Malonic acid, enolate, reaction with

It can be assumed that the small amount of piperidine in the reaction mixture is completely protonated by malonic acid because piperidine is more basic than pyridine. Hence, only the less basic pyridine is available for the formation of the malonic acid enolate D from free malonic acid and for the formation of the malonic acid dianion from the malonic acid mono-carboxylate C. The pKa value of malonic acid with regard to its C,H acidity should be close to the pKa value of malonic acid diethyl ester (p= 13.3). The pKa value of malonic acid monocarboxylate C with regard to its C,H acidity should be larger by at least a factor 10. Hence, the concentration of the malonic acid enolate D in the reaction mixture must be by many orders of magnitude higher than that of any malonic acid dianion. Due to the advantages associated with this enormous concentration D could be the actual nucleophile in Knoevenagel condensations. 

The synthesis of barbiturate 36 (see Scheme 4.7) was performed next. The sodium enolate of diethyl malonate was reacted with 43, providing 44, which was converted to 2,2-disubstituted malonate 45 by reaction with allyl bromide. Reaction of 45 with urea in the presence of t-BuOK as base afforded the barbiturate 46, which was submitted to oxidative one-carbon demolition by the action of KMn04 to give carboxylic acid 47. Compound 47 was esterified with ethanol to give the target 36, but unfortunately in modest yields. 

Subsequently the isobufadienolide (51) was obtained directly from the enol ether-aldehyde (45) by condensation with malonic acid. This reaction, which requires the presence of a secondary amine and for which the following mechanism has been proposed, has been applied to the A -analogue of (45) in both the 5a- and A -series, and the resulting A -b -isobufadienolides have been further converted into their 14,15-epoxides. 

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). ... 

Alkyl halides are converted to carboxylic acids by reaction with the enolate derived from diethyl malonate, followed by saponification and decarboxylation. 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

Ethyl 3-oxobutanoate, commonly called ethyl acetoacetate or ace tome tic ester, is much like malonic ester in that its ct hydrogens are flanked by two carbonyl groups. It is therefore readily converted into its enolate ion, which can be alkylated by reaction with an alkyl halide. A second alkylation can also be carried out if desired, since acetoacetic ester has two acidic a hydrogens. 

The decarboxylation reaction usually proceeds from the dissociated form of a carboxyl group. As a result, the primary reaction intermediate is more or less a carbanion-like species. In one case, the carbanion is stabilized by the adjacent carbonyl group to form an enolate intermediate as seen in the case of decarboxylation of malonic acid and tropic acid derivatives. In the other case, the anion is stabilized by the aid of the thiazolium ring of TPP. This is the case of transketolases. The formation of carbanion equivalents is essentially important in the synthetic chemistry no matter what methods one takes, i.e., enzymatic or ordinary chemical. They undergo C—C bond-forming reactions with carbonyl compounds as well as a number of reactions with electrophiles, such as protonation, Michael-type addition, substitution with pyrophosphate and halides and so on. In this context,... 

Both CO2 activation and enolate formation are combined in the preparation of malonic acid derivatives. The reaction of CO2 with methacrylic esters or methacry-lonitrile and under visible light irradiation produced the corresponding aluminum porphyrin malonate complex. When diethylzinc was added to this system, Al(TPP)Et could be regenerated by axial ligand exchange reactions, and the malonic acid derivatives were formed catalytically with respect to the aluminum porphyrins in a one-pot photosynthetic route (Scheme 1). The first step in this... 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

There are also reactions in which electrophilic radicals react with relatively nucleophilic alkenes. These reactions are represented by a group of procedures in which a radical intermediate is formed by oxidation of the enol of a readily enolized compound. This reaction was initially developed for /i-kctoacids.227 The method has been extended to /1-diketones, malonic acids, and cyanoacetic acid.228... 

With diketene, intermediates of type (III) were isolated and subsequently cyclized under basic conditions following step (b). In the case of 3-oxo-carboxylic acid esters or 3-acyl Meldrum s acids, cyclization step (b) immediately follows reaction step (a), if a slight excess of amine is employed (85TH1 87TH1). Note that conversion of (III) to (V) involves the (IH)-enol (Table I cf. 75BSF2731). The relatively low yield in the case of malonic acid ester, as well as the failure of the reaction with the non-enolizable diphenyl phosphinylacetic ester and cyanoacetate, points to the participation of an enol structure of (III). 

Oxidation of arylmethyl ketoximes by phenyliodoso diacetate in glacial acetic acid was second order overall, first order each in substrate and oxidant.145 Iodine allowed the oxidative dimerization of glycine ester enolates with low to moderate diastereoselec-tivity that is consistent with kinetic control.146 Although malonic acid is not oxidized by iodate under acidic conditions, oxidation proceeds in the presence of catalytic ruthenium(III). A mechanism is put forward to account for the observed orders of reaction.147 The rate of periodate oxidation of m-toluidine in acetone-water increases with ionic strength.148... 

Attempts to react enol(ate)s of esters with aliphatic aldehydes are doomed as the aldehyde will simply condense with itself. If the ester is replaced by a malonate 60, there is so much enol(ate) from the (5-dicarbonyl compound that the reaction is good. This style of aldol reaction is often called a Knoevenagel reaction10 and needs only a buffered mixture of amine and carboxylic acid. The enol reacts with the aldehyde 61 in the usual way and enolisation of the product 62 usually means that dehydration occurs under the conditions of the reaction. 

Fig. 12.11. Mechanism of the tert-butylation of malonic acid diethyl ester. From the point of view of tert-butyl chloride it is an SN1 reaction with the malonic ester enol (B) acting as the nucleophile.

One equivalent of NaOEt in EtOH deprotonates malonic acid diethyl ester completely to give the sodium enolate A (Figure 10.33). This enolate is monoalkylated upon addition of an alkylating reagent such as BuBr, and a substituted malonic ester C is formed. During the alkylation reaction, the substituted malonic ester C reacts to a certain extent with some of the enolate A, resulting in the butylated enolate B and unsubstituted neutral malonic ester. It is for this reason that the reaction mixture contains two nucleophiles— the original enolate A and the butylated enolate B. The alkylation of A with butyl bromide is much faster than that of B, since A is less sterically hindered than B. The main product is therefore the product of monoalkylation. Distillation can be used to separate the main product from small amounts of the product of dialkylation. 

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