Carbon Dioxide → 5-chloro-6-fluoro-1H-indole-7-carboxylic acid

HRID 855245Notes

Reaction equation

HRID 855245 reaction equation
C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2.[C:17](=[O:19])=[O:18].O>CCCCCC.C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([C:17]([OH:19])=[O:18])[C:15]=1[F:16])[NH:12][CH:11]=[CH:10]2

Participants

7

Reactant 4

HCID 280Carbon DioxideHCID 962WaterHCID 27736475-chloro-6-fluoro-1H-indoleHCID 178418339Butyllithium

Product 1

HCID 251136475-chloro-6-fluoro-1H-indole-7-carboxylic acid

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent3×HCID 8058HexaneSolvent

Conditions

Temperature
-75 °C

Procedure

1.56 ml (2.49 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 3.2 ml THF at −78° C. under nitrogen. 211 mg (1.24 mmol) of 5-chloro-6-fluoro-1H-indole as a 3:1 mixture of regioisomers dissolved in 0.8 ml THF were added within 15 min keeping the temperature below −70° C. After 5 min 279 mg (2.49 mmol) of potassium-tert-butylate dissolved in 1 ml THF were added within 15 min. The reaction mixture was stirred for 2 h at −75° C. to give a clear orange solution. Solid carbon dioxide was added at that temperature and the reaction mixture was allowed to warm to rt within 30 min. Water was added and the reaction mixture was extracted twice with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was stirred with n-hexane and a trace of diethyl ether for 2 h and filtered to yield 121 mg (46 of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid as a light brown solid. 1H NMR (DMSO-d6, 300 MHz): δ 13.6 (br, 1H), 11.3 (br, 1H), 8.00 (d, 1H), 7.42 (s, 1H), 6.52 (s, 1H).

Workup

  1. additionwere added within 15 min
  2. customthe temperature below −70° C
  3. additionwere added within 15 min
  4. customto give a clear orange solution
  5. temperatureto warm to rt within 30 min
  6. extractionthe reaction mixture was extracted twice with diethyl ether
  7. extractionextracted twice with diethyl ether
  8. washThe combined organic layers were washed with saturated aqueous NaCl solution
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. customthe solvent was evaporated
  12. stirringThe residue was stirred with n-hexane
  13. waita trace of diethyl ether for 2 h
  14. filtrationfiltered

Sources & evidence

ORD record
ord-a0271c27dd1f4f3582b28c6d93415a91
Source dataset
uspto-grants-2007_08
Patent number
US07259183B2

Reaction notes

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