P-Cresol → 4-Methylphenyl 2,4,5-trifluorobenzoate

HRID 2048043Notes

Reaction equation

HRID 2048043 reaction equation
S(Cl)(Cl)=O.[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH3:17][C:18]1[CH:23]=[CH:22][C:21](O)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[F:5][C:6]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:7]=1[C:8]([O:10][C:21]1[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=1)=[O:9]

Participants

6

Reactant 4

HCID 2879P-CresolHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 5211702,4,5-Trifluorobenzoic acid

Product 1

HCID 580424084-Methylphenyl 2,4,5-trifluorobenzoateYield 66.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
55 °C

Procedure

Thionyl chloride (50 mL, 680 mmol) was added to 2,4,5-trifluorobenzoic acid (10 g, 57 mmol) and the mixture stirred at 55° C. for 18 hours. After cooling, the excess thionyl chloride was removed in vacuo. The resulting crude oil was azeotroped twice with DCM (30 mL) and toluene (20 mL) and the residue redissolved in DCM (50 mL), then cooled to 0° C. with an ice bath. A mixture of 4-methylphenol (6.4 g, 59 mmol) and triethylamine (10 mL, 71 mmol) in DCM (20 mL) was added over 30 minutes. The reaction was allowed to warm up to room temperature over 1 hour. The crude reaction mixture was partitioned between EtOAc (200 mL) and saturated sodium bicarbonate solution (70 mL). The aqueous layer was further extracted with EtOAc (100 mL). The combined organic extracts were combined, washed with saturated sodium bicarbonate solution (70 mL) and water (100 mL). The organic layer was dried over magnesium sulfate and concentrated to provide a crude solid, which was purified by silica gel chromatography eluting with 5% EtOAc in heptane to provide the title compound (10.08 g, 66%) as a white solid.

Workup

  1. temperatureAfter cooling
  2. customthe excess thionyl chloride was removed in vacuo
  3. customThe resulting crude oil was azeotroped twice with DCM (30 mL) and toluene (20 mL)
  4. dissolutionthe residue redissolved in DCM (50 mL)
  5. temperaturecooled to 0° C. with an ice bath
  6. additionwas added over 30 minutes
  7. temperatureto warm up to room temperature over 1 hour
  8. customThe crude reaction mixture
  9. customwas partitioned between EtOAc (200 mL) and saturated sodium bicarbonate solution (70 mL)
  10. extractionThe aqueous layer was further extracted with EtOAc (100 mL)
  11. washwashed with saturated sodium bicarbonate solution (70 mL) and water (100 mL)
  12. dry with materialThe organic layer was dried over magnesium sulfate
  13. concentrationconcentrated
  14. customto provide a crude solid, which
  15. customwas purified by silica gel chromatography
  16. washeluting with 5% EtOAc in heptane

Sources & evidence

ORD record
ord-6ecc7b1ae1d74bc1846ea3b2e32090ca
Source dataset
uspto-grants-2013_11
Patent number
US08592629B2

Reaction notes

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