Enolizable aldehydes, Michael

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... 

An intramolecular tandem Michael aldol reaction was described for esters that have an enolizable aldehyde in the molecule. The lithium ester enolate generated through the Michael reaction undergoes an intramolecular aldol reaction. Thus, the reaction of unsaturated esters 153 with lithium benzylthiolate provided the expected cyclization products 156 and 157 via (w-formylenolate 154 in an excellent cis stereoselectivity (Scheme 49)no. 

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. 

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... 

The triple Michael/Michael/aldol sequence developed by Enders shown in Scheme 7.8 can probably be considered as one of the most impressive demonstrations of the ability and power of enantioselective organocatalytic cascade reactions for the generation of molecular complexity from very simple and cheap starting materials." In this reaction, a nitroalkene, an enolizable aldehyde and an a,p-unsaturated aldehyde reacted with each other in the... 

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. 

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. 

Benzofuran-3(2/f)-ones (396) exist in the keto form but undergo ready enolization. Acetylation with acetic anhydride and sodium acetate affords 3-acetoxybenzo[6]furans, but reaction under acidic conditions usually supplies these products admixed with 3-acetoxy-2-acetylbenzo[6]furans. Alkylation usually furnishes a mixture of O- and C-alkylated products. 3-Acetoxy-6-methoxy-4-methylbenzo[6]furan, on Vilsmeier reaction, supplies the 3-chlorobenzo[6]furan-2-carbaldehyde, the product expected from an enolizable ketone (72AJC545). Benzofuran-3(2//)-ones react normally with carbonyl reagents. Grignard reagents react in the expected way and dehydration of the intermediate affords a 3-substituted benzo[6]furan. The methylene group is reactive so that self condensation, condensation with aldehydes and ketones and reaction with Michael acceptors all occur readily. 

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. 

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. 

Diethylphosphonomethyl-3-methylisoxazole was alkylated and olefinated by reaction of its anion with alkyl halides and aldehydes <1999S2027>. Reactions of 3-methyl-4-nitro-5-styrylisoxazole with bis-enolizable ketones have been investigated. Michael adducts were obtained in good yields with substoichiometric amounts of base while spiroisoxazolines were the major products when the base was employed in large excess <2002TL4157>. 

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.

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. 

However, even though this reaction proceeds in a very efficient way when an aromatic aldehyde is employed as the Michael donor, the use of aliphatic aldehydes is much more problematic due to the intrinsic instability of enoliz-able aldehydes in the basic media required in the reactions catalyzed by A-heterocyclic carbenes. In fact, pre-catalyst 119a performed poorly in this case, but this limitation was overcome with the use of bicyclic triazolium salt 120a derived from phenylalanine as catalyst precursor. This new A-heterocyclic... 

These problems could be minimized by the use of bulky and readily enolizable malonates and a sterically hindered organocatalyst such as 145. Accordingly, substrate 144, bearing a nucleophilic malonate and an electrophilic aldehyde group, was utilized for the cascade Michael-aldol condensation process (Scheme 1.54) [90]. The process is catalyzed efficiently by readily available (S)-diphenylprolinol triethylsilyl ether 145 to give synthetically useful, highly functionalized chiral cyclopentenes. 

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). ... 

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