Diethyl malonate: acylation alkylation

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. 

I c + ester (diethyl malonate) is alkylated or acylated on the carbon that is a to both... 

IV-Alkyl-substituted phthalimides 9 were easily transformed into mono-, di- or trisubslituted pyrazoles 10 via a one-pot addition/decyclization/cyclocondensation sequence <02JCS(P1)207>. 5-Silylpyrazoles can be prepared from condensation of silylalkynones with hydrazines <02T4975>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted pyrazolin-5-ones <02T3639>. 

Alkylation or acylation of malonic ester (diethyl malonate), followed by hydrolysis and decarboxylation, to give substituted acetic acids, (p. 1079)... 

Hell-Volhard-Zelinsky (HVZ) reaction Reaction of a carboxylic acid with Br2 and PBr3 to give an a-bromo acyl bromide, often hydrolyzed to an a-bromo acid. (p. 1051) malonic ester synthesis Alkylation or acylation of malonic ester (diethyl malonate), followed by hydrolysis and decarboxylation, to give substituted acetic acids, (p. 1076)... 

Transesterification of an ester is catalyzed by acid or base and has been used in the preparation of simple alkyl, benzyl, and t-butyl esters. Thus the mono (13) and benzyl ester (14) of malonic acid are prepared from diethyl malonate by alkoxide catalysed transesterification [49]. Benzyl cyanoacetic ester may be similarly prepared. t-Butyl acetate in the presence of either an A -acyl or a free amino acid and perchloric acid catalyst forms the t-butyl esters of the amino acid by analogous transesterification [50]. 

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. 

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 antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

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