Aldehydes Michael addition acceptors

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

Another important reaction in synthetic chemistry leading to C-C bond formation is the Michael addition. The reaction typically involves a conjugate or nucleophilic 1,4-addition of carbanions to a,/l-unsaturated aldehydes, ketones, esters, nitriles, or sulfones 157) (Scheme 21). A base is used to form the carbanion by abstracting a proton from an activated methylene precursor (donor), which attacks the alkene (acceptor). Strong bases are usually used in this reaction, leading to the formation of byproducts arising from side reactions such as condensations, dimerizations, or rearrangements. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

As mentioned above, the enantioselective Michael addition of P-keto esters to a,P-unsaturated carbonyl compounds represents a useful method for the construction of densely functionalized chiral quaternary carbon centers. One characteristic feature of designer chiral phase-transfer catalyst lh in this type of transformation is that it enables the use of a,p-unsaturated aldehydes as an acceptor, leading to the... 

As an extension of this highly enantioselective Michael addition of silyl nitronates with a, p-unsaturated aldehydes, the reactions with cyclic a,p-unsaturated ketones as a Michael acceptor were also tested (Scheme 9.15). Cyclohexenone and cyclohepte-none were employed as a useful Michael acceptor with various silyl nitronates in the presence of catalyst (R,R)-6c, and gave the corresponding enol silyl ethers 28 with excellent stereoselectivities [30]. 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Among Michael acceptors, direct addition is most likely with unsaturated aldehydes and acid chlorides, Michael addition most likely with ketones or esters. Hence Grignard reagents add directly to aldehyde (10) and Michael fashion to ester (11). 

Conjugate addition. Schlessinger et have reported a general synthesis of 1,4-dicarbonyl compounds based on utilization of (1) as a 2-carbon Michael acceptor. Michael additions were realized with enamines, sodium enolates of /3-dicarbonyl compounds, and lithium enolates of esters. The products can be converted into aldehydes by hydrolysis in aqueous acetonitrile with perchloric acid. 

For example, the addition to vinyl sulfones has attracted a lot of attention mainly because of the synthetic possibilities that the sulfone group affords in terms of its wide possibilities to undergo a wide variety of transformations. iPBP 15a and prolinal-deiived aminal 12b catalysts have proved their usefulness in the Michael addition of aldehydes to this particular class of Michael acceptors, showing that good yields of the desired Michael adducts could be obtained under the optimized conditions, although with moderate enantios-electivities (Scheme One of the main problems of this particular... 

Alkylidenemalonates and malononitriles constitute another class of doubly activated olefins that can be used as highly electrophilic Michael acceptors in this reaction. For example, the Michael addition of aldehydes with these compounds has been reported to proceed with very good yields and enantioselectivities using 0-TMS diphenylprolinol 31a as catalyst (Scheme 2.29). On the other hand, the Michael addition of ketones to alkylidenemalonates has... 

Finally, it has to be mentioned that not only gew-disubstituted diactivated olefins but also a,p-disubstituted Michael acceptors have been employed in this transformation. For example, the Michael addition of a series of aldehydes to... 

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