Malonic 2- -, diethyl esters, preparation

Preparation 202.—Diethyl Malonate [Diethyl ester of yrroy>an-diadd ... 

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. 

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... 

Preparation of the intermediate for Allobarbitone (diethyl diallyl malonate). Diethyl malonate is dissolved in anhydrous alcohol and treated with one mole of clean sodium meted per every one mole of the ester. To this solution add one mole of allyl chloride and reflux for about 4 hours. Another equimolar ratio (1 mole of sodium per mole of ester) of sodium is added, followed by the same ratio of allyl chloride (1 mole per 1 mole), and this mixture is boiled for 2 hours. The alcohol is removed by distillation and the ester is extracted with benzene and distilled or evaporated in vacuo, recrystallized with a suitable "dry" solvent, and filtered. Evaporate again to remove traces of solvent. Keep this product, and any other substances that require dry reagents or solvents, stored away from contact with the atmosphere. When evaporating, filter the air coming into the evaporating vessel with a suitable drying agent. Use a little common sense. 

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... 

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. 

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 ... 

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... 

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. 

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. 

Preparation of Diethyl ester of ethyl-(l-methyl butyl) malonate ... 

Preparation of diethyl ester of allyl-(l -methyl butyl) malonate (//) Condensation of (/) above with urea and Hi) Preparation of the sodium salt. 

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%). 

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]. 

Malonic ester synthesis (Section 21 7) Synthetic method for the preparation of carboxylic acids involving alkylation of the enolate of diethyl malonate... 

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 ... 

Diethyl bis (hydroxymethyl) malonate is a useful intermediate for preparing substituted malonic esters. 

The malonic ester synthesis can also be used to prepare cydoalkane-carboxvlic acids. For example, when 1,4-dibromobutanc is treated with diethyl malonate in the presence of 2 equivalents of sodium ethoxide base, the second alkylation step occurs intrcunotecidariy to yield a cyclic product. Hydrolysis and decarboxylation then give cvclopentanecarboxylic acid. Three-, four-, five-. 

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 ... 

V-(3-Ethoxy-4-decyloxyphenyl)aminomethylenemalonate (309) was prepared in the reaction of the amidine (308), diethyl malonate, and ethyl orthoformate in the presence of ammonium chloride at 125-130°C for 1 hr (68FRP1531495). The crude ester (309) was applied without purification in the cyclization step. 

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