Carbon Dioxide → 5,6-difluoro-1H-indole-7-carboxylic acid

HRID 855243Notes

Reaction equation

HRID 855243 reaction equation
C([Li])CCC.[F: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>[F: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 27787325,6-Difluoro-1H-indoleHCID 178418339Butyllithium

Product 1

HCID 693460795,6-difluoro-1H-indole-7-carboxylic acidYield 51%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8058HexaneSolvent

Conditions

Temperature
-75 °C

Procedure

1.25 ml (2 mmol) of a 1.6 M butyl lithium solution in hexane were diluted with 4 ml THF at −78° C. under nitrogen. 224 mg (2 mmol) of potassium-tert-butylate and then 156 mg (1 mmol) of 5,6-difluoro-1H-indol were added. The reaction was exothermal and an orange solution was obtained, which was stirred for 2 h at −75° C. 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 three times with diethyl ether. The aqueous layer was acidified with 1N aqueous HCl solution and extracted three times 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 15 min and filtered to yield 100 mg (51%) product as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): 13.6 (br, 1H), 11.2 (br, 1H), 7.85 (dd, 1H), 7.42 (s, 1H), 6.53 (s, 1H).

Workup

  1. customan orange solution was obtained
  2. temperatureto warm to rt within 30 min
  3. extractionthe reaction mixture was extracted three times with diethyl ether
  4. extractionextracted three times with diethyl ether
  5. washThe combined organic layers were washed with saturated aqueous NaCl solution
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. customthe solvent was evaporated
  9. stirringThe residue was stirred with n-hexane
  10. waita trace of diethyl ether for 15 min
  11. filtrationfiltered

Sources & evidence

ORD record
ord-80e81ade200e4506be79ab961d9da6ea
Source dataset
uspto-grants-2007_08
Patent number
US07259183B2

Reaction notes

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