Phosphorus oxychloride → 2-Chloro-3-phenylpyridine

HRID 220449Notes

Reaction equation

HRID 220449 reaction equation
[C:1]1([C:7]2[CH:8]=[N+:9]([O-])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][CH:11]=[CH:10][N:9]=1

Participants

3

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 27631493-Phenylpyridine-N-oxide

Product 1

HCID 27628072-Chloro-3-phenylpyridineYield 28.4%

Procedure

Dissolve 3-phenyl-pyridine 1-oxide (1.0 g, 5.84 mmol) in phosphorus oxychloride (14 mL, 153 mmol). Heat the reaction to 105° C. for 6 hours, cool to ambient temperature and pour reaction mixture slowly onto ice with stirring to quench the excess phosphorus oxychloride. Basify with concentrated ammonium hydroxide and extract with dichloromethane. Wash the organic extract with brine, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: ethyl acetate-hexanes) to give 315 mg (28%) of 2-chloro-3-phenyl-pyridine as a yellow liquid. MS (m/z): 190 (M+1, 100), 192 (M+1, 60). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, 1H, J=4.6, 2.0 Hz), 7.87 (dd, 1H, J=7.5, 1.8 Hz), 7.54-7.41 (m, 6H). 1-(3-phenyl-pyridin-2-yl)-piperazine: Heat a mixture of 2-chloro-3-phenyl-pyridine (1.12 g, 5.9 mmol) and piperazine (5.08 g, 59.0 mmol) in a sealed tube at 165° C. for 23 hours. Cool to ambient temperature. Dissolve the reaction mixture in water and ethyl acetate. Extract the aqueous layer with ethyl acetate (3×). Wash the organic extracts with water (2×) and brine. Re-extract the water washes with ethyl acetate. Combine all ethyl acetate extracts, dry over sodium sulfate, filter and concentrate under reduced pressure. Purify the residue by silica gel chromatography (eluent: 2N ammonia in methanol-dichloromethane) to give 1.36 g (96%) of the title preparation as a yellow oil. HRMS-FAB (m/z): [M+H]+ calc'd for C15H18N3, 240.1500; found, 240.1492.

Workup

  1. temperatureHeat
  2. customthe reaction to 105° C. for 6 hours
  3. additionpour
  4. customreaction mixture slowly onto ice
  5. customto quench the excess phosphorus oxychloride
  6. extractionBasify with concentrated ammonium hydroxide and extract with dichloromethane
  7. washWash the
  8. extractionorganic extract with brine
  9. dry with materialdry over sodium sulfate
  10. filtrationfilter
  11. concentrationconcentrate under reduced pressure
  12. customPurify the residue by silica gel chromatography (eluent: ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-568cbabf5ac340b3bbb14bcc60e4d46d
Source dataset
uspto-grants-2012_06
Patent number
US08202873B2

Reaction notes

Loading…