Malonic acid, acetamido-, diethyl

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

An aqueous solution of sodium nitrite that is treated with HC1 contains nitrosyl cations 0=N . These can react with the enol E of the malonic acid diethyl ester (cf. Figure 12.9, bottom). First, a nitroso compound (F) is formed, which then undergoes acid-catalyzed isomerization to give the oxime A. Usually, the oxime is reduced by zinc, which is dissolved in acetic acid, to yield an amine that normally undergoes in situ acetylation in acetic acid. In this way the (acetamido)malonic acid diethyl ester B is obtained as the reduction/acetylation product, which can be employed, for example, in the synthesis of amino acids (Figure 13.39). 

Figure 13.39 shows that malonic ester syntheses can also lead to acetic acid derivatives with a heteroatom in the a-position. The benzylation of (acetamido)malonic acid diethyl ester... 

The reaction of cyclic oxonium derivatives of polyhedral boron hydrides with acetamido diethyl-malonate (glycine anion equivalent for amino acid synthesis), a variation of the classical Sdrensen synthesis of amino acids, followed by acidic hydrolysis and decarboxylation was proposed as a route to boron hydride-based aminoacids (Figure 24.10) [31,51]. 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

Mildly basic liquiddiquid conditions with a stoichiometric amount of catalyst prevent hydrolysis during alkylation [101] and, more recently, it has been established that solid-liquid or microwave promoted reactions of dry materials are more effective for monoalkylation [102-106] of the esters and also permits dialkylation without hydrolysis. Soliddiquid phase-transfer catalytic conditions using potassium f-butoxide have been used successfully for the C-alkylation of diethyl acetamido-malonate and provides a convenient route to a-amino acids [105, 107] use of potassium hydroxide results in the trans-esterification of the malonate, resulting from hydrolysis followed by O-alkylation. The rate of C-alkylation of malonic esters under soliddiquid phase-transfer catalytic conditions may be enhanced by the addition of 18-crown-6 to the system. The overall rate is greater than the sum of the individual rates observed for the ammonium salt or the crown ether [108]. 

Acylaminomalonic esters and related reagents are widely used for the synthesis of a-amino acids. The method differs from those syntheses already discussed in that the amino group is incorporated into the system from the outset. A popular reagent is diethyl acetamidomalonate (35). The acetamido group can readily be introduced into the reactive methylene position in diethyl malonate by first converting the latter into the hydroxy-imino derivative (33) by reaction with nitrous acid or an alkyl nitrite (cf. Section 4.2.7, p. 413). This derivative is then reduced catalytically to diethyl aminomalonate (34) which is acetylated using acetic anhydride. 

The second example is an interesting synthesis of the heterocyclic amino acid tryptophan (R = 3-indolymethyl) which involves the initial base catalysed 1,4-addition (the Michael reaction, Section 5.11.6, p. 681) of diethyl acetamido-malonate to the oc,/ -unsaturated aldehyde, acrylaldehyde, yielding the aldehydic derivative (38). The derived phenylhydrazone (39) is then cyclised under acidic conditions (see Expt 8.26) to form the indolylacetamidomalonate derivative (40) which is then converted into the corresponding a-amino acid (i.e. tryptophan) in the usual way (Expt 5.184). 

Amino acids can bo prepared by reaction of alkyl halides with diethyl acetamido-malonate, followed by heating the initial alkylation product with aqueous HCl. Show how you would prepare alanine, CHaCHlNHalCOOH, one of the 20 amino acids found in proteins, and propose a mechanism for acid-catalyzed conversion of the initial alkylation product to the amino acid. (See Section 26.4.)... 

More interesting is the Michael addition of diethyl acetamido malonate as an amino acid precursor [Eq. (56)] [94,95]. 

Ethyl nicotinoylacetate with formaldehyde and diethyl acetamido-malonate gave LXVII which on being treated with dilute hydrohromic acid followed by saponification gave LXVIII from which myosmine and nicotine were prepared (96). 

Ethylene oxide added to an ice-cold suspension of diethyl acetamido-(5-amino-3-indolylmethyl) malonate in methanol containing p-toluenesulfonic acid, and stirred 18 hrs. at room temp. diethyl acetamido-[5-bis-(2-hydroxyethyl)-amino-3-indolylmethyl] malonate (Y 99%) dissolved in pyridine, treated with methanesulfonyl chloride, and heated 20 min. in an oil bath at 80-90° after the exothermic reaction has subsided -> diethyl acetamido- [5-bis- (2-chlorethyl) -amino-3-indolylmethyl]malonate (Y 40-50%).—Other chlorodehydroxylation methods were not successful. J. DeGraw and L. Goodman, J. Org. Ghem. 27, 1395 (1962). 

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