Carbon Dioxide → 4-fluoro-1H-indole-7-carboxylic Acid

HRID 855232Notes

Reaction equation

HRID 855232 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[C:17](=[O:19])=[O:18].O>C1COCC1.CCCCCC>[F:11][C:5]1[CH:4]=[CH:3][C:2]([C:17]([OH:19])=[O:18])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2

Participants

7

Reactant 4

HCID 280Carbon DioxideHCID 962WaterHCID 43429567-bromo-4-fluoro-1H-indoleHCID 178418339Butyllithium

Product 1

HCID 115792174-fluoro-1H-indole-7-carboxylic AcidYield 80%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Conditions

Temperature
-78 °C

Procedure

492 mg (2.30 mmol) of 7-bromo-4-fluoro-1H-indole were dissolved in 14 ml THF. The reaction mixture was cooled to −78° C. and 4.31 ml of a 1.6 M butyl lithium solution in hexane were added under nitrogen in such a way, that the temperature did not exceed a maximum of −70° C. The yellow solution was stirred at 0 to 5° C. after complete addition for 30 min. The reaction mixture was cooled to −78° C. and dry ice was added. The reaction mixture was warmed to rt, stirred for 15 min and poured onto 100 ml water. The aqueous layer was washed twice with diethyl ether, acidified with 1N aqueous HCl solution and extracted twice with DCM. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The crude residue was stirred with hexane for 15 min, filtered and dried to yield 328 mg (80%) of 4-fluoro-1H-indole-7-carboxylic acid as an off-white solid. MS (ISP) 177.9 (M−H)−.

Workup

  1. customa maximum of −70° C
  2. additionafter complete addition for 30 min
  3. temperatureThe reaction mixture was cooled to −78° C.
  4. temperatureThe reaction mixture was warmed to rt
  5. stirringstirred for 15 min
  6. washThe aqueous layer was washed twice with diethyl ether
  7. extractionextracted twice with DCM
  8. washThe combined organic layers were washed with saturated aqueous sodium chloride solution
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. customthe solvent was evaporated
  12. stirringThe crude residue was stirred with hexane for 15 min
  13. filtrationfiltered
  14. customdried

Sources & evidence

ORD record
ord-0895aa27126e4d66aa91a937dc7e7f38
Source dataset
uspto-grants-2007_08
Patent number
US07259183B2

Reaction notes

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