Ethyl phthalimidomalonate

A. Ethyl Sodium Phthalimidoinalonate.—To a solution of 9.2 g. (0.4 gram atom) of sodium in 300 cc. of absolute alcohol at 60° is added, with efficient stirring, 126 g. (0.41 mole) of ethyl phthalimidomalonate (Org. Syn. Coll. Vol. i, 266). The mixture is rapidly chilled to 0° and the crystalline product filtered at once by suction and washed successively with two 200-cc. portions of absolute alcohol and two 200-cc. portions of ether. After first drying in a vacuum desiccator and then heating for eight hours imder 15 mm. pressure in a flask suspended in an oil bath at 145-155° (Note i), it weighs 108-III g. (82-85 per cent of the theoretical amount). 

Ethyl pentadecylate, 16, 37 Ethyl pentanehexacarboxylate, 10, 59 Ethyl phenylacetate, 16, 33 Ethyl -phenylacetoacetate, 18, 36 Ethyl -y-phenylbctyrate, 18, 25, 26 Ethyl phenylcyanopyruvate, 11, 40 Ethyl /J-phenylethyl ketone, 16, 49 Ethyl phenylmalonate, 16, 33 18, 84 Ethyl phenyloxaloacetate, 16, 33 Ethyl phthalimidomalonate, 14, 58 Ethyl pjmelate, 11, 42 17, 91 Ethyl propanetetracarboxylate, 10, 58 Ethyl propionate, 17, 34 Ethyl tso-propylmalonate, 11, 20, 21 Ethyl salicylate, 10, 51 11, 43 Ethyl sebacate, 14, 20 Ethyl sodium phthalimidomalonate, 14, 58... 

Phthalimides from halides. A soln. of ethyl phthalimidomalonate in dimethyl-formamide added to Na-methoxide, distilled in vacuo until the resulting methanol is removed, more dimethylformamide and 2-chlorethyl chloromethyl... 

B. Ethyl I -Methyllhiol- -phthalimidopropane-, 3 -dicarboxylate. —A mixture of 85 g. (0.26 mole) of ethyl sodium phthalimidomalonate and 43 g. (0.39 mole) of, fl-chloroethyl methyl sulfide (p. 18) is heated in an oil bath at 160-165° in a i-l. three-necked flask, fitted with a condenser, a thermometer, and a stoppered... 

The ethyl sodium phthalimidomalonate crystallizes with 1.5 molecules of alcohol, which is removed only on heating above 140° in vacuo. 

Diethyl sodium phthalimidomalonate (Barger and Weichselbaum, Organic Syntheses, 1943, Coll. Vol. II, 3B4) (6.52 g) was dissolved in boiling methyl ethyl ketone (BO ml) and a solution of p-nitrobenzyl chloride (3.44 g 1.0 mol) in the same solvent (20 ml) was added. Sodium iodide (ca 0.5 g) dissolved in hot methyl ethyl ketone (10 ml) was introduced, and produced an immediate precipitation. The mixture was refluxed for 1.5 hours, cooled, filtered, evaporated under vacuum and the residual gum crystallized from ethanol. The di-ethyl-p-nitrobenzyl-phthalimidomalonate formed colorless prisms (B8%), MP 103° to 105°C, sharpening to 104° to 105°C on recrystallizing from ethanol. 

Serine has been prepared by the Strecker method from glycol-aldehyde 1 and from ethoxyacetaldehyde,2 3 by the condensation of ethyl formate with ethyl hippurate followed by reduction and hydrolysis,4 5 from the reaction product of chloromethyl ether with ethyl sodium phthalimidomalonate,6 and by amination of a-bromo-/3-methoxypropionic acid with subsequent demethyla-tion.7... 

A. Triethyl a-phtkalimidoethane-a,a, -tricarboxylate. Three hundred and twenty-seven grams (1.0 mole) of diethyl sodium phthalimidomalonate and 735 g. (6.0 moles) of ethyl chloro-acetate (b.p. 144-145°) are placed in a 2-1. Claisen flask fitted with a reflux condenser and rubber stoppers. The mixture is heated under reflux in an oil bath at 150-160° for 2.25 hours. The excess ethyl chloroacetate is removed by distillation at 30 mm. until the heating bath temperature reaches 150° and no more distillate is obtained (Note 1). The brown residual mass is... 

In a 6oo-cc. beaker 210 g. (0.87 mole) of ethyl bromomal-onate (p. 34) (Note 1) and 165 g. (0.89 mole) of potassium phthalimide (p. 8) are intimately stirred together. The mixture is stirred approximately every ten minutes. If no spontaneous reaction starts in half an hour (Note 1), it is necessary to initiate the reaction by heating to no-1200. The mixture then becomes liquid and can be stirred easily. It turns to a light brown color, especially near the top where it comes in contact with the air. When the temperature begins to drop, the mixture is heated in an oil bath at no0 for one hour to insure completion of the reaction. The mixture is then poured into a mortar where it solidifies to a solid mass (Note 2). When cold, the mixture is ground up with water and filtered to remove most of the potassium bromide. The precipitate is then reground with water and refiltered, finally washing the precipitate well with water. The solid material on the filter consists of some potassium bromide, some phthalimide, and the phthalimidomalonic ester. 

The Gabriel-malonic ester synthesis begins with (V-phthalimidomalonic ester. Think of (V-phthalimidomalonic ester as a molecule of glycine (aminoacetic acid) with the amino group protected as an amide (a phthalimide in this case) to keep it from acting as a nucleophile. The acid is protected as an ethyl ester, and the a position is further activated by the additional (temporary) ester group of diethyl malonate. 

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