Diisopropylamine → 4-Bromo-3-fluorobenzamide

HRID 539023Notes

Reaction equation

HRID 539023 reaction equation
[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[Cl-].[NH4+].C([NH:21]C(C)C)(C)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:21])=[O:7])=[CH:4][C:3]=1[F:11]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 24386Thionyl Chloride2×HCID 25517Ammonium ChlorideHCID 27733414-Bromo-3-fluorobenzoic acid

Product 1

HCID 219047754-Bromo-3-fluorobenzamideYield 63%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
70 °C

Procedure

To a suspension of 4-bromo-3-fluorobenzoic acid (1.50 g, 6.85 mmol) in toluene (10 mL) at ambient temperature was added thionyl chloride (1.0 mL, 14 mmol). The reaction mixture was heated at 70° C. for 17 hours, at reflux for 1.5 hours, stirred at ambient temperature for 75 hours, heated at reflux for 18.5 hours, and stirred at ambient temperature for 1 hour. Thionyl chloride (0.25 mL, 3.4 mmol) was added and the reaction mixture was heated at reflux for 3 hours. The reaction was cooled and condensed to an oily solid mixture. Toluene (10 mL), ammonium chloride (0.73 g, 14 mmol) and diisopropylamine (3.6 mL, 21 mmol) were added, and the mixture was stirred at ambient temperature for 17 hours, heated at 50° C. for 5 hours, then cooled to ambient temperature. The reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL), separated, and the aqueous layer further extracted with EtOAc (15 mL). The combined organic extracts were washed with 1N HCl (20 mL), 1N NaOH (20 mL), brine (20 mL), dried (MgSO4), filtered, and concentrated to afford 4-bromo-3-fluorobenzamide (0.938 g, 63%) as a light-yellow solid which was carried on without further purification.

Workup

  1. temperatureat reflux for 1.5 hours
  2. temperatureheated
  3. temperatureat reflux for 18.5 hours
  4. stirringstirred at ambient temperature for 1 hour
  5. temperaturethe reaction mixture was heated
  6. temperatureat reflux for 3 hours
  7. temperatureThe reaction was cooled
  8. customcondensed to an oily solid mixture
  9. stirringthe mixture was stirred at ambient temperature for 17 hours
  10. temperatureheated at 50° C. for 5 hours
  11. temperaturecooled to ambient temperature
  12. customThe reaction mixture was partitioned between EtOAc (10 mL) and H2O (10 mL)
  13. customseparated
  14. extractionthe aqueous layer further extracted with EtOAc (15 mL)
  15. washThe combined organic extracts were washed with 1N HCl (20 mL), 1N NaOH (20 mL), brine (20 mL)
  16. dry with materialdried (MgSO4)
  17. filtrationfiltered
  18. concentrationconcentrated

Sources & evidence

ORD record
ord-7488e70768f14e20ac3fa97a942570d2
Source dataset
uspto-grants-2014_10
Patent number
US08865726B2

Reaction notes

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