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

HRID 578955Notes

Reaction equation

HRID 578955 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×

Conditions

Temperature
170 °C

Procedure

Combine 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). Nitrogen gas was bubbled through this mixture vigorously for 1 minute 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 mixture was then heated in an oil bath (170° C.) and stirred for 1 hour, then 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. The combined organics from filtration were concentrated in vacuo at ˜40° C. and then at 90° C. for 45 minutes to give a residue. The residue 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, 3 H) 3.63 (s, 3 H) 3.91 (s, 2 H) 7.29 (d, J=8.08 Hz, 1 H) 7.71 (t, J=7.33 Hz, 1 H)

Workup

  1. customNitrogen gas was bubbled through this mixture vigorously for 1 minute
  2. temperaturecooled to ambient temperature
  3. customThe EtOAc layer was decanted
  4. waitThe chunky dark precipitate that was left in the flask
  5. additionwas diluted with additional EtOAc portions
  6. customsonicated until a fine suspension
  7. customresulted
  8. filtrationThe combined organics from filtration
  9. concentrationwere concentrated in vacuo at ˜40° C.
  10. customat 90° C. for 45 minutes to give a residue
  11. customThe residue was purified

Sources & evidence

ORD record
ord-4c67f1705f9b4f19b3547a80ac007201
Source dataset
uspto-grants-2015_05
Patent number
US09040522B2

Reaction notes

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