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

HRID 713055Notes

Reaction equation

HRID 713055 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.C(N(CC)CC)C.[CH3:50][OH:51].CN([CH:55]=[O:56])C>C([O-])(=O)C.[Pd+2].C([O-])(=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

A reaction vessel charged with 1-(4-bromo-2-fluoro-phenyl)-2-methyl-propan-2-ol (2.35 g, 9.51 mmol), palladium acetate (214 mg, 0.95 mmol), 3-diphenylphosphanylpropyl-diphenyl-phosphane (404 mg, 0.95 mmol) and triethylamine (4.24 mL, 30.4 mmol) in DMF (26 mL) was added MeOH (20 mL). The reaction vessel was charged to 50 psi with CO gas and heated at 80° C. for 15 hours. The reaction mixture was allowed to cool, partitioned between EtOAc and brine solution. The layers were separated and the aqueous layer was extracted once more with EtOAc. The combined organics were washed with brine (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo to an orange oil. The residue was purified by silica gel column chromatography using 0-30% EtOAc-hexanes as eluent 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 reaction vessel was charged to 50 psi with CO gas
  2. temperatureto cool
  3. custompartitioned between EtOAc and brine solution
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted once more with EtOAc
  6. washThe combined organics were washed with brine (2×10 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo to an orange oil
  10. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-46468f66e2a84113bcf5a829f65e0fc4
Source dataset
uspto-grants-2015_11
Patent number
US09181273B2

Reaction notes

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