Aldehydes as Michael Donors

° leading to very interesting results in this reaction and also showing that microwave activation could be a useful tool for achieving better conversion in much lower reaction times without loss of selectivity, which, consequently, allowed the use of lower catalyst loadings. ° Prolinal-deiived diaminal 12b, 

Chiral secondary amines attached to solid supports have also been used as a methodological approach to the development of recyclable catalysts. In these cases, cKck 1,3-dipolar cycloaddition reactions between a modified solid support incorporating an alkyne moiety and a substituted pyrrolidine 

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On the other hand, several primary amines have also been successfully employed as catalysts in the reaction using aldehydes as Michael donors. Important representative examples are shown in Figure 2.7, like bifunctional sulfamide 36 and primary amine-thioureas 37a and 23b,the latter being developed by Jacobsen and very similar to that used by the same group in the reaction with ketones as donors (see Scheme 2.7) and which performs exceptionally well in the Michael reaction of a,a-disubstituted aldehydes to both aromatic and aliphatic nitroolefins. 

Scheme 6.6 The intramolecular Stetter reaction using aliphatic aldehydes as Michael donors.

Feringa et al. developed aqueous Michael reactions catalyzed by Yb(OTf)3 (Eq. 1) [4]. fi-keto esters and a-nitro esters could be used as Michael donors for the reaction. a,y3-Unsaturated ketones and a,/5-unsaturated aldehydes without /S-substituents were good Michael acceptors for the reaction but the reaction did not proceed with ethyl acrylate or acrylonitrile. The reported yields were excellent, though the reaction required prolonged reaction time (3-5 days). 

Michael additions. 1,5-Ketoaldehydes are formed on the admixture of vinyl ketones, aldehydes, and MCjSiNEt at room temperature and without solvent. It is unusual that the aldehydes behave as Michael donors. 

Finally, it has also to be mentioned that enolizable a,p-unsaturated aldehydes have also been employed as Michael donors in this context (Scheme 2.18). This reaction proceeds via formation of a dienamine nucleophilic intermediate, which undergoes regioselective a-addition leading to the formation of the corresponding Michael adduct containing an a-substituted p,y-unsatu-rated aldehyde moiety. The conditions had to be carefully optimized and required the use of a y,y-disubstituted a,p-unsaturated aldehyde reagent and involved the use of catalyst 31a in the presence of AcOH as Bronsted acid cocatalyst and acetonitrile as solvent. In situ reduction of the Michael adducts was... 

The diflferent reactivity of aldehydes and ketones toward condensation with amines is also a differentiating element when using enals or enones as Michael donors under iminium activation. As in the enamine activation case, working with a,p-unsaturated aldehydes usually leads to faster reactions or better conversions but the same reaction with enones in many cases turns out to be a very slow or even non-existent reaction. Stereochemical control is also more problematic when a,p-unsaturated ketones are employed because the presence... 

It has to be pointed out that simple enolizable aldehydes and ketones, which are not acidic enough compounds to be directly used as pro-nucleophiles in this context, can nevertheless be employed as Michael donors in the reaction with enals or enones, which have been previously activated as the corresponding iminium ion, but their use requires prior activation via enamine activation. In these cases, it is usually proposed that the amine catalyst is involved in a dual activation profile interacting with both the Michael donor and the acceptor, although the enamine activation of the pro-nucleophile is mandatory for the reaction to occur, the activation of the acceptor being of less relevance in most cases. For these reasons, this chemistry has been covered in Chapter 2. 

Bis(phenylsulfonyl)methane has also been employed as an acidic carbon pronucleophile related to malonates and 1,3-diketones with success in the Michael reaction with ot,p-unsaturated aldehydes using 31c as catalyst (Scheme 3.6). The reaction showed a remarkable substrate scope when alkyl-substituted enals were employed but failed when cinnamaldehyde was tested as Michael acceptor. Alternatively, a more acidic cyclic gem-bissulfone has been used as Michael donor, keeping the high yields and enantioselectivities observed for the reaction and also allowing to expand the scope of the reaction to several aromatic enals.In all cases, the chemistry of the sulfonyl group was employed to generate a methyl group after metal-mediated desulfuration or, alternatively. 

It also has to be remembered that enolizable aldehydes or ketones can also be used as Michael donors in this reaction using thiourea-containing catalysts for... 

J0rgensen [111] and Vicario [112] independently described the conjugate addition of both triazole and tetrazole based nucleophiles to a,P-unsaturated aldehyde substrates as an alternative method for C-N bond formation. These reactions were catalysed by the diarylprolinol and imidazolidinone scaffolds with equal efficiency showing the complementarity and efficacy of both these catalyst architectures. In addition, Jprgensen has also shown succinimide to be an effective Michael donor (see Sect. 2.3.5 Scheme 49 for further details) [113]. 

The Morita-Baylis-Hillman reaction and its aza-variant - the reaction of an electron-deficient alkene with an aldehyde (MBH) or an imine (aza-MBH) - provide a convenient route to highly functionalized allylic alcohols and amines. This reaction is catalyzed by simple amines or phosphines, which can react as a Michael donor with an electron-deficient alkene, generating an enolate intermediate. This intermediate in turn undergoes the aldol or Mannich reaction with electrophilic C=0 or C=N bonds, respectively, to deliver allylic alcohols and amines. 

Enders and coworkers [300] used the lithiated carbanion of the chiral ami-nonitrile 1.70 as a Michael donor. Additions of this species to a,P-unsaturated esters are performed at -100°C. After removal of the chiral residue with aqueous CuS04, 3-branched-4-ketoesters are obtained with a high enantiomeric excess (Figure 7.66). 2-Cyclohexenone can also be used as an acceptor with equally good results [1453], Dienolate 7.100 has also been proposed as a chiral Michael donor [1454], but its reactions with a,p-unsaturated aldehydes give low chemical yields. 

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