concentrated in vacuo
  15. customthe residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution
  16. customThe layers were separated
  17. washorganic washed with brine
  18. dry with materialdried over sodium sulfate
  19. filtrationfiltered
  20. concentrationconcentrated
  21. customto give a reddish solid
  22. custompurified by silica gel chromatography (50 g, 20-100% ethyl acetate/heptane)
  23. customThe major peak was isolated
  24. customto afford

Sources & evidence

ORD record
ord-f28d4bba03af49f48b945c14fe9a924b
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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