Ethyl propiolate → (3,4-Difluoro-phenyl)-propynoic acid ethyl ester

HRID 1799771Notes

Reaction equation

HRID 1799771 reaction equation
[Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:15])[C:13]#[CH:14])[CH3:10].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=1[F:24]>C1COCC1.C(OCC)C.[Zn+2].[Br-].[Br-].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:15])[C:13]#[C:14][C:20]1[CH:21]=[CH:22][C:17]([F:16])=[C:18]([F:24])[CH:19]=1)[CH3:10]

Participants

8

Reactant 3

HCID 12182Ethyl propiolateHCID 27244441,2-Difluoro-4-iodobenzeneHCID 2724682Lithium diisopropylamide

Product 1

HCID 58312680(3,4-Difluoro-phenyl)-propynoic acid ethyl ester

Reagents, catalysts & solvents 4

HCID 10421208Zinc bromideCatalystHCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent4×

Conditions

Temperature
-78 °C

Procedure

Under argon atmosphere, a four neck flask was charged with THF (135 ml) and 2 M LDA in THF (60.9 ml, 0.12 mol, 1.18 eq.) and cooled to −78° C. Propynoic acid ethyl ester (12.2 g, 0.12 mol, 1.18 eq.) dissolved in THF (36 ml) was added dropwise within 30 min. Then, ZnBr2 (28.5 g, 0.12 mol, 1.2 eq.) dissolved in THF (45 ml) was added dropwise within 30 min. After the addition of 1,2-Difluoro-4-iodo-benzene (25.0 g, 0.10 mol) and tetrakis(triphenylphosphine) palladium(0) (6.02 g, 5.15 mmol, 5 mol %), the reaction mixture was allowed to warm to r.t. and stirred for another 3 h at the same temperature. The reaction mixture was diluted with diethylether and washed with saturated aqueous NH4I, saturated aqueous NaHCO3 and brine. The organic phase was dried with Na2SO4, concentrated under reduced pressure and dried under vacuum. The residue was purified by silica gel filtration (heptane/ethyl acetate 98:2) to yield 16.6 g (76%) of Vc as light yellow oil.

Workup

  1. additionwas added dropwise within 30 min
  2. additionwas added dropwise within 30 min
  3. temperatureto warm to r.t.
  4. washwashed with saturated aqueous NH4I, saturated aqueous NaHCO3 and brine
  5. dry with materialThe organic phase was dried with Na2SO4
  6. concentrationconcentrated under reduced pressure
  7. customdried under vacuum
  8. filtrationThe residue was purified by silica gel filtration (heptane/ethyl acetate 98:2)
  9. customto yield 16.6 g (76%) of Vc as light yellow oil

Sources & evidence

ORD record
ord-6529e96bffbc4c32bd3111f3c9bcba43
Source dataset
uspto-grants-2013_01
Patent number
US08344161B2

Reaction notes

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