Sulfuric Acid → 6-Bromo-5-fluoroquinoline

HRID 655269Notes

Reaction equation

HRID 655269 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[C:3]([F:9])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:18][CH:13]=[CH:14]2

Participants

5

Reactant 3

HCID 1118Sulfuric AcidHCID 7416NitrobenzeneHCID 8218484-Bromo-3-fluoroaniline

Product 1

HCID 145483386-Bromo-5-fluoroquinoline

Reagents, catalysts & solvents 1

HCID 753GlycerolSolvent

Procedure

A mixture of 4-bromo-3-fluoro-phenylamine (100 g, 526 mmol), ferrous sulfate (30 g), glycerol (200 g), nitrobenzene (40 g) and concentrated sulfuric acid (100 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 5 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return a mixture of 6-bromo-5-fluoro-quinoline and 6-bromo-7-fluoro-quinoline as a white solid (80 g, 68%). This mixture was heated to reflux in petroleum ether. The solution was cooled to r.t., filtered and dried to return 6-bromo-7-fluoro-quinoline as a white solid. To the solution was added HCl/MeOH, and a white solid precipitated from the solution. The solid was filtered and basified. The resulting precipitate was collected by filtration and dried to obtain 6-bromo-5-fluoro-quinoline as white solid. 1H-NMR (DMSO-d6, 300 MHz): 9.0 (d, 1H), 8.5 (d, 1H), 8.0 (m, 1H), 7.8 (d, 1H), 7.7 (m, 1H); MS: m/z 228 [M+H+]+.

Workup

  1. temperaturewere heated gently
  2. customAfter the first vigorous reaction
  3. temperaturethe mixture was heated
  4. temperatureto reflux for 5 hours
  5. customNitrobenzene was evaporated in vacuo
  6. customseparated
  7. customwhich was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1)
  8. additiona mixture of 6-bromo-5-fluoro-quinoline and 6-bromo-7-fluoro-quinoline as a white solid (80 g, 68%)
  9. temperatureThis mixture was heated
  10. temperatureto reflux in petroleum ether
  11. filtrationfiltered
  12. customdried
  13. additionTo the solution was added HCl/MeOH
  14. customa white solid precipitated from the solution
  15. filtrationThe solid was filtered
  16. filtrationThe resulting precipitate was collected by filtration
  17. customdried

Sources & evidence

ORD record
ord-54062296bb724991a35c9a03830b979b
Source dataset
uspto-grants-2011_12
Patent number
US08071581B2

Reaction notes

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