Diethyl malonate, enolate anion

The reaction of diethyl malonate (90) with sodium hydride generates enolate anion 91 as the conjugate base, and hydrogen gas is the conjugate acid. It has the three resonance contributors shown in the illustration, although 91A has the highest concentration of electron density, and 91 will react as a carbanion nucleophile. There is one extra resonance form in the malonate enolate anion relative to a simple ester due to the second carbonyl unit, and it means that 91 is more stable than the enolate derived from a monoester. In part, this accounts for the enhanced acidity and easier formation of the enolate anion using a weaker base. Once formed, 91 is a carbon nucleophile and it will react with both aldehydes and ketones, as well as with other esters. 

Rather than pyridine or ammonia, bases such as sodium hydride or sodium ethoxide can be used to generate a malonate enolate anion. Such enolates are easier to control, from a synthetic viewpoint, and allow a wider range of reactions. For this reason, they are collected into this section. An example is the reaction of the sodium enolate of diethyl 2-methylmalonate with the bromine moiety in phthalimide derivative 4.42. This displacement reaction was followed by removal of the phthalimidoyl group, hydrolysis of the esters and decarboxylation to give 2-methyl-6-aminohexanoic acid (4.4J),23 Phthalimide 4.42 was prepared by reaction of 1,4-dibromobutane with potassium phthalimide.23 The length of the carbon chain in the... 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

Stable enolates such as diethyl malonate anions react with allyl sulfones (or acetates) in the presence of nickel complexes to give a mixture of the a- and /-product83. The regioselectivity is generally poor in the nickel-catalyzed reaction, but the molybdenum-catalyzed reaction is selective for alkylation at the more substituted allylic site, thereby creating a quaternary carbon center84. 

Diethyl malonate can be converted into its enolate anion, which may then be used to participate in an Sn2 reaction with an alkyl halide (see Section 10.7). Ester hydrolysis and mild heating leads to production... 

The mechanistic steps can be deduced by inspection of structures and conditions. Enolate anion formation from diethyl malonate under basic conditions is indicated, and that this must attack the epoxide in an Sn2 reaction is implicated by the addition of the malonate moiety and disappearance of the epoxide. The subsequent ring formation follows logically from the addition anion, and is analogous to base hydrolysis of an ester. Ester hydrolysis followed by decarboxylation of the P-keto acid is then implicated by the acidic conditions and structural relationships. 

Diethyl malonate has been proposed for use as a proton source in these cyclization reactions [124], It is not a sufficiently strong acid to protonate the radical-anion rapidly. However it irreversibly protonates the enol intermediate generated after carbon-caibon bond formation. In one case, control of stereochemistry in favour of the traHS-sunstituted five membered ring 39 was achieved by the addition of cerium(Ill) ions [124],... 

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. 

The extra ester group is not normally added to the preformed ketone as ethyl acetoacetate 41 is available and the diester is available diethyl malonate 59. If it is necessary to make the 1,3-dicarbonyl compound, this can be done by methods described in chapters 19 and 20. The carboxylic acid 56 can be disconnected at the branchpoint to an alkyl halide and the synthon 58 that could be realised as the anion of diethyl malonate 59 or the lithium enolate of ethyl acetate. 

The malonic ester synthesis is similar to the acetoacetic ester synthesis. It begins with deprotonation of diethyl malonate (pKa = 11) to produce an enolate anion that is the synthetic equivalent of the enolate anion derived from acetic acid ... 

Nitro-l-(phenylsulfonyl)-l//-indole 829 undergoes nucleophilic addition reactions with enolates of diethyl malonate and cyclohexanone, lithium dimethylcuprate (Scheme 159), and indole anion (Equation 209) to afford the corresponding 3-substituted 2-nitroindoles in low to high yields <1997TL5603, 1999TL7615>. 

Most barbiturates are made from diethyl malonate. The methylene protons between the two carbonyl groups are acidic and will give a highly stabilized enolate anion. 

The enolate anion of diethyl malonate can be alkylated by an 8, 2 displacement of bromide to give diethyl n-butylmalonate ... 

The second step involves an elimination of the tertiary amine (ElcB mechanism) and a coniac. addition of the enolate anion of diethyl malonate to the resulting enone. This device prevent v reactive enone from combining with itself by releasing it only in the presence of an excess c -.ii nucleophile. 

There are two classical reaction sequences in organic chemistry that rely on enolate alkylation. One is the malonic ester synthesis.61 jjj synthetic example taken from the Clive and Hisaindee synthesis of brevioxime,62 diethyl malonate was treated with a base such as sodium ethoxide, under thermodynamic control conditions. The resulting enolate anion is treated with the indicated alkyl halide to give the alkylated product 81 (in 72% yield).Saponification of 81 to the dicarboxylic acid (82, in 99% yield), was followed by decarboxylation (sec. 2.9.D) and formation of the substituted acid 83, in 94% yield. ... 

The 1,4- (conjugate) addition SBe pf carbon nucleophile to an a, 3-unsaturated carbonyl system is well known, usually reversible, and usually referred to as Michael addition. 83 Enolates and carbanions are common partners in Michael additions.The anion of diethyl malonate (534) reacts with MVK, for... 

Under ordinary conditions, aryl or alkenyl halides do not react with enolate anions, although reaction can occur with aryl halides bearing strongly electronegative substituents in the ortho and para positions. 2,4-Dinitrochlorobenzene, for example, with ethyl cyanoacetate gives ethyl (2,4-dinitrophenyl)cyanoacetate (90%) by an addition-elimination pathway. Unactivated aryl halides may react with enolates under more vigorous conditions, particularly sodium amide in liquid ammonia. Under these conditions, the reaction of bromobenzene with diethyl-malonate, for example, takes place by an elimination-addition sequence in which benzyne is an intermediate (1.8). 

Alkylations. Many bases which are weaker than t-BuOK are capable of essentially quantitative conversion of active methylene compounds into the corresponding enolates or other anions. However, the alkylation of diethyl malonate with a bicyclic secondary tosylate (eq 1) and the alkylation of ethyl n-butylaceto-acetate with -BuI (eq 2f provide examples of cases where the use of f-BuOK in f-BuOH is very effective. In the latter reaction, cleavage of the product via a retro-Claisen reaction is minimized with the sterically hindered base and yields obtained are higher than when Sodium Ethoxide or EtOK in EtOH, Sodium in diox-ane or toluene, or Sodium Hydride in toluene are used for the enolate formation. 

Phenylenediamine similarly produces the symmetrical compound (55). Suitable enolate anions, e.g. acetylacetone or diethyl malonate, give rise to... 

In the late nineteenth century, Michael found that the enolate anion (46) derived from diethyl malonate reacts with ethyl acrylate at the P-carbon (as shown in the illustration) to give an enolate anion, 47, as the product. Remember from Chapter 22 (Section 22.7.4) that the a-proton of a 1,3-dicarbonyl compound such as diethyl malonate is rather acidic (pK of about 11), and even a relatively weak base will deprotonate to form the enolate anion. Michael addition of 46 with ethyl acrylate will give enolate anion 47, and aqueous acid workup leads to the isolated product, 48. Attack at the -carbon is possible because that carbon is less hindered than the acyl carbon, so reaction at the C=C unit is somewhat faster than attack at the acyl carbon. Michael addition occurs with relatively stable carbanion nucleophiles, such as malonate derivative 46 and some other common nucleophiles. Other conjugated carbonyl derivatives react similarly. 

The enolate anion of diethyl malonate is a nucleophile and reacts by an pathway with methyl and primary haloalkanes, a-haloketones, and a-haloesters. In the following example, the anion of diethyl malonate is alkylated with l-bromo-3-methoxypropane. 

Nucleophilic addition of enolate anions to o , 8-unsaturated carbonyl compounds was first reported in 1887 by the American chemist Arthur Michael. Following are two examples of Michael reactions. In the first example, the nucleophile adding to the conjugated system is the enolate anion of diethyl malonate. In the second example, the nucleophile is the enolate anion of ethyl acetoacetate. 

Diethyl malonate = 13.3) is converted completely to its enolate anion using one equivalent of sodium ethoxide. 

A variation in this approach used the lithium enolate of diethyl malonate in a reaction with the allylic acetate moiety in 1.187. Malonate anion reacted with an intermediate 7c-allyl palladium species [formed from the allylic acetate moiety in 1.187, catalyzed hy the palladium (0) species] to give ethyl 6-(N-Boc amino)-7-(4-benzyloxypheny l)-2-carboethoxyhept-4-enoate, 1.188. ... 

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