Carbonyl compounds Michael addition acceptors

Hydrolysis of the ester functional groups of this Michael product followed by decarboxylation yields a 5-keto acid. In general, the Michael addition of 1,3-dicarbonyl donors to typical a,P-unsaturated carbonyl compounds (Michael acceptors) yields 1,5-dicarbonyl compounds. 

Enamines react with acceptor-substituted alkenes (Michael acceptors) in a conjugate addition reaction for example with o ,/3-unsaturated carbonyl compounds or nitriles such as acrylonitrile 8. With respect to the acceptor-substituted alkene the reaction is similar to a Michael addition ... 

Enamines behave in much the same way as enolate ions and enter into many of the same kinds of reactions. In the Stork reaction, for example, an enamine adds to an aqQ-unsaturated carbonyl acceptor in a Michael-like process. The initial product is then hydrolyzed by aqueous acid (Section 19.8) to yield a 1,5-dicarbonyi compound. The overall reaction is thus a three-step sequence of (11 enamine formation from a ketone, (2) Michael addition to an a,j3-unsaturated carbonyl compound, and (3) enamine hydrolysis back to a ketone. 

Strategy The overall result of an enamine reaction is the Michael addition of a ketone as donor to an cr,/3-unsaturated carbonyl compound as acceptor, yielding a 1,5-dicarbonyl product. The C—C bond made in the Michael addition step is the one between the a- carbon of the ketone donor and the /3 carbon of the unsaturated acceptor. 

Allyl- and vinylsilane chemistry was one of the first areas of reagent synthesis impacted by CM methodology. Allylsilanes are commonly employed in nucleophilic additions to carbonyl compounds, epoxides, and Michael acceptors (the Sakurai reaction) vinylsilanes are useful reagents for palladium-coupling reactions. As the ubiquitous application of CM to this substrate class has recently been described in several excellent reviews, this topic will not be discussed in detail, with the exception of the use of silane moieties to direct CM stereoselectivity (previously discussed in Section 11.06.3.2). 

Nitroolefins are excellent Michael acceptors which react with a broad range of nucleophiles in a Michael fashion. The resulting functionalized nitroalkanes can be readily converted into amines by reduction reactions or to carbonyl compounds by a Nef reaction . The addition of nucleophiles to nitroolefins is complicated by the subsequent addition of the resulting nitronate to remaining nitroolefin. Whereas such a side-reaction is quite fast for lithium and magnesium nitronates. it is slow for zinc... 

Resin-bound amines can be converted into imines [710,711] or enamines by reaction with carbonyl compounds (Entries 6 and 7, Table 3.39). Resin-bound enamines have also been prepared by Michael addition of resin-bound secondary amines to acceptor-substituted alkynes [712], by Hg(II)-catalyzed addition of resin-bound secondary amines to unactivated alkynes [713], by addition of C-nucleophiles to resin-bound imino ethers [714], and by chemical modification of other resin-bound enamines [712,713,715], Acceptor-substituted enamines ( push-pull alkenes) are not always susceptible to hydrolytic cleavage by TFA alone and might require aqueous acids to undergo hydrolysis [716]. 

The chiral, nonracemic oxazepine derivative (46 Scheme 18) was studied as donor in the Michael addition to prochiral a,p-unsaturated carbonyl compounds.134-133 The products were obtained with 44-55% ee after removal of the chiral auxiliary group. With 1-nitrocyclohexene as acceptor, somewhat better se-lectivities (62% ee) were observed.136... 

A highly selective method for the preparation of optically active 3-substituted or 3, y-disubstituted-S-keto esters and related compounds is based on asymmetric Michael additions of chiral hydrazones (156), derived from (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) or its enantiomer (RAMP), to unsaturated esters (154).167-172 Overall, a carbonyl compound (153) is converted to the Michael adduct (155) as outlined in Scheme 55. The actual asymmetric 1,4-addition of the lithiated hydrazone affords the adduct (157) with virtually complete diastereoselection in a variety of cases (Table 3). Some of the products were used for the synthesis of pheromones,169 others were converted to 8-lactones.170 The Michael acceptor (158) also reacts selectively with SAMP hydrazones.171 Tetrahydroquinolindiones of type (159) are prepared from cyclic 1,3-diketones via SAMP derivatives like (160), as indicated in Scheme 56.172... 

The aza-Michael reaction yields, complementary to the Mannich reaction, P-amino carbonyl compounds. If acrylates are applied as Michael acceptors, P-alanine derivatives such as 64 and 65 are obtained. The aza-Michael reaction can be catalyzed by Bronsted acids or different metal ions. Good results are also obtained with FeCl3, as shown in Scheme 8.29. The addition of HNEt2 to ethyl acrylate (41f), for example, requires 10mol% of the catalyst and a reaction time of almost 2 days [94], The addition of piperidine to a-amino acrylate 41g is much faster and yields a,P-diaminocarboxylic acid derivative 65 [95]. 

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... 

Cheap and readily available L-proline has been used numerous times for the intermediate and reversible generation of chiral iminium ions from a,/ -unsaturated carbonyl compounds. For example, Yamaguchi et al. reported in 1993 that the rubidium salt of L-proline catalyzes the addition of di-iso-propyl malonate to the acyclic Michael acceptors 40a-c (Scheme 4.13), with enantiomeric excesses as high as 77% [22], With 2-cycloheptenone and 2-cyclohexenone as substrates ca 90% yield and ee of 59% and 49% were obtained. Later the enantioselectivity of this process was increased to a maximum of 88% ee in the addition of di-tert-butyl malonate to the E-pentenone 40a in the presence of 20 mol% Rb-L-prolinate and 20 mol% CsF [23], Taguchi and Kawara employed the L-proline-derived ammonium salts 41a and... 

The 1,4-addition (or conjugate addition) of resonance-stabilized carbanions. The Michael Addition is thermodynamically controlled the reaction donors are active methylenes such as malonates and nitroalkanes, and the acceptors are activated olefins such as a,P-unsaturated carbonyl compounds. 

According to Figure 13.44, ketones often do not engage in base-catalyzed aldol additions because of a lack of driving force. Hence, ketones also are less suitable electrophiles than aldehydes in aldol condensations. However, for ketones, too, the elimination step is irreversible and they can therefore form a,/i-unsaturated carbonyl compounds. It is not always possible to isolate the a,/3-unsaturated carbonyl compounds thus formed. If the 0-/1 atom is not sterically hindered, these products can act as electrophiles and add any residual ketone enolate the f/,/1-unsaturated carbonyl compound acts as a Michael acceptor in this case (Section 13.6.1). 

The conjugate addition of nucleophiles to a,/3-unsaturated carbonyl compounds at the /3-position was described in Section 18.10. Enolate and related carbanion nucleophiles also add in a conjugate manner to a./Tunsaturated carbonyl compounds in a process known as the Michael reaction or Michael addition. In many of the examples the enolate ion is one that is stabilized by two carbonyl (or similar) groups. The ,/3-unsatura(cd compound is called the Michael acceptor. 

Each step in the Robinson annelation is controlled by the various devices you have already met. In the conjugate addition step, the a,j3-uniaturated carbonyl compound is usually butenone or another ketone and they are suitable Michael acceptors. There is much more variation in the enol equivalent, Compounds with 1,3-dicarbonyi groups are popular so ester groups can be added to ketones and removed afterwards by hydrolysis and decarboxylation, Kcto ester react well in the Robinson annelation. The ester group stabilizes the enolate but is not very electrophilic. In this example McOK is the base for the conjugate addition and a weaker base is used for the aldol. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Michael acceptor is a powerful tool for carbon-carbon bond formation with simultaneous introduction of a new stereogenic center The binaphthyl derived phosphoramidite els, , )- ligand showed remarkable stereoselectivities in copper-catalyzed 1,4-addition of alkylzinc reagents to a,3-unsaturated carbonyl compounds. ... 

Another frequent use of (1) and its enantiomer is the stereospecific conjugate addition of carbonyl compounds to a,p-unsaturated systems. Most published examples contain chiral imine derivatives of cyclic ketones, which add to a,p-unsaturated esters and ketones in a highly stereoselective manner (eq 13 and eq 14). When the ketone is not symmetrically substituted, reaction usually occurs at the most substituted a-position, including those cases where the ketone is a-substituted by oxygen (eq 15). High stereoselectivity can also be achieved when the Michael acceptor is other than an unsaturated ketone or ester, such as a vinyl sulfone (eq 16). Intramolecular variations of this transformation have also been described (eq 17). ... 

This adduct is in equilibrium with the stable enolate from the keto-ester and elimination now gives an unsaturated carbonyl compound. Such chemistry is associated with the aldol reactions we discussed in Chapter 27. The new enone has two carbonyl groups at one end of the double bond and is therefore a very good Michael acceptor (Chapter 29). A second molecule of enolate does a conjugate addition to complete the carbon skeleton of the molecule. Now the ammonia attacks either of... 

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