Sodium hydride → 2-Chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine

HRID 450451Notes

Reaction equation

HRID 450451 reaction equation
[H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][N:5]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([F:21])=[CH:14][C:13]=1F>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:13]2[CH:14]=[C:15]([F:21])[C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=2[F:11])[CH:7]=[CH:6][N:5]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 750121,2,4-Trifluoro-5-nitrobenzeneHCID 178516507HCID 178516507, compound

Product 1

HCID 552369312-Chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridineYield 401.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

Sodium hydride (136 mg, 3.4 mmol, 60% in mineral) was added to a 0° C. solution of 2-chloropyridin-4-ol (2 g, 15.4 mmol) in DMF (38 mL) under Ar. The mixture was stirred at 0° C. for 1 h. A solution of 1,2,4-trifluoro-5-nitrobenzene (626 mg, 3.1 mmol) in DMF (7.6 ml) was added and the reaction was stirred under Ar at 90° C. for 3 h. The mixture was cooled to RT and stirred overnight. The solvent was removed under reduced pressure and the crude product was partitioned between water (50 ml) and EtOAc (50 ml). The mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated under reduced pressure and purified by silica gel column chromatography (hexanes/EtOAc) to yield 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (3.57 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.43-8.33 (m, 2H), 7.85-7.79 (m, 1H), 7.33 (d, 1H), 7.20-7.18 (m, 1H); MS (ESI) m/z: 287.0 (M+H+).

Workup

  1. stirringthe reaction was stirred under Ar at 90° C. for 3 h
  2. temperatureThe mixture was cooled to RT
  3. stirringstirred overnight
  4. customThe solvent was removed under reduced pressure
  5. customthe crude product was partitioned between water (50 ml) and EtOAc (50 ml)
  6. extractionThe mixture was extracted with EtOAc (3×50 ml)
  7. washThe combined organic extracts were washed with brine
  8. dry with materialdried (Na2SO4)
  9. concentrationconcentrated under reduced pressure
  10. custompurified by silica gel column chromatography (hexanes/EtOAc)

Sources & evidence

ORD record
ord-e03efce524b545b69e155f911cbe7e5d
Source dataset
uspto-grants-2013_07
Patent number
US08486951B2

Reaction notes

Loading…