Acetic Acid → (5-Formyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester

HRID 402913Notes

Reaction equation

HRID 402913 reaction equation
[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:15]#N)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2].C(O)(=[O:21])C.N1C=CC=CC=1>[Ni].O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([CH:15]=[O:21])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:17])[CH3:2]

Participants

6

Reactant 3

HCID 176Acetic AcidHCID 1049PyridineHCID 59192033(5-Cyano-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester

Product 1

HCID 59192011(5-Formyl-2-methyl-benzofuran-3-yl)-acetic acid ethyl esterYield 60%

Reagents, catalysts & solvents 2

HCID 935NickelCatalystHCID 962WaterSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of (5-cyano-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (4.31 g, 17.7 mmol), NaPH2O2.H2O (14.99 g, 141 mmol) and Raney nickel (3.06 g, 35.4 mmol) in a mixture of water (50 mL), acetic acid (50 mL) and pyridine (100 mL) is heated for 2 h at 100° C. under an argon atmosphere. After cooling to room temperature the reaction mixture is filtered over hyflo and the filtrate concentrated by rotary evaporation. The residue is partitioned between water and TBME, the layers are separated and the aqueous phase is extracted with TBME. The combined organic layers are washed with a 1 M aqueous HCl solution, a saturated aqueous NaHCO3 solution and brine. After drying over Na2SO4 and evaporation of the solvent in vacuo the crude product is obtained as a brown oil. Further purification by flash column chromatography (silica gel gradient of cyclohexane/EtOAc 100:0 to 6:1) affords the title compound as colorless crystals (2.59 g, 10.5 mmol, 60%). 1H NMR (400 MHz, CDCl3, 298 K): δ=10.08 (s, 1H), 8.07 (s, 1H), 7.82 (d, J=8.9 Hz, 1H), 7.52 (d, J=8.9 Hz, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.66 (s, 2H), 2.49 (s, 3H), 1.27 (t, J=7.1 Hz, 3H). MS (ES+): 247 (M(C14H14O4)+H)+.

Workup

  1. temperatureAfter cooling to room temperature the reaction mixture
  2. filtrationis filtered over hyflo
  3. concentrationthe filtrate concentrated by rotary evaporation
  4. customThe residue is partitioned between water and TBME
  5. customthe layers are separated
  6. extractionthe aqueous phase is extracted with TBME
  7. washThe combined organic layers are washed with a 1 M aqueous HCl solution
  8. dry with materialAfter drying over Na2SO4 and evaporation of the solvent in vacuo the crude product
  9. customis obtained as a brown oil
  10. customFurther purification by flash column chromatography (silica gel gradient of cyclohexane/EtOAc 100:0 to 6:1)

Sources & evidence

ORD record
ord-15235aa523b14dcb970559e68a38ed74
Source dataset
uspto-grants-2014_06
Patent number
US08742132B2

Reaction notes

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