1,4-Dibromobenzene → Methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate

HRID 575026Notes

Reaction equation

HRID 575026 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]=[C:15]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]1>O1CCCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2([OH:14])[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16]2)=[CH:3][CH:4]=1

Participants

5

Reactant 3

HCID 78041,4-DibromobenzeneHCID 13992367Methyl 3-oxocyclobutane-1-carboxylateHCID 178418339Butyllithium

Product 1

HCID 53418816Methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylateYield 274.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

Into a 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tetrahydrofuran (12 L), 1,4-dibromobenzene (2020 g, 8.56 mol, 1.03 equiv), followed by the addition of n-BuLi (3566 mL, 1.03 equiv, 2.4 M) dropwise with stirring at −78° C. The mixture was stirred at −78° C. for 1 h. Into another 20-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of methyl 3-oxocyclobutane-1-carboxylate (1064 g, 8.30 mol, 1.00 equiv) in tetrahydrofuran (4 L). To this was added the resulting solution in the first flask dropwise with stirring at −78° C. The resulting solution was stirred overnight at 25° C. This reaction was repeated for 2 more times. The reaction was then quenched by the addition of 15 L of saturated aqueous NH4Cl, concentrated under vacuum, diluted with 15 L of H2O and extracted with 2×5 L of ethyl acetate. The organic layers were combined, washed with 1×8 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 6500 g (92%) of methyl 3-(4-bromophenyl)-3-hydroxycyclobutane-1-carboxylate as a dark red oil.

Workup

  1. customInto a 20-L 4-necked round-bottom flask purged
  2. temperaturemaintained with an inert atmosphere of nitrogen
  3. stirringThe mixture was stirred at −78° C. for 1 h
  4. customInto another 20-L 4-necked round-bottom flask purged
  5. temperaturemaintained with an inert atmosphere of nitrogen
  6. additionTo this was added the resulting solution in the first flask dropwise
  7. stirringwith stirring at −78° C
  8. stirringThe resulting solution was stirred overnight at 25° C
  9. customThe reaction was then quenched by the addition of 15 L of saturated aqueous NH4Cl
  10. concentrationconcentrated under vacuum
  11. additiondiluted with 15 L of H2O
  12. extractionextracted with 2×5 L of ethyl acetate
  13. washwashed with 1×8 L of brine
  14. dry with materialdried over anhydrous sodium sulfate
  15. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-e645baa9b1f1474ea420ff701cd01820
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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