Alkylation of diethyl malonate

Section 21 8 Alkylation of diethyl malonate followed by reaction with urea gives derivatives of barbituric acid called barbiturates, which are useful sleep promoting drugs... 

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

Alkylation, of diethyl malonate with 3-chlorocyclopentene, 32, 52 of diethyl methylmalonate with M-decyl bromide, 38, 49 of diethyl phthalimidomalonate,... 

For the alkylation of diethyl malonate, Na metal (ca. 40 mmol) was dissolved in EtOH (15 mL) (freshly distilled from Mg), and diethyl malonate (6.07 mL, 40 mmol) and BocNH(CH2)4C1, prepared as above, were added dropwise. The mixture was refluxed for 8 h, the solvents were concentrated under reduced pressure, and an aqueous workup was carried out. Removal of the organic solvent under reduced pressure gave an oil, which contained significant amounts of diethyl malonate and impurities. The product was purified by flash chromatography [silica gel (5 x 16 cm), CHCI /]. The fractions were analyzed by TLC (CHC13). This procedure gave diester 20 as a pale clear oil yield 1.63 g (32%) TLC (CHClj) R, 0.90 TLC (CHCl3/MeOH/AcOH 85 10 5) Rf 0.79. 

Tethered diacid 18 was as easily prepared as 8 was (Scheme 6).10 Knoevenagel adduct 20 was deprotonated with NaH and then alkylated with dibromide 9 to give 21 in 59% yield. Alkylation of diethyl malonate with 21 gave 22 in 85% yield, and ozonolysis of 22 and acidic alcoholysis delivered 18 in 88% yield. 

Alkylation of diethyl malonate with benzyl bromide is the first step in the preparation of 3-phenylpropanoic acid. 

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

Alkylation of diethyl malonate is followed by saponification and decarboxylation to give a carboxylic 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. 

Another important example leads to the preparation of diethyl phenylmalonate. This compound cannot be made by alkylation of diethyl malonate as aryl halides do not undergo nucleophilic substitution (Chapter 23). 

Previously cyclopropane-1,1-dicarboxylic acid had been prepared2-4 by hydrolysis of the corresponding diester. The preparation of 1,1-dicarboalkoxycyclopropanes by a conventional double alkylation of diethyl malonate with 1,2-dibromoethane was severely complicated by the recovery of unreacted diethylmalonate. This required a rather difficult distillation to separate starting material and product. In fact, many commercially offered lots of cyclopropane diester contain extensive amounts of diethyl malonate. Furthermore, preparation of the diacid required a separate and relatively slow saponification of the diester.5... 

Wang, Y, R. Deng, M. Aiqiao, and Y. Jiang, Solid-Liquid Phase Transfer Catalytic Synthesis XII Microwave Irradiated Alkylation of Diethyl Malonate, Synth. Commun., 25, 1761 (1995). 

Cyclopropane-1,1-dicarboxylic acid. This compound can be obtained in high yield by double alkylation of diethyl malonate with 1,2-dibromoethane under phase-transfer conditions. Malonic acid cannot be alkylated in this way. 

The synthesis of [ C]-labeled esters using a C-alkylation of diethyl malonate under microwave-enhanced solid-liquid phase transfer catalysis (PTC) conditions and a subsequent microwave-enhanced decarboalkoxylation (Krapcho reaction) [167] indicates that an alternative approach to the preparation of [ C]-labeled fatty acids/esters [168] with less harsh conditions may be possible. 

Alkylations. Many bases which are weaker than t-BuOK are capable of essentially quantitative conversion of active methylene compounds into the corresponding enolates or other anions. However, the alkylation of diethyl malonate with a bicyclic secondary tosylate (eq 1) and the alkylation of ethyl n-butylaceto-acetate with -BuI (eq 2f provide examples of cases where the use of f-BuOK in f-BuOH is very effective. In the latter reaction, cleavage of the product via a retro-Claisen reaction is minimized with the sterically hindered base and yields obtained are higher than when Sodium Ethoxide or EtOK in EtOH, Sodium in diox-ane or toluene, or Sodium Hydride in toluene are used for the enolate formation. 

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