Enolizable aldehydes, Michael addition

The first asymmetric direct Michael addition of enolizable aldehydes RCH2CH=0 to vinyl sulfones CH2=C(S02Ph)2 catalysed by /V-Pr -2,2 -bipyrrolidine (146) has been reported. The 1,4-adducts were obtained in good yields and enantioselectivities... 

Most examples of quinone dehydrogenations adjacoit to have been earned out on steroidal ketones and are essentially limited to readily enolizable species. Reactions on esters and amides (Table 8) are far less common and, because of their relatively low ease of enolization, require hanh conditions. Thus, unless stabilization of the intermediate carbonium ion is possible, - elevated temperatures and prolonged reaction times are required (Table 8), which increases the incidence of unwanted side reactions. Frequent by-products are those arising as a result of Diels-Alder reactions or Michael addition to the quinone." Allylic alcohols may be rapidly oxidized to aldehydes or ketones under these conditions and requite prior protection. 

Surfaces with basic sites form enolates from both the aldehydes and ketones, leading to multiple aldol condensations and Michael additions. " Candidate molecules must be enolizable, i.e., contain an a-hydrogen atom. Aldol condensation / Michael addition products cover the range from a,p-unsaturated aldehydes, saturated aldehydes, hydrogenated products (alcohols), and the heavier aromatics resulting from multiple condensations. The presence of coordina-... 

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

A similar cascade reaction was reported by Melchiorre and co-workers [69] in 2008. Initially, this triple cascade reaction between an enolizable aldehyde, 2-cyanoacrylate, and enal consists of the aldehyde addition to a 2-cyanoacrylate derivative (108), promoted by a diphenylprolinol derivative (VII). Next, the resulting adduct reacts with enal via a Michael addition promoted by the same catalyst. Finally, an intramolecular aldol reaction takes place between the formed enamine and the aldehyde, leading to the cyclohexane 109. It should be noticed that the use of an acid as a co-catalyst is cmcial to obtain high levels of stereoselectivity. 

Headley and coworkers developed suJfamides St9a [109], 99b [110], and 100 (Figure 22.8) [111] bearing the (S)-pyrrolidine and 1,3-dialkylimidazolium structural units, which exhibited a high catalytic performance in asymmetric Michael additions of enolizable aldehydes or ketones to P-nitrostyrene derivatives. Sulfa-mide 100 [111] and ClL-catalyst 101 synthesized by Xu and coworkers [112], in... 

Later, the same group expanded this chemistry further by developing a cascade Michael addition/cross-benzoin condensation sequence of enolizable aldehydes 43 and activated enones 44 [27]. The reaction proceeded by means of enamine activation of aliphatic aldehydes to induce an asymmetric Michael addition to activated enones followed by an intramolecular cross-benzoin condensation (Scheme 9.30). Compared with their previous work, complex cyclopentanones with complementary substitution patterns were observed. Screening of the reaction parameters revealed that the chiral triazolium catalyst was necessary to ensure a satisfactory stereochemical outcome. Further mechanistic insights indicated that the high diasteroselectivity observed attributed to the secondary amine-induced epimerizing of the a-position of intermediate aldehyde 89. 

The simplest enolizable aldehyde, acetaldehyde, was until recently not examined in organocatalytic reactions due to its high reactivity as electrophile or as nucleophile leading to intractable mixture of products resulting from side reactions. The groups of List [63] and Hayashi [64] reported independently the use of acetaldehyde as donor in Michael addition to nitroalkenes (Scheme 34.24). They both selected diphenylprolinol silyl ether (6) as the best catalyst but employed different solvents (acetonitrile or DMF/Pr OH for List, and 1,4-dioxane for Hayashi) at room temperature. Similar selectivities were observed under both conditions but higher yields were obtained with Hayashi s conditions. 

The anions, generated in situ by desilylation of silylacetylenes, allylsilanes, propargylsilanes, a-silyloxetanones, bis(trimethylsilylmethyl) sulfides, and other silane derivatives,can undergo nucleophilic addition to ketones and aldehydes (eq 11). Al-(C,C-bis(trimethylsilyl)methyl) amido derivatives can add to aldehydes followed by Peterson alkenation to form acyl enamines. Treatment of 2-trimethylsilyl-l,3-dithianes can generate dithianyl anions, which are capable of carbocyclization via direct addition to carbonyl or Michael addition (eq 12). The fluoride-catalyzed Michael additions are more general than Lewis acid-catalyzed reactions and proceed well even for those compounds with enolizable protons and/or severe steric hindrance (eq 13). ... 

Proline and proline derivatives have been utilized extensively as chiral catalysts for a wide range of asymmetric transformations [40, 132]. Gelman has documented a remarkable case in which enolizable aldehydes undergo selective Michael additions to enone acceptors (Equation 28) [133]. Diphenylpro-linol methyl ether (165) proved superior to other prolinol derivatives in terms of enantioselectivity and reactivity. As an example, the addition of oc-tanal (163) to ethyl vinyl ketone (164) in the presence of 5 mol% of 165 was carried out without solvent to furnish 166 in 87% yield and >95% ee. 

Knoevenagel condensation of aldehydes with malononitrile under mechanochemi-cal mixing in the presence of MgO resulted in adducts of general structure 138 (Scheme 27), which were further treated with either ethylacetoacetate or 5,5-dimethylcyclohexane-l,3-dione to provide products 139 and 140 [63]. The transformation of 138 and 139 or 140 proceeded via a Michael-type nucleophilic addition of the enolizable ketoester or dione, followed by intramolecular cyclization. 

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 use of ot,p-unsaturated aldehydes as Michael acceptors always represents a challenging situation because of the tendency of enals to undergo 1,2- rather than the desired 1,4- addition reaction. Moreover, working under phase-transfer catalysis conditions incorporates an additional element of difficulty, because of the propensity of enolizable enals to undergo self-condensation side reactions. For this reason, there are only a few examples reporting enantioselective Michael reactions with ot,p-unsaturated aldehydes as Michael acceptors under PTC conditions, both coming from the Maruoka research team and also both making use of chiral tV-spiro quaternary ammonium salts as catalysts. 

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