Malonic acid diethyl ester, preparation

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. 

By interaction of malonic acid diethyl ester with sodium ethylate (molar ratio 1 1) and then with ethyl bromide (molar ratio 1 1) was prepared ethylmalonic... 

Meprobamate has been synthesized by several procedures (See Figure U). The first step is to synthesize 2-methyl-2-propyl-1,3-propanediol. This has been done1 1 by reacting 2-methyl pentanal and formaldehyde in presence of KOH. The diol has also been prepared by reducing 2-methyl-2-n-propyl malonic acid, diethyl ester with lithium aluminum... 

It may be prepared by the condensation of [2-(phenylsulfinyl) ethyl]- malonic acid diethyl ester with hydrazobenzene in the presence of sodium ethoxide in absolute ethanol. Completion of reaction is achieved by the addition of xylene and subsequent heating at about 130°C whereby the ethanol liberated as a produet of eondensation is removed eompletely. The crude product is extracted with a suitable solvent and finally recrystallized from ethanol. 

To a flame-dried test tube equipped with a magnetic stirring bar was added 2-(2,3-butadienyl)-2-(5-methyl-3-hexynyl)malonic acid diethyl ester (365a) (0.0480 g, 0.16 mmol) and toluene (0.5 mL). The test tube was evacuated and charged with CO for three times and [Rh(CO)2Cl]2 (3.2 mg, 0.008 mmol) was added. The mixture was stirred and heated at 90 C overnight under CO atmosphere (1 atm). The solvent was removed in vacuo and the residue was purified by preparative TLC (Si02, hexanes ether = 75 25, Rf = 0.4) to afford 366a as a pale yellow oil, which solidified in the freezer to afford a colorless solid (0.0400 g, 76%). 

The physical properties of cyanoacetic acid [372-09-8] and two of its ester derivatives are Hsted ia Table 11 (82). The parent acid is a strong organic acid with a dissociation constant at 25°C of 3.36 x 10. It is prepared by the reaction of chloroacetic acid with sodium cyanide. It is hygroscopic and highly soluble ia alcohols and diethyl ether but iasoluble ia both aromatic and aUphatic hydrocarbons. It undergoes typical nitrile and acid reactions but the presence of the nitrile and the carboxyUc acid on the same carbon cause the hydrogens on C-2 to be readily replaced. The resulting malonic acid derivative decarboxylates to a substituted acrylonitrile ... 

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... 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

Friedel-Crafts acylation of benzo[6]thiophene and its derivatives with succinic anhydride132,439,662,663 or the ester chloride of succinic acid614, 618, 650,662 gives a y-keto acid (or ester), which is reduced to the corresponding y-(benzo[6]thienyl)butyric acid by the Huang Minion or Clemmensen method. y-(Benzo[6]thienyl)butyric acids may alternatively be prepared by the diethyl malonate synthesis on the appropriate halide,439,499 by the Arndt-Eistert reaction on the corresponding propionyl chloride,409,618 or by cyclization.347,618 The ketones (317 R = Hor OMe)347 have been prepared by cyclization... 

The heart of the preparation of capsaicin is a malonic ester synthesis. The first step is bromination of the primary alcohol by phosphorous tribromide. The resulting primary alkyl bromide is used to alkylate the sodium salt of diethyl malonate. A substituted malonic acid derivative is obtained following basic hydrolysis of the ester groups. 

The checkers prepared this ester on a 0.7-mol scale by a modification of the previously published method.2 The modification was effected as follows. The ethereal extract from the formaldehyde-diethyl malonate reaction, after drying over sodium sulfate for 3 hr, was concentrated in a rotary evaporator and the residue was stored in a refrigerator overnight. The crude ester was obtained as white crystals, mp 47-50°C yield 85.6%. The checkers found that the ester prepared in this manner gave superior yields of the acrylic acid. 

Olefinic esters may be obtained directly by the Knoevenagel reaction. Alkyl hydrogen malonates are used in place of malonic acid. Decarboxylation then gives the ester directly as in the preparation of ethyl 2-heptenoate (78%) and methyl m-nitrocinnamate (87%). Alkyl hydrogen malonates are readily available by partial hydrolysis of dialkyl malonates. The use of malonic ester in the condensation leads to olefinic diesters, namely, alkylidenemalonates such as ethyl heptylidenemalonate (68%). A small amount of organic acid is added to the amine catalyst since the salts rather than the free amines have been shown to be the catalysts in condensations of this type. Various catalysts have been studied in the preparation of diethyl methylenemalonate. Increased yields are obtained in the presence of copper salts. Trimethylacetalde-hyde and malonic ester are condensed by acetic anhydride and zinc chloride. Acetic anhydride is also used for the condensation of furfural and malonic ester to furfurylidenemalonic ester (82%). ... 

An intramolecular malonic ester synthesis can be used to form rings having three to six atoms, provided the appropriate dihalide is used as starting material. For example, cyclopentanecarbox-ylic acid can be prepared from diethyl malonate and 1,4-dibromobutane (BrCH2CH2CH2CH2Br) by the following sequence of reactions ... 

The third oxide of carbon, the so-called suboxide C3O2, is a gas at ordinary temperatures (it bods at +6°C) and may be prepared by heating malonic acid or its diethyl ester with a large excess of phosphorus pentoxide at 300°C. Its preparation from, and conversion into, compounds containing the —C—C-C- nucleus are consistent with its structure, 0-C—C—C—O. The action of water regenerates malonic acid, ammonia yields malonamide, and HCl malonyl chloride ... 

Quinoxaline-2-carboxaldehyde has been converted into the 2-carboxylic acid by oxidation with potassium permanganate in acetone and reduced to the 2-hydroxymethyl compound by treatment with formalin and potassium hydroxide. It also undergoes other typical reactions of aromatic aldehydes such as benzoin formation on reaction with potassium cyanide - and condensation reactions with malonic acid and its diethyl ester and Schiff base formation. Acid-catalyzed reaction of quinoxaline-2-carboxaldehyde with ethylene glycol gives the cyclic acetal the diethylacetal has been prepared by reaction of 2-dibromomethylquinoxaline with sodium ethoxide. " An indirect preparation of the oxime 11 is achieved by treatment of 2-nitromethyl-quinoxaline (10) with diazomethane followed by thermolysis of the resulting nitronic ester. 

It is very easy to halogenate malonic acid and its esters and alkyl or arylalkyl derivatives. Chloromalonic acid is obtained by hydrolysis of diethyl chloro-malonate, which is formed when chlorine is passed into the malonic ester at 70°.575 Cloves576 describes the preparation of 2-chlorobutyric acid by way of diethyl ethylmalonate. 

A combination of two of the reactions discussed in this chapter—alkylation of an a-carbon and decarboxylation of a j8-dicarboxylic acid—can be used to prepare carboxylic acids of any desired chain length. The procedure is called the malonic ester synthesis because the starting material for the synthesis is the diethyl ester of malonic acid. The first two carbons of the carboxylic acid come from malonic ester, and the rest of the carboxylic acid comes from the alkyl halide used in the second step of the reaction. 

It is prepared by the interaction of diethyl ester of ethyl malonic acid and iso-pentyl chloride in the presence of sodium metal, when ethyl is isopentyl ester of diethyl malonic acid is obtained as an intermediate compound. This on condensation with urea in the presence of sodium ethoxide results into the formation of amobarbital. 

An alternative preparation of a nitrile is illustrated by the reaction of the half-ester of 2,2-diethyl malonate 1.51) ivith SOCI2 and then NH3 to give the amide. Subsequent heating with phosphorus pentoxide led to dehydration and gave nitrile 1.52 Catalytic hydrogenation reduced the nitrile to an aminomethyl group, and acid hydrolysis gave 2,2-diethyl-3-aminopropanoic acid 1.53). 2-Ethyl-2-cyclohexyl-3-aminopropanoic acid and 2-ethyl-2-benzyl-3-aminopropanoic acid were also prepared by this method.30... 

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]. 

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