Sodium hydride → HCID 68433186, compound

HRID 1474252Notes

Reaction equation

HRID 1474252 reaction equation
[H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H][H].[Cl:20][C:21]1[C:22](F)=[CH:23][C:24]([F:29])=[C:25]([CH:28]=1)[C:26]#[N:27]>CN(C=O)C.CCOCC>[Cl:20][C:21]1[CH:28]=[C:25]([C:26]#[N:27])[C:24]([F:29])=[CH:23][C:22]=1[CH:4]([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]

Participants

7

Reactant 4

HCID 24758Sodium hydrideHCID 68324Di-tert-butyl malonateHCID 223926295-Chloro-2,4-difluorobenzonitrileHCID 178418361HCID 178418361, compound

Product 1

HCID 68433186HCID 68433186, compound

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent2×

Procedure

To sodium hydride (60% in mineral oil, 3.75 g, 94 mmol) under nitrogen was added dry DMF (150 mL) and the suspension was cooled in an ice bath. Di-t-butyl malonate (8.1 g, 37.5 mmol) was added dropwise over 15 minutes via syringe with hydrogen evolution. The suspension was stirred for 30 minutes after which time 5-chloro-2,4-difluorobenzonitrile (5.0 g, 28.8 mmol) in DMF (10 mL) was added dropwise over 15 minutes and the reaction was heated to 80° C. for 12 hours when TLC (15% ethyl acetate/hexanes) indicated mostly product. The reaction was diluted with ether and quenched into water containing aq. ammonium chloride. The mixture was extracted twice with ethyl acetate and the organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel (2-10% ethyl acetate/hexanes) to give the title product. NMR indicated about a 6:1 mixture of product and the isomeric di-t-butyl, 2-(4-chloro-2-cyano-5-fluorophenyl)malonate. 1H-NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 18H), 5.05 (s, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.71 (d, J=6.0, 1H) (major isomer) and 1.46 (s, 18H), 4.95 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.78 (d, J=6.0, 1H) (minor isomer).

Workup

  1. temperaturethe suspension was cooled in an ice bath
  2. additionwas added dropwise over 15 minutes
  3. customquenched into water containing aq. ammonium chloride
  4. extractionThe mixture was extracted twice with ethyl acetate
  5. washthe organic layers were washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified on silica gel (2-10% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-8d1693222f0147d28b4b4f4c1e61e431
Source dataset
uspto-grants-2015_04
Patent number
US09018211B2

Reaction notes

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