Conjugate additions ethyl acetoacetate

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... 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

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. 

Recently, very effective asymmetric conjugate addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported, as shown in Scheme 4.10. The reaction of ethyl acetoacetate with nitrostyrene is carried out in the presence of 5 mol% of the preformed complex of magnesium triflate and chiral bis(oxazoline) ligands and a small amount ofW-methylmorpholine (NMM) to give the adduct with selectivity of 91%. The selectivity depends on ligands. The effect of ligands is presented in Scheme 4.10.63... 

However, the reaction is not quite that simple, and to understand and utilize the Claisen reaction we have to consider pAT values again. Loss of ethoxide from the addition anion is not really favourable, since ethoxide is not a particularly good leaving group. This is because ethoxide is a strong base, the conjugate base of a weak acid (see Section 6.1.4). So far then, the reaction will be reversible. What makes it actually proceed further is the fact that ethoxide is a strong base, and able to ionize acids. The ethyl acetoacetate prodnct is a 1,3-dicarbonyl componnd and has relatively acidic protons on the methylene between the two carbonyls (see Section 10.1). With... 

The disulfide dimers of 2-aminothiophenols have also been used in the syntheses of benzothiazines. In this case, nitrogen acts as a nucleophile and sulfur as an electrophile. Reagents that have nucleophilic carbons adjacent to an electrophilic carbon can be reacted with these disulfides. Examples include a,(3-unsaturated esters that undergo conjugate addition followed by enolate addition to sulfur (Equation 86) <1983J(P1)567>, and 1,3-dicarbonyl compounds such as ethyl acetoacetate <2005AXEo2716> and dimethyl malonate <2006ARK(xv)68> (Scheme 63). 

Robinson, R. Extension of the theory of addition to conjugated unsaturated systems. II. The C-alkylation of certain derivatives of (i-aminocrotonic acid and the mechanism of the alkylation of ethyl acetoacetate and similar substances. J. Chem. Soc., Abstracts 1916,109, 1038-1046. 

This experiment illustrates how two important synthetic reactions can be combined to prepare an a,)8-unsaturated ketone, 6-ethoxycarbonyl-3,5-diphenyl-2-cyclohexenone. The first step in this synthesis is a sodium hydroxide-catalyzed conjugate addition of ethyl acetoacetate to transchalcone (a Michael addition reaction). Sodium hydroxide serves as a source of hydroxide ion to catalyze the reaction. In the reactions that follow, Ph and Et are abbreviations for the phenyl and ethyl groups, respectively. 

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. 

More recently, Klimochkin et al employed the same catalyst, (R,R)-1, at a lower catalyst loading of 1 mol% in the enantioselective conjugate addition of ethyl acetoacetate to nitroalkenes to give the corresponding chiral Michael products in only moderate yields but with generally high diastereoselectivi-ties of 86-98% de, as shown in Scheme 2.4. The utility of these products... 

Scheme 2.4 Conjugate additions of ethyl acetoacetate to nitroalkenes and ethyl malonate to 1-nitropropene with a preformed diamine nickel catalyst.

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