Conjugate addition to a,0-unsaturated aldehydes and ketones

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... 

The preparation and some synthetic applications of lithium dialkylcuprates were described earlier (Section 14.11). The most prominent feature of these reagents is then-capacity to undergo conjugate addition to a, 3-unsaturated aldehydes and ketones. 

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

Conjugate additions. The silyl cuprate rcapcnt (PhMc,Si),CuLi (1) undergoes conjugate addition to a,(3-unsaturated aldehydes, ketones, or esters to form (3-silyl carbonyl compounds. Methylation of the intermediate enolate in acyclic systems is highly dia-stereoselective in favor of the isomer in which the silyl and methyl groups have the anti-... 

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. 

Conjugate addition of phenyl trimethylsilyl selenide to a,/3-unsaturated aldehydes and ketones has been attained by using triphenylphosphine, zinc chloride, or trimethylsilyl trifluoro-methanesulfonate as the catalyst. Combination of this reaction with selenoxide elimination provides a one-pot procedure for a-alkoxyalkylation of a,/3-unsaturated ketones (eq 3). 

Both primary and secondary amines add to a,/3-unsaturated aldehydes and ketones to yield /3-amino aldehydes and ketones rather than the alternative imines. Under typical reaction conditions, both modes of addition occur rapidly. But because the reactions are reversible, they generally proceed with thermodynamic control rather than kinetic control (Section 14.3), so the more stable conjugate addition product is often obtained to the complete exclusion of the less stable direct addition product. 

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a, 3-unsaturated carbonyl compounds. This reaction, called the Michael reaction, has been described for anions derived from (3-diketones in Section 18.13. The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the (3-carbon atom of a,(3-unsaturated aldehydes, ketones, and esters. For example,... 

Electrophilic addition of hydrogen halides to a,/f-unsaturated aldehydes and ketones places the halogen on the /3 carbon. This orientation is opposite to that observed for related additions to conjugated dienes ... 

Water can add reversibly to tr,/3-unsaturated aldehydes and ketones to yield /3-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. A related addition to an rt,j0-unsaturated carboxylic acid occurs in numerous biological pathways, such as the citric acid cycle of food metabolism where c/.s-aconitate is converted into isocitrate by conjugate addition of water to a double bond. 

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. 

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 condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

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