4'-Fluoroacetophenone → 2-(5-Chloropyridin-2-yl)-1-(4-fluorophenyl)ethan-1-one

HRID 2300195Notes

Reaction equation

HRID 2300195 reaction equation
[H-].[Na+].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=1>C1COCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)=[O:5])=[N:15][CH:16]=1

Participants

5

Reactant 3

HCID 98284'-FluoroacetophenoneHCID 24758Sodium hydrideHCID 276852,5-Dichloropyridine

Product 1

HCID 183760322-(5-Chloropyridin-2-yl)-1-(4-fluorophenyl)ethan-1-oneYield 8.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Procedure

Sodium hydride (Aldrich, 60% in oil, 13.03 g) was suspended in anhydrous THF (250 ml). 4-Fluoroacetophenone (15 g, 108.6 mmol) in anhydrous THF (100 ml) was added dropwise and the mixture heated to reflux for 1 h under nitrogen. The solution was cooled to 0° and 2,5 dichloropyridine (16.07 g) in anhydrous THF (75 ml) was added dropwise. The mixture was then heated to reflux overnight before being recooled to 0° and quenched with water dropwise (CAUTION! Hydrogen gas evolved, exothermic). The resulting reaction mixture was washed with brine and the organic phase dried and concentrated to give a mobile brown oil which was adsorbed onto silica gel and purified by Biotage chromatography with cyclohexane:ethyl acetate (40:1) as eluant. Combination and concentration of appropriate fractions gave the title compound as a yellow solid (2.31 g, 8.5%) which exists as a mixture of keto:enol forms, 1:2. NMR (CDCl3) δ 4.44 (2H, s, keto CH2); 6.0 (apparent 2H, s, enol CH═); 7.05-7.15 (10H, m); 7.26 (1H, d, J 9 Hz); 7.6-7.65 (apparent 3H, 2x dd, J 9 & 2 Hz); 7.8 (4H, dd, J 9 & 5 Hz); 8.35 (apparent 2H, J 3 Hz, N═CH); 8.52 (1H, J 3 Hz, N═CH) Tlc SiO2 cyclohexane:ethyl acetate (3:1) Rf 0.56 detection uv254.

Workup

  1. temperaturethe mixture heated
  2. temperatureto reflux for 1 h under nitrogen
  3. temperatureThe solution was cooled to 0°
  4. temperatureThe mixture was then heated
  5. temperatureto reflux overnight
  6. custombefore being recooled to 0°
  7. customquenched with water dropwise (CAUTION! Hydrogen gas evolved, exothermic)
  8. customThe resulting reaction mixture
  9. washwas washed with brine
  10. customthe organic phase dried
  11. concentrationconcentrated
  12. customto give a mobile brown oil which
  13. custompurified by Biotage chromatography with cyclohexane:ethyl acetate (40:1) as eluant

Sources & evidence

ORD record
ord-7c84d97895e04a16bfe0321c37708c13
Source dataset
uspto-grants-2002_12
Patent number
US06498166B1

Reaction notes

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