Malonic acid alkylation

CH OfiSj, H2C(S03H)2- a colourless, crystalline solid which readily absorbs water vapour decomposes on distillation. The potassium salt is prepared by heating methylene chloride with an aqueous solution of potassium sulphite under pressure at 150-I60" C. The free acid is obtained by decomposing the sparingly soluble barium salt with sulphuric acid. The aryl esters are very stable, but the alkyl esters decompose on heating to give ethers. Resembles malonic acid in some of its reactions. 

Converting the C 2 alkylated derivative to the corresponding malonic acid deriva tive by ester hydrolysis gives a compound susceptible to thermal decarboxylation Tern peratures of approximately 180°C are normally required... 

These compounds are prepared m a manner analogous to that of barbituric acid itself Diethyl malonate is alkylated twice then treated with urea... 

Substances that form carbanions, such as nitro compounds, hydrocyanic acid, malonic acid, or acetylacetone, react with vinyl ethers in the presence of water, replacing the alkyl group under mild conditions (245). 

Reaction with Alkyl Halide. The active methylene group of an Al-acylamino-malonic acid ester or Ai-acylamino cyanoacetic acid ester condenses readily with primary alkyl hahdes. 

A cyclic malonste derivative (acidic methylene) used in place of malonate in alkylations or reactions with aldehydes... 

The product of malonic ester alkylation has one acidic o hydrogen atom left, so the alkylation process can be repeated a second time to yield a dialkyl-ated malonic ester. 

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

MalONIC ACID, ETHYLHYDROXY, DIETHYL ESTER, BENZOATE, 45, 37 Mfsitaidehydf, 47, 1 Mesitylcne, condensation with dichloro methyl methyl ether, 47, 1 Methalljl chloride in alkylation of 2,4-pentanedione with potassium carbonate, 47, 87... 

CH3.(CH2)2.C(C02.C2H5XC0.N3) mw 198.23 N 21.20% OB to C02 -153.36% ypl oil, expl. Sol in eth and CC14. Prepn is by reacting the K salt, of the half (or mono) ethyl ester of propyl malonic acid with nitrous acid Refs 1) Beil, not found 2) T. Curtius W, Lehmann, Transformation of alkylated malonic acids into a-amino acids. III. Synthesis of cr-aminovaleric acid, propylmalonylazidic acid. . JPraktChem 125, 211-302 (1930) CA 24, 3215(1930)... 

Bohman and Allenmark resolved a series of sulphoxide derivatives of unsaturated malonic acids of the general structure 228. The classical method of resolution via formation of diastereoisomeric salts with cinchonine and quinine has also been used by Kapovits and coworkers " to resolve sulphoxides 229, 230, 231 and 232 which are precursors of chiral sulphuranes. Miko/ajczyk and his coworkers achieved optical resolution of sulphoxide 233 by utilizing the phosphonic acid moiety for salt formation with quinine. The racemic sulphinylacetic acid 234, which has a second centre of chirality on the a-carbon atom, was resolved into pure diastereoisomers by Holmberg. Racemic 2-hydroxy- and 4-hydroxyphenyl alkyl sulphoxides were separated via the diastereoisomeric 2- or 4-(tetra-0-acetyl-D-glucopyranosyloxy)phenyl alkyl sulphoxides 235. The optically active sulphoxides were recovered from the isolated diastereoisomers 235 by deacetylation with base and cleavage of the acetal. Racemic 1,3-dithian-l-oxide 236... 

C-Alkylation of malonic acid esters Malonic acid esters, alkyl halides... 

P-keto acid X = alkyl or aryl = ketone substituted malonic acid X=OH = substituted acetic acid... 

One of the most recent developments in the field of Ni-catalyzed reactions of alkyl halides with organozinc derivatives is a study of Terao et al.411 They reported the use of three additives in the couplings 1,3-butadiene, N,N-bis(penta-2,4-dienyl)benzylamine 308a, and 2,2-bis(penta-2,4-dienyl)malonic acid dimethyl ester 308b. Addition of tetraene 308b to the reaction mixtures significantly increased the product yields (Scheme 157). The remarkable effect of these additives was explained by the formation of the bis-7r-allylic complex 309 as the key intermediate (Scheme 158). 

Consider now what happens when the two carboxyl groups react to form a small ring, for example the anhydride. The angle between the carboxyl carbons must be reduced much further, perhaps to around 90°, in the product and in the transition state leading to it. Compared with malonic acid itself, this process has less far to go in the dimethyl compound because the two alkyl groups have already forced the carboxyls part of the way towards each other. The observed diminution in bond angle caused by the introduction of the two alkyl substituents thus specifically favours the formation of the small ring. 

Method C The malonic ester (15 mmol) is stirred with aqueous NaOH (50%, 30 ml) and TEBA-CI (3.54 g, 15 mmol). The alkylating agent (0.25 mmol) is then added and the mixture is stirred for 1 h at room temperature. The mixture is diluted with H,0 (75 ml) and extracted with Et,0 (3 x 25 ml). The dried (MgS04) extracts are evaporated to give the alkylated ester. Acidification of the aqueous phase with cone. HCI and extraction with Et,0 (3 x 25 ml) yields the alkylated malonic acid or r-butyl ester. 

Note that the primary effect of the alkyl substituents is steric, rather than electronic, with only branching on the carbon attached to the parent malonic acid effective in closing the jaws to strengthen the intramolecular hydrogen bond. Taking the "melting of one water molecule from the dianion to contribute... 

Yet hands-on experience with 1 and other related compounds showed that free malonic acid groups on fullerenes are rather unstable even under physiological conditions and readily decarboxylate into side products, some of which may show toxicity under certain circumstances (Beuerle et al., 2007). To avoid these potential side effects new polar derivatives of 1 like 3, 4 and 5 have been synthesized (Beuerle et al., 2005 Witte et al., 2007). In these trisadducts the polar endgroups are attached via alkyl spacers to the fullerene core and thus no unwanted decarboxylation... 

Bis-acceptor-substituted diazomethanes are most conveniently prepared by diazo group transfer to CH acidic compounds either with sulfonyl azides under basic conditions [949,950] or with l-alkyl-2-azidopyridinium salts [951] under neutral or acidic conditions [952-954]. Diazo group transfer with both types of reagents usually proceeds in high yield with malonic acid derivatives, 3-keto esters and amides, 1,3-diketones, or p, y-unsaturated carbonyl compounds [955,956]. Cyano-, sulfonyl, or nitrodiazomethanes, which can be unstable or sensitive to bases, can often only be prepared with 2-azidopyridinium salts, which accomplish diazo group transfer under neutral or slightly acidic reaction conditions. Other problematic substrates include amides of the type Z-CHj-CONHR and P-imino esters or the tautomeric 3-amino-2-propenoic esters, which upon diazo group transfer cyclize to 1,2,3-triazoles [957-959]. 

Alkylation of enolate is an important synthetic method.27 The alkylation of relatively acidic compounds such as /i-dikctoncs, /i-ketoesters, and esters of malonic acid can be carried out in alcohols as solvents using metal alkoxides as bases. The presence of two electron-withdrawing substituents facilitates formation of the enolate resulting from removal of a proton from the carbon situated between them. Alkylation then occurs by an Sn2 process. Some examples of alkylation reactions involving relatively acidic carbon acids are shown in Scheme 1.5. These reactions are all mechanistically similar in that a... 

Relatively acidic carbon acids such as malonic esters and jS-keto esters were the first class of carbanions for which reliable conditions for alkylation were developed. The reason being that these carbanions are formed using easily accessible alkoxide ions. The preparation of 2-substiuted /i-kcto esters (entries 1, 4, and 8) and 2-substituted derivatives of malonic ester (entries 2 and 7) by the methods illustrated in Scheme 1.5 are useful for the synthesis of ketones and carboxylic acids, since both /1-ketoacids and malonic acids undergo facile decarboxylation ... 

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