Conjugate addition to a, 3-unsaturated aldehydes and

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... 

Dihydrothiopyran-4-ones have been efficiently obtained from terminal alkynes through conjugate addition to a,/3-unsaturated aldehydes followed by oxidation to the enynone and cyclization <2007MC13>. The [2+2] photocycloaddition of ethylidenemalononitrile to the 2,2-dimethyldihydrothiopyranone is both regio- and stereo- specific <2007S1426>. 

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-... 

Conjugate additions to a,/3-unsaturated ketones and aldehydes (Section 19.14)... 

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,... 

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). 

In 2010, Chen and co-workers [134] developed the first organocatalytic asymmetric conjugate addition of a, 3-unsaturated aldehydes via iminium catalysis. In the presence of diarylprolinol silylether 7 and o-fluorobenzoic acid (OFBA), the reaction proceeded well to afford the highly valued adducts with excellent enantioselectivities and with up to outstanding diastereoselectivities (Scheme 5.67). To emphasize the synthetic utility of the reaction, a number of natural-product-like or drug-like molecules with versatile skeletons have been efficiently constructed from the corresponding Michael adducts. 

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 generation of an iminium ion of a,P-unsaturated carbonyl compounds lowers the LUMO energy. As a result, the a-CH acidity increases as well as the ability to participate in conjugate additions. The first organocatalyzed 1,4-addition to a, 3-unsaturated aldehydes was reported by the MacMillan group [78]. For theoretical explorations of the configurative outcome of Michael additions of pyrroles and indoles to crotonaldehyde see Reference [79]. This transformation has been widely used in Friedel-Crafts alkylations of a,(3-unsaturated carbonyl compounds (see Reference [lb] and reports cited therein). Comparable examples of this transformation with ( )-crotonaldehyde in the intermolecular series were found in aryl alkylation with trifluoroborate (58 and 60) [80], indole alkylation (62) [81], Friedel-Crafts alkylation of electron-rich benzenes (64) [82], and Friedel-Crafts alkylation with phosphonates (65) [83] (Scheme 4.21). 

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. 

Preliminary mechanistic studies show no polymerization of the unsaturated aldehydes under Cinchona alkaloid catalysis, thereby indicating that the chiral tertiary amine catalyst does not act as a nucleophilic promoter, similar to Baylis-Hilhnan type reactions (Scheme 1). Rather, the quinuclidine nitrogen acts in a Brpnsted basic deprotonation-activation of various cychc and acyclic 1,3-dicarbonyl donors. The conjugate addition of the 1,3-dicarbonyl donors to a,(3-unsaturated aldehydes generated substrates with aU-carbon quaternary centers in excellent yields and stereoselectivities (Scheme 2) Utility of these aU-carbon quaternary adducts was demonstrated in the seven-step synthesis of (H-)-tanikolide 14, an antifungal metabolite. 

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