Diethyl acetamidomalonate

The most widely used method for the laboratory synthesis of a ammo acids is a modification of the malonic ester synthesis (Section 21 7) The key reagent is diethyl acetamidomalonate a derivative of malonic ester that already has the critical nitrogen substituent m place at the a carbon atom The side chain is introduced by alkylating diethyl acetamidomalonate m the same way as diethyl malonate itself is alkylated... 

Alkyl halides by reaction with the enolate anion derived from diethyl acetamidomalonate... 

Treat the sodium salt of diethyl acetamidomalonate with isopropyl bromide Remove the amide and ester functions by hydrolysis in aqueous acid then heat to cause (CH3)2CHC(C02H)2... 

Diethyl acetamidomalonate [1068-90-2] M 217.2, m 96. Crystd from benzene/pet ether. 

DIETHYL ACETAMIDOMALONATE (Malonic acid, acetamido-, diethyl ester)... 

The reaction mixture is filtered with suction and the cake is washed thoroughly with two 200-ml. portions of glacial acetic acid (Note 4). The combined filtrate and washings are evaporated under reduced pressure on the steam bath until a thick oil, which generally partially crystallizes, remains. To purify the crude product, 100 ml. of water is added, and the flask is warmed on a steam bath until the solid melts. The mixture of water and oil is stirred rapidly in an ice bath, and diethyl acetamidomalonate crystallizes as a fine white product. After cooling in an ice bath for an additional hour, the product is collected by filtration, washed once with cold water, and dried in air at 50°. A second crop is obtained by concentrating the mother liquor under reduced pressure. The yield of diethyl acetamidomalonate, m.p. 95-97° (Note 5), is 52-53 g. (77-78%) based on malonic ester. 

Prolonging the stirring to 24 hours has no effect on the yield of diethyl acetamidomalonate. 

The diethyl acetamidomalonate obtained is of high purity. If a product of inferior quality is obtained, it may be recrystallized from hot water, using 2.5 cc. per g. Upon cooling, the product separates first as an oil. With rapid stirring, it is converted to fine white crystals which are easily washed with cold water. Diethyl acetamidomalonate may be recrystallized in this manner with 97% recovery. The first crop amounts to 91% and the mother liquors may be concentrated to yield an additional 6%. 

Diethyl acetamidomalonate was first reported by Cherchez in 1931, when in an attempt to carry out a carbon alkylation of diethyl aminomalonate with acetyl chloride he obtained a quantitative yield of diethyl acetamidomalonate. This method of preparation, however, is not practical since diethyl aminomalonate is unstable and is made in relatively poor yields. 

Snyder and Smith prepared diethyl acetamidomalonate in 40% yield by reduction of diethyl isonitrosomalonate in ethanol over palladium on charcoal followed by direct acetylation of diethyl aminomalonate in the filtrate with acetic anhydride. Ghosh and Dutta used zinc dust instead of palladium. A modification using Raney nickel is described by Akabori et al. Shaw and Nolan reported a 98% yield by conversion of diethyl oximino-malonate-sodium acetate complex. 

Diethyl acetamidomalonate is useful in the synthesis of ce-amino acids by alkylation, as, for example, histidine and tryptophan. 

Alkylation of diethyl acetamidomalonate with the bromomethyl-pyrimidine (88) yielded 6-acetamido-6-ethoxycarbonyl-6,6-dihydro-2-methylthiopyrido[2,3-d]pyrimidin-7(8//)-one (90), via the cyclization of the intermediate ester (89). 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

In a deceivingly simple process apparently involving a butatriene intermediate, a one-pot preparation of ethyl 5-methylpyrrole-2-carboxylate (6) from diethyl acetamidomalonate (4) and l,4-dichloro-2-butyne (5) has been described <96JOC9068>. 

An interesting ring opening of a fatty oxirane has been reported by Loupy [69]. Diethyl acetamidomalonate opens the oxirane ring according to Scheme 8.47. 

Diels-Alder reaction, see Addition Diethyl acetamidomalonate (Correction), 46, 32... 

Sodium salt of diethyl acetamidomalonate 480 reacts with ethyl 2,3-butadienoate in the presence of a catalytic amount of EtONa to afford /fy-unsaturated enoate 481, which can be easily decarboxylated leading to /3-methyleneglutamic acid hydrochloride 482 [220],... 

From diethyl acetamidomalonate and 2-(4-fluorophenoxy)ethyl bromide a spiro-benzopyranyl amino acid 101 could be prepared (88TL5493). 

The multistep synthesis shown in Figures 16-39 and 16-40 leads to the synthesis of an amino acid. (Note that the diethyl acetamidomalonate shown in Figure 16-40 is the product of the reaction in Figure 16-39.) The example in the figures is a natural amino acid however, you can synthesize other (not natural) amino acids with this procedure. 

The lipo-amino acids are generally synthesized as racemic mixtures which are resolved into optically pure a-amino acids by chemical or enzymatic methods.113" 137 133 The synthesis is based on the alkylation of diethyl acetamidomalonate followed by hydrolysis and decarboxylation. 129 138 140 Also, 20% DMF has been used in the hydrolysis step, as it is suitable for industrial scale preparation. 138] Alternatively, lipidated a-amino acids are synthesized by reacting a-bromoalkanoic acid with ammonium hydroxide. 141 ... 

S,2J )-2-Aminodecanoic Acid, H-DL-Ade-OH, from Diethyl Acetamidomalonate Typical Procedure 11381... 

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