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8th February 2011 @ 00:52
Preparation of starting material for the Ugi reaction via an alternative route to MW34-1

See also:
  • Upscaling - Preparation of 2-Phenylethyl isocyanide (MW34-2)
  • Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37)
  • Scale-up - Preparation of 2-Phenylethyl isocyanide (MW34-2)

  • Scheme MW34-3.png


    Hazard and Risk Assessment:
    HRAF MW34-3.pdf



    Start time: 11:50 AM 08/02/2011
    End time: 7:00 PM 09/02/2011

    A solution of 2-phenylethylamine (5.00 g, 41.3 mmol, M.W. 121.2 g/mol) was heated to reflux in ethyl formate (25 mL, M.W. 74.1 g/mol, bp 52-54°C) and heated to reflux for 21 h. Reaction control via TLC showed a complete consumption of the starting material (hexane:ethyl acetate = 1:1, stain: KMnO4, Rf [starting material]=0.05, Rf [product]=0.25).
    The remaining ethyl formiate and the by-product ethanol were removed under reduced pressure obtaining 2-phenylethylformamide as a yellow liquid.
    2-phenylethylformamide and triethylamine (12.5g, 124 mmol, 17 mL, 3.0 eq., M.W. 101.2, d=0.726 g/mL) were dissoved in dry DCM (50 mL) and phosphoryl chloride (41.3 mmol, 6.32 g, 3.84 mL, 1.0 eq., M.W. 153.3, d=1.645 g/mL) was dropwise added at 0°C. The mixture was stirred for 1 h at 0°C and a further 4 h at room temperature.

    - quenched with water
    - neutralized with NaHCO3, acidic wash (difficult separation of the layers)
    - evaporated, dried over magnesium sulfate

    Crude yield: 5.41 g (41.2 mmol, 100%) dark brown liquid
    [M.W. 131.2 g/mol]
    1H NMR: Data: 1H NMR MW34-3.pdf: small solvent impurities (triethylamine?)

    Purification: Column chromatography (silica gel, hexane:ethyl acetate = 4:1; Rf = 0.5)
    Yield 4.42 g (33.7 mmol, 82%) yellow liquid

    Note: Store 2-phenylethyl isocyanide in the freezer at -20°C.

    Procedure from reference: [1]
    (translated from German)
    Example 2: 2-phenylethyl isocyanide
    Phenylethylamine is heated at reflux temperature in ethyl formiate (excess) for several hours. The solvent and the ethanol by-product are evaporated and to give 2-aminophenylethyl formiate in a qunatiative yield.
    The formiat is dissolved in DCM and 3 equivalents of triethylamine are added. The mixture is cooled to 0°C and 1 equivalent of phosphoryl chloride is added slowly and stirred at this temperature for 2 h and a further 3 h at room temperature. The reaction is quenched by addition of water and neutralized to pH 8 by addition of NaHCO3. The organic layer is seperated and the aqueous layer is extracted with dichloromethane several times. The combined organic layers are dried and evaporated to obtain 2-phenylethyl isocyanide in a relatively pure form and can be used directly in the next step.
    Alternatively, 2-phenylethyl isocyanide can be distilled under vacuum.
    Yield 65%.

    References:
    [1] “Novel Synthesis of Praziquantel“, A. Dömling, Patent Application 2009, WO 2009/11533(A1), Language: German.
    Attached Files
    Scheme MW34-3.png
    HRAF MW34-3.pdf
    1H NMR MW34-3.pdf
    1H NMR MW34-3 JCAMP-DX.dx