Malonic ester synthesis of carboxylic acids

One of the best methods of amino acid synthesis is a combination of the Gabriel synthesis of amines (Section 19-20) with the malonic ester synthesis of carboxylic acids (Section 22-16). The conventional malonic ester synthesis involves alkylation of diethyl malonate, followed by hydrolysis and decarboxylation to give an alkylated acetic acid. 

One of the most valuable methods of preparing ketones makes use of ethyl acetoacetate acetoacetic ester), CH3COCH2COOC2H5, and is called the acetoacetic ester synthesis of ketones. This synthesis closely parallels the malonic ester synthesis of carboxylic acids. 

Malonic Ester Synthesis of Carboxylic Acids (Section 23-2)... 

The thermal decarboxylation of malonic acid derivatives is the last step m a multistep synthesis of carboxylic acids known as the malonic ester synthesis This synthetic method will be described m Section 21 7... 

Malonic acid ester synthesis is a classic but still one of the most important C—C bond-forming reactions, because it is widely applicable to various types of compounds and the reaction can be performed under mild conditions without special care to remove the trace amount of water and oxygen contained in the solvent. This reaction is especially useful in the synthesis of carboxylic acids. One important class of carboxylic acids is arylpropionates because optically active ones are known to have anti-inflammatory activity and other interesting physiological... 

Section 19.18 The Malonic Ester Synthesis Synthesis of Carboxylic Acids... 

What alkyl bromide(s) should be used in the malonic ester synthesis of each of the following carboxylic acids ... 

It will be recalled that dibasic acids which contain two carboxyl groups in combination with the same carbon atom, readily pass into monobasic acids, with loss of carbon dioxide, when heated. This fact renders the malonic ester synthesis of great value in the preparation of monobasic acids. When the acids which have been just used as illustrations are heated, they decompose according to the equations,—... 

Malonic ester synthesis synthesis of carboxylic acids (Section 18.18). The steps in the reaction are shown on page 885. 

Similar to the use of ethyl acetoacetate as a synthetic equivalent to acetone, malonic ester is a popular choice as a synthetic equivalent to ethyl acetate in the synthesis of carboxylic acids (Scheme 1.5, entries 2 and 3). 

The previous question shows the first two steps in a common synthesis of carboxylic acids starting from a p-keto diester (also called a malonic ester). 

The malonic ester synthesis is a method for the preparation of carboxylic acids and is represented by the general equation... 

Among the methods for preparing carboxylic acids carboxylation of a Grignard reagent and preparation and hydrolysis of a nitrile convert RBr to RCO2H The malonic ester synthesis converts RBr to RCH2CO2H... 

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... 

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

As noted previously, the overall effect of the malonic ester synthesis is to convert an alkyl halide into a carboxylic acid while lengthening the carbon chain by two atoms. 

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

Malonic ester synthesis (Section 22.7) The synthesis of a carboxylic acid by alkylation of an alkyl halide, followed by-hydrolysis 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 ... 

Compounds 137 and 138 are thus synthons for carboxylic acids this is another indirect method for the a alkylation of a carboxylic acid, representing an alternative to the malonic ester synthesis (10-104) and to 10-106 and 10-109. The method can be adapted to the preparation of optically active carboxylic acids by the use of a chiral reagent. Note that, unlike 132, 137 can be alkylated even if R is alkyl. However, the C=N bond of 137 and 138 cannot be effectively reduced, so that aldehyde synthesis is not feasible here. ... 

After the C—C bond is formed, the carboxyl group used for the activation of the position should be removed. This will be the decarboxylahon of malonic acid-type compounds, which is the same type of the famous synthehc reaction, i.e., malonic ester synthesis (Fig. 5). 

Carboxylic acids can be alkylated in the a position by conversion of their salts to dianions [which actually have the enolate structures RCH=C(0 )21497] by treatment with a strong base such as lithium diisopropylamide.1498 The use of Li as the counterion is important, because it increases the solubility of the dianionic salt. The reaction has been applied1499 to primary alkyl, allylic, and benzylic halides, and to carboxylic acids of the form RCHjCOOH and RR"CHCOOH.1454 This method, which is an example of the alkylation of a dianion at its more nucleophilic position (see p. 368), is an alternative to the malonic ester synthesis (0-94) as a means of preparing carboxylic acids and has the advantage that acids of the form RR R"CCOOH can also be prepared. In a related reaction, methylated aromatic acids can be alkylated at the methyl group by a similar procedure.1500... 

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