Acetoacetate proton production

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

Intermediates such as 224 resulting from the nudeophilic addition of C,H-acidic compounds to allenyl ketones such as 222 do not only yield simple addition products such as 225 by proton transfer (Scheme 7.34) [259]. If the C,H-acidic compound contains at least one carbonyl group, a ring dosure is also possible to give pyran derivatives such as 226. The reaction of a similar allenyl ketone with dimethyl mal-onate, methyl acetoacetate or methyl cyanoacetate leads to a-pyrones by an analogous route however, the yields are low (20-32%) [260], The formation of oxaphos-pholenes 229 from ketones 227 and trivalent phosphorus compounds 228 can similarly be explained by nucleophilic attack at the central carbon atom of the allene followed by a second attack of the oxygen atom of the ketone at the phosphorus atom [261, 262], Treatment of the allenic ester 230 with copper(I) chloride and tributyltin hydride in N-methylpyrrolidone (NMP) affords the cephalosporin derivative 232 [263], The authors postulated a Michael addition of copper(I) hydride to the electron-... 

The nucleophile will be the enolate anion from ethyl acetoacetate, which attacks the P-carbon of the electrophile, generating an addition complex that then acquires a proton at the a-position with restoration of the carbonyl group. The product is a 8-ketoester with an ester side-chain that has a... 

The Robinson annulation of ethyl acetoacetate and tra i -chalcone was investigated with pulverized NaOH in [BMIMjPFg as the base catalyst at 100°C 110). The mixture was neutralized before extraction with toluene. The product, 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone, was obtained by purification in a silica gel chromatography column. A yield of 48% was obtained (Scheme 7). The ionic liquid could be recycled and reused with no diminution of product yield. The C2 position in imidazolium cations is an acidic proton donor and may have reacted... 

The final step drives the reaction to completion. Ethyl acetoacetate is more acidic than any of the other species present, and it is converted to its conjugate base in the final step. A full equivalent of base is needed to bring the reaction to completion. The /i-kctocstcr product is obtained after neutralization and workup. As a practical matter, the alkoxide used as the base must be the same as the alcohol portion of the ester to prevent product mixtures resulting from ester interchange. Because the final proton transfer cannot occur when a-substituted esters are used, such compounds do not condense under the normal reaction conditions. This limitation can be overcome by use of a very strong base that converts the reactant ester completely to its enolate. Entry 2 of Scheme 2.13 illustrates the use of triphenylmethylsodium for this purpose. 

Keto esters such as acetoacetate without a substituent at the a-carbon. namely with two acidic protons, first attack the central carbon of the allenylpal-ladium to form the zr-allyl complex 89. Then intramolecular attack of the enolate oxygen of the 0-keto ester at the rr-ully l system takes place to form the nieihv-lenedihydrofuran 90 as a primary product, which is easily isomerized to the turn 91. The /3-diketone 92 reacts similarly to give the furan 93[40], The reaction can be applied to the synthesis of the phenyIthiomethyl-substituted furan 94. which is useful for the synthesis of natural products such as neoliacine. [41]... 

Nucleophilic attack of the enolate anion to the carhonyl carhon of another ethyl acetate gives an alkoxide tetrahedral intermediate. The resulting alkoxide reforms the carhonyl group hy ejecting the ethoxide anion. This ethoxide anion deprotonates the a-hydrogen, and produces a new enolate anion of the resulting condensed product, which is protonated in the next step upon acidification during work-up and yields the ethyl acetoacetate. 

In biochemical decarboxylation reactions where the reactant contains a 3-keto group, the e-amino group of a lysyl side chain of the protein backbone can form an iminium derivative with the substrate.82 Upon loss of carbon dioxide, the delocalized, weakly basic product will not react faster than carbon dioxide can separate. Benner83 showed that the stereochemical consequence of decarboxylation of acetoacetate by acetoacetate decarboxylase involves protonation of the product from either face, consistent with a passive, uncatalyzed step, which is consistent with the view we have presented. 

The a-protons of a ketone like propanone are only weakly acidic and so a powerful base (e.g. lithium diisopropylamide) is required to generate the enolate ion needed for the alkylation. An alternative method of preparing the same product by using a milder base is to start with ethyl acetoacetate (a [3-keto ester) (Fig.G). The a-protons in this structure are more acidic because they are flanked by two carbonyl groups. Thus, the enolate can be formed using a weaker base like sodium ethoxide. Once the... 

The ketone carbonyl group of ethyl acetoacetate must be converted to a C = C double bond in the a,/3 position of the other ketone. This conversion corresponds to an aldol condensation with dehydration. Note that the proton we must remove is not the most acidic proton, but its removal forms the enolate that is needed to give the observed product. 

The point is that the base used, ethoxide ion EtCT, is too weak (EtOH has a pKd of about 16) to remove the proton completely from ethyl acetate (pkTa about 25), but is strong enough to remove a proton from the acetoacetate product (p about 10), Under the conditions of the reaction, a small amount of the enolate of ethyl acetate is produced—just enough to let the reaction happen—but the product is completely converted into its enolate. The neutral product, ethyl acetoacetate itself, is formed on acidic work-up. 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

The alkylation of p-keto ester enolates followed by decarboxylation affords substituted ketones (acetoacetic ester synthesis). The ester group acts as a temporary activating group. Retro-Claisen condensation can be a serious problem during hydrolysis of the ester, particularly in basic solution if the product has no protons between the carbonyl groups. In these cases, the hydrolysis should be carried out under acidic conditions or using one of the methods of decarbalkoxylation described in the next section. 

Treatment of methyl 2-(methoxymethylene)acetoacetate (287) with aniline produced the corresponding enaminoketoester 288 in 97% yield. Formation of the orange Li salt followed by passage of dry gaseous formaldehyde at -78°C and warming gave the oxo-5-lactone 289. Facile conversion to the natural alkaloid was achieved in 66% yield through dissolution of 289 in liquid ammonia. The spectral data of the product confirmed that it was a mixture of the two isomers 285/286. Thus, for example, the methylene protons adjacent to the carbonyl appeared as two triplets at 2.45 and 2.50 ppm in the ratio of 1.5 2.5 (Scheme 26) (216). 

Variations of the malonic ester and acetoacetic ester sequenees lead to many useful synthetic opportunities. In the examples quoted, the base-solvent pair used was ethanol-sodium ethoxide, where the alkoxide is the conjugate base of tbe solvent. If NaOEt-EtOH were used with a methyl ester, transesterification would give a mixture of methyl and ethyl esters as products. For both malonic ester and acetoacetic ester removal of the most acidic proton (a to both carbonyls) also gives the more thermodynamically stable enolate. Either NaOEt-EtOH or LDA-THF will generate the desired enolate. The malonic ester synthesis is most useful for the synthesis of highly substituted monoacids, and tbe acetoacetic ester synthesis is used to prepare substituted methyl ketones. 

The thermal decomposition of acetoacetic acid involves the loss of carbon dioxide and the production of the enol form of acetone. It is believed that the reaction occurs by an internal proton transfer and a cyclic transition state (Westheimer and Jones, 1941). The analogous reaction that would generate metaphosphate involves the thermal decomposition of a 2-keto-... 

According to Kambe et al., the mechanism of reaction consists not in the reduction of methyl acetoacetate by photochemically produced hydrogen, but in the electrochemical reduction of the C=0 bond and proton by photogenerated electrons. Thus, the hydrogen production sites on the surface of Raney Ni are different from methyl 3-hydroxybutyrate production sites. 

In Chapter 23, we introduced the idea that the last-formed anion in any dianion or trianion is the most reactive. Methyl acetoacetate is usually alkylated on the central carbon atom because that is the site of the most stable enolate. But methyl acetoacetate dianion—formed by removing a second proton from the usual enolate with a very strong base (usually butyl-lithium)—reacts first on the less stable anion the terminal methyl group. Protonation of the more stable enolate then leads to the product. Butyllithium can be used as a base because the anionic enolate intermediate is not electrophilic. 

As is well known, the dietary carbohydrates are normally catabolized to give the neutral end products carbon dioxide and water. The intermediately formed organic acids such as lactic acid or tri- and dicarbonic acids of the Krebs cycle solely influence the acid-base balance if they are excreted in their ionic form, leaving behind the protons that would normally be oxidized together with the acidic anion to the neutral end products mentioned above. The same is true for the fatty acids, originating from the dietary fats. Under special circumstances, the fatty acid, degradation leads to the accumulation of ketone bodies. The excretion of acetoacetic and of jS-hydroxybutyric acid in their ionic form results in acidosis, as observed in diabetes. Under normal conditions, however, there is no influence of dietary fat on the acid-base balance. 

II) Similarly, protons are formed during the production of acetoacetate and 3-hydroxybutyrate from fatty acids (Chapter 33)... 

In Experiment 28A, the yeast reduction of ethyl acetoacetate forms a product that is predominantly the (S)-enantiomer of ethyl 3-hydroxybutanoate. In this part of the experiment, we will use NMR to determine the percentages of each of the enantiomers in the product. The 300 MHz proton NMR spectrum of racemic ethyl 3-hydroxybutanoate is shown in Figure 1. The expansions of fhe individual patterns from Figure 1 are shown in Figure 2. The methyl protons (HJ appear as a doublet at 1.23 ppm, and the methyl protons (H, ) appear as a triplet at 1.28 ppm. The methylene protons (H and H ) are diastereotopic (nonequivalent) and appear at 2.40 and 2.49 ppm (each a doublet of doublefs). The hydroxyl group appears at about 3.1 ppm. The quartet at 4.17 ppm results from the methylene protons (HJ split by the protons (Hjj).The methane proton (H ) is buried under the quartet at about 4.2 ppm. 

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