Ethyl acetoacetate, enolate anion

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

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... 

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. 

The proportion of the /rans-O-alkylated product [101] increases in the order no ligand < 18-crown-6 < [2.2.2]-cryptand. This difference was attributed to the fact that the enolate anion in a crown-ether complex is still capable of interacting with the cation, which stabilizes conformation [96]. For the cryptate, however, cation-anion interactions are less likely and electrostatic repulsion will force the anion to adopt conformation [99], which is the same as that of the free anion in DMSO. This explanation was substantiated by the fact that the anion was found to have structure [96] in the solid state of the potassium acetoacetate complex of 18-crown-6 (Cambillau et al., 1978). Using 23Na NMR, Cornelis et al. (1978) have recently concluded that the active nucleophilic species is the ion pair formed between 18-crown-6 and sodium ethyl acetoacetate, in which Na+ is co-ordinated to both the anion and the ligand. 

The same viewpoint can taken for the ester function in a P-ketoester such as ethyl acetoacetate. Again, acidity of the a-protons is increased because there are two carbonyl groups, and generation of an enolate anion is facilitated. Although mono- or... 

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... 

Active methylene anions also displace the 5-halogen substituent for example, the 5-chloro derivative (152) (X = Cl) reacts with the sodium salt of ethyl acetoacetate to give (90) (R = Et) which is readily hydrolyzed and decarboxylated (Scheme 22) <82M793>. The 5-chloro substituent in (152) (X = Cl) is also readily displaced by the lithium enolate of 3-(methoxycarbonyl)quinuclidine (153) to give (154) which on hydrolysis with sodium hydroxide and then decarboxylation with hydrochloric... 

The enolate anion attacks the carbonyl carbon of a second molecule of ester and gives a P-ketoester. Thus, the Claisen condensation is a nucleophilic acyl substitution reaction. Eor example, two molecules of ethyl acetate condense together to form the enolate of ethyl acetoacetate, which upon addition of an acid produces ethyl acetoacetate (P-ketoester). 

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. 

Both l,3-oxazin-4-ones and -2,4-diones are attacked by nucleophiles at C-2. Enolate anions, for example, yield open-chain intermediates initially, but these normally ring-close again to form pyridones <80H(14)1333>. Certainly this is the case when sodium ethoxide in ethanol is employed to generate the enolate thus diones (35) react with ethyl acetoacetate... 

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. 

Now suppose that we want to use the enolate anion derived from acetone (pKa = 20) as a nucleophile in a substitution reaction. This anion requires the use of a very strong base to generate it, and its high reactivity often causes low yields of the desired product. Instead, we may choose to use its synthetic equivalent, the enolate anion derived from ethyl acetoacetate (pA a =11) ... 

Alkylation of the enolate anion derived from ethyl acetoacetate followed by removal of the ester group is known as the acetoacetic ester synthesis and is an excellent method for the preparation of methyl ketones. The product of an acetoacetic ester synthesis is the same as the product that would be produced by the addition of the same... 

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. 

O-Alkylation is most pronounced when the enolate is least solvated. When the potassium salt of ethyl acetoacetate is treated with ethyl sulfate in the polar aprotic solvent HMPA, the major product (83%) results from O-alkylation. In THF, where ion clustering occurs, all of the product is C-alkylated. In r-butyl alcohol, where the acetoacetate anion is hydrogen bonded by solvent, again only C-alkylation is observed. 

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