Monosubstituted malonic esters

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 ... 

The synthetic utility of alkylation of enolates is utilized in the syntheses of malonic ester (3.3) and acetoacetic ester (3.2). For example, carbanion generated from malonic ester undergoes an Sn2 reaction with alkyl halide to yield alkyl-substituted malonic ester. The monosubstituted malonic ester still has an active hydrogen atom. The second alkyl group (same or different) can be introduced in a similar manner. Acid-catalyzed hydrolysis or base-catalyzed hydrolysis of mono- or disubstituted derivative of malonic ester followed by acidification gives the corresponding mono- or disubstituted malonic acid, which on decarboxylation yields the corresponding monocarboxylic acid (Scheme 3.3). 

A further example is the zinc stearate-catalyzed addition of malonic ester derivatives to acetylene. The reaction also takes place with monosubstituted malonic esters [46]. C-vinyl malonic esters have found an application, for example, in the synthesis of barbiturates. 

Derivatives of malonic acid convert phenols into coumarins malonyl chloride at ambient temperature and with titanium(IV) chloride leads to a 4-hydroxycou-marin [2283] whereas pyridinols condense with monosubstituted malonic esters... 

Two general methods can be used, the choice depending on whether the parent ester is a dialkyl- or a monoalkylacetate. Many functional variations can be tolerated, including monosubstituted malonates, and y- and (5-lactones (5). 

Carrie and co-workers studied the cycloaddition of oxime esters derived from methyl cyanoacetate and malonate esters 82 (Scheme 8.20) with diazomethane and some monosubstituted derivatives. Thermally labile 1,2,3-triazolines 83 were obtained when tosyloxy- and benzoyloxyimines were used (141), while methyl acetoxyimino-cyanoacetate (82, X = CN, Y = C02Me, = Ac) gave products derived from both a 1,2,3- and a 1,2,4-triazoline, depending on the stmcture of the diazo compound (142). Not unexpectedly, diazomethane reacted with the corresponding imino-malononitrile (82, X = Y = CN) system at the nitrile function rather than at the C=N bond (143). 

Chiral malonate esters have been used successfully in asymmetric cyclopropanations, as shown by the example in Scheme 6.39, part of a total synthesis of steroids such as estrone [143,144]. The key step in this sequence is an intramolecular Sn2 alkylation of the monosubstituted malonate. The rationale for the diastereoselec-tivity is shown in the illustrated transition structure. Note that the enolate has C2 symmetry, so it doesn t matter which face of the enolate is considered. The illustrated conformation has the ester residues syn to the enolate oxygens to relieve Al>3 strain, with the enolate oxygens and the carbinol methines eclipsed. The allyl halide moiety is oriented away from the dimethylphenyl substituent, exposing the alkene Re face to the enolate. The crude selectivity is about 90% as determined by conversion to the dimethyl ester and comparison of optical rotations [143], but a single diastereomer may be isolated in 67% yield by preparative HPLC [144], This reaction deserves special note because it was conducted on a reasonably large scale ... 

Oxidatively generated electrophilic malonyl radicals react regiospecifically with thiophene to form (2-thienyl)malonic ester <88H(27)2627>. Treatment of thiophene with cerium(IV) sulfate and an excess of dimethyl malonate in methanol at room temperature yields 2-thienylmalonic ester in 85% yield. In this case, the initially formed cr-radical is oxidized by the cerium(IV) sulfate. 2-Methylthiophene similarly gives the 5-malonyl-substituted product. Benzo[i]thiophene leads to the 2-malonyl-benzo[Z)]thiophene in 41% yield. Monosubstituted malonates could also be used in this reaction. Thiophene and 2-acetylthiophene react with triethyl methanetricarboxylate in the presence of Mn(III) to form the corresponding thienylmethane tricarboxylic esters. Yields are about 55% <91S567>. 

The malonic ester synthesis is useful for the preparation of monosubstituted and disubstituted acetic acids of the following types. 

As with the acetoacetic ester synthesis, we have already encountered all the important chemistry of the malonic ester synthesis, although not in this particular pattern. Let us illustrate this synthesis by choosing 5-methoxypentanoic acid as a target molecule. The two carbons shown in color are provided by diethyl malonate. The remaining three carbons and the methoxy group represent the —R group of a monosubstituted acetic acid. 

No reaction of soft carbon nucleophiles takes place with propargylic acet-ates[37], but soft carbon nucleophiles, such as / -keto esters and malonates, react with propargylic carbonates under neutral conditions using dppe as a ligand. The carbon nucleophile attacks the central carbon of the cr-allenylpal-ladium complex 81 to form the rr-allylpalladium complex 82, which reacts further with the carbon nucleophile to give the alkene 83. Thus two molecules of the a-monosubstituted /3-keto ester 84, which has one active proton, are... 

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