Enolate anions, malonate

The alkylation reactions of enolate anions of both ketones and esters have been extensively utilized in synthesis. Both very stable enolates, such as those derived from (i-ketoesters, / -diketones, and malonate esters, as well as less stable enolates of monofunctional ketones, esters, nitriles, etc., are reactive. Many aspects of the relationships between reactivity, stereochemistry, and mechanism have been clarified. A starting point for the discussion of these reactions is the structure of the enolates. Because of the delocalized nature of enolates, an electrophile can attack either at oxygen or at carbon. 

The reactive species is the corresponding enolate-anion 4 of malonic ester 1. The anion can be obtained by deprotonation with a base it is stabilized by resonance. The alkylation step with an alkyl halide 2 proceeds by a Sn2 reaction ... 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

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. 

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 conversion of acetyl-CoA into malonyl-CoA increases the acidity of the a-hydrogens, and thus provides a better nucleophile for the Claisen condensation. In the biosynthetic sequence, no acy-lated malonic acid derivatives are produced, and no label from [14C]bicarbonate is incorporated, so the carboxyl group introduced into malonyl-CoA is simultaneously lost by a decarboxylation reaction during the Claisen condensation (Figure 3.1). Accordingly, the carboxylation step helps to activate the a-carbon and facilitate Claisen condensation, and the carboxyl is immediately removed on completion of this task. An alternative rationalization is that decarboxylation of the malonyl ester is used to generate the acetyl enolate anion without any requirement for a strong base. 

Michael reactions of this sort work best when they follow a catalytic cycle. Malonate anion 28 adds to an enone to give the enolate anion 30 that collects a proton from malonate 27 and forms another molecule of the anion 28 for the next cycle. 

In chapter 21 we mentioned nitro compounds as promoters of conjugate addition they also stabilise anions strongly but do not usually act as electrophiles so that self-condensation is not found with nitro compounds. The nitro group is more than twice as good as a carbonyl group at stabilising an enolate anion. Nitromethane (p/ a 10) 1 has a lower pKa than malonates 4 (pKa 13). In fact it dissolves in aqueous NaOH as the enolate anion 3 formed in a way 2 that looks like enolate anion formation. 

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 ... 

The reaction under these conditions is sometimes called the Knoevenagel reaction after its nine-leenth century inventor, and presumably uses the enolate anion of the monocarboxylate of the malonic acid. Though this enolate is dianion, its extensive delocalization and the intramolecular hydrogen bond make it really quite stable. 

Diesters (malonates and substituted derivatives) combine three useful features in conjugate addition reactions they form stable enolate anions that undergo clean conjugate addition if required, one of the ester groups can be removed by hydrolysis and decarboxylation and, finally, the remaining acid or ester is ideal for conversion into other functional groups,... 

In this sequence, malonic ester was used as a synthetic equivalent of the enolate anion derived from acetic acid. The presence of an additional carboxyl substituent served as an auxiliary tool to stabilize the enolate species. This approach was extended to the alkylation of enolates of more complicated structure, but here it was mandatory to create first the required )8-dicarbonyl system by supplementing the initial structure with an additional carbonyl substituent. This auxiliary operation, while being generally viable, noticeably... 

In many of these cases, both the enolate anion and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters. The (E) enolates gave the syn pair of enantiomers (p. 166), while (Z) enolates gave the anti pair. Nitro compounds add to conjugated ketones in the presence of a dipeptide and a piperazine. ° Malonate derivatives also add to conjugated ketones, and keto esters add to conjugated esters.Addition of chiral additives to the reaction, such as metal-salen complexes,proline derivatives, or (—)-sparteine, ... 

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. 

Mono- and dialkylations of malonic acid esters generally are performed in an alcoholic solution of a metal alkoxide. Alkylation of a monoalkylated malonic ester requires the presence of another equivalent of alkoxide and the appropriate alkyl halide. The alkylation works well with RCH2X (X=l, Br, OTs), PhCH2X (X=C1, Br) and even with unhindered sec alkyl bromides." Subsequent hydrolysis of the diester under acidic or basic conditions followed by heat-induced decarboxylation yields the a-alkylated carboxylic acid. Thus, dialkyl malonates are the synthetic equivalents (SE) of acetate enolate anions and can be used to obtain mono- or disubstituted carboxylic acids. 

One can speed up alkylation relative to elimination by stabilizing an enolate anion with an additional ewg, making the anion softer and less basic. For example, the acidic CH2 of malonates, CH2(COOEt>2, or acetoacetates, CH3COCH2COOEt, deprotonates easily and makes an excellent nucleophile. The ester can later be hydrolyzed to the acid (Section 8.8.1) and removed by decarboxylation via path Ei. This ester is a detachable ewg that makes the enolate less basic and softer, favoring substitution over elimination. 

The vinyl stannane 170 was converted into the vinyl-lithium and then the vinyl cuprate as described for 161 and added to the enolate anion of 171. Notice the protection of the malonate ester group in 162 by deprotonation with sodium hydride. The product 172 is all anti across the hve-membered ring and all E, but there is of course no control at the remote stereogenic centre on the side chain. 

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