Malonic acid derivatives saponification

Synthesis (Mayer and Testa, 1997 Cleij et al., 1999 Kleemann et al., 1999) a) Treatment of ethyl 4-isobutylphenylacetate and diethyl carbonate with sodium ethoxide gives diethyl 4-isobutylphenylmalonate, which is methylated using methyl iodide and sodium ethoxide. Saponification followed by decarboxylation of the resulting malonic acid derivative affords ibuprofen. 

On their side, Yin and Linker [216] made use of a 2-C-branched hexopyranoside, the synthesis of which was achieved by addition of dimethyl malonate to tri-O-benzyl-D-glucal (TUPAC name 3,4,6-tri-0-benzyl-l,5-anhydro-2-deoxy-D-araZtino-hex-l-enitol, Scheme 45) [217], Thus, saponification of the 2-C-[bis(meth-oxycarbonyl)]methyl derivative 184 to the corresponding malonic acid 185 was followed by heating in refluxing toluene. This led to decarboxylation and lactoniza-tion giving 186. The method was optimized and applied to the synthesis of pentoses and disaccharides. 

A half-ester of malonic acid such as 111, prepared in 70% yield by partial saponification of the di-ester, is oxidized by lead tetraacetate in benzene at 50° to the a-acetoxy derivative V, which loses carbon dioxide at 200° to give the a-acetoxy ester VI. Yields are in the range 35-80%. That the half-esters are oxidized much... 

Malonic ester synthesis (Section 20.11) Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl malonate, followed by saponification and decarboxylation. 

Ester enolates undergo alkylation reactions. When ethyl 3-methylpentanoate (110) reacts with sodium ethoxide in ethanol and then with bromoethane, the product is 111. Alkylation of malonate derivatives leads to an interesting sequence of reactions that are useful in synthesis. The reaction of diethyl malonate (90) and NaOEt in ethanol, followed by reaction with benzyl bromide, gives 112. In a second reaction, 112 reacts with NaOEt in ethanol and then with iodomethane to give 113. Saponification of 113 (see Chapter 20, Section 20.2) gives the dicarboxylic acid, 114, and heating leads to decarboxylation (Section 22.8) and formation of acid 115. This overall sequence converted malonic acid via the diester to a substituted carboxylic acid, and it is known as the malonic ester synthesis. 

The coupling of 3-tert-butyl [1 - " C]malonate (393) with the /3-amino acid derivative 395 to give amide 396 was developed as an alternative route to the 1,4 addition of 395 to the corresponding [l- " C]acrylate 394, which might have failed due to radiation-induced polymerization. Subsequent treatment with 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadi-phosphetane-2,4-disulfide (Lawesson s reagent) followed by Raney nickel-mediated desulfurization of the thioamide function formed converted 396 into the target /3-amino acid ester 397. Intramolecular ester condensation upon treatment of 397 with sodium methoxide and concluding saponification and decarboxylation of the f-butyl ester function afforded the trisubstituted 4-[2- " C]piperidone derivative 398. 

The second classical reaction mentioned above is the acetoacetic ester synthesis. this reaction, an ester of acetoacetic acid (3-oxobutanoic acid) such as ethyl acetoacetate is treated with base under thermodynamic control conditions and alkylated, as with the malonic ester synthesis. Reaction with sodium ethoxide in ethanol (since an ethyl ester is being used) generated the enolate and quenching with benzyl bromide led to 84. Saponification and decarboxylation (as above) gave a substituted ketone (85). Although the malonic ester synthesis and the acetoacetic ester synthesis are fundamentally similar, the different substrates lead to formation of either a highly substituted acid or a ketone. The reaction is not restricted to acetoacetate derivatives, and any p-keto-ester can be used (ethyl 3-oxopentanoate for example). ... 

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