Malonic acid synthesis intramolecular

An intramolecular malonic ester synthesis can be used to form rings having three to six atoms, provided the appropriate dihalide is used as starting material. For example, cyclopentanecarbox-ylic acid can be prepared from diethyl malonate and 1,4-dibromobutane (BrCH2CH2CH2CH2Br) by the following sequence of reactions ... 

The malonic ester synthesis can also be used to prepare cyc/oalkane-carboxylic acids. For example, when 1,4-dibromobutane is treated with diethyl malonate in the presence of 2 equivalents of sodium ethoxide base, the second alkylation step occurs intramolecularly to yield a cyclic product. Hydrolysis and decarboxylation then give [Pg.919]

In the laboratory of D. Ma, the asymmetric synthesis of several metabotropic glutamate receptor antagonists derived from a-alkylated phenylglycines was undertaken. The preparation of (S)-1-aminoindan-1,5-dicarboxylic acid (AIDA) started with the Perkin reaction of 3-bromobenzaldehyde and malonic acid. The resulting ( )-cinnamic acid derivative was hydrogenated and the following intramolecular Friedel-Crafts acylation afforded the corresponding indanone, which was then converted to (S)-AIDA. 

An alternative analysis (74b) removes malonic acid from phenol—the logic being that ester formation will make the Friedel-Crafts part of the reaction intramolecular. In the event, this is a one step procedure with acid catalysis. The Warfarin synthesis uses weak base catalysis. ... 

Heterocycles are almost invariably formed by inter- and intramolecular Schiff base or lactam formation. We cite here the classical Knorr pyrrole synthesis (see Scheme 1.3.4) and Baeyer s barbituric acid synthesis, where the amide nitrogen atoms of urea are nucleophilic enough to add to malonic acid esters (Scheme 1.4.2). 

This racemic synthesis of actinophyllic acid (3) was accomplished in eight steps with an overall 15% yield from the readily available indole di-ferf-butyl malonate 9. The intramolecular oxidative coupling of ketone and malonate enolates and an aza-Cope-Mannich rearrangement for the construction of the unprecedented actinophyllic acid ring skeleton are the key transformations. 

This and other information show that nine Cg units from malonyl-coenzyme A and one C3 unit from propionyl-coenzyme A condense to form the linear polyketide intermediate shown below. These units are joined by acylation reactions that are the biosynthetic equivalent of the malonic ester synthesis we studied in Section 18.7. These reactions are also similar to the acylation steps we saw in fatty acid biosynthesis (Special Topic E in WileyPLUS). Once formed, the linear polyketide cyclizes by enzymatic reactions akin to intramolecular aldol additions and dehydrations (Section 19.6). These steps form the tetracyclic core of akiavinone. Phenolic hydroxyl groups in akiavinone arise by enolization of ketone carbonyl groups present after the aldol condensation steps. Several other transformations ultimately lead to daunomycin ... 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

We have been particularly enamored with the development of experiments involving carbon-carbon bond formation, especially as part of tandem reactions occurring in a single container (see the Diels-Alder reaction. Figure 1). One such reaction is the synthesis of simple esters of coumarin-3-carboxylic acids via a Knoevenagel condensation between malonic esters and various a-hydroxybenzaldehydes, followed by intramolecular nucleophilic acyl substitution. This conversion, catalyzed by piperidine, has been carried out under a variety of conditions, for example, at room temperature without solvent... 

In more recent applications, Takajo and Kambe have reported a new synthesis of perhydropyrimid-ines (90) by a double Mannich reaction (one step is intramolecular) using hydrobenzamide (87) and methyl cyanoacetate (89 equation 15). The reaction is general for other highly acidic methylene compounds including malononitrile, dimethyl malonate and nitroethane. In some cases, the intramolecular Mannich step is slow and side products arising from decomposition of the initial adduct are formed. This phenomenon is temperature dependent, indicating that intermediates in the reaction are formed reversibly. 

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