Enolate anions, addition reactions enols from

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

It is conceptually easier to consider initially the aldol reaction rather than the reverse aldol reaction. This involves generating an enolate anion from the dihydroxyacetone phosphate by removing a proton from the position a to the ketone group. This enolate anion then behaves as a nucleophile towards the aldehyde group of glyceraldehyde 3-phosphate, and an addition reaction occurs, which is completed by abstraction of a proton, typically from solvent. In the reverse reaction, the leaving group would be the enolate anion of dihydroxyacetone phosphate. 

One of the simplest biochemical addition reactions is the hydration of carbon dioxide to form carbonic acid, which is released from the zinc-containing carbonic anhydrase (left, Fig. 13-1) as HC03-. Aconitase (center, Fig. 13-4) is shown here removing a water molecule from isocitrate, an intermediate compound in the citric acid cycle. The H20 that is removed will become bonded to an iron atom of the Fe4S4 cluster at the active site as indicated by the black H20. An enolate anion derived from acetyl-CoA adds to the carbonyl group of oxaloacetate to form citrate in the active site of citrate synthase (right, Fig. 13-9) to initiate the citric acid cycle. 

Michael reaction (Section 23.10) the 1,4-addition reaction of a stabilized enolate anion such as that from a 1.3-diketone to an a,p-unsaturated carbonyl compound. 

The search for endothelin antagonists as potential compounds for treating cardiovascular disease was noted in Chapter 5 (see atrasentan). A composed with a considerably simpler structure incorporates a pyrimidine ring in the side chain. Condensation of benzophenone (94) with ethyl chloro-acetate and sodium methoxide initially proceeds to addition of the enolate from the acetate to the benzophenone carbonyl. The aUcoxide anion on the first-formed quaternary carbon then displaces chlorine on the acetate to leave behind the oxirane in the observed product (95). Methanolysis of the epoxide in the product in the presence of boron triflor-ide leads to the ether-alcohol (96). Reaction of this with the pyrimidine (97) in the presence of base leads to displacement of the methanesulfonyl group by the aUcoxide from 96. Saponification of the ester group in that product gives the corresponding acid, ambrisentan (98). " ... 

Selectivity is more complicated with a methyl or chloro substituent. Again, meta substitution is always significant, but ortho substitution can account for 50-70% of the mixture in some cases [2]. More reactive anions (1,3-dithianyl) and less substituted carbanions (e.g., tert-butyl lithioacetate) tend to favor ortho substitution. Representative examples are shown in Table 3. Entries 2-4 show that variation of reaction temperatures from -100 °C to 0 °C has no significant effect in that highly selective system. The added activating effect of the Cl substituent allows addition of the pinacolone enolate anion (entry 11), whereas no addition to the anisole nor toluene ligand is observed with the same anion. 

Michael addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

Addition reactions of (l-methoxyalkyl)triphenylphosphonium ylides, derived from the corresponding phosphonium salts (82) and n-BuLi, to aldehydes at — 78 °C followed by quenching the reaction mixture with aqueous NH4CI at the same temperature alforded a-hydroxyketones instead of the expected enol ethers.This is the first example of phosphonium ylides acting as an acyl anion equivalent. Flash vacuum pyrolysis (FVP) in a conventional flow system at 10 (84), prepared in a few steps... 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

This chapter will discuss carbanion-like reactions that utilize enolate anions. The acid-base reactions used to form enolate anions will be discussed. Formation of enolate anions from aldehyde, ketones, and esters will lead to substitution reactions, acyl addition reactions, and acyl substitution reactions. Several classical named reactions that arise from these three fundamental reactions of enolate anions are presented. In addition, phosphonium salts wiU be prepared from alkyl halides and converted to ylids, which react with aldehydes or ketones to form alkenes. These ylids are treated as phosphorus-stabilized car-banions in terms of their reactivity. 

It is clear from this last example that an enolate anion behaves as a carbon nucleophile and gives the same sort of acyl addition reaction as another previously discussed carbanion, an alkyne anion (see Chapter 18, Section 18.3.2). The products are different, of course, but from the standpoint of comparing reactions, the only real difference between an enolate anion and an alkyne anion is the structure and complexity of the enolate anion as a carbon nucleophile and the functionality in the fined acyl addition product. 

In the aldol reaction, enolate anions derived from aldehydes or ketones react with a second molecule of aldehyde or ketone to give a carbonyl addition reaction and create a new carbon-carbon bond. 

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