Malonic acid, amino-, diethyl ester

DIETHYL AMINOMALONATE HYDROCHLORIDE (Malonic acid, amino-, diethyl ester, hydrochloride)... 

Malonic acid, amino-, diethyl ester, HYDROCHLORIDE, 40, 24 Malonic acid, bts(hydroxymethyl)-, DIETHYL ETHER, 40, 27 Malonitrile, condensation with tetra-cyanoethylene, 41, 99 2-Mercaptopyrimidine, 43, 6S hydrochloride of, 43, 68 Mercuric oxide in preparation of bromo-cyclopropane, 43, 9 Mesityl isocyanide, 41,103 5-Methallyl-l,2,3,4,5-pentachlorocyclo-pentadiene, 43, 92 Methane, dimesityl-, 43, 57 Methanesiileinyl chloride, 40, 62 Methanesulfonic acid, solvent for making peroxybenzoic acid from benzoic acid, 43, 93... 

The starting material is prepared by reacting 2-amino-6-methylpyridine with ethoxymethyl-ene-malonic acid diethyl ester and then reacting that product with sodium hydroxide. 

The starting material may be produced by reacting 6-amino-2-methylthiopyrimidine with ethoxymethylene malonic acid diethyl ester. The intermediate thus produced is converted by boiling in diphenyl ether to 6-ethoxycarbonyl-2-methylthio-5-oxo-5,B-dihydropyrido-[2,3-d]pyrimidine. That is hydrolyzed by sodium hydroxide to cleave the ethoxy group and then ethylated with diethyl sulfate to give the starting material. 

Amino-6-methylpyridine Ethoxymethylene malonic acid diethyl ester Sodium hydroxide Ethyl iodide... 

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). 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

The reaction of 2-amino-3-nitrosopyridines with compounds containing an activated methylene group permits unambiguous synthesis of various derivatives of pyrido[2,3-b]pyrazine. For example, the pyridine 58 reacts in the presence of sodium ethoxide with a variety of arylacetonitriles and cyanoacetic acid derivatives to provide various 2-substituted 3-amino compounds (59). " " Diethyl malonate reacts similarly to give the 2-carboxylic acid 60, its ester being presumably hydrolyzed in the alkaline reaction conditions. Ethyl acetoacetate yields the 2-acetyl-3-oxo compound 61, and acetylacetone ° provides the 2-acetyl-3-methyl compound 62. The latter condensation proceeds poorly in ethanolic sodium ethoxide, but heating the nitroso compound with acetylacetone under reflux in pyridine gives a 59% yield of the product 62. °... 

Stepwise Degradation to Amino Adds. There are several approaches to the transformation of a di- or poly-carboxylic acid to an amino acid. The most satisfactory procedure makes use of the ester acids and their salts. They react with hydrazine to form hydrazide acids, which may be degraded through the azide acids to amino acids. From substituted malonic esters a-amino acids are obtained. (For the preparation of a-amino acids from substituted cyanoacetic esters, see p. 359.) Thus, the potassium salt of the monoethyl ester of methylmalonic acid, which is prqjared by half hydroly of the diethyl ester, pves alanine ethyl ester hydrochloride in 67% yield. Many other amino acids have... 

Transesterification of an ester is catalyzed by acid or base and has been used in the preparation of simple alkyl, benzyl, and t-butyl esters. Thus the mono (13) and benzyl ester (14) of malonic acid are prepared from diethyl malonate by alkoxide catalysed transesterification [49]. Benzyl cyanoacetic ester may be similarly prepared. t-Butyl acetate in the presence of either an A -acyl or a free amino acid and perchloric acid catalyst forms the t-butyl esters of the amino acid by analogous transesterification [50]. 

The most widely used method for the laboratory synthesis of a-amino acids is a modification of the malonic ester synthesis (Section 21.7). The key reagent is diethyl acetamidomalonate, a derivative of malonic ester that aheady has the critical nitrogen substituent in place at the a-caibon atom. The side chain is introduced by alkylating diethyl acetamidomalonate in the same way as diethyl malonate itself is alkylated. 

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 ... 

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. 

A third amino acid synthesis begins with diethyl a-bromomalonate. First the Br is replaced by a protected amino group using the Gabriel synthesis (see Section 10.6). Then the side chain of the amino acid is added by an alkylation reaction that resembles the malonic ester synthesis (see Section 20.4). Hydrolysis of the ester and amide bonds followed by decarboxylation of the diacid produces the amino acid. An example that shows the use of this method to prepare aspartic acid is shown in the following sequence ... 

One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines (Section 19-20) with the malonic ester synthesis of carboxylic acids (Section 22-16). The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid. 

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. 

The second method for preparing amino acids is based on the malonic ester synthesis. Recall from Section 23.9 that this synthesis converts diethyl malonate to a carboxylic acid with a new alkyl group on its a carbon atom. 

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