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

HRID 450442Notes

Reaction equation

HRID 450442 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 N,N-dimethylformamide (150 mL) was added to 60% NaH in mineral oil (2.72 g, 67.9 mmol) under an atmosphere of argon. The mixture was cooled in an ice bath and stirred. To this suspension was added, portion-wise, a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) in DMF (30.0 mL). The reaction mixture was stirred cold for 5 minutes and the cooling bath was removed. The reaction 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 hours. The reaction mixture was cooled to RT. The mixture was concentrated to dryness. EtOH (50 mL) and MeOH (20 mL) were added and the sample was stirred with gentle warming and then cooled to RT. The yellow solid was collected by filtration, and rinsed with EtOH (50 mL) and hexanes (20 mL). The solid was 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. temperatureThe mixture was cooled in an ice bath
  2. additionTo this suspension was added
  3. stirringThe reaction mixture was stirred cold for 5 minutes
  4. customthe cooling bath was removed
  5. stirringstirred for 20 minutes
  6. temperaturethe reaction mixture heated at 90° C. for 3 hours
  7. temperatureThe reaction mixture was cooled to RT
  8. concentrationThe mixture was concentrated to dryness
  9. additionEtOH (50 mL) and MeOH (20 mL) were added
  10. stirringthe sample was stirred
  11. temperaturewith gentle warming
  12. temperaturecooled to RT
  13. filtrationThe yellow solid was collected by filtration
  14. washrinsed with EtOH (50 mL) and hexanes (20 mL)
  15. customThe solid was dried under vacuum overnight

Sources & evidence

ORD record
ord-abd372361265458296cff1e3274cc0e7
Source dataset
uspto-grants-2013_07
Patent number
US08486951B2

Reaction notes

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