Pyridine → methyl 5-bromo-6-chloro-1H-indole-3-carboxylate

HRID 338318Notes

Reaction equation

HRID 338318 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.ClC(Cl)(Cl)[C:20](Cl)=[O:21].[C:25](=O)([O-])[O-:26].[K+].[K+]>CN(C1C=CN=CC=1)C.CO.O1CCCC1>[Br:1][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:25]([O:21][CH3:20])=[O:26]

Participants

8

Reactant 4

HCID 1049PyridineHCID 6420Trichloroacetyl chlorideHCID 11430Potassium CarbonateHCID 144196195-Bromo-6-chloro-1H-indole

Product 1

HCID 86698569methyl 5-bromo-6-chloro-1H-indole-3-carboxylateYield 99%

Reagents, catalysts & solvents 3

HCID 142844-(Dimethylamino)pyridineCatalystHCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 5-bromo-6-chloro-1H-indole (15.1 g, 65.5 mmol), tetrahydrofuran (100 mL), pyridine (18.4 mL, 229 mmol) and DMAP (808 mg, 6.55 mmol) was cooled to 0° C. and treated with trichloroacetyl chloride (22.1 mL, 197 mmol) dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 64 hours then cooled to 10° C. Methanol (100 mL) was added dropwise to the reaction mixture over 10 minutes, producing a dark homogenous solution. Potassium carbonate (54.9 g, 393 mmol) was then added portion-wise and the ice bath was removed. Stirring was kept at a vigorous pace and allowed to continue for 2 hours, during which time the reaction turned dark green and produced an exotherm. The reaction was quenched slowly with 1M HCl (until acidic pH was maintained) and diluted with ethyl acetate. The organic layer was washed with 1M HCl. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were then washed carefully with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a brown solid (18.7 g, 99%).

Workup

  1. temperaturethen cooled to 10° C
  2. customproducing a dark homogenous solution
  3. customthe ice bath was removed
  4. stirringStirring
  5. waitto continue for 2 hours, during which time
  6. customproduced an exotherm
  7. customThe reaction was quenched slowly with 1M HCl (until acidic pH was maintained)
  8. additiondiluted with ethyl acetate
  9. washThe organic layer was washed with 1M HCl
  10. extractionThe aqueous layer was back-extracted twice with ethyl acetate
  11. washThe combined organic layers were then washed carefully with saturated sodium bicarbonate solution
  12. dry with materialThe organic layer was dried over magnesium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-093b5746754242d5ba0a8c9a328a2669
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

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