Hydrochloric Acid → (2,4-Difluorophenyl)(2-hydroxy-4-methoxyphenyl)methanone

HRID 733061Notes

Reaction equation

HRID 733061 reaction equation
[Cl-].[Al+3].[Cl-].[Cl-].C[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1.[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].Cl>ClCCCl>[F:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:17]=1[C:18]([C:12]1[CH:11]=[CH:10][C:9]([O:13][CH3:14])=[CH:8][C:7]=1[OH:6])=[O:19]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 90251,3-DimethoxybenzeneHCID 5880812,4-Difluorobenzoyl chlorideHCID 6451240Aluminum(III) Chloride

Product 1

HCID 57839205(2,4-Difluorophenyl)(2-hydroxy-4-methoxyphenyl)methanoneYield 44.8%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

Aluminum chloride (2.03 g, 15.2 mmol) was added in portions to a solution of 1,3-dimethoxybenzene (1.86 mL, 15.2 mmol) and 2,4-difluorobenzoyl chloride (1.86 mL, 15.2 mmol) in 1,2-dichloroethane at 0° C. The mixture was allowed to warm to rt over 3 h then heated at reflux for 6 h. The resultant mixture was allowed to cool to rt, then poured into a mixture of ice (˜100 g) and concentrated hydrochloric acid (˜20 mL). The organic layer was separated. The aqueous solution was stirred at ambient temperature overnight, and extracted with dichloromethane. The organic layers were washed with aqueous sodium bicarbonate and dried over magnesium sulfate. The solvents were evaporated in vacuo to give crude product. A portion of the product was purified by flash chromatography on silica gel, using a gradient of 1%-10% EtOAc/heptane as the eluent to give the title compound 3i (1.8 g). MS: m/z 264.9 (MH+). 1H NMR (CDCl3): δ 3.90 (s, 3H), 6.42 (d of d, 1 H, J=9.0 and 2.5 Hz), 6.50 (d, 1 H, J=2.5 Hz), 6.91-7.04 (m, 2 H), 7.27-7.29 (m, 1 H), 7.44-7.50 (m, 1 H) and 12.44 (s, 1 H).

Workup

  1. temperaturethen heated
  2. temperatureat reflux for 6 h
  3. temperatureto cool to rt
  4. customThe organic layer was separated
  5. extractionextracted with dichloromethane
  6. washThe organic layers were washed with aqueous sodium bicarbonate
  7. dry with materialdried over magnesium sulfate
  8. customThe solvents were evaporated in vacuo
  9. customto give crude product
  10. customA portion of the product was purified by flash chromatography on silica gel

Sources & evidence

ORD record
ord-589dc00cf8ec431fa4004e71c173424b
Source dataset
uspto-grants-2009_09
Patent number
US07589103B2

Reaction notes

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