Phosphoric Acid → N-(4-bromo-2,6-dimethylphenyl)-2-(4-fluorophenyl)imidazole

HRID 2171950Notes

Reaction equation

HRID 2171950 reaction equation
[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH:11]([CH:13]=O)=O.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[Cl-].[NH4+:25].P(=O)(O)(O)O>CO>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([N:6]2[CH:13]=[CH:11][N:25]=[C:20]2[C:19]2[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=2)=[C:4]([CH3:10])[CH:3]=1

Participants

7

Reactant 5

HCID 1004Phosphoric AcidHCID 7860GlyoxalHCID 25517Ammonium ChlorideHCID 680234-FluorobenzaldehydeHCID 905494-Bromo-2,6-xylidine

Product 1

HCID 68802622N-(4-bromo-2,6-dimethylphenyl)-2-(4-fluorophenyl)imidazoleYield 13.2%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

55.0 g (275 mmol) 4-bromo-2,6-dimethylaniline and 39.0 g glyoxal (40% solution, 275 mmol) were stirred in 500 mL methanol in a 1 L round bottom flask for 16 hours. 68.3 g 4-fluorobenzaldehyde (550 mmol) and 29.4 g (550 mmol) ammonium chloride were then added and the mixture was allowed to achieve reflux for 2 hours. 38.5 mL phosphoric acid (85%) was added dropwise over 10 minutes and the mixture continued at reflux for 18 hours. The mixture was then evaporated of methanol and the residue poured into 700 mL water. 50% NaOH was added until the pH=9 and the mixture then extracted three times with ethyl acetate in a separatory funnel. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated of solvent to give a dark residue. The ligand was purified on a large column of silica using a gradient of 20% ethyl acetate/hexanes-30% ethyl acetate/hexanes. The product fractions were evaporated of solvent and the residue distilled via kugelrohr distillation. The resultant product was recrystallized from hexanes to give 12.5 g N-(4-bromo-2,6-dimethylphenyl)-2-(4-fluorophenyl)imidazole as a clean white solid. MS confirmed.

Workup

  1. temperatureto achieve reflux for 2 hours
  2. temperatureat reflux for 18 hours
  3. customThe mixture was then evaporated of methanol
  4. additionthe residue poured into 700 mL water
  5. addition50% NaOH was added until the pH=9
  6. extractionthe mixture then extracted three times with ethyl acetate in a separatory funnel
  7. dry with materialThe combined organic layers were dried over anhydrous MgSO4
  8. filtrationfiltered
  9. customevaporated of solvent
  10. customto give a dark residue
  11. customThe ligand was purified on a large column of silica using a gradient of 20% ethyl acetate/hexanes-30% ethyl acetate/hexanes
  12. customThe product fractions were evaporated of solvent
  13. distillationthe residue distilled via kugelrohr distillation
  14. customThe resultant product was recrystallized from hexanes

Sources & evidence

ORD record
ord-37dbe427be2647338080b7ee40c70ce9
Source dataset
uspto-grants-2015_06
Patent number
US09051344B2

Reaction notes

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