Aldehydes to nitroalkenes

General comments about the Michael reaction procedures are analogous to those developed in the aldol and Mannich reactions.For example, the O-TMS-protected diphenylprolinol compound 20 in cooperation with benzoic acid catalyses the asymmetric Michael addition of aldehydes to nitroalkenes, in a simple, practical and efficient procedure. Benzoic acid promotes the rapid formation of the enamine intermediate and the reaction takes place in the highly concentrated organic phase of the aqueous biphasic system. 

Veverkova E, Polackova V, Liptakovi L, Kazmerova E, Meciarovi M, Toma S, Sebesta R. Organocatalyst efficiency in the michael additions of aldehydes to nitroalkenes in water and in a ball-mill. ChemCatChem 2012 4 1013-8. 

Scheme 2.12 Enantioselective Michael addition of aldehydes to nitroalkenes catalyzed by 31a and 3a.

Scheme 2.18 Enantioselective Michael addition of enolizable ot,p-unsaturated aldehydes to nitroalkenes via dienamine catalysis.

Addition of benzoic acid enhanced the reactivity of the catalyst in the Michael addition of aldehydes. Therefore, less reactive trisubstituted nitroalkenes could also be used. Acetic acid as acidic additive also helped in the addition of unsaturated aldehydes to nitroalkenes (Scheme 8.3). This reaction proceeds via dienamine activation of unsaturated aldehydes. 

Replacement of phenyl groups with AT-methyl imidazole moieties in the catalyst Cl structure led to catalyst C4 (Figure 8.2). ° This catalyst worked efficiently in aqueous media. Catalyst C4 catalysed Michael additions of aldehydes to nitroalkenes in a mixture of brine and NaHCOs. 

Michael additions of aldehydes to nitroalkene with catalyst Cl can also be performed under solvent-free conditions in a ball-mill. The reaction was considerably more efficient under ball-milling conditions than with conventional stirring. Ball-milling reactions proceeded faster and afforded the... 

Scheme 8.3 Michael addition of unsaturated aldehydes to nitroalkenes.

Paixao and coworkers showed that a sulfur-modified catalyst C5 was able to efficiently catalyse the Michael addition of malonates to enals in EtOH/ brine mixture (Scheme 8.7). The sulfur-containing catalyst was efficient for the Michael addition of aldehydes to nitroalkenes in polyethylene glycol (PEG). The most important feature of this system was its reusability. After extraction of the reaction products, the PEG solution containing the organocatalyst was reused at least four times with no adverse effects on yield or enantioselectivity. ... 

In 2006 Palomo and coworkers tested several prolinamides in the asymmetric Michael addition of aliphatic aldehydes to nitroalkenes. Hydroxy-proline-derived amides 13 were found to be the most active catalysts for this transformation, establishing the importance of the hydrojy group not only for reaction stereocontrol, but also for catalyst activity. However, 3-hydro>y-prolinamide 13b gave less satisfactory results in terms of stereocontrol, compared to the 4-hydro>y-prolinamide analogue 13a (Scheme 11.11). 

Scheme 11.38 Michael addition of aliphatic aldehydes to nitroalkenes (A) and asymmetric a-alkylation of carbonyl compounds (B) using pyrrolidine (S)-36.

The amine-catalysed asymmetric conjugate addition of aldehydes to nitroalkenes is a powerful tool for stereoselective carbon-carbon bond formation, and hence, a large number of chiral amine catalysts have been developed to date. ° In most amine-catalysed reactions, q n-conjugate adducts were obtained as major diastereomers. For instance, the reaction catalysed by a chiral pyrrolidine (5 )-6 gave a sy -conjugate adduct with excellent enantioselectivity (Scheme 17.13). In contrast, the reaction using a biphenyl-based amine catalyst (S)-7 is complementary to most amine-catalysed... 

Scheme 19.38 Michael addition of disubstituted aldehydes to nitroalkenes promoted by a chiral primary amine-thiourea.

Scheme 19.43 Polymer-supported chiral primary amine-urea catalysed conjugate addition of ketones and aldehydes to nitroalkenes.

Two recent publications on the mechanism of the organocatalytic enantioselective Michael addition of aldehydes to nitroalkenes have led to the revision of some of the structures depicted in Scheme 2.11 (see Ref. 199). 

SCHEME 5.6. Michael addition of a,a-disubstituted aldehydes to nitroalkenes. 

Based on their previous achievements in die Michael reaction of unmodified aldehyde [51], Chen and co-workers [16] recently developed the pyrrolidinyl-camphor derivatives as a new class of organocatalysts for the Michael addition of a,a-disubstituted aldehydes to nitroalkenes. In the presence of 22, the reactions were proceeded in high to excellent yields and enantioselectivities for symmetric a,a-disubstituted aldehydes and a wide range of p-nitroalkenes. However, poor enan-tiocontrol was obtained for unsymmetric a,a-disubstituted aldehydes (Scheme 5.8). 

Aminothiourea-prolinal dithioacetal (234), in the presence of PhC02H, can catalyse Michael addition of ketones R CH2COR and aldehydes to nitroalkenes at 3 mol% loading to afford the 3yn-configured products with <99 1 dr and <99% ee under solvent-free conditions at room temperature. The related carbohydrate-derived thiourea is believed to activate both 8-diketones and nitroalkenes via coordination (235) the Michael adducts were obtained in <89% ee " Another variant of the thiourea motif with a cinchona alkaloid scaffold exhibited higher stereocontrol in the same reaction (<98% ee), carried out in MeCN at —40°C ... 

On the other hand, several other analogues of proline were also capable of inducing chirality for the Michael addition of various aldehydes to nitroalkenes. 

Scheme 1.45 Silylated biphenylprolinol-catalysed Michael additions of aldehydes to nitroalkenes.

An unusual anh-selective conjugate addition of aldehydes to nitroalkenes is catalysed by a biphenyl-based chiral secondary amine (104). An NMR study shows the diastere- 0 oselectivity arises in the C-C bond-forming step. ... 

The proline-derived biaryls (369a,b) have been developed as yet another example of organocatalyst types for the addition of aldehydes to -nitroalkenes, matching the performance of its counterparts (<96% ee and <99 1 dr in favour of the iyn-diastereoisomer) ... 

Interestingly, unusual anh -diastereoselectivity (3.3 1) was observed for the conjugate addition of aldehydes to nitroalkenes, catalysed by the axially chiral amine (370), but still with high enantioselectivity (96% ee). ... 

Further to this work, the same group published another multicatalytic reaction in aqueous buffer, which involved two aldehydic substrates with similar reactivities but different polarities [11]. The biphasic reaction allowed the differentiation of the two aldehydes, which reacted in a controlled manner to generate the desired cross-product. Two catalysts were used, and each catalyst triggered an individual reaction step in either aqueous or organic phase. L-Proline, soluble in the aqueous phase, catalyzed the addition of nitromethane with the less hydrophobic aldehyde (Scheme 12.6). Diphenylprolinol trimethylsilyl ether 5, which is an efficient catalyst for the conjugated addition of aldehydes to nitroalkenes, catalyzed the reaction of the... 

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