Chloroacetone → 1-(4-(Benzyloxy)benzofuran-2-yl)ethanone

HRID 625130Notes

Reaction equation

HRID 625130 reaction equation
[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:25][C:26](=[O:28])[CH3:27].O1C2C=CC=CC=2C=C1>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:1]([O:8][C:9]1[C:10]2[CH:11]=[C:25]([C:26](=[O:28])[CH3:27])[O:17][C:13]=2[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 6571ChloroacetoneHCID 9223BenzofuranHCID 10796Cesium carbonate2×HCID 141628792-(Benzyloxy)-6-hydroxybenzaldehyde

Product 1

HCID 898726561-(4-(Benzyloxy)benzofuran-2-yl)ethanoneYield 90.1%

Reagents, catalysts & solvents 2

HCID 10796Cesium carbonateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
55 °C

Procedure

A solution of 2-(benzyloxy)-6-hydroxybenzaldehyde (Example 38B, 11.10 g, 48.63 mmole) in N,N-dimethylformamide (120 mL) was treated with powdered anhydrous cesium carbonate (15.8 g, 48.63 mmol) added all at once. The resulting mixture was stirred in vacuo for 10 min and then flushed with nitrogen. The reaction flask was placed in a water bath (22° C.) and treated with chloroacetone (4.65 mL, 58.4 mmol) added dropwise over 10 min. The resulting mixture was then stirred at 22° C. for 18 h (no starting aldehyde left by tlc and formation of the intermediate alkylated aldehyde). The reaction mixture was then maintained under vacuum (10 mbar) for 15 min to remove any un-reacted chloroacetone and then flushed with nitrogen. Then anhydrous cesium carbonate (1.0 g, 3.1 mmol) was added and the mixture was heated at 55° C. and stirred for 40 h (more cesium carbonate, 1 g, was added after 24 h and 32 h) till complete conversion of the intermediate alkylated aldehyde into the benzofuran as monitored by TLC. The solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (400 mL), washed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4.5×12 cm, elution toluene-ethyl acetate 2-4%) gave 11.67 g (90% yield) of the title benzofuran as a light yellow solid. Recrystallization from a mixture of ethyl acetate (40 mL) and hexane (40 mL) gave colorless prisms (10.50 g). LC (Method A): 2.162 min. HRMS (ESI) calcd for C17H15O3 [M+H]+ m/z 267.1016, found 267.1022. 1H NMR (CDCl3, 600 MHz) δ ppm: 2.56 (s, 3H), 5.20 (s, 2H), 6.73 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.3-7.5 (m, 6H), 7.63 (s, 1H).

Workup

  1. additionadded all at once
  2. customflushed with nitrogen
  3. customThe reaction flask was placed in a water bath
  4. additionadded dropwise over 10 min
  5. temperatureThe reaction mixture was then maintained under vacuum (10 mbar) for 15 min
  6. customto remove any un-reacted chloroacetone
  7. customflushed with nitrogen
  8. filtrationThe solid was filtered
  9. washwashed with N,N-dimethylformamide
  10. customThe filtrate was evaporated in vacuo
  11. additionthe residual oil was diluted with ethyl acetate (400 mL)
  12. washwashed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine
  13. dry with materialAfter drying over anhydrous magnesium sulfate, evaporation of the solvent
  14. customgave a thick syrup

Sources & evidence

ORD record
ord-02ab43f36aba4f7382151fb6caa5d78d
Source dataset
uspto-grants-2016_04
Patent number
US09303065B2

Reaction notes

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