Toluene → 4-Isopropoxy-3-(trifluoromethyl)benzoic acid

HRID 1066778Notes

Reaction equation

HRID 1066778 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[F:16][C:17]([F:22])([F:21])C([O-])=O.[K+].C1(C)C=CC=CC=1.[OH-].[Na+]>CN(C=O)C.CO.[Cu]I>[CH:13]([O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[C:17]([F:22])([F:21])[F:16])([CH3:15])[CH3:14]

Participants

8

Reactant 4

HCID 1140TolueneHCID 14798Sodium HydroxideHCID 21956810Methyl 3-bromo-4-isopropoxybenzoateHCID 23662811Potassium trifluoroacetate

Product 1

HCID 225977674-Isopropoxy-3-(trifluoromethyl)benzoic acidYield 89.2%

Reagents, catalysts & solvents 3

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

Methyl 3-bromo-4-iso-propyloxybenzoate (828 mg; 3.03 mmol) in DMF (25 ml) was treated with potassium trifluoroacetate (922 mg; 6.06 mmol), copper (I) iodide (1.15 g; 6.06 mmol) and toluene (50 ml). The resulting mixture was heated at reflux for 1.5 h (Dean and Stark with removal of ca 50 ml of distillate) followed by reflux for 18 h then cooled. The mixture was poured into Et2O (100 ml) and H2O (100 ml). The two-phase mixture was stirred at room temperature for 0.5 h then filtered through Celite. The two phases were separated, the aq. phase further extracted with EtO (50 ml) and the organic extracts combined, washed with saturated, aq. Na2S2O3, H2O, saturated brine, dried (MgSO4) and evaporated in vacuo to give a brown oil. This was dissolved in MeOH (ca 20 ml) and treated with 2M NaOH (2 ml; 4 mmol) and the resulting solution heated at reflux for 3 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc and H2O. The phases were separated, the aq. phase acidified to pH1 with 2M HCl in the presence of EtOAc and the phases separated. The aq. phase was further extracted with EtOAc, the extracts combined, washed with H2O, saturated brine, dried (MgSO4) and evaporated to dryness in vacuo to give the title compound as a white solid (671 mg; 89%).

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureat reflux for 1.5 h
  3. custom(Dean and Stark with removal of ca 50 ml of distillate)
  4. temperatureby reflux for 18 h
  5. temperaturethen cooled
  6. additionThe mixture was poured into Et2O (100 ml) and H2O (100 ml)
  7. filtrationthen filtered through Celite
  8. customThe two phases were separated
  9. extractionthe aq. phase further extracted with EtO (50 ml)
  10. washwashed with saturated, aq. Na2S2O3, H2O, saturated brine
  11. dry with materialdried (MgSO4)
  12. customevaporated in vacuo
  13. customto give a brown oil
  14. temperaturethe resulting solution heated
  15. temperatureat reflux for 3 h
  16. customThe volatiles were removed in vacuo
  17. customthe residue partitioned between EtOAc and H2O
  18. customThe phases were separated
  19. customthe phases separated
  20. extractionThe aq. phase was further extracted with EtOAc
  21. washwashed with H2O, saturated brine
  22. dry with materialdried (MgSO4)
  23. customevaporated to dryness in vacuo

Sources & evidence

ORD record
ord-65f18a9e94d24f47afe3b6f2a495f1e7
Source dataset
uspto-grants-2001_06
Patent number
US06245778B1

Reaction notes

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