Reaction #8584

Reaction equation

6-chloro-2-picoline

ethyl 4-fluorobenzoate

lithium bis(trimethylsilyl)amide

→

2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone

Yield 66.0%

Solvents

tetrahydrofuran

Conditions

Workup

1. 1
   Otherover 1 hour
2. 2
   workup.ADDITIONUpon complete addition
3. 3
   Otherthe cold bath was removed
4. 4
   TemperatureThe mixture was cooled to room temperature
5. 5
   Otherquenched by the addition of water
6. 6
   workup.ADDITIONEther was added
7. 7
   Washthe organic layer was washed with brine
8. 8
   ExtractionThe aqueous layer was extracted with ether
9. 9
   Dryingthe combined organics were dried over magnesium sulfate
10. 10
    FiltrationFiltration and concentration
11. 11
    Othergave a solid residue which
12. 12
    Otherwas purified by recrystallization from ethyl acetate-hexanes

Procedure

To a cold (0° C.) solution of 6-chloro-2-picoline (21.4 mL, 196.0 mmol) and ethyl 4-fluorobenzoate (57.5 mL, 391.2 mmol) in tetrahydrofuran (311 mL) was added lithium bis(trimethylsilyl)amide (391 mL, 1.0 M in tetrahydrofuran, 391.0 mmol) dropwise via a pressure equalizing funnel over 1 hour. Upon complete addition, the cold bath was removed and the resultant solution was heated to 45° C. for 15 hours. The mixture was cooled to room temperature and quenched by the addition of water. Ether was added and the organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration gave a solid residue which was purified by recrystallization from ethyl acetate-hexanes to provide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g, 66%) as a tinted off-white solid existing as a keto-enol tautomeric mixture. 1H NMR (CDCl3): for the keto tautomer δ 8.11 (m, 2 H), 7.66 (t, 1 H), 7.30–7.25 (m 2 H), 7.17 (t, 2 H), 4.48 (s 2 H), 19F NMR (CDCl3) δ −104.72 (keto), −111.64 (enol); MS m/z 250 (M+1).

Source