Potassium Carbonate → 1-(2-Fluoro-3-methoxy-6-nitrophenyl)propan-2-one

HRID 1163046Notes

Reaction equation

HRID 1163046 reaction equation
[F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[F:1][C:2]1[C:7]([O:17][CH3:16])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14]

Participants

4

Reactant 2

HCID 11430Potassium CarbonateHCID 142688761-(2,3-Difluoro-6-nitrophenyl)propan-2-one

Product 1

HCID 220307431-(2-Fluoro-3-methoxy-6-nitrophenyl)propan-2-oneYield 73.6%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

A mixture of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (183 g) and potassium carbonate (100 g) in methanol (1 L) was heated at reflux for 3 h. The reaction mixture was then cooled and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (1 L), filtered and washed with water. The separated aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether and filtered to provide 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one (121 g, 71%) as a yellow solid. LC/MS; (M+H)+=228.2. N. A mixture of 1-(2-fluoro-3-methoxy-6-nitrophenyl)-propan-2-one from previous step (454 mg, 21 mmol) and pyridinium chloride (0.9 g, 7.8 mmol) was stirred at 180° C. for 75 min. The reaction was cooled to room temperature, diluted with 1N HCl (3 mL) and ethyl acetate (10 mL) and filtered. The filtrate was washed with brine (2×), dried and concentrated in vacuo to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (410 mg, 96%) as a grey solid, which was used without further purification for the next step. LC/MS; (M+H)+=214. 1HNMR (CDCl3): δ 2.37 (s, 3H), 4.22 (s, 2H), 6.95 (dd, 1H), 7.95 (d, 1H, J=9.35 Hz). O. 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from previous step (50 g, 0.234 mol) was added to 2 liter round bottom flask. Water (1 L) was added, and the yellow suspension was stirred at RT. Sodium dithionite (225 g, 5.5 eq) was added in one portion and the reaction mixture was stirred and kept <30° C. until HPLC analysis indicated no starting material remained (typically less than 1 hour). Upon completion, the reaction mixture was cooled to 0° C. and the tan solid product was collected by vacuum filtration. The wet product was dried at <50° C. under house vacuum to afford 4-fluoro-2-methyl-1H-indol-5-ol (31.4 g, 81% yield) which was isolated as a tan crystalline powder. The material had an HPLC purity of >99.8. 1H NMR (CDCl3, 400 MHz) δ 7.8 (s, 1H), 6.9-6.7 (m, 2H), 6.2 (s, 1H), 4.7 (s, 1H), 2.4 (s, 3H). 13C NMR (CDCl3, 100 MHz) δ 145.7, 143.4, 137.5, 136.7, 134.4, 120.1, 112.7, 106.8, 95.4, 13.3.

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 3 h
  3. temperatureThe reaction mixture was then cooled
  4. concentrationconcentrated in vacuo
  5. customto remove most of the methanol
  6. additionThe residue was diluted with ethyl acetate (1 L)
  7. filtrationfiltered
  8. washwashed with water
  9. extractionextracted with ethyl acetate (2×500 mL)
  10. washThe combined organic layer was washed with brine
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated in vacuo
  13. customto give a brown solid
  14. customThe solid was triturated with diethyl ether
  15. filtrationfiltered

Sources & evidence

ORD record
ord-03f4771348bc4be184c0d554d44c4d5f
Source dataset
uspto-grants-2010_10
Patent number
US07820814B2

Reaction notes

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