Nitric Acid → 2-Fluoro-5-methoxyaniline

HRID 495429Notes

Reaction equation

HRID 495429 reaction equation
Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4](Br)[C:3]=1[O:10][CH3:11].[N+:12]([O-])(O)=O>S(=O)(=O)(O)O.C(O)C.[Pd]>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:10][CH3:11])=[CH:2][C:7]=1[NH2:12]

Participants

6

Reactant 2

HCID 944Nitric AcidHCID 27739651,3-Dibromo-5-fluoro-2-methoxybenzene

Product 1

HCID 135590752-Fluoro-5-methoxyanilineYield 59%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 1118Sulfuric AcidSolvent2×

Conditions

Temperature
20 °C

Procedure

To a stirred mixture of 2,6-dibromo-4-fluoroanisole (52.5 g, 0.185 mol) in 98% sulfuric acid (152 mL) at 15° C. was added, dropwise over 0.5 h, a solution of nitric acid (9.2 mL) and sulfuric acid (152 mL) with external ice-bath cooling. The mixture was stirred at 20° C. over 4 h, then was poured into ice water (1 kg) and extracted with dichloromethane (3×150 mL). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give a brown oil. Chromatography on silica with 1-50% ether in hexane gradient elution gave an off-white solid, a solution of which in ethanol (250 mL) was hydrogenated at 20° C. and 4 bar over 10% palladium on carbon (3.5 g) for 18 h. Catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a residue which was partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography on silica with 20-50% ether in hexane gradient elution gave the title compound (15.3 g, 59%) as an oil.

Workup

  1. additionwas added, dropwise over 0.5 h
  2. extractionextracted with dichloromethane (3×150 mL)
  3. dry with materialThe combined extracts were dried (Na2SO4)
  4. customevaporated in vacuo
  5. customto give a brown oil
  6. washChromatography on silica with 1-50% ether in hexane gradient elution
  7. customgave an off-white solid
  8. customwas hydrogenated at 20° C.
  9. customCatalyst was removed by filtration
  10. customthe filtrate was evaporated in vacuo
  11. customto give a residue which
  12. customwas partitioned between saturated aqueous NaHCO3 (300 mL) and dichloromethane (3×100 mL)
  13. dry with materialThe combined organic extracts were dried (Na2SO4)
  14. customevaporated in vacuo
  15. customto give an oil
  16. washChromatography on silica with 20-50% ether in hexane gradient elution

Sources & evidence

ORD record
ord-1697e1e3b3cd43a683c5d31a7f773282
Source dataset
uspto-grants-2005_09
Patent number
US06939871B2

Reaction notes

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