Aminomalonate

JCS2689) and 5-bromomethylpyrimidine (458) and diethyl benzyloxycarbonyl-aminomalonate (459) give initially, diethyl a-benzyloxycarbonylamino-a-(pyrimidin-5-ylmethyOmalonate (460) which can be degraded to 2-amino-3-(pyrimidin-5 -yl)propionic acid (461) (65JHCl>. 

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

B. Diethyl aminomalonate hydrochloride. The crude diethyl aminomalonate is diluted with 80 ml. of dry ether and filtered to remove a small amount of white solid. The filtrate is collected in a 250-ml. Erlenmeyer flask and cooled in an ice bath. Dry hydrogen chloride is passed just over the solution while it is being stirred mechanically (Note 6). The fine white crystals which precipitate are collected by suction filtration and washed three times with a total of 60 ml. of dry ether (Note 7). The filtrate and washings are treated again with hydrogen chloride, and a second crop of diethyl aminomalonate hydrochloride is collected and washed as before. This process is repeated until no further precipitation results from passing hydrogen chloride into the solution. A total of 16.5-17.4 g. (78-82% yield based on diethyl malonate) of diethyl aminomalonate hydrochloride, m.p. 162-163°, is obtained. Recrystallization from alcohol-ether affords a purer product, 164-165°. 

Diethyl aminomalonate is a useful intermediate, lending itself to N-acylation the N-acyl derivatives may be alkylated by procedures as established for syntheses via malonic ester. 

Intermediate carbenes are also involved in the alkylation by haloforms of carbanions derived from Schiff bases of a-ammo esters [126] or aminomalonates... 

The major development in the Knorr pyrrole synthesis has been access to the amine component. For example, use of preformed diethyl aminomalonate with 1,3-diketones affords much higher yields of pyrroles 14. Reaction of 6-dicarbonyl compounds with hydroxylamine 0-sulfonic acid gives pyrroles 15 in one step. Weinreb a-aminoamides have found use in the Knorr pyrrole synthesis of a wide variety of pyrroles 16. °... 

The formic acid Is distilled off, and the remainder dissolved in warm benzene and washed with a bicarbonate solution to a neutral reaction. After the benzene has been distilled off, the aminomalonic ester xylidide is obtained. This Is treated with an equal quantity of sodium ethylate and boiled with twice the theoretical quantity of tetramethylene bromide in absolute alcohol. 

B) Preparation of 7-Chloro-3-Methoxycarbony/-5-Phenyl-2-0xo-2,3-Dihydro-iH-Benzo [fl-1,4-Diazepine (4347 CB) A solution of 9.2 g (0.04 mol) of compound 4356 CB in 20 ml of methanol is added dropwise, in the course of one hour and 30 minutes, to a boiling solution of 9.2 g (0.05 mol) of the hydrochloride of methyl aminomalonate in 30 ml of methanol. When this is completed, heating under reflux is continued for 30 minutes and the product then concentrated to dryness under reduced pressure. The residue is taken up in water and ether, the ethereal layer separated, the product washed with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure. The residue, which consists of the methyl ester, could not be obtained in the crystalline state. It is dissolved in 25 ml of acetic acid, heated under reflux for 15 minutes, the product evaporated to dryness and the residual oil taken up in ether. A colorless solid separates which... 

Methylimidazole HCI 2-Amino-5-chloro-2 -fluoro-benzophenone Ethyl aminomalonate hydrochloride... 

IB) 1-(2-Amino-5-chlorophenyl)-1-(2-fluorophenyl)-3,3-bis-(ethoxycarbonyl)-2-a2a-prop-1-ene A mixture of 88 g of the product obtained above, 300 g of ethyl aminomalonate hydrochloride and 60 ml of acetic acid in 2.3 liters of absolute ethanol is heated to the reflux temperature for 6 hours. The alcohol and the acetic acid are evaporated in vacuo and the residue is taken up in ether. The solution is washed with a dilute sodium bicarbonate solution and... 

Diethyl aminomalonate, from reduction of diethyl isonitrosomalonate, 40, 2 ... 

An intramolecular ring expansion of aziridine esters can be accomplished by installing an appropriate nucleophilic entity in these substrates. Conversion of the ester moiety into carboxamides derived from aminomalonate ester gives compounds 44 containing the requisite nucleophilic site in the malonate moiety (Scheme 35). 

A. G. Ogston in 1948 explained the dilemma of how an enzyme can enan-tiospecifically produce a chiral product from a prochiral molecule such as citric acid or 2-aminomalonic acid. He pointed out two requirements three-point contact at three active sites (a, b, and c ) and catalytic dissimilarity between the two active sites (a and b ) associated with the pro-R and pro-5 groups (a and b) of the prochiral molecule as shown in Fig. 3.2. 

Reagent and conditions i, diethyl chloromalonate, DMF ii, DBN, MeOH iii, AcOH, H2O iv, AcONa, diethyl aminomalonate HCI, MeOH/H20 v, MeONa, MeOH vi, 2,5-dimethoxyTHF, 4-chloropyridine hydrochloride, dioxane vii, pyrrolidine viii, (a)POCI3, (b) 10%NaOH... 

A facile synthesis of 5-substituted 3-aminopyrrole-2-carboxylates has been developed wherein condensation of diethyl aminomalonate with a-cyano ketones 46 was facilitated by prior formation of the p-toluenesulfonyl enol ether 47 <00JOC2603>. Addition of the amine component is followed by cyclization and decarboxylation to afford the pyrroles 48. 

The low percentage of obtaining products belonging to the a-kainic acid series (at best 50%) was attributed to unfavorable transition states with repulsion between one of the aminomalonate ester groups and the isoprenyl chain. These difficulties were circumvented by using a simple a-amino ester (131) in lieu of the aminomalonate group this has led to a simple synthesis of a-kainic acid (Scheme 33) (178). 

This sequence was obviously not amenable to a synthesis of optically active a-allokainic acid given the fact that an aminomalonate group was necessary. After unfruitful assays with menthyl esters, the Swiss group was rewarded by the discovery that the phenylmenthyl group (180) brings sufficient asymmetry to the reaction intermediate to afford products with a high percentage of favorable diastereoisomer (Scheme 35) (181). 

Diethyl acetylenedicarboxylate as di-eneophile, 40, 86,87 Diethylamine, condensation with tri-chloroacetyl chloride, 41, 21 Diethyl aminomalonate, from reduction of diethyl isonitrosomalonate, 40, 24... 

Hydroxypyrrole-2,4-dicarboxylates (1311) were obtained in 51-55% yields in the cyclocondensation of aminomalonates (1310) and EMME in boiling ethanol for 4 hr in the presence of sodium ethoxide (75FES917 84M18). In the first step, the central carbon atom of the aminomethy-lenemalonates (1310) reacted with EMME, and not the amino group. 

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