Malonic ester, carboxylic acids from decarboxylation

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

An important example of this reaction is the malonic ester synthesis, in which both Z groups are COOEt. The product can be hydrolyzed and decarboxylated (12-38) to give a carboxylic acid. An illustration is the preparation of 2-ethyl-pentanoic acid from malonic ester ... 

Decarboxylation may also be required in cases other than those involving derivatives of acetoacetic or malonic esters. The usefulness of this operation stems from the tremendous synthetic potential of carboxylic acids and their derivatives as substrates employed in C-C bond-forming reactions such as a-alkylation, Michael addition, the Diels-Alder reaction, etc. As the immediate result of these reactions, acid derivatives containing diverse structural backbones are formed. Hence the scope of these methods in synthetic practice depends heavily upon the opportunity to remove the carboxyl group after it has... 

For purposes of classification the 4-aminopyrazoles are considered to be 4-imino-2-pyrazolines and analogs of 2-pyrazolin-4-ones. These compounds are listed in Table XL. Such compounds can be prepared by direct cyclization using ethyl diazoacetate and ethyl cyanoacetate.92 This is the same as eq. 243, except that the malonic ester is replaced by ethyl cyanoacetate. Purines can be hydrolyzed to 4-imino-2-pyrazolines by using strong acid.1210 1846 By far the most frequently used preparation is reduction of appropriately substituted pyrazoles, such as 4-nitro,368,812,819,1015,1019,1049 4-nitroso1165 or 4-aryl-azo.671 974,995 The hydrolysis of the carbethoxy 4-imino-2-pyrazolines derived from ethyl cyanoacetate and ethyl diazoacetate forms 4-imino-2-pyrazolin-3-carboxylic acid which is readily decarboxylated to the parent compound.92... 

The bisacylation of methylene-active compounds mentioned above can be avoided by using acylimidazoles in place of acyl halides (acylimidazoles are obtained from the carboxylic acid and sulfinyldiimidazole) for example, reaction of the magnesium enolate of ethyl hydrogen malonate and an acylimid-azole, with concomitant decarboxylation, gives the corresponding / -oxo ester 430... 

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. 

Hydrolysis of the dialkylated jS-keto esters and malonates is not easy, and usually harsh conditions are required. Also decarboxylation occurs only at high temperature. On the other hand, hydrolysis and decarboxylation reactions of substituted allyl -keto esters and allyl malonates using Et3N-HC02H proceed at room temperature under neutral conditions. THP-protected allyl jS-keto ester 597 was converted to 598 at room temperature without deprotection of THP [213]. The free mono-carboxylic acid 600 was obtained smoothly from the disubstituted diallyl malonate 599 [214]. 

By far, the most often used nucleophiles are malonates, which can be deproto-nated by the aUcoxide formed in the reaction of allyl carbonates or by an added base such as NaH. This standard nucleophile has been applied in all types of aUylations, and many applications are also reported in this monograph. The nucleophihc species can also be generated by 1,4-addition, for example, of alkoxides, generated from carbonates, onto alkylidenemalonates both inter- and intramolecularly [92]. The substitution products can be subjected to a thermal desalkoxycarboxylation or, after hydrolysis, decarboxylation, giving rise to carboxylic esters or acids [93]. Therefore, in combination with this decomposition, malonates can also be used as surrogates for ester enolates [94], which generally cannot be used as nucleophiles in allylations. 

Recall from Section 18.4C that hydrolysis of an ester in aqueous sodium hydroxide (saponification) followed by acidification of the reaction mixture with aqueous HCl converts an ester to a carboxylic acid. Also recall from Section 17.9 that j8-ketoacids and j8-dicarboxylic adds (substituted malonic acids) readily undergo decarboxylation (lose CO2) when heated. Both the Claisen and Dieckmann condensations yield esters of j8-ketoacids. The following equations illustrate the results of a Claisen condensation followed by hydrolysis of the ester, acidification, and decarboxylation. 

When this reaction is carried out on the parent diethyl malonate, acetic acid results, and the process is of no practical synthetic utility. As with the synthesis of ketones starting from P-keto esters, this process is far more usefiil when combined with the alkylation reaction. One or two alkylations of malonic ester give substituted diesters that can be hydrolyzed and decarboxylated to give carboxylic acids (Fig. 19.62). Substituted acetic acids are potential sources of esters, acid halides, and any other compound that can be made from a carboxylic acid. 

Loss of CO2 occurs readily only from the neutral carboxylic acid. If the ester is hydrolyzed with base, acid must be added to protonate the resulting carboxylate salt in order for decarboxylation to occur. Decarboxylation of substituted propanedioic (malonic) acids follows the same mechanism. 

The growing living species 1 can be quenched cleanly with so-diomalonic ester to form the target hetero-telechelic polymers (17). The terminal (head) function X (arising from 1 ) may be acetate or imide that in turn leads to a carboxylic acid or an amine, respectively. Another terminal carries a malonate (from the malonate terminator), which can be converted to a carboxylic acid by hydrolysis/ decarboxylation. One of the advantages of the polymer synthesis via the base-stabilized species is the rather high operational temperature up to +60 °C. 

The conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. 

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