Ethyl acetoacetate, enolate

Figure 4.11 Molecular structures of typical crown-ether complexes with alkali metal cations (a) sodium-water-benzo-I5-crown-5 showing pentagonal-pyramidal coordination of Na by 6 oxygen atoms (b) 18-crown-6-potassium-ethyl acetoacetate enolate showing unsymmelrical coordination of K by 8 oxygen atoms and (c) the RbNCS ion pair coordinated by dibenzo-I8-crown-6 to give seven-fold coordination about Rb.

Medium Still basic. Sources The ethyl acetoacetate enolate anion has a p/ifabH of... 

One possible retrosynthesis of a ketone is disconnection at the alpha carbon. The alpha carbon was the nucleophile (enolate), and the other carbon was the electrophile (an alkyl halide). If the TM is a derivative of acetone, then this disconnection leads to the enolate of acetone. Rather than using the unstable enolate of acetone in a synthesis, the use of the ethyl acetoacetate enolate as a synthetic equivalent is preferred. 

Ethyl acetoacetate is a tautomeric substance which at room temperature exists as an equilibrium mixture of the keto and enol forms, the latter form being present to the extent of about 7%. 

Thus the sodio derivative (I) of the enol form of ethyl acetoacetate is obtained. This mechanism can clearly apply also to the condensation of an ester with a suitable ketone or nitrile, as in the above reactions (ii) and (iii) respectively. 

Mono and Di-iubstitution Derivatives. The enolic sodium derivative of ethyl acetoacetate (E) is prepared by mixing ethanolic solutions of the ester and of sodium ethoxide. It should not be prepared by the direct action of metallic sodium on the ester, as the reaction is slow and the nascent hydrogen evolved reduces some of the ester to ethyl p4iydroxy- butyrate, CH3CH(OH)CHjCOOEt. 

Ethyl malonate, like ethyl acetoacetate, exists as a tautomeric mixture of keto and enol forms, although in the case of ethyl malonate... 

Substitution Derivatives of Ethyl Malonate, Ethyl malonate resembles ethyl acetoacetate in that it gives rise to mono- and di-substituted derivatives in precisely similar circumstances. Thus when ethanolic solutions of ethyl malonate and of sodium ethoxide are mixed, the sodium derivative (A) of the enol form is produced in solution. On boiling this solution with an alkyl halide, e.g, methyl iodide, the methyl derivative (B) of the keto form is obtained. When this is treated again in ethanolic solution with sodium ethoxide, the... 

Space does not permit any further detailed discussion except for a brief account of two interesting subjects. The first is concerned with keto-enol tautomerism. The classical example is ethyl acetoacetate, which can exist in the keto form (I) and the enol form (II) ... 

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... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

Acetoacetic ester synthesis (Section 21 6) A synthetic method for the preparation of ketones in which alkylation of the enolate of ethyl acetoacetate... 

Carbon is alkylated ia the form of enolates or as carbanions. The enolates are ambident ia activity and can react at an oxygen or a carbon. For example, refluxing equimolar amounts of dimethyl sulfate and ethyl acetoacetate with potassium carbonate gives a 36% yield of the 0-methylation product, ie, ethyl 3-methoxy-2-butenoate, and 30% of the C-methylation product, ie, ethyl 2-methyl-3-oxobutanoate (26). Generally, only one alkyl group of the sulfate reacts with beta-diketones, beta-ketoesters, or malonates (27). Factors affecting the 0 C alkylation ratio have been extensively studied (28). Reaction ia the presence of soHd Al O results mosdy ia C-alkylation of ethyl acetoacetate (29). 

The leaving group in the alkylating reagent has a major effect on whether C- or O-alkylation occurs. In the case of the lithium enolate of acetophenone, for example, C-alkylation is predominant with methyl iodide, but C- and O-alkylation occur to approximately equal extents with dimethyl sulfate. The C- versus O-alkylation ratio has also been studied for the potassium salt of ethyl acetoacetate as a function of both solvent and leaving group. ... 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

Anions of (3-keto esters are said to be synthetically equivalent to the enolates of ketones. The anion of ethyl acetoacetate is synthetically equivalent to the enolate of acetone, for example. The use of synthetically equivalent groups is a common tactic in synthetic organic chemistry. One of the skills that characterize the most creative practitioners of organic synthesis is an ability to recognize situations in which otherwise difficult transfonnations can be achieved through the use of synthetically equivalent reagents. 

Most of the reactions of ester enolates described so far have centered on stabilized enolates derived from 1,3-dicarbonyl compounds such as diethyl malonate and ethyl acetoacetate. Although the synthetic value of these and related stabilized enolates is clear-, chemists have long been interested in extending the usefulness of nonstabilized enolates derived from simple esters. Consider the deprotonation of an ester as represented by the acid—base reaction... 

Electrostatic interactions can guide alkylation under certain conditions. Examine the electrostatic potential map of the potassium enolate of ethyl acetoacetate. Is carbon or oxygen more electron rich Are electrostatic interactions likely to favor addition of oxygen or carbon Examine atomic charges and electrostatic potential maps for diethylsulfate, ethyl chloride, ethyl bromide and ethyl iodide, pay attention to the backside of the electrophilic carbon. Order the systems from most to least electron poor. Which reaction is most likely to be guided by electrostatics Least likely Can the experimental results be fully explained on this basis ... 

Electrostatic potential map of the potassium enolate of ethyl acetoacetate shows negatively-charged regions (in red) and positively-charged regions (in blue). 

Treatment of 1,3-dicarbonyl eompounds with two equivalents of strong base ean give a dianion that will react selectively with alkyl halides. For example, ethyl acetoacetate reacts first with NaH to form an enolate, and then with n-BuLi to form a dianion. This then adds t-PrI. 

The proposed mechanism for the Conrad-Limpach reaction is shown below. Condensation of an aniline with a 3-keto-ester (i.e., ethyl acetoacetate 5) with loss of water provides enamino-ester 6. Enolization furnishes 10 which undergoes thermal cyclization, analogous to the Gould-Jacobs reaction, via 6n electrocyclization to yield intermediate 11. Compound 11 suffers loss of alcohol followed by tautomerization to give 4-hydroxy-2-methylquinoline 7. An alternative to the proposed formation of 10 is ejection of alcohol from 6 furnishing ketene 13, which then undergoes 671 electrocyclization to provide 12. 

If the refractivity of the pure tautomeric constituents is known, the composition of the equilibrium mixture can be determined. This method has been used to study, for example, the keto and enol tautomers of ethyl acetoacetate. So far it has not been applied to heterocyclic compounds in this series the isolation of the pure... 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

A change in the pK of the molecule by elimination of the acidic enol function and inclusion of basic nitrogen leads to a marked change in biologic activity. That agent, chromonar (13) shows activity as a coronary vasodilator. Alkylation of ethyl acetoacetate with 2-chlorotriethylamine affords the substituted ketoester (10). Condensation with resorcinol in the presence of sulfuric acid affords directly the substituted coumarin (11). 

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. 

G If one of the carbonyl partners is much more acidic than the other and so is transformed into its enolate ion in preference to the other, then a mixed aldol reaction is likely to be successful. Ethyl acetoacetate, for instance, is completely converted into its enolate ion in preference to enolate ion formation from monocarbonyl partners. Thus, aldol condensations of monoketones with ethyl acetoacetate occur preferentially to give the mixed product. 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

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