Ethyl 3-oxocyclobutanecarboxylate → Ethyl 3-(4-fluorophenyl)-3-hydroxycyclobutanecarboxylate

HRID 920767Notes

Reaction equation

HRID 920767 reaction equation
[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([Mg]Br)=[CH:14][CH:13]=1>CCOCC>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2([OH:1])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]2)=[CH:14][CH:13]=1

Participants

4

Reactant 2

HCID 22467070Ethyl 3-oxocyclobutanecarboxylateHCID 178418676HCID 178418676, compound

Product 1

HCID 118061643Ethyl 3-(4-fluorophenyl)-3-hydroxycyclobutanecarboxylateYield 51%

Reagents, catalysts & solvents 1

HCID 3283Diethyl EtherSolvent

Procedure

To a stirred solution of ethyl 3-oxocyclobutanecarboxylate (2 g, 14.07 mmol) in dry Et2O (30 mL), cooled to −80° C., was added 4-fluorophenyl magnesium bromide (16.88 mL, 16.88 mmol, 1 M in THF) dropwise. The reaction mixture was then allowed to warm to RT and stir for an additional 2 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl (50 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude reaction mixture was purified by silica gel chromatography (24 g REDISEP® column, eluting with 15% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 276A as a colorless liquid (1.7 g, 51%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.54 (dd, J=5.5, 9.0 Hz, 2H), 7.15 (t, J=8.8 Hz, 2H), 4.09 (q, J=7.4 Hz, 2H), 2.83-2.71 (m, 1H), 2.61 (s, 2H), 2.55-2.51 (m, 2H), 1.24-1.12 (t, 3H).

Workup

  1. customThe reaction mixture was quenched with a saturated aq. solution of NH4Cl (50 mL)
  2. extractionextracted with EtOAc (3×30 mL)
  3. washThe combined organic layer was washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude reaction mixture
  8. customwas purified by silica gel chromatography (24 g REDISEP® column, eluting with 15% EtOAc in hexanes)
  9. additionFractions containing the product
  10. customevaporated

Sources & evidence

ORD record
ord-a531a1cb1b9a4d04be8a9d1cb18b5b30
Source dataset
uspto-grants-2016_03
Patent number
US09273058B2

Reaction notes

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