Benzoic acid, 4-fluoro-, ethyl ester → 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone

HRID 8488

Reaction equation

HRID 8488 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=[O:15])=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:14]([C:13]2[CH:19]=[CH:20][C:10]([F:9])=[CH:11][CH:12]=2)=[O:15])[CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 67976Benzoic acid, 4-fluoro-, ethyl esterHCID 876016-Chloro-2-picolineHCID 2733832Lithium Hexamethyldisilazide

Product 1

HCID 219486712-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneYield 66%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
45 °C

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).

Workup

  1. customover 1 hour
  2. additionUpon complete addition
  3. customthe cold bath was removed
  4. temperatureThe mixture was cooled to room temperature
  5. customquenched by the addition of water
  6. additionEther was added
  7. washthe organic layer was washed with brine
  8. extractionThe aqueous layer was extracted with ether
  9. dry with materialthe combined organics were dried over magnesium sulfate
  10. filtrationFiltration and concentration
  11. customgave a solid residue which
  12. customwas purified by recrystallization from ethyl acetate-hexanes

Sources & evidence

ORD record
ord-355d452942e54325bec58b0626c5dd9e
Source dataset
uspto-grants-2006_08
Patent number
US07087618B2

Linked notes

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