Alkylation of malonate ester with alkyl halides and sodium hydride

J. Med. Chem, 1994, 37, 1339.

Reagents:

Diethyl acetamidomalonate :1 eq

Sodium hydride : 1.1 eq

Absolute ethanol : solvent

Alkyl halide : 1 eq

Alkyl malonate ester product : 60 – 80% expected yield

Procedure:

To a solution of Na (1.1 eq) in absolute ethanol (3 mL/mmol of sodium) at 0 oC is added a solution of diethyl acetamidomalonate (1 eq) and after 20 minutes of stirring the alkyl halide (1 eq) is also added.  The orange-yellow solution should turn light or less intense in color.  The mixture is stirred at room temperature for 4h (or longer and warming to higher temperature may be need).  The solvent is concentrated in vacuo and the residue is dissolved with ethyl acetate and water.  The organic layer is separated and washed with water (2x), brine, and dried over MgSO4 and evaporated in vacuo to give the alky malonate product.   When possible the product may be recrystallized from ethanol/water.

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