Malonic acid, substituted decarboxylation

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 ... 

The protons attached to C-2 of malonic acid are not duectly involved in the process and so may be replaced by other substituents without much effect on the ease of decarboxylation. Analogs of malonic acid substituted at C-2 undergo efficient thermal decarboxylation. 

Although heating benzene-1,2-diamine with malonic acid in aqueous hydrochloric acid affords the parent dione 26 (R = H) in 62% yield,277 the method cannot be extended to substituted malonic acids because decarboxylation intervenes however, the reaction of benzene-1,2-diamines with diethyl malonate and its derivatives constitutes a general procedure for the synthesis of l,5-benzodiazepine-2,4-diones 26 selected examples are given.278... 

One of the most valuable methods of preparing carboxylic acids makes use of ethyl malonate (malonic ester), CH2(COOC2H5)>, and is called the malonic ester synthesis. This synthesis depends upon (a) the high acidity of the a-hydrogens of malonic ester, and (b) the extreme ease with which malonic acid and substituted malonic acids undergo decarboxylation. (As we shall sec, this combination of properties is more than a happy accident, and can be traced to a single underlying cause.)... 

This is a modified malonic aster synthesis made possible by (1) the high acidity of the a-hydrogens of malonic ester (2) the extreme ease with which malonic acid and substituted malonic acids undergo decarboxylation, ... 

Reactions. Heating an aqueous solution of malonic acid above 70°C results in its decomposition to acetic acid and carbon dioxide. Malonic acid is a useful tool for synthesizing a-unsaturated carboxyUc acids because of its abiUty to undergo decarboxylation and condensation with aldehydes or ketones at the methylene group. Cinnamic acids are formed from the reaction of malonic acid and benzaldehyde derivatives (1). If aUphatic aldehydes are used acryhc acids result (2). Similarly this facile decarboxylation combined with the condensation with an activated double bond yields a-substituted acetic acid derivatives. For example, 4-thiazohdine acetic acids (2) are readily prepared from 2,5-dihydro-l,3-thiazoles (3). A further feature of malonic acid is that it does not form an anhydride when heated with phosphorous pentoxide [1314-56-3] but rather carbon suboxide [504-64-3] [0=C=C=0], a toxic gas that reacts with water to reform malonic acid. 

With active methylene compounds, the carbanion substitutes for the hydroxyl group of aHyl alcohol (17,20). Reaction of aHyl alcohol with acetylacetone at 85°C for 3 h yields 70% monoaHyl compound and 26% diaHyl compound. Malonic acid ester in which the hydrogen atom of its active methylene is substituted by A/-acetyl, undergoes the same substitution reaction with aHyl alcohol and subsequendy yields a-amino acid by decarboxylation (21). 

After hydrolysis, fluonnated derivatives of alanine are obtained in both cases because decarboxylation of the substituted malonic acid occurs (equation 109)... 

Decarboxylation is not a general reaction of carboxylic acids. Rather, it is unique to compounds that have a second carbonyl group two atoms away from the —COoH. That is, only substituted malonic acids and /3-keto acids undergo loss of CC>2 on heating. The decarboxylation reaction occurs by a cyclic mechanism and involves initial formation of an enol, thereby accounting for the need to have a second carbonyl group appropriately positioned. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

By hydrolysis of substituted malonic esters with 50 per cent, potassium hydroxide, followed by decarboxylation of the resulting malonic acid by heating above the m.p. or, better, by rendering the aqueous solution of the potassium salt of the dibasic acid strongly acid and refluxing the mixture, for example ... 

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 ... 

Step 3 Hydrolysis of the substituted malonic ester gives the malonic acid, which undergoes decarboxylation (loss of COi) to form a substituted acetic acid. 

However, 2,4,6-trisubstituted pyrylium salts with certain active methyl and methylene compounds undergo ring fission and subsequent cyclization to benzenoid products. 2,4,6-Triphenylpyrylium ion (261 Z = O) in this way forms 2,4,6-triphenylnitrobenzene (299) with nitromethane and the substituted benzoic acid (300) with malonic acid, the latter reaction involving a decarboxylation. In reactions of this type, 1,3-oxazinium salts react with active hydrogen compounds to give pyridines (Scheme 25). 

Decarboxylation of racemic substituted malonic acids in the presence of small amounts of Cu(I)Cl and cinchonidine gives the corresponding esters in up to 31% ee (Scheme 128) (308). 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

When it is required to prepare an a-bromo acid from a carboxylic acid which is not particularly readily available commercially, but which can be synthesised by the malonic acid route (Section 5.11.6, p. 680), advantage may be taken of the ease of bromination in the a-position of the intermediate alkylmalonic acid. The substituted bromomalonic acid undergoes ready decarboxylation on heating to yield the a-bromo acid (e.g. 2-bromo-3-methylpentanoic acid, Expt 5.166). 

The hydrolysis product is a substituted derivative of malonic acid and undergoes decarboxylation on being heated. The product of this decarboxylation is aspartic acid (in its protonated form under conditions of acid hydrolysis). 

If the original reaction is carried out under more vigorous conditions with malonic acid 67, the decarboxylation occurs during the reaction to give the unsaturated acid in one step. This is a simple way to make11 substituted cinnamic acids 68. 

Fig. 13.56. Mechanism of the Knoevenagel condensations in Figure 13.55. The C,H( )-acidic reaction partneris malonicacidin the form of the malonic acid enolate D (malonic acid "monoanion"). The decarboxylation proceeds as a fragmentation of the pyridinium-substituted malonic acid carboxylate F to furnish the ,/Tunsaturated ester (G) and pyridine. This fragmentation resembles the decomposition of the sodium salts H of ,/Tdibrominated carboxylic acids to yield the a,/Tunsaturated bromides I and sodium bromide.

Diesters (malonates and substituted derivatives) combine three useful features in conjugate addition reactions they form stable enolate anions that undergo clean conjugate addition if required, one of the ester groups can be removed by hydrolysis and decarboxylation and, finally, the remaining acid or ester is ideal for conversion into other functional groups,... 

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