Malonic ester, amino

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

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 ... 

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 a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

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]. 

The beginning of the synthesis of an amino acid via an amido malonic ester. 

Chorazepate Chorazepate, 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzo-diazepin-3-carboxylic acid (5.1.34), which is used in the form of a dipotassium salt, is synthesized by yet another interesting synthetic scheme. 2-Amino-5-chlorobenzonitrile is used as the initial compound, which upon reaction with phenyhnagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine (5.1.32). Reacting this with amino-malonic ester gives a heterocyclization product, 7-chloro-l,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one (5.1.33), which upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt (5.1.34), chlorazepate [30-32]. 

The next member of this homologous series, a-amino-adipic acid, has been prepared by Sorensen from phthalimidosodium malonic ester and chlorobutyronitrile in the following way —... 

Mono- and difluoromethylation involving the halogenofluoromethanes can be performed on malonic esters. A Curtius reaction, further performed on only one of the ester functions, leads to a-fluoromethyl amino acid (Figure 5.26). °... 

Naphthoresorcinol has been prepared by heating l-amino-3-hydroxy-4-naphthalenesulfonic acid or its salt in water or slightly acidic solution2 and by cyclization of ethyl phenylacetylmalo-nate 3 or of ethyl phenylacetoacetate.4 Phenylacetylmalonic ester has been prepared by condensing phenylacetyl chloride and malonic ester in ether with sodium.3... 

Scheme 12 shows a series of reactions between 2-bromomethyl-pyridine and compounds containing active methylene groups the sequence 12(a) may be varied by using derivatives of acetylacetone or malonic ester instead of a j8-ketoester.40 Reactions 12(b) and 12(c) provide useful routes to 3-hydroxy and 3-amino compounds, which are noted for their instability in air (although 62 was stable in air for several weeks).30... 

Preparation of mono-adducts of fullerene - for studies on electrostatic interactions - was undertaken by cyclopropanation of fullerene with appropriately functionalised malonic esters 1 (Bingel reaction) to form 2. Coupling with the tert-butyl protected oligoamide-amino-dendron 3 and subsequent hydrolysis lead to the water-soluble fullerene dendron 5, which can carry up to nine negative charges after depro to nation. After association with the zinc complex of cytochrome C, photoinduced electron transfer (PET) from the redox protein to the fullerene can be accomplished, which was studied by fluorescence spectroscopy. 

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

The regiospecific nucleophilic displacement of 1,2-cyclic sulfamidates 130 with methyl thioglycolate or a-amino esters 130 can be accompanied by lactamization (thermal, base mediated, or cyanide catalyzed) to give thiomorpho-lin-3-ones and piperazin-2-ones 131 (Scheme 19) <20030L811>. If malonate esters, phosphonate-stabilized esters, or aryl-substituted enolates were used as nucleophiles in this reaction, trisubstituted pyrrolidines were obtained in high yield <2004OL4727>. 

Fig. 13.39. Synthesis of an a-amino acid through malonic ester synthesis, here using the example of phenylalanine (in the form of its hydrobromide).

A) produces the disubstituted malonic ester B. Hydrobromic acid hydrolyzes the ester functions of B—which, upon heating, is followed by the usual decarboxylation—as well as the acetamido group. The reaction product is the hydrobromide C of the a-amino acid phenylalanine. 

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