The Malonic Ester Synthesis

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. 

The malonic ester synthesis is conceptually analogous to the acetoacetic ester synthesis. The overall transformation is 

Diethyl malonate (also known as malonic ester) serves as a source of the synthon O 

The properties of diethyl malonate that make the malonic ester synthesis a useful procedure are the same as those responsible for the synthetic value of ethyl acetoacetate. The protons at C-2 of diethyl malonate are relatively acidic, and one is readily removed on treatment with sodium ethoxide. 

Show how you could prepare 3-methyl-2-butanone by double alkylation of ethyl acetoacetate. 

Recognize, too, that the reaction sequence is one that is characteristic of P-keto esters in general and not limited to just ethyl acetoacetate and its derivatives. Thus, 

The starting material in the preceding example is obtained by alkylation of ethyl acetoacetate with allyl bromide. 

The starting material in this reaction is the P-keto ester product formed by the Dieckmann cyclization seen in part (a) of Problem 20.14. The P-keto esters formed by Claisen condensations (Sections 20.5 and 20.7) and the acylation of ketones with esters (Section 20.8) can also be employed as reactants in analogous alkylation-saponification-decarboxylation sequences. 

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By the malonic ester synthesis (compare Section 111,165), for example ... 

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... 

In a typical example of the malonic ester synthesis 6 heptenoic acid has been pre pared from 5 bromo 1 pentene... 

By performing two successive alkylation steps the malonic ester synthesis can be applied to the synthesis of a a disubstituted derivatives of acetic acid... 

The malonic ester synthesis has been adapted to the preparation of cyclo alkanecarboxyhc acids from dihaloalkanes... 

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... 

The most widely used method for the laboratory synthesis of a ammo acids is a modification of the malonic ester synthesis (Section 21 7) The key reagent is diethyl acetamidomalonate a derivative of malonic ester that already has the critical nitrogen substituent m place at the a carbon atom The side chain is introduced by alkylating diethyl acetamidomalonate m the same way as diethyl malonate itself is alkylated... 

The synthetic importance of the malonic ester synthesis follows from the fact that the substituted malonic ester can easily be hydrolyzed, and subsequently decarboxylates to yield a substituted acetic acid 9. This route to substituted acetic acids is an important method in organic synthesis ... 

One of the oldest and best known carbonyl alkylation reactions is the malonic ester synthesis, a method for preparing a carboxylic add from an alkyl halide while lengthening the carbon chain by two atoms. 

The malonic ester synthesis can also be used to prepare cydoalkane-carboxvlic acids. For example, when 1,4-dibromobutanc is treated with diethyl malonate in the presence of 2 equivalents of sodium ethoxide base, the second alkylation step occurs intrcunotecidariy to yield a cyclic product. Hydrolysis and decarboxylation then give cvclopentanecarboxylic acid. Three-, four-, five-. 

Using the Malonic Ester Synthesis to Prepare a Carboxylic Acid... 

Strategy The malonic ester synthesis converts an alkyl halide into a carboxylic acid having two more carbons. Thus, a seven-carbon acid chain must be derived from the five-carbon alkyl halide 1-bromopentane. 

Monoalkylated and dialkylated acetic acids can be prepared by the malonic ester synthesis, but trialkylated acetic acids (R3CCO2H) can t be prepared. Explain. 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

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. 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

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. ... 

When an aromatic ring is treated with diethyl oxomalonate, (Et00C)2C=0, the product is an arylmalonic acid derivative, ArC(OH)(COOEt)2, which can be converted to an arylmalonic acid, ArCH(COOEt)2. This is therefore a way of applying the malonic ester synthesis (10-104) to an aryl group (see also 13-12). Of course, the opposite mechanism applies here The aryl species is the nucleophile. 

Malonic esters have two ester groups, each of which may react as in the acetoacetic ester synthesis due to their similar structure (see the preceding section). The malonic ester synthesis provides a method for preparing a substituted acetic acid. Figure 15-14 shows the structure of one type of malonic ester. Figure 15-15 outlines the basic malonic ester synthesis. May repeat in that figure refers to the reaction with a second molecule of RX (or R X). 

In most cases, the product of the malonic ester synthesis isn t the final product you re looking for. Commonly, the next step after the reaction in Figure 15-15 is hydrolysis and decarboxylation. Figure 15-16 shows this step. 

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