Alkyl halide malonic ester synthesis with

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... 

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 ... 

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... 

The first stage of the malonic ester synthesis is the alkylation of diethyl malonate with an alkyl halide. 

In both the acetoacetic ester synthesis and the malonic ester synthesis, it is possible to add two different alkyl groups to the a-carbon in sequential steps. First the enolate ion is generated by reaction with sodium ethoxide and alkylated. Then the enolate ion of the alkylated product is generated by reaction with a second equivalent of sodium ethoxide, and that anion is alkylated with another alkyl halide. An example is provided by the following equation ... 

The malonic ester synthesis converts a primary or secondary alkyl halide into a carboxylic acid with two more carbons (a substituted acetic acid). Identify the component that originates from malonic ester (the acid component). The rest of the molecule comes from the alkyl halide, which should be primary or methyl. 

Malonic ester synthesis (Section 22.7) a multistep sequence for converting an alkyl halide into a carboxylic acid with the addition of two carbon atoms to the chain. 

With Malonic Ester.— The malonic ester synthesis (p. 274) is also applicable in this case, the sodium malonic ester reacting with aryl halides Just as it does with alkyl halides ... 

The a>bromo carboxylic acid required for preparation of the a>alkoxy acid is often obtained by a malonic ester synthesis the malonic ester is treated with an alkyl halide, the alkylmalonic acid obtained by hydrolysis of the product is brominated by elemental bromine at a low temperature, and the resulting a>bromo dicarboxylic acid is decarboxylated.54 This has led to a particularly important synthesis of aldehydes which utilizes the decarbonylation of -hydroxy or a-alkoxy acids for conversion of an alkyl halide RX into the aldehyde RCHO containing one more carbon atom ... 

A malonic ester synthesis forms a carboyxiic acid with two more carbon atoms than the alkyl halide. 

In the first part of the malonic ester synthesis, the a-carbon of the diester is alkylated (Section 19.8). A proton is easily removed from the a-carbon because it is flanked by two ester groups (pK =13). The resulting a-carbanion reacts with an alkyl halide, forming an a-substituted malonic ester. Because alkylation is an Sn2 reaction, it works best with methyl halides and primary alkyl halides (Section 10.2). Heating the a-substituted malonic ester in an acidic aqueous solution hydrolyzes it to an a-substituted malonic acid, which, upon further heating, loses CO2, forming a carboxylic acid with two more carbons than the alkyl halide. 

One-pot malonic ester synthesis. A separate hydrolysis step can be avoided by use of the dilithium salt of ethyl malonate, prepared by reaction of the ester with 2 eq. of hthium isopropylcyclohexylamide (4, 306-309) in THF at -78°. HMPT and the alkyl halide are then added and the reaction mixture is allowed to come to room temperature for 2 hr. Decarboxylation is then effected by overnight reflux. 

There are two classical reaction sequences in organic chemistry that rely on enolate alkylation. One is the malonic ester synthesis.61 jjj synthetic example taken from the Clive and Hisaindee synthesis of brevioxime,62 diethyl malonate was treated with a base such as sodium ethoxide, under thermodynamic control conditions. The resulting enolate anion is treated with the indicated alkyl halide to give the alkylated product 81 (in 72% yield).Saponification of 81 to the dicarboxylic acid (82, in 99% yield), was followed by decarboxylation (sec. 2.9.D) and formation of the substituted acid 83, in 94% yield. ... 

Notice the similarity to the malonic ester synthesis. Ethyl acetoacetate is the starting material. It is first deprotonated, then treated with an alkyl halide, and then treated with aqueous acid at elevated temperature. Ethyl acetoacetate can also be dialkylated to produce ketones as follows ... 

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. 

The carbonyl carbon and the a-carbon of the carboxylic acid being synthesized come from malonic ester, and the rest of the carboxylic acid comes from the alkyl halide used in the second step of the synthesis. Thus, a malonic ester synthesis forms a carboxylic acid with two more carbons than the alkyl halide. 

The synthesis of barbiturates is relatively simple and relies on reactions that are now familiar enolate alkylations and nucleophilic acyl substitutions. Starting with diethyl malonate, or malonic ester, alkylation of the corresponding enolate ion with simple alkyl halides provides a wealth of different disubstituted malonic esters. Reaction with urea, (H2N)2C=0, then gives the product barbiturates by a twofold nucleophilic acyl substitution reaction of the ester groups with the -NH2 groups of urea (Figure 22.7). Amobarbi-tal (Amytal), pentobarbital (Nembutal), and secobarbital (Seconal) are typical examples. 

The malonate ester synthesis resembles the acetoacetate ester synthesis. It is used to prepare alkylated derivatives of acetic acid and other carboxylic acids rather than derivatives of acetone or other ketones prepared by the acetoacetic ester synthesis. The a-hydrogen atom of diethyl malonate is sufficiently acidic to be deprotonated by ethoxide ion. Subsequent alkylation with a primary or secondary alkyl halide yields an alkylated malonate ester. 

Malonic ester synthesis Diethyl malonate can be converted into a substituted carboxylic acid upon treatment with ethoxide, followed by an alkyl halide, followed by aqueous acid. 

A malonic ester synthesis begins with the deprotonation of diethyl malonate (using ethoxide as a base). The resulting resonance-stabilized conjugate base is then treated with the alkyl halide above, tliereby installing the alkyl group. Subsequent hydrolysis and decarboxylation give the product, as shown ... 

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