Dimethylformamide → 2-Fluoropyridine-3-carbaldehyde

HRID 75204Notes

Reaction equation

HRID 75204 reaction equation
C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.CN(C)[CH:22]=[O:23]>C1COCC1>[F:13][C:14]1[N:15]=[CH:16][CH:17]=[CH:18][C:19]=1[CH:22]=[O:23]

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 7912DiisopropylamineHCID 97462-FluoropyridineHCID 178418339Butyllithium

Product 1

HCID 114349442-Fluoropyridine-3-carbaldehydeYield 45.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of n-butyllithium (77 mL, 2.5 M in hexane, 0.19 mol) was added to a solution of N,N-diisopropylamine (27 mL, 0.19 mol) in dry THF (400 mL) under an atmosphere of nitrogen at −78° C. After the addition, the mixture was warmed to 0° C. for 15 minutes and then cooled again to −78° C. 2-Fluoropyridine (15.0 mL, 0.174 mol) was added dropwise to the mixture and stirred at −78° C. After 45 minutes, a pale yellow precipitate formed. N,N-Dimethylformamide (27 mL, 0.35 mol) was added slowly via syringe maintaining temperature below −55° C. After ten minutes, the cooling bath was removed and the mixture slowly warmed to room temperature. The reaction was quenched with NH4Cl/H2O and then 4 M HCl to adjust the pH ˜7. NaHCO3/H2O was then added to adjust the pH 9-10, and then extracted three times with Et2O. The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to a yellow oil. The residue was purified by chromatography on silica gel, eluting with 25% EtOAc/hexane to provide 2-fluoronicotinaldehyde as a pale yellow oil (10.0 g, 45%). 1H NMR (CDCl3) δ 10.33 (s, 1H), 8.49 (m, 1H), 8.32 (m, 1H), 7.40 (m, 1H). LC/MS: 126 (M+H)+.

Workup

  1. additionAfter the addition
  2. temperaturecooled again to −78° C
  3. customa pale yellow precipitate formed
  4. temperaturemaintaining temperature below −55° C
  5. waitAfter ten minutes
  6. customthe cooling bath was removed
  7. temperaturethe mixture slowly warmed to room temperature
  8. customThe reaction was quenched with NH4Cl/H2O
  9. additionNaHCO3/H2O was then added
  10. extractionextracted three times with Et2O
  11. washThe combined extracts were washed with brine
  12. dry with materialdried over MgSO4
  13. filtrationfiltered
  14. concentrationconcentrated to a yellow oil
  15. customThe residue was purified by chromatography on silica gel
  16. washeluting with 25% EtOAc/hexane

Sources & evidence

ORD record
ord-d805b613b33740e5ba5f5420fdfe18c3
Source dataset
uspto-grants-2014_09
Patent number
US08835423B2

Reaction notes

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