Alkylation of malonic ester

Mildly basic liquiddiquid conditions with a stoichiometric amount of catalyst prevent hydrolysis during alkylation [101] and, more recently, it has been established that solid-liquid or microwave promoted reactions of dry materials are more effective for monoalkylation [102-106] of the esters and also permits dialkylation without hydrolysis. Soliddiquid phase-transfer catalytic conditions using potassium f-butoxide have been used successfully for the C-alkylation of diethyl acetamido-malonate and provides a convenient route to a-amino acids [105, 107] use of potassium hydroxide results in the trans-esterification of the malonate, resulting from hydrolysis followed by O-alkylation. The rate of C-alkylation of malonic esters under soliddiquid phase-transfer catalytic conditions may be enhanced by the addition of 18-crown-6 to the system. The overall rate is greater than the sum of the individual rates observed for the ammonium salt or the crown ether [108]. 

Diethyl A2-cyclopentenylmalonate has been prepared by the alkylation of malonic ester with 3-chlorocyclopentene.4 6 6 7 8... 

Allen, J. C., J. I. G. Cadogen, B. W. Harris, and D. H. Hey Synthetic Aspects of Free Radical Addition. Part I. Radical-alkylation of Malonic Ester and Related Compounds. J. chem. Soc. 1962, 4468. 

Figure 4.24 Alkylation of malonic ester with iodoethane in the presence of TBAHS as a phase-transfer catalyst.

C-Alkylation of the sodio derivative is accomplished by a technique similar to the alkylation of malonic ester. Primary halogen compounds, quaternary ammonium salts,and an alkene oxide have been used as alkylating agents. Alkylation by secondary halides has been less successful. Hydrolysis of the substituted esters to acetylated amino acids is described for leucine (64%) and phenylalanine (83%). Hydrolysis with deacylation has been used to prepare histidine (45%) and phenylalanine (67%). Glutamic acid (75%) is obtained from substituted acylaminomalonates prepared by the Michael condensation of methyl acrylate and the acylated amino esters. ... 

Alkylation of malonic ester with an equimolar ponion of ethylene bromide or trimethylene bromide produces ring closure to give diethyl esters of 1,1-cyclopropane- and 1,1-cyclobutane-dicarboxylic acids, respectively. Five- and six-membered rings also have been formed in this manner. ... 

Alkylation of malonic ester by one-half equivalent of an a,-polymethylene bromide gives an a,a,o), o)-tetracarboxylic ester which is hydrolyzed and decarboxylated to an a, fxi-dicarboxylic acid having four more carbon atoms than the dibromide. Good descriptions include those for 1,12-... 

Alkylation of malonic esters by halo esters leads to tricarboxylic esters. The halogen atom of the alkylating halo ester has been in the alpha, beta, and delta positions. 

An interesting preparation of 2-cyclohexenylmalonates involves alkylation of malonic esters with 1,2 dibromocyclohexane. Dehydrohalogenation accompanies alkylation to give the olefinic malonates in 55-65% yields. " "... 

Fair yields of halomalonic esters are obtained by alkylation of malonic esters with ethylene bromide, " o-chlorobenzyl halides, and 1-bromo-4-chl orobutan e. 

It will be observed that throughout this discussion of carbanions no mention has been made of the intermediate formation of an enol or of enolization. It now seems extremely probable that in reactions such as aldol formation (p. 176), the Claisen condensation (p. 185), acetoacetic or malonic ester reactions (pp. 182, 201), and the halogenation of ketones (pp. 206, 207) the carbanion is the actual reaction intermediate and that the formation of an enol simply represents an alternative non-essential course of reaction for the carbanion. In the alkylation of malonic ester, for example, a carbanion (XXV and XXVI) may be formed by reaction of the neutral ester with ethoxide ion. 

Alkylation of malonic ester. This alkylation can be done with a solution of sodium ethoxide in ethanol and requires one mole of reagent per alkyl group introduced. An example is Perkin s synthesis of diethyl cyclobutane-1,1-dicarboxylate by alkylation with triraethylene chlorobromide. When trimethylene dibromide was... 

Alkylation of malonate esters. Special procedures can be applied to form either... 

Alkylation of malonic esters and other active methylene compounds is useful in synthesis because the alkylated products can be subjected to hydrolysis and decarboxylation (1.10). Direct decarboxylation under neutral conditions with an alkali metal salt (e.g. lithium chloride) in a dipolar aprotic solvent (e.g. DMF) is a popular alternative method. ... 

Sodium alcohol C-Alkylation of malonic esters with tosylates... 

Some amino acid analogues such as a-[met/zy/- C]methylphenylalanine and a-[ C-methyl]methyltyrosine have been synthesized by alkylations of malonic esters (Gee and Langstrom 1991) as well as a-[met/zy/- C]methyltryptophan (Bourne et al. 1991 Pulak et al. 1996). a-aminoisobutyric acid, labeled in either the carboxylic position (Dunzendorfer et al. 1981) or 2-position (Prenant et al. 1995a), or the 3-position (Oberdorfer et al. 1993 Schmall et al. 1996) and P-aminoisobutyric acid (Alauddin et al. 1997) are other examples. Other... 

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. 

An alternative starting reaction to the afore mentioned one is the malonic ester synthesis. This comprises the alkylation of malonic ester with dimethylpropargyl chloride 727, readily available from acetone, acetylene, HCl, and the subsequent reactions, similar to the ones above [197] (Reaction scheme 70). 

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