Malonic ester synthesis decarboxylation

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... 

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 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 ... 

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-. 

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 ... 

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 ... 

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. 

Fig. 13.37. Malonic ester synthesis of alkylated acetic acids II hydrolysis and decarboxylation of the all lated malonic ester.

Controlled, stepwise dialkylation may be performed as exemplified in equation 73, which shows a typical malonic ester synthesis including hydrolysis and decarboxylation to give an a,a-dialkylated acid. Acetoacetic ester synthesis and cyanoacetic ester syntheses give ketones (CH3COCHRR ) and nitriles (RR CHCN), respectively. 

The Sorensen method of amino acid synthesis uses a modification of the malonic ester synthesis. In this modification an N-protected malonic ester is alkylated, hydrolyzed and decarboxylated to give an a-amino acid, as shown in equation 77. 

Although the acetoacetic ester synthesis and the malonic ester synthesis are used to prepare ketones and carboxylic acids, the same alkylation, without the hydrolysis and decarboxylation steps, can be employed to prepare substituted /3-ketoesters and /3-diesters. In fact, any compound with two anion stabilizing groups on the same carbon can be deprotonated and then alkylated by the same general procedure. Several examples are shown in the following equations. The first example shows the alkylation of a /3-ketoester. Close examination shows the similarity of the starting material to ethyl acetoacetate. Although sodium hydride is used as a base in this example, sodium ethoxide could also be employed. 

A third amino acid synthesis begins with diethyl a-bromomalonate. First the Br is replaced by a protected amino group using the Gabriel synthesis (see Section 10.6). Then the side chain of the amino acid is added by an alkylation reaction that resembles the malonic ester synthesis (see Section 20.4). Hydrolysis of the ester and amide bonds followed by decarboxylation of the diacid produces the amino acid. An example that shows the use of this method to prepare aspartic acid is shown in the following sequence ... 

Both acidic H atoms of a malonic ester can be replaced by alkyl groups. These dialky-lated malonic esters are formed by successively removing the acidic protons with sodium alkoxide and treatment of the enolates with an alkylating reagent. The subsequent hydrolysis and decarboxylation of these dialkylated malonic esters affords a,a-dialkylated acetic acids as another class of products accessible via the malonic ester synthesis. 

The malonic ester synthesis makes substituted derivatives of acetic acid. Malonic ester (diethyl malonate) is alkylated or acylated on the more acidic carbon that is a to both carbonyl groups, and the resulting derivative is hydrolyzed and allowed to decarboxylate. 

The product of a malonic ester synthesis is a substituted acetic acid, with the substituent being the group used to alkylate malonic ester. In effect, the second carboxyl group is temporary, allowing the ester to be easily deprotonated and alkylated. Hydrolysis and decarboxylation remove the temporary carboxyl group, leaving the substituted acetic acid. 

The acetoacetic ester synthesis is similar to the malonic ester synthesis, but the final products are ketones specifically, substituted derivatives of acetone. In the acetoacetic ester synthesis, substituents are added to the enolate ion of ethyl acetoacetate (acetoacetic ester), followed by hydrolysis and decarboxylation to produce an alkylated derivative of acetone. 

The /3-keto acid decarboxylates by the same mechanism as the alkylmalonic acid in the malonic ester synthesis. A six-membered cyclic transition state splits out carbon dioxide to give the enol form of the substituted acetone. This decarboxylation usually takes place spontaneously at the temperature of the hydrolysis. 

The product of this Michael addition may be treated like any other substituted malonic ester in the malonic ester synthesis. Hydrolysis and decarboxylation lead to a S-keto acid. It is not easy to imagine other ways to synthesize this interesting keto acid. 

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. 

The chiral monodeuterated ethanols 28 and 33 were obtained by Simon s method [33] and their tosylates, 29 and 34, reacted with malonic ester anion to afford 30 and 35. The expected inversion of configuration in the malonic ester synthesis was confirmed by decarboxylating the derived acids 31 and 36 to (35)- and (3R)-[3-2H,]butanoic acids, respectively, the chiroptical properties of which were already known [34]. The chirally deuterated CoA esters 32 and 37, prepared from 31 and 36, were rearranged on methylmalonyl-CoA mutase from P. shermanii and, after hydrolysis, the methylsuccinate products were isolated. In a parallel experiment the... 

Three methods for the conversion of 3-chlorocarbonyl-1,2,5-thiadiazole (81) to ketones were investigated by Gill. The Lund procedure for the malonic ester synthesis of ketones proved quite successful for the preparation of 3-acetyl-1,2,5-thiadiazole (83). Condensation of 81 with diethyl ethoxymagnesiomalonate provides the ketodiester (82) which undergoes acid hydrolysis and decarboxylation to 83 in 90 % yield. The same reaction sequence employing the sodio derivative of malonic ester was much less efficient. 

Decarboxylation of Di- and Poly-basic Acids (Malonic Ester Synthesis)... 

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