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

HRID 1472596Notes

Reaction equation

HRID 1472596 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 65.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

Anhydrous DMF (150 mL) was added to 60% NaH in mineral oil (2.72 g, 67.9 mmol) under an Ar atmosphere, cooled in an ice bath, treated portion-wise with a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) in DMF (30 mL) and stirred cold for 5 minutes. The cooling bath was removed and the mixture was warmed to RT and stirred for 20 minutes. 1,2,4-Trifluoro-5-nitrobenzene (13.12 g, 74.1 mmol) was added and the reaction mixture heated at 90° C. for 3 h. The reaction mixture was cooled to RT, concentrated to dryness, treated with EtOH (50 mL) and MeOH (20 mL), warmed gently, then cooled to RT. The yellow solid was collected by filtration, rinsed with EtOH (50 mL) and hexanes (20 mL) and dried under vacuum overnight to provide 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine as a yellow solid (11.68 g, 63% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J=10.2, 7.0 Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d, J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 [M+H]+

Workup

  1. temperaturecooled in an ice bath
  2. customThe cooling bath was removed
  3. stirringstirred for 20 minutes
  4. temperaturethe reaction mixture heated at 90° C. for 3 h
  5. temperatureThe reaction mixture was cooled to RT
  6. concentrationconcentrated to dryness
  7. additiontreated with EtOH (50 mL) and MeOH (20 mL)
  8. temperaturewarmed gently
  9. temperaturecooled to RT
  10. filtrationThe yellow solid was collected by filtration
  11. washrinsed with EtOH (50 mL) and hexanes (20 mL)
  12. customdried under vacuum overnight

Sources & evidence

ORD record
ord-51d5467fb0b944dea2bb305ddc920df7
Source dataset
uspto-grants-2015_04
Patent number
US09012635B2

Reaction notes

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