Malonate, diethyl, enol form

Other 1,3-dicarbonyl compounds also exist largely in the enol form. In some examples there is an additional stabilizing factor, intramolecular hydrogen bonding. Diethyl malonate (diethyl propane-dioate) has a symmetrical enol stabilized by conjugation. The enol form is also stabilized by a very diethyl maionate favourable intramolecular hydrogen bond in a six-membered ring. 

This allows interconversion of the two tautomerism in the enol form of diethyl malonate identical enol structures by proton transfer, that is, by tautomerism. 

Another unusual phosphate ester reported is that of the enol from malonic ester (17), formed by reaction of sodio diethyl malonate with diethyl phos-phorochloridate. 

The rate of ceric oxidation of malonic add and its diethyl ester in acetic acid/sul-furic acid solutions has recently been reported by Vaidya et al. (1987). They find no evidence for precursor complex formation in either system. The reactive Ce(IV) species appear to be Ce(S04)2 ( 2) and CefSO ) " k 2). The second-order rate parameter for the oxidation of malonic add is 40 times greater than that for the ester. Oxidation of the ester is proposed to occur through the enol form yielding a malonyl radical analogous to that identified by Amjad and McAuley. Foersterling et al. (1987) find that the second-order rate constant for malonic acid oxidation by Ce(lV) in sulfuric acid is in excellent agreement with the value of Vaidya et al. They observe that Ce(III) does inhibit the reaction in sulfuric add, which they attribute to a reversible Ce(IV) malonic acid rate-controlling step. 

Sometimes, the keto form is stabilized more due to resonance than the stabilization in the enol form due to intramolecular hydrogen bonding. This explains the larger percentage of the keto form as compared to the enol form of ethyl acetoacetate. The resonance effect is more pronounced in diethyl malonate, where the keto form is stabiHzed and hence only traces of enol are present (Scheme 3.48). 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

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... 

By analogy, the chemical Claisen condensation using the enolate anion from diethyl malonate in Figure 2.10 proceeds much more favourably than that using the enolate from ethyl acetate. The same acetoacetic acid product can be formed in the malonate condensation by hydrolysis of the acylated malonate intermediate and decarboxylation of the gem-diacid. 

An aqueous solution of sodium nitrite that is treated with HC1 contains nitrosyl cations 0=N . These can react with the enol E of the malonic acid diethyl ester (cf. Figure 12.9, bottom). First, a nitroso compound (F) is formed, which then undergoes acid-catalyzed isomerization to give the oxime A. Usually, the oxime is reduced by zinc, which is dissolved in acetic acid, to yield an amine that normally undergoes in situ acetylation in acetic acid. In this way the (acetamido)malonic acid diethyl ester B is obtained as the reduction/acetylation product, which can be employed, for example, in the synthesis of amino acids (Figure 13.39). 

One equivalent of NaOEt in EtOH deprotonates diethyl malonate completely to give the sodium enolate A (Figure 13.36). 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. 

Acidities of / -Dicarbonyl Compounds Table 22-1 compares the acidities of some carbonyl compounds with the acidities of alcohols and water. Notice the large increase in acidity for compounds with two carbonyl groups beta to each other. The a protons of the jS-dicarbonyl compounds are more acidic than the hydroxyl protons of water and alcohols. This enhanced acidity results from increased stability of the enolate ion. The negative charge is delocalized over two carbonyl groups rather than just one, as shown by the resonance forms for the enolate ion of diethyl malonate (also called malonic ester). 

Monoalkylation of malonic ester proceeds much more readily than alkylation of simple esters. The enolate is formed from diethyl malonate and alcoholic sodium ethoxide solution. Alkylation is effected in good yield by the use of primary bromides, diethyl sulfate, or ethyl p-toluene-sulfonate. In addition to the simpler primary alkylmalonates listed in Table 51, many higher members have been prepared. The list includes substituted malonates made from diethyl malonate and the following... 

The enolate derived from diethyl malonate reacts with a variety of electrophiles (not just alkyl halides) to form new carbon-... 

As we learned in Section 23.3, the a hydrogens between two carbonyl groups are especially acidic, and so they are more readily removed than other a H atoms. As a result, the p-dicarbonyl compound always becomes the enolate component of the aldol reaction. Figure 24.2 shows the steps for the crossed aldol reaction between diethyl malonate and benzaidehyde. In this type of crossed aldol reaction, the initial P-hydroxy carbonyl compound always loses water to form the highly conjugated product. 

Diethyl malonate on reaction with sodium metal gives rise to sodium malonic ester which on treatment with ethyl bromide results into the formation of diethyl ester of ethyl malonic acid with the elimination of hydrobromic acid. The resulting ester on further reaction with 2-bromopentane gives the desired eompound, i.e., diethyl ester of ethyl (1-methyl butyl) malonic acid which on subsequent treatment with thiourea forms thiopental with the elimination of two moles of ethanol. Ultimately, the enol-iorm of thiopental when reaeted with a ealeulated amoimt of sodium hydroxide, it gives thiopental sodium. 

Pelkey and Gribble showed that the enolate of diethyl malonate adds to 3-nitro-l-(phenylsulfonyl)indole (6a) at C-2 to form the trani-3-nitro-2-substituted indo-line 7 [7, 8]. The stereochemistry is confirmed on the basis of coupling constants. Other enolates also add to 3-nitroindoles 6 to form the tran -indolines 7 in moderate to good yields [8] (Table 1). 

ZZZ Construction of Pyrimidines. To make use of this reaction for pyrimidine synthesis, a diamino compound, usually urea, thiourea, or guanidine, can be reaeted with the diaeid malonic acid (HOOC-CH2-COOH) (Scheme 4.22) or preferably its diethyl ester. In its simplest form, the reaetion has been used to make barbiturie acid (4.21 see also Chapter 8, section 8.2). Salts can be made from barbiturie aeid with aqueous base this reaction ean be viewed as removing a C-H proton from C-5, or from the corresponding enol (found in stmeture 4.23). 

The TT-allylpalladium intermediate 130, formed by the intramolecular carbopalladalion of 129, could be trapped with the enolate of diethyl malonate, with BusSnPh, with piperidine, or with phenol to afford a variety of cycloocta-1,3-diene derivatives 131-134 (Scheme 43).[ ii... 

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