Diethyl dimethyl malonate

Physical Properties. Industrially, the most important esters are dimethyl malonate [108-59-8] and diethyl malonate [105-53-3] whose physical properties are summarized in Table 2. Both are sparingly soluble in water (1 g/50 mL for the diethyl ester) and miscible in all proportions with ether and alcohol. 

Carbon Monoxide Process. This process involves the insertion of carbon monoxide [630-08-0] into a chloroacetate. According to the hterature (34) in the first step ethyl chloroacetate [105-39-5] reacts with carbon monoxide in ethanol [64-17-5] in the presence of dicobalt octacarbonyl [15226-74-1], Co2(CO)g, at typical temperature of 100°C under a pressure of 1800 kPa (18 bars) and at pH 5.7. Upon completion of the reaction the sodium chloride formed is separated along with the catalyst. The ethanol, as well as the low boiling point components, is distilled and the nonconverted ethyl chloroacetate recovered through distillation in a further column. The cmde diethyl malonate obtained is further purified by redistillation. This process also apphes for dimethyl malonate and diisopropyl malonate. 

Health and Safety Factors. Dimethyl malonate and diethyl malonate do not present any specific danger of health ha2ard if handled with the usual precautions. Nevertheless, inhalation and skin contact should be avoided. Dimethyl malonate has a LD q (oral, rats) of 4520 mg/kg and is classified as nonirritant (skin irritation, rabbits). Diethyl malonate has an LD q (oral, rats) greater than 5000 mg/kg and is also classified as nonirritant (skin irritation, rabbits). Transport classification for both esters is RID/ADR 3, IMDH-Code, lATA-ICAO not restricted. 

The primary synthesis of alkoxypyrimidines is exemplified in the condensation of dimethyl malonate with O-methylurea in methanolic sodium methoxide at room temperature to give the 2-methoxypyrimidine (854) (64M207) in the condensation of diethyl phenoxymalonate with formamidine in ethanolic sodium methoxide to give the 5-phenoxypyrimidine (855) (64ZOB1321) and in the condensation of butyl 2,4-dimethoxyacetoacetate with thiourea to give 5-methoxy-6-methoxymethyl-2-thiouracil (856) (58JA1664). 

The preparation described here of 3-cyclopentene-1-carboxylic acid from dimethyl malonate and cis-1,4-dichloro-2-butene is an optimized version of a method reported earlier3 for obtaining this often used and versatile building block.6 The procedure is simple and efficient and requires only standard laboratory equipment. 3-Cyclopentene-1-carboxylic acid has previously been prepared through reaction of diethyl malonate with cis-1,4-dichloro(or dibromo)-2-butene in the presence of ethanolic sodium ethoxide, followed by hydrolysis of the isolated diethyl 3-cyclopentene-1,1-dicarboxylate intermediate, fractional recrystallization of the resultant diacid to remove the unwanted vinylcyclopropyl isomer, and finally decarboxylation.2>7 Alternatively, this compound can be obtained from the vinylcyclopropyl isomer (prepared from diethyl malonate and trans-1,4-dichloro-2-butene)8 or from cyclopentadiene9 or cyclopentene.10 In comparison with the present procedure, however, all these methods suffer from poor selectivity, low yields, length, or need of special equipment or reagents, if not a combination of these drawbacks. 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

Treatment of diethyl malonate and related compounds with 1,2-dihaloethane in the presence of base constitutes a classical method of cyclopropane synthesis296"300. The reaction can be conveniently carried out under PTC conditions. An improved method utilizing solid-liquid phase transfer catalysis has been reported298. The reaction of dimethyl or diethyl malonate with 1,2-dibromoalkanes except for 1,2-dibromethane tends to give only low yields of 2-alkylcyclopropane-l, 1-dicarboxylic esters. By the use of di-tm-butyl malonate, their preparations in satisfactory yields are realized (equation 134)297. The 2-alkylcyclopropane derivatives are also obtained from the reaction of dimethyl malonate and cyclic sulfates derived from alkane-1,2-diols (equation 135)301. Asymmetric synthesis... 

Health and Safety Factors. Dimethyl malonate and diethyl malonate do noi present any specific danger of healih hazard iT handled vvith the usual precautions. Nevertheless, inhalation and skin eoruacl should be avoided. 

Dimethyl malonate (4.04 g, 30.6 mmol), potassium t-butoxide (3.43 g, 30.6 mmol) and anhydrous N,N-dimethylformamide (15 ml) were mixed and stirred for 10 minutes in a nitrogen atmosphere at 90°C. The mixture was then cooled to room temperature, and to the cooled mixture was added a solution of diethyl 2-(3-chloro-4-nitrophenyl)-2-methylmalonate (5.04 g, 15.3 mmol) prepared in the manner as described in Japanese Patent Publication No. 47-45, 746) in anhydrous N,N-dimethylformamide (15 ml). The resulting mixture was stirred at 90°C for 3 hours, and then poured into 1 N hydrochloric acid (30 ml). The mixture was subjected to extraction using two portions of diethyl ether. The ether extracts were combined, washed successively with water and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried extract was placed under reduced pressure to give 7.97 g of yellow oil. The oil was adsorbed on silica gel (16 g) and subjected to... 

With these two esters, the choice of base is important nucleophilic addition can occur at the ester carbonyl, which could lead to transesterification (with alkoxides), hydrolysis (with hydroxide), or amide formation (with amide anions). The best choice is usually an alkoxide Identical with the alkoxide component of the ester (that is, ethoxide for diethyl malonate methoxide for dimethyl malonate). Alkoxides (pKd 16) are basic enough to deprotonate between two carbonyl groups but, should substitution occur at C=0, there is no overall reaction. 

Dimethyl malonate (200 mmol) was dissolved in 300 ml DMF, cooled to 0 °C, and lithium hydride (500 mmol) added in one portion. To the cooled mixture was slowly added cis-l,4-dichloro-2-butene (228 mmol) and the mixture stirred 72 hours. Thereafter, the mixture was diluted with 500 ml 20% diethyl ether/hexanes then poured into 350 ml cold water. After washing with 300 apiece water and brine, the product was isolated in 50% yield, mp = 63.4 °C. H-NMR and IR data supplied. 

The same type of reaction was observed with 2-chlorocyclohexanone and the sodium salts of dimethyl malonate and diethyl methylmalonate, affording bicyclo[3.1.0]hexan-6-ols (5) and with 2-chlorocycloheptanone and the sodium salts of diethyl malonate and diethyl methylmalonate, affording bicyclo[4.1.0]heptan-7-ols (6). ... 

Potent nucleophiles can be generated from C-H acidic compounds by deprotonation. Diethyl malonate reacted with diethyl cyclopropane-1,1-dicarboxylate (1) in the presence of sodium ethoxide to give tetraethyl butane-1,1,4,4-tetraoate (2). Isopropylidene cyelo-propanedicarboxylate (3) underwent an analogous reaction when treated with dimethyl malonate or methyl 2-oxocyclohexanecarboxylate. ... 

From 3(5)-hydroxypyrazoles. 5-Hydroxy-l-phenyl-lH-pyrazole-4-carboxylic acid ethyl ester 303, derived from diethyl (ethoxymethylene)-malonate and phenylhydrazine hydrochloride, when methylated with dimethyl sulfate in aqueous sodium hydroxide solution afforded pyrazole 304 together with pyrazol-3-one 305 in 16% and 33% yield, respectively (95JHC1341) (Scheme 68). 

It is, however, possible to obtain either pyrido[2,3-rf]pyrimidine-2,4,7(1/7,377,8//)-triones or, to a lesser extent, py rido[2,3-acetic acid 99 affords ethyl 1,3-dimethyl-2,4,7-trioxo-l,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carboxylate. Further examples of this pathway are the reaction of diethyl (ethoxymethylene)malonate with 6-amino-165 or 6-(methylamino)-l,3-dimethyluracil 222 neat at 220-230 °C, or with 6-amino-2-methoxypyrimidin-4(3/7)-one223 in acetic acid to yield the corresponding ethyl 2,4,7-trioxo-l, 2,3,4,7,8-hexahydropyrido[2,3-[Pg.118]

The reaction of (f /Z)-4-arylidenepyrazol-3-ones 491a-c with reactive methylene compounds such as diethyl or dimethyl malonate, ethyl cyanoacetate or cyano-acetamide in alcoholic solution containing sodium hydroxide afforded the corresponding addition products 492c-j. These adducts were found to be almost exclusively enol tautomers (79AP478) (Scheme 151). 

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