Enals aromatic

Recently, Bode et al. were able to demonstrate that the products formed after generation of the homoenolate equivalents 67 are determined by the catalytic base [64]. Strong bases such as KOt-Bu led to carbon-carbon bond-formation (y-butyrolactones), while weaker bases such as diisopropylethylamine (DIPEA) allowed for protonation of the homoenolate and the subsequent generation of activated carboxylates. The combination of triazolium catalyst 72 and DIPEA in THF as solvent required no additional additives and enabled milder reaction conditions (60 °C), accompanied by still high conversions in the formation of saturated esters out of unsaturated aldehydes (Scheme 9.21). Aliphatic and aromatic enals 62, as well as primary alcohols, secondary alcohols and phenols, are suitable substrates. a-Substituted unsaturated aldehydes did not yield the desired products 73. 

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. 

There is also another similar case in which 5-oxohexanal was employed as functionalized Michael donor undergoing Michael addition/intramolecular aldol reaction with aromatic enals (Scheme 7.3), which also ended up with a final dehydration step leading to the formation of functionalized cyclohexenes. Under the optimized reaction conditions, the final compounds were obtained in moderate yields but with excellent enantioselect vities and as single diaster-eoisomers. It should be pointed out that, from the mechanistic point of view, a dual activation of the 5-oxohexanal via enamine formation) and the a,p-unsaturated aldehyde via iminium ion formation) might operate in this case in the catalytic cycle, although no mechanistic proposal was provided by the authors. 

Seheme 7.38 NHC-catalyzed as)mimetric cross-annulation of aromatic enals and isatins reported by Ye. 

Scheme 7.56 NHC-catalyzed asymmetric self-annulation of aromatic enals reported by Scheidt.

Best results were obtained with aromatic enals that achieved a total trans diastereoselectivity with superb enantioselectivities (up to 99%). Later on, some other groups expanded the scope of the reaction. In 2009, Rios and co-workers [16] studied the reaction of 2-bromoketoesters instead of 2-bromomalonates, adding a new chiral center to the reaction, with good results. One year later, Vicario and co-workers [17] expanded the scope of the reaction by using water as a solvent. Another important contribution was recently made by Campagne and co-workers [18]. They used a-substituted-a,(3-unsaturated aldehydes with excellent results. 

On the other hand, Wang and co-workers [28, 29] made two important contributions to the synthesis of cyclopentene derivatives. Both reactions were initiated with a carbo-conjugated addition of malonates derivatives. The first one was a double Michael addition between enals and 7-malonate-a,(3-imsaturated esters catalyzed by XII rendering the final cyclopentanes with three stereogenic centers in good yields (87-92%) and excellent stereoselectivities (84—99% ee) [28]. As for the second one, Wang and co-workers focus on the synthesis of cyclopentenes. This reaction was based on a Michael-aldol sequence followed by dehydration, between aromatic enals and dimethyl 2-oxoethylmalonate [29]. A set of densely functionahzed chiral cyclopentenes were synthesized in high yields (63-89%) and excellent enantiose-lectivities (91-97% ee) (Scheme 10.13). 

The substrate scope of the reaction is shown in Scheme 10.2. Aliphatic and aromatic enals, branched enolizable aldehydes, and different substituted unsaturated 2-indolones could be used to afford the corresponding spirooxindoles in excellent yields and high stereoselectivity. Later, Chen and coworkers expanded the substrate scope of this reaction using maleimides and imines instead of enals to afford the spiro products in excellent yields and stereoselectivities [11]. 

The broad substrate scope of this reaction was demonstrated by using different aliphatic and aromatic enals along with several N-H-free oxindoles. In all the examples, excellent yields and stereoselectivities were obtained. Moreover, the substrate scope of the reaction was extended to other heterocycles such as pyrazolones... 

One of the first 1,3-dicarbonylic carbon nucleophiles added in asymmetric fashion to iminium activated enals was malonates. In 2006, Jorgensen et al. reported the reaction between malonates and enals catalyzed by catalyst 28 [20]. The final products 42 were obtained in good yields and excellent enantioselectivities. The only limitation of this methodology is that only aromatic enals could be used. To overcome this hmitation, Oriyama and coworkers employed catalyst 43 to promote the reaction between crotonaldehyde and malonates in moderate yields and enanti-oselectivities (Scheme 33.6) [21]. 

Soon after this, the research groups of Aleman [44], Rios [45], and Palomo ]46] reported, almost at the same hme, the first formal methyl addition to enals. Aleman and Rios used bis(phenylsulfonyl)methane as nucleophile while Palomo used a more active cyclic gem-bis(sulfone) (66). In the first two works, the reaction was limited to aliphatic enals, while the methodology reported by Palomo allows the use of both aliphatic or aromatic enals. In aU the cases, the results in terms of yield and enantioselectivity were excellent (Scheme 33.14). 

The first organocatalytic oxo-Michael addition to enals was reported by Jot-gensen in 2007 [65], Jorgensen used as a suitable nucleophile benzaldehyde oxime, which reacts with enals with catalysis by 28. The resulting product, reduced directly to the alcohol due its UabiUty, was obtained in excellent yields and enan-tioselectivities (Scheme 33.20). The oxime moiety can easily be cleaved to afford the 1,3-diols without loss of enantiomeric purity. However, aromatic enals turned out to be unreactive in this transformation. 

Since the early example of a proline-catalyzed asymmetric domino Michael-aldol reaction reported by Bui and Barbas in 2000 [57], a number of these reactions have been successfully developed by several groups. For example, Wang et al. have reported the synthesis of chiral densely functionalized cyclopentenes on the basis of a domino Michael-aldol reaction followed by dehydration between aromatic enals and dimethyl 2-oxoethylmalonate [67]. High yields (63-89%) and enanhose-lectivities (91-97% ee) were obtained by using (S)-diphenylprolinol sUyl ethers as catalysts. On the other hand, the condensation of P-nitroketones 36 onto enals in the presence of 8 was shown by Hong et al. to afford the corresponding domino Michael-aldol products 37 through the iminium-enamine activation mode [68]. 

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