Chloroacetone → 1-[6-Methoxy-4-(phenylmethoxy)-2-benzofuranyl]ethanone

HRID 1424327Notes

Reaction equation

HRID 1424327 reaction equation
[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([OH:19])[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[CH2:27][C:28](=[O:30])[CH3:29].O1C2C=CC=CC=2C=C1>CN(C)C=O.O1CCCC1.C(OCC)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]1[C:10]2[CH:11]=[C:27]([C:28](=[O:30])[CH3:29])[O:19][C:13]=2[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 6571ChloroacetoneHCID 9223BenzofuranHCID 10796Cesium carbonateHCID 89872641HCID 89872641, compound

Product 1

HCID 898726231-[6-Methoxy-4-(phenylmethoxy)-2-benzofuranyl]ethanoneYield 88.4%

Reagents, catalysts & solvents 4

HCID 521998p-Toluenesulfonic acid monohydrateCatalystHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of 2-(benzyloxy)-6-hydroxy-4-methoxybenzaldehyde (Example 1C, 3.46 g, 13.4 mmol) in N,N-dimethylformamide (50 mL) was treated with powdered anhydrous cesium carbonate (4.58 g, 14.05 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 (1.74 g, 18.7 mmol) added dropwise over 5 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 solid was filtered and washed with N,N-dimethylformamide. The filtrate was evaporated in vacuo and the residual oil was diluted with ethyl acetate (300 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. This syrup was diluted with tetrahydrofuran (50 mL) and ethyl acetate (50 mL), treated p-toluenesulfonic acid monohydrate (0.2 g) and stirred at 20° C. for 1 h (tlc indicated complete cyclization of the intermediate alkylated aldehyde to the benzofuran). The reaction mixture was diluted with ethyl acetate (300 mL), washed with saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, evaporation of the solvent gave a thick syrup. Chromatography on silica gel (4×12 cm, elution toluene-ethyl acetate 2-4%) gave 3.51 g (88% yield) of the title benzofuran as a yellow solid. Recrystallization from ethyl acetate (10 mL) and hexane (20 mL) gave the title material as large yellow prisms (3.15 g). LC (Method D): 2.148 min. HRMS (ESI) calcd for C18H17O4 [M+H]+ m/z 297.1121. found 297.1092. 1H NMR (CDCl3, 600 MHz) δ 2.51 (s, 3H), 3.82 (s, 3H), 5.13 (s, 2H), 6.37 (d, J=1.77 Hz, 1H), 6.63 (broad s, 1H), 7.34 (broad t, 1H), 7.39 (broad t, 2H), 7.44 (broad d, 2H), 7.55 (d, J=0.7 Hz, 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 5 min
  5. filtrationThe solid was filtered
  6. washwashed with N,N-dimethylformamide
  7. customThe filtrate was evaporated in vacuo
  8. additionthe residual oil was diluted with ethyl acetate (300 mL)
  9. washwashed with cold 0.1 N hydrochloric acid, saturated sodium bicarbonate and brine
  10. dry with materialAfter drying over anhydrous magnesium sulfate, evaporation of the solvent
  11. customgave a thick syrup
  12. stirringstirred at 20° C. for 1 h (tlc
  13. washwashed with saturated sodium bicarbonate and brine
  14. dry with materialAfter drying over anhydrous magnesium sulfate, evaporation of the solvent
  15. customgave a thick syrup

Sources & evidence

ORD record
ord-4cc78f382d644b038dd199ed996050e0
Source dataset
uspto-grants-2015_01
Patent number
US08927688B2

Reaction notes

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