Diethyl malonate applications

Diethyl malonate has uses other than m the synthesis of carboxylic acids One particu larly valuable application lies m the preparation of barbituric acid by nucleophilic acyl substitution with urea... 

This route was not applicable for the preparation of 2- and 4-nitrophenyl derivatives of 252 (R = 2-N02, 4-NO,), as the amidines obtained from 2-and 4-nitroanilines were not soluble in diethyl malonate (49JOC277). 

Deprotonation of methylene groups containing two electron-withdrawing alkoxycarbonyl groups with an appropriate base easily converts them into their corresponding enolate anions. These enolate anions are able to attack carbon electrophiles to form new C —C bonds. One of the important applications of this reaction is to construct small carbocyclic rings, in particular cyclobutanes. For example, intermolecular condensation of l,3-dibromo-2,2-dimethylpropane (1) and the dipotassium salt of diethyl malonate (2) gives diethyl 3,3-dimethylcyclobutane-l,l-dicarboxylate (3).18... 

A spectacular application allowed the synthesis of fenestranes by a three-step sequential action of cobalt nanoparticles and a palladium catalyst [131]. The cascade reaction started with a PKR of enyne 105, accomplished by the cobalt catalyst giving 106, followed by the formation of allyl-7r3 palladium complex 107 which reacted with a nucleophile derived from diethyl malonate, to give enyne 108. The final step was a second PKR that gave 109 in good yield. They used cobalt nanoparticles as with Co/charcoal the third step did not take place, apparently due to damage in this catalyst after the allylation step (Scheme 31). 

The carbanions are involved in a number of displacement reactions. The synthetic applications of diethyl malonate (2.22) and acetoacetic ester (ethyl acetoacetate) (2.23) are due to the formation of the corresponding carbanions (Scheme 2.20) (also see Chapter 3). 

The Michael addition reaction in water suspension medium is also applicable to carbon-carbon bond formation. A mixture of 70a, methyl acetylacetate (76), 72 and water was stirred for 5 h at room temperature, then the reaction product was filtered and dried to give the addition product 77 in 98% yield [34]. Although a similar solvent-free Michael addition reaction of 70a with diethyl malonate at 60 °C has been reported, organic solvent was still necessary to isolate the product from the reaction mixture [36]. 

Another example demonstrating the wide application of this procedure is the reaction of 2-bromo-3-oxo-steroids with an excess of diethyl malonate in the presence of 1,1,3,3-tetramethyl-guanidine to form cyclopropanedicarboxylate 5 as well as the cyanocyclopropanemonocar-boxylate 6. The product 6 is formed via nucleophilic displacement of bromine at C2 by a tetramethylguanide moiety. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Thermal condensation of pyrazoles with substituted diethyl malonates or triethyl methane-tricarboxylate provides an easy way to 2-substituted derivatives (300). Yields range between 30% and 60% and combined with an easy availability of the malonates this approach could be attractive (Equation (40)) <89S629>. An alternative approach starting from 3,5-dihydroxy pyrazoles and 1,3-dicarbonyl compounds is applicable for a wide range of substituents (Equation (41)) <82JOC295>. 

High-dilution conditions for the intramolecular application of the malonic ester synthesis to the preparation of macrocyclic diesters have been reported yields between 9 and 50% are obtained. Dialklacyl phosphonates provide a new method for the acetylation of enolates including the sodium enolate of diethyl malonate. An alternative method for the generation of diester enolates involves the reductive a-deacetoxylation of an a-acetoxy diester (Scheme 30). The... 

Among the other notable applications are addition of the radical from diethyl malonate to alkynes and alkenes (eq 6), addition of a 1,3-dioxalane-derived radical to formaldehyde (eq 7), and addition of s-alcohols to alkenes (eq 8). Novel radical mediated alkylations of a dipeptide makes use of DTBP as an initator (eqs 9 and 10). ... 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

Substantial applications in synthesis have been established for (jR)-(+)-trans-styryl p-tolyl sulphoxide (63), which gives (64) on Michael reaction with diethyl malonate on the basis that the most stable conformation of the a-sulphinyl carbanion has the lone pair on carbon trans to sulphinyl oxygen in a polar solvent. The addition of a proton to (64) gives as the major (51%)... 

Reductive cyclization of o-nitrophenylacetic acids is a very general method of oxindole synthesis (see Section 3.06.2.1.1 for the application of this method to indoles in general). The main problem is efficient construction of the desired phenylacetic acid. One method involves base-catalyzed condensation of substituted nitrotoluenes with diethyl oxalate followed by oxidation of the 3-arylpyruvate (equation 200) (63CB253). Nucleophilic substitution of o-nitrophenyl trifluoromethanesulfonate esters, which are readily prepared from phenols, by dimethyl malonate provides another route (equation 201) (79TL2857). 

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