Diethyl Malonate → Diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate

HRID 1966138Notes

Reaction equation

HRID 1966138 reaction equation
[H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH:16]([CH2:25]Cl)[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[CH2:18]([O:17][CH:16]1[CH2:25][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:3]([O:11][CH2:12][CH3:13])=[O:10])[CH2:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1

Participants

5

Reactant 3

HCID 7761Diethyl MalonateHCID 24758Sodium hydride2×HCID 3468282{[(1-Bromo-3-chloropropan-2-yl)oxy]methyl}benzene

Product 1

HCID 12815110Diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a suspension of sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) in 1,4-dioxane (69 mL) was added diethyl malonate (17.7 mL, 0.117 mol) dropwise. The mixture was stirred for 1.5 hours at ambient temperature after complete addition. To this mixture was added [2-bromo-1-(chloromethyl)ethoxy]methylbenzene (prepared according to the procedure found in Organic Letters (2004), 6(11), pp. 1853-1856; 32.0 g, 0.121 mol) dropwise and the resulting mixture was stirred for 1 hour at ambient temperature, then heated at reflux for 16 hours. The mixture was cooled briefly in an ice bath and sodium hydride (60% dispersion in mineral oil, 4.67 g, 0.117 mol) was added portionwise. The mixture was heated to reflux for a further 24 hours. Upon cooling to room temperature, the mixture was poured into pH 7 buffer and brine, and the product was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, decanted and concentrated. Flash column chromatography, eluting with a gradient of 5-60% ethyl acetate in hexanes afforded product (26.9 g, 75%).

Workup

  1. additionafter complete addition
  2. customprepared
  3. stirring32.0 g, 0.121 mol) dropwise and the resulting mixture was stirred for 1 hour at ambient temperature
  4. temperatureheated
  5. temperatureat reflux for 16 hours
  6. temperatureThe mixture was cooled briefly in an ice bath
  7. temperatureThe mixture was heated
  8. temperatureto reflux for a further 24 hours
  9. temperatureUpon cooling to room temperature
  10. additionthe mixture was poured into pH 7 buffer
  11. extractionbrine, and the product was extracted with three portions of ethyl acetate
  12. washThe combined extracts were washed with brine
  13. dry with materialdried over sodium sulfate
  14. customdecanted
  15. concentrationconcentrated
  16. washFlash column chromatography, eluting with a gradient of 5-60% ethyl acetate in hexanes afforded product (26.9 g, 75%)

Sources & evidence

ORD record
ord-c9da5f4a0b464acc87aebf269b1eb602
Source dataset
uspto-grants-2013_04
Patent number
US08420629B2

Reaction notes

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