Malonate esters alkylation

Tabushi and Fujiyoshi have prepared alkylated cyclam derivatives for the purpose of suspending these systems from a polymer backbone. They have utilized a malonic ester alkylation reaction followed by cyclization and reduction to accomplish this end. ... 

The product of malonic ester alkylation has one acidic o hydrogen atom left, so the alkylation process can be repeated a second time to yield a dialkyl-ated malonic ester. 

Alkylation on a stabilized carbanion using a C-labeled alkyl iodide (e.g., malonic ester alkylation, see Gee and Langstrom 1991). 

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. 

We knew, however, that we could do Sn2 chemistry at this position because we had converted diol 48 to dinitrile 57. Therefore, we capitalized on this conversion, elaborating dinitrile 57 kingianin J by a series of steiicaUy undemanding reactions. Thus, reduction to the dialdehyde and then to the diol 62 was followed by mesylation, malonic ester alkylation, dealkylative decarboxylation, and hydrolysis (Scheme 24). 

In contrary to the host molecules mentioned before, the molecular skeleton of 27 consists exclusively of carbon atoms. The cyclization is achieved by sixfold malonic ester alkylation. Expe-... 

There are many syntheses of acids where a carbon-carbon bond is formed such as carbonation of Grignard reagents, malonic ester alkylation, and Reformatsky reactions. Some are covered in Chapter 7, and you can review others in your introductory text. 

The alkyl halides are also of great importance in synthetic operations (e.g.) using Grigard reagents (p. 280). acetoacetic ester (p. 269) and malonic ester (p. 2- S)-... 

Ethane tetracarboxylic ethyl ester can be regarded as composed of two malonic ester residues, each acting as a mono-alkyl substituent to the other. The two remaining hydrogen atoms therefore still retain acidic properties, and consequently the ester gives with sodium ethoxide a di-sodium derivative. 

The sodiocompound may be written [CHtCOOCjHjij] Na, and it must always be home in mind that the anion is mesomeric. The system reacts smoothly with an alkyl halide to give a C-substituted malonic ester, evidently through the carbanion (I) ... 

The mono-alkyl malonic ester may be hydrolysed by alcoholic potassium... 

The monosubstituted malonic ester still possesses an activated hydrogen atom in its CH group it can be converted into a sodio derivative (the anion is likewise mesomeric) and this caused to react with an alkyl halide to give a C-disubstituted malonic ester. The procedure may accordingly be employed for the synthesis of dialkyImalonic and dialkylacetic acids ... 

Less basic malonic ester anions may be employed for the twofold alkylation of dibro-... 

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

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... 

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

All lation of Garbanions. Concentrated N a OH—hen syl triethyl amm onium chloride is the base/catalyst system normally used for this type of process (20). Classes of compounds alkylated in this way include phenylacetonitriles, ben2ylketones, simple aUphatic ketones, certain aldehydes, aryl sulfones, P-ketosulfones, P-ketoesters, malonic esters and nitriles, phenylacetic esters, indene, and fluorene (see Alkylation). 

Diethyl aminomalonate is a useful intermediate, lending itself to N-acylation the N-acyl derivatives may be alkylated by procedures as established for syntheses via malonic ester. 

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

---