Methanol → Methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate

HRID 1405408Notes

Reaction equation

HRID 1405408 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:12])([OH:11])[CH3:10])=[C:4]([F:13])[CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.[CH3:50][OH:51].CN([CH:55]=[O:56])C>C(O[Pd]OC(=O)C)(=O)C>[F:13][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([OH:11])([CH3:12])[CH3:10])[C:50]([O:56][CH3:55])=[O:51]

Participants

7

Reactant 5

HCID 887MethanolHCID 6228DimethylformamideHCID 8471TriethylamineHCID 812191,3-Bis(diphenylphosphino)propaneHCID 65145016HCID 65145016, compound

Product 1

HCID 68153482Methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoateYield 85%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
80 °C

Procedure

1-(4-Bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (2.35 g, 9.51 mmol), diacetoxypalladium (214 mg, 0.951 mmol), 3-diphenylphosphanylpropyl-diphenyl-phosphane (404 mg, 0.951 mmol), and Et3N (4.24 mL, 30.4 mmol) in DMF (26 mL) were treated with MeOH (20.0 mL, 495 mmol). The vessel was charged to 50 psi with CO (266 mg, 9.51 mmol) and then vented. This operation was repeated twice. The reaction was charged to 50 psi and heated at 80° C. for 15 h. The reaction mixture was allowed to cool, vented and partitioned between EtOAc/brine. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were washed twice with brine, dried over Na2SO4, filtered and concentrated to an orange oil. The residue was purified by silica gel flash column chromatography using 0-30% EtOAc in hexanes to yield methyl 3-fluoro-4-(2-hydroxy-2-methyl-propyl)benzoate (1.83 g, 85%) ESI-MS m/z calc. 226.1, found 227.5 (M+1)+; Retention time: 1.29 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J=7.9, 1.7 Hz, 1H), 7.71 (dd, J=10.3, 1.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 2.88 (d, J=1.3 Hz, 2H), 1.26 (s, 6H).

Workup

  1. additionThe vessel was charged to 50 psi with CO (266 mg, 9.51 mmol)
  2. additionThe reaction was charged to 50 psi
  3. temperatureto cool
  4. custompartitioned between EtOAc/brine
  5. customThe layers were separated
  6. extractionthe aqueous layer was extracted with EtOAc
  7. washThe combined organics were washed twice with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated to an orange oil
  11. customThe residue was purified by silica gel flash column chromatography

Sources & evidence

ORD record
ord-9092e8ca26a5498eb009509c0e086f44
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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