Nucleophilic Addition to a,3-Unsaturated Aldehydes and Ketones

Conjugate Nucleophilic Addition to a, /3-Unsaturated Aldehydes and Ketones 727... 

P carbon atom of an a 3 unsatu rated carbonyl compound is elec trophilic nucleophiles especially weakly basic ones yield the prod ucts of conjugate addition to a 3 unsaturated aldehydes and ketones... 

There are many examples of nucleophilic reagents that add to a, 3-unsaturated aldehydes and ketones in a manner in which the addition is formally 1,4. This result is called conjugate addition. Under basic conditions, these transformations involve initial attack by the nucleophile to the p-carbon atom, followed by electrophilic addition (normally of a proton) on the carbonyl oxygen the nucleophile and electrophile add at the 1 and 4 positions relative to one another. The enolate formed in the early stages of the reaction is generally quickly protonated to give an enol. The enol wiU subsequently tautomer-ize to the ketone. A general mechanistic scheme is shown below for the 1,4 addition of water to an a,p-unsaturated carbonyl system. 

We saw in Section 19.13 that certain nucleophiles, such as amines, react with a,/3-unsaturated aldehydes and ketones to give the conjugate addition product, rather than the direct addition product. 

We begin by introducing the chemistry of enolates and enols. Especially important is a reaction between enolate ions and carbonyl compounds, called the aldol condensation. This process is widely used to form carbon-carbon bonds both in the laboratory and in nature. Among the possible products of aldol condensation are a,/3-unsaturated aldehydes and ketones, which contain conjugated carbon-carbon and carbon-oxygen tt bonds. As expected, electrophilic additions may take place at either bond. However, more significantly, a, -unsaturated carbonyl compounds are also subject to nucleophilic attack, a reaction that may involve the entire conjugated system. 

The new methodology is particularly effective for the conjugate alkylation to a,/3-unsaturated aldehydes, which, among various conjugate acceptors, are prone to be more susceptible to 1,2 addition with a number of nucleophiles than a,/3-unsaturated ketones, esters, and amides, as exemplified in Sch. 97 [135]. 

The conjugate addition of a nucleophile to an a ,/3-unsaturated aldehyde or ketone is caused by the same electronic factors that are responsible for direct addition. The electronegative oxygen atom of the a,/3-unsaturated carbonyl compound withdraws electrons from the (3 carbon, thereby making it electron-poor and more electrophilic than a typical alkene carbon. 

As noted previously, conjugate addition of a nucleophile to the /3 carbon of an a,/3-unsaturated aldehyde or ketone leads to an enolate ion intermediate, which is protonated on the a carbon to give the saturated product (Figure 19.16). The net effect is addition of the nucleophile to the C=Cbond, with the carbonyl group itself unchanged. In fact, of course, the carbonyl group is crucial to the success of the reaction. The C=C bond would not be activated for addition, and no reaction would occur, without the carbonyl group. 

Unsaturated aldehydes and ketones often react with nucleophiles to give the product of conjugate addition, or 1,4 addition. Particularly useful is the reaction with a diorganocopper reagent, which results in the addition of an alkyl, aryl, or alkenyl group. 

As we saw in Chapter 6, carbon-carbon double bonds are attacked by electrophiles but not by nucleophiles. An exception to this generalization is the reactivity of a,jS-unsaturated aldehydes and ketones toward nucleophiles. Even though an isolated carbon-carbon double bond does not react with 2° amines such as dimethylamine, 3-buten-2-one reacts readily by regioselective addition. 

With this in mind, let s now explore the outcome of a reaction in which an enolate ion is used as a nucleophile to attack an a,(3-unsaturated aldehyde or ketone. In general, enolates are less reactive than Grignard reagents but more reactive than lithium dialkyl cuprates. As such, both 1,2-addition and 1,4-addition are observed, and a mixture of products is obtained. In contrast, doubly stabilized enolates are sufficiently stabifized to produce 1,4 conjugate addition exclusively. 

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