Conjugated compounds, reaction with enolate anions

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

In many of these cases, both the enolate anion and substrate can exist as (Z) or (E) isomers. With enolates derived from ketones or carboxylic esters. The (E) enolates gave the syn pair of enantiomers (p. 166), while (Z) enolates gave the anti pair. Nitro compounds add to conjugated ketones in the presence of a dipeptide and a piperazine. ° Malonate derivatives also add to conjugated ketones, and keto esters add to conjugated esters.Addition of chiral additives to the reaction, such as metal-salen complexes,proline derivatives, or (—)-sparteine, ... 

For acylations with reactive esters, such as formate or oxalate (see Section 3.6.4.5), sodium alkoxides are still the bases of choice, but sodium hydride, dimsyl sodium, sodium or potassium amide or sodium metal have all been used for the in situ generation of the enolate anion. A typical example is shown in Scheme 47. Acylation by esters results in the production of 1 equiv. of the alkoxide ion, along with the p-dicarbonyl compound proton transfer then results in the production of the conjugate base of the dicarbonyl compound. This process normally leads to the more stable anion in the acylation of an unsymme-trical ketone. The acyl group thus becomes attached to the less-substituted a-position of the ketone. The less stable 0-acylated products are normally not observed in such reversible base-catalyzed reactions. Methyl alkyl ketones are normally acylated on the methyl group where both a-carbons are substituted to the same extent, acylation occurs at the less-hindered site. Acylation is observed only rarely at a methine carbon as the more stable p-diketone enolate cannot be formed. 

When a nucleophile donates electrons to the C=C unit of the conjugated system, it is commonly called Michael addition (or the Michael reaction), after Arthur Michael (United States 1853-1942). A generalized form of this reaction shows that the conjugated carbonyl compound 43 is attacked by a nucleophile (Y ) to form a new bond (C-Y). Reactions of this type are also called 1,4 addition or conjugate addition. The two donated electrons from Y are used to form this new bond, which leads to breaking the Ji-bond in 43. The two electrons in the n-bond are transferred to the a-carbon to form enolate anion 44, which is resonance stabilized. Workup with aqueous acid gives the isolated product, 45. There are many examples of this reaction, and some of them generate new carbon-carbon bonds when Y is a carbon nucleophile. 

In the late nineteenth century, Michael found that the enolate anion (46) derived from diethyl malonate reacts with ethyl acrylate at the P-carbon (as shown in the illustration) to give an enolate anion, 47, as the product. Remember from Chapter 22 (Section 22.7.4) that the a-proton of a 1,3-dicarbonyl compound such as diethyl malonate is rather acidic (pK of about 11), and even a relatively weak base will deprotonate to form the enolate anion. Michael addition of 46 with ethyl acrylate will give enolate anion 47, and aqueous acid workup leads to the isolated product, 48. Attack at the -carbon is possible because that carbon is less hindered than the acyl carbon, so reaction at the C=C unit is somewhat faster than attack at the acyl carbon. Michael addition occurs with relatively stable carbanion nucleophiles, such as malonate derivative 46 and some other common nucleophiles. Other conjugated carbonyl derivatives react similarly. 

The addition at the p-position of an a,p-unsaturated carbonyl compound is described as conjugate addition, Michael addition, or 1,4-addition. It can be exemplified by the reaction in Figure 17.57, the addition of a cyanide ion to an enone. Students are often puzzled by the term 1,4-addition. Despite the way we usually write this mechanism, with the enolate anion being... 

Enolate anions, whether stabilized (like the anions of diethylmalonate or ethyl acetoacetate) or not, add invariably and predictably at the conjugate position of unsaturated carbonyl compounds. An example is shown in Figure 17.67. The anion of diethylmalonate adds 1,4 to the enone, and the intermediate is reprotonated. The diester can be hydrolyzed and decarboxylated to give the final product. The key feature of this reaction, which is very extensively used in synthesis, is that we have synthesized a 1,5-dicarbonyl compound—and this is the standard synthesis of molecules with this pattern of substitution. 

Another intermediate for which Die Is-Alder trapping provided convincing evidence is the oxy-allyl cation. This compound can be made from a,oc -dibromoketones on treatment with zinc metal. The first step is the formation of a zinc enolate (compare the Reformatsky reaction), which can be drawn in terms of the attack of zinc on oxygen or bromine. Now the other bromine can leave as an anion. It could not do so before because it was next to an electron-withdrawing carbonyl group. Now it is next to an electron-rich enolate so the cation is stabilized by conjugation. 

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