Ethyl malonate, alkylation

Substitution Derivatives of Ethyl Malonate, Ethyl malonate resembles ethyl acetoacetate in that it gives rise to mono- and di-substituted derivatives in precisely similar circumstances. Thus when ethanolic solutions of ethyl malonate and of sodium ethoxide are mixed, the sodium derivative (A) of the enol form is produced in solution. On boiling this solution with an alkyl halide, e.g, methyl iodide, the methyl derivative (B) of the keto form is obtained. When this is treated again in ethanolic solution with sodium ethoxide, the... 

It follows therefore that ethyl malonate can be used (just as ethyl aceto- acetate) to prepare any mono or di-substituted acetic acid the limitations are identical, namely the substituents must necessarily be alkyl groups (or aryl-alkyl groups such as CjHjCHj), and tri-substituted acetic acids cannot be prepared. Ethyl malonate undergoes no reaction equivalent to the ketonic hydrolysis of ethyl acetoacetate, and the concentration of the alkali used for the hydrolysis is therefore not important. 

Where R and R are identical, the dialkylmalonic ester may be prepared in one operation by treating 1 mol of ethyl malonate with 2 mots each of sodium ethoxide and the alkyl halide (usually bromide or iodide). 

The reaction can be applied to allyl malonates. Alkylation of diallyl mal-onate (734) with bromoacetate and acetoxymethylation afford the mixed triester 735. Treatment of the tricster 735 with Pd catalyst affords allyl ethyl itaconate (736). In a similar way, a-methylene lactone and the lactam 737 can be prepared[462]. 

Ethylmalonic Acid.—Like acetoacetic ester (see p. 83), diethylmalonate contains the gioup CO.CHj.CO. By the action of sodium or sodium alroholate, the hydrogen atoms of the methylene group are successively replaceable by sodium. The sodium atoms are in turn replaceable by alkyl or acyl groups. Thus, in the present preparation, ethyl malonic ester is obtained by the action of ethyl iodide on the monosodium compound. If this substance be treated with a second molecule of sodium alcoholate and a second molecule of alkyl iodide, a second radical would be in roduced, and a compound formed of the general formula... 

The addition of a phenylsulfoxide moiety to the end of the side chain markedly changes the activity of this class of compounds. This product, sulfinpyrazone (97-11), stimulates uric acid excretion, making it a valuable dmg for dealing with the elevated serum uric acid levels associated with gout. The compound is stiU one of the more important uricosuric agents available today. The starting ester (96-9) is available by alkylation of the dianion from ethyl malonate with 2-chloroethylphenyl thioether. Condensation with diphenylhydrazine (97-3) in the presence of a base then affords the pyrrazolodione (97-10). Oxidation of sulfur with a controlled amount of hydrogen peroxide leads to the sulfoxide and thus sulfinpyrazone (97-11) [107]. 

IS) By ethyl cyanoacetate. Attempted base-catalyzed condensations of ethyl malonate and ethyl acetoaoetate -with the simple episulfides have been unsuccessful. However, 2-iminothioplianes are obtainable from ethyl cyanoacetate and alkene sulfides.108 In the alkylation of ethyl cyanoacetate with propylene sulfide and isobutylene sulfide, mjcloophilic attack by the carb nion is on the primary carbon atom of the episulfide (Eq. 53). 

Malonate anions react with the ri2-ethylene-Fe(CO)4 complex to afford after demetallation ethyl malonate derivatives. Reaction of nucleophiles with tetracar-bonyliron-activated c/.Jl-unsatu rated carbonyl compounds leads after protonation of the intermediate alkyl-Fe(CO)4 anions to the products of Michael addition. 

Naphthyridones 22, which are of interest as pharmacological preparations, have been synthesized by the reaction of vicinal aminopyridinecarbonitriles 23 with diethyl malonate. Alkylation of these products with ethyl monobromoacetate results in N-substituted compounds 24 (1990ZC20)... 

The magnesium etiolate is prepared from 2.1 equivalents of potassium ethyl malonate (16) by treatment w ith 2.0 equivalents of alkyl Grignard (usually methyl or ethyl since these are commercially available). The resulting dianion, shown in Scheme 6.4 as 17. has strong nuclcophilicity at the carbon. 

Alkylation or acylation of ethyl malonate, ethyl acetoacetate, or other compounds containing methylene groups activated by strongly electron-attracting groups are very fruitful preparative methods. Reactions according to the schemes ... 

The preparation of diethyl butylmalonate380 is an example of alkylation by an alkyl halide A cooled and stirred solution of sodium alkoxide (from 115 g of sodium and 2.5 1 of anhydrous ethanol) is treated gradually with refractionated ethyl malonate (b.p. within 5° 825 g) with further cooling as necessary, this ester is followed by butyl bromide (685 g) during 1 h. Then the solution is heated on a water-bath until neutral to litmus (2-3 h), after which alcohol (21) is distilled off from a water-bath, the residue is treated with its own volume of water, and the organic phase is separated and distilled in a vacuum. A forerun of unchanged malonic ester is followed by the diethyl butylmalonate (89-92%, 960-990 g), b.p. 144-145°/40 mm. 

One-pot malonic ester synthesis. A separate hydrolysis step can be avoided by use of the dilithium salt of ethyl malonate, prepared by reaction of the ester with 2 eq. of hthium isopropylcyclohexylamide (4, 306-309) in THF at -78°. HMPT and the alkyl halide are then added and the reaction mixture is allowed to come to room temperature for 2 hr. Decarboxylation is then effected by overnight reflux. 

If it is desired to introduce two different radicals the synthesis is carried out in steps From ethyl malonate can be obtained the ester formed by the replacement of one hydrogen by an alkyl group, for example, CH3CH(COOC2H5)2. This, like the ester of malonic acid, reacts with sodium and forms a derivative which may be condensed with a molecule of another alkyl halide, thus,—... 

This simple solid liquid system can be efficiently applied in many important reactions involving carbanions and other organic anions. It is particularly useful for alkylation of ethyl malonate, cyanoacetate and acetylacetate(lO) e.g. 

A quaternary ammonium hydroxide type of anion exchange resin, Amberlite IRA-400 (OH ), is an effective catalyst for the alkylation of ethyl malonate, ethyl cyanoacetate, or cyanoacetamide with various alkyl halides.— E Molar equivalents of 2-ethylcyanoacetamide and allyl bromide stirred 2 hrs. at room temp, with Amberlite IRA-400 (OH ) in ethanol-water 2-allyl-2-ethylcyano-acetamide. Y 82%. F. e. s. K. Shimo and S. Wakamatsu, J. Org. Ghem. 28, 504 (1963). 

In (alkene)iron complexes, either neutral or cationic, the electron density at the alkene is reduced. This allows for nucleophilic addition to such complexes. For example, malonates are added to give ethyl malonate derivatives after aqueous workup. Reaction of the intermediate anionic T -alkyl-Fp complexes with alkyl halides leads to migratory insertion of a carbonyl ligand and provides acylated products (Scheme 4-73). ... 

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