Sodium hydride → 2-(2,5-Difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester

HRID 1183586Notes

Reaction equation

HRID 1183586 reaction equation
[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[C:22]([F:28])=[CH:21][C:20]=1F>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:20]1[CH:21]=[C:22]([F:28])[C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=1[F:18])([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 25047Diethyl isobutylmalonateHCID 750121,2,4-Trifluoro-5-nitrobenzene

Product 1

HCID 579955742-(2,5-Difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl esterYield 90.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

2-Isobutylmalonic acid diethyl ester (40.0 g, 0.185 mol) in DMF (50 mL) was added dropwise to a stirred suspension of sodium hydride (60% in mineral oil, 8.0 g, 0.33 mol) in 200 mL DMF (200 mL) over 20 min. at 0° C. under nitrogen. The mixture was stirred for 0.5 h at room temperature, cooled to 0° C. and 1,2,4-trifluoro-5-nitro-benzene (30.0 g, 169.5 mmol) in DMF (150 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 h, poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL) and dried (MgSO4). Evaporation of solvent under reduced pressure gave a brown oil which was purified by column chromatography over silica gel (Heptane-EtOAc, gradient) to give 57.0 g (90%) of 2-(2,5-difluoro-4-nitrophenyl)-2-isobutylmalonic acid diethyl ester as yellow oil. 1H NMR (300 MHz, CDCl3/TMS): δ 7.87 (dd, J=12.3, 6.0 Hz, 1H), 7.79 (dd, J=10.1, 6.4 Hz, 1H), 4.30-4.18 (m, 4H), 2.27 (d, J=5.8 Hz, 2H), 1.60-1.50 (m, 1H), 1.26 (t, J=7.1 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 168.2, 155.1 (d, 1JCF=252.3 Hz), 150.9 (d, 1JCF=263.2 Hz), 135.7, 135.1, 120.0 (dd, 2JCF=26.0, 3JCF=4.0 Hz), 113.0 (d, 2JCF=29.0 Hz), 62.3, 43.1, 24.9, 23.8, 13.8.

Workup

  1. temperaturecooled to 0° C.
  2. customThe resulting reaction mixture
  3. stirringwas stirred at room temperature for 16 h
  4. extractionextracted with EtOAc (3×100 mL)
  5. washThe combined organic phases were washed with water (3×100 mL), brine (100 mL)
  6. dry with materialdried (MgSO4)
  7. customEvaporation of solvent under reduced pressure
  8. customgave a brown oil which
  9. customwas purified by column chromatography over silica gel (Heptane-EtOAc, gradient)

Sources & evidence

ORD record
ord-f6395f76ec2644a4ade2d9d0e3114e13
Source dataset
uspto-grants-2014_03
Patent number
US08664249B2

Reaction notes

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