Dimethyl malonate → Methyl 4-cyano-3-fluoro-2-methylphenylacetate

HRID 526458Notes

Reaction equation

HRID 526458 reaction equation
Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[C:3]=1[CH3:11].C(OC)(=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+]>CCOC(C)=O.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:3]([CH3:11])[C:4]=1[F:10])#[N:7]

Participants

7

Reactant 4

HCID 7943Dimethyl malonateHCID 11430Potassium CarbonateHCID 516893Potassium BicarbonateHCID 595569134-Bromo-2-fluoro-3-methylbenzonitrile

Product 1

HCID 117601564Methyl 4-cyano-3-fluoro-2-methylphenylacetateYield 54.3%

Reagents, catalysts & solvents 2

HCID 2734635Tri-tert-butylphosphine tetrafluoroborateCatalystHCID 8857Ethyl AcetateSolvent2×

Procedure

Combined 4-bromo-2-fluoro-3-methylbenzonitrile (2 g, 9.34 mmol), dimethyl malonate (12.28 mL, 107 mmol), potassium carbonate (1.937 g, 14.02 mmol) and potassium hydrogencarbonate (1.403 g, 14.02 mmol). Purged with nitrogen for 1 min and then tri-tert-butylphosphonium tetrafluoroborate (0.030 g, 0.103 mmol), and bis(dibenzylidineacetone)palladium (0) (0.027 g, 0.047 mmol) were added. The reaction was placed in a pre-heated oil bath (170° C.). After 1 hour the mixture was cooled to ambient temperature and diluted with EtOAc (80 mL). The EtOAc layer was decanted and passed through a plug of Celite® (˜7 cm wide and 1.5 cm thick). The chunky dark precipitate that was left in the flask was diluted with additional EtOAc portions and sonicated until a fine suspension resulted. The EtOAc triturates were also passed through the Celite® plug and then concentrated in vacuo at ˜40° C. and then at 90° C. for 45 minutes to give a residue which was purified using flash column chromatography to give the title compound (1.05 g, 5.07 mmol, 54.2%) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.17 (d, J=2.27 Hz, 3H) 3.63 (s, 3H) 3.91 (s, 2H) 7.29 (d, J=8.08 Hz, 1H) 7.71 (t, J=7.33 Hz, 1H).

Workup

  1. customPurged with nitrogen for 1 min
  2. customThe reaction was placed in a pre-heated oil bath
  3. custom(170° C.)
  4. customThe EtOAc layer was decanted
  5. waitThe chunky dark precipitate that was left in the flask
  6. additionwas diluted with additional EtOAc portions
  7. customsonicated until a fine suspension
  8. customresulted
  9. concentrationconcentrated in vacuo at ˜40° C.
  10. customat 90° C. for 45 minutes to give a residue which
  11. customwas purified

Sources & evidence

ORD record
ord-b2885bc5ba8d474580ffc0c4988b638d
Source dataset
uspto-grants-2016_05
Patent number
US09345713B2

Reaction notes

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