Ketones as Michael acceptors

Using methyl vinyl ketone as Michael acceptor, it was found (42) that a variety of donors gave optically active products when quinine was used as the chiral catalyst. Figure 7 lists the donors. Unfortunately in none of these cases... 

The reactivity of the dimetallic compounds 186a and 186b was then investigated and these species were less reactive than their formulas would lead to predict, as no reaction occurred with ketones, esters, Michael acceptors or trimethylsilyl chloride. In the presence of BF3 OEt2, addition occurred to aldehydes and led after /3-elimination to the corresponding olefination products 189 with good to excellent (E) stereoselectivity (equation 92)127. 

C-Nucleophiles have recently been added asymmetrically to azodicarboxylates as Michael-acceptors, resulting in a-amination of the nucleophilic component. Examples of this type of reaction, which is based on activation of the aldehyde or ketone component by enamine formation, are summarized in Scheme 4.27. Please note that this type of reaction is covered in more detail in chapter 7 of this book. 

The neutral 1,4- and 1,2-quinone methides react as Michael acceptors. However, the reactivity of these quinone methides is substantially different from that of simple Michael acceptors. The 1,6-addition of protonated nucleophiles NuH to simple Michael acceptors results in a small decrease in the stabilization of product by the two conjugated 7T-orbitals, compared to the more extended three conjugated 7T-orbitals of reactant. However, the favorable ketonization of the initial enol product (Scheme 1) confers a substantial thermodynamic driving force to nucleophile addition. By comparison, the 1,6-addition of NuH to a 1,4-quinone methide results in a large increase in the -stabilization energy due to the formation of a fully aromatic ring (Scheme 2A). This aromatic stabilization is present to a smaller extent at the reactant quinone methide, where it is represented as the contributing zwitterionic valence bond structure for the 4-0 -substituted benzyl carbocation (Scheme 1). The ketonization of the product phenol (Scheme 2B) is unfavorable by ca. 19 kcal/mol.1,2... 

To date, this type of phase-transfer-catalyzed Michael reaction of 28 has been investigated with either acrylates or alkyl vinyl ketones as an acceptor, under the influence of different catalysts and bases. Typical results are listed in Table 4.6 in order to determine the characteristics of each system. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

Allenic ketones are important materials due to their interesting utility as Michael acceptors, Diels-Alder dienophiles, and 1,3-dipoles in unusual [8+2] annulation and building blocks in furan. For the first time, oxidation of homopropar-gilic alcohols to 1,2-allenic ketones with t-BuOOH as oxidant and RuClj as catalyst... 

NaBHj/NiC or Raney nickel, the menthyloxy group is removed with NaBH /KOH to give 3,4-disubstituted butyrolactones with a high diastereo- and enantioselectivity (Figure 7.69). Corey and Houpis [1458] have described asymmetric Michael reactions of ketone enolates with a 2-thiophenyl crotonate of 8-phenmenthol. Chirality has also been introduced on the amino group of 2-ami-nomethyiacrylates to perform the asymmetric addition of the anion of the tert-Bu ester of cyclopentanecarboxylate [1459], More important developments have been reported with chiral a,p-unsaturated sulfoxides and nitro compounds as Michael acceptors (see below). 

A particularly difficult situation arises when combining in the same reaction the use of these rather unreactive acceptors such as enones with the incorporation of ketones as Michael donors in which the formation of the intermediate enamine by condensation with the amine catalyst is much more difficult. For this reason, the organocatalytic Michael addition of ketones to enones still remains rather unexplored. An example has been outlined in Scheme 2.22, in which it has been shown that pyrrolidine-sulfonamide 3a could catalyze the Michael reaction between cyclic ketones and enones with remarkably good results, although the reaction scope was exclusively studied for the case of cyclic six-membered ring ketones as nucleophiles and 1,4-diaryl substituted enones as electrophiles. In this system the authors also pointed toward a mechanism involving exclusively enamine-type activation of the nucleophile, with no contribution of any intermediate iminium species which could eventually activate the electrophile. Surprisingly, the use of primary amines as catalysts in this transformation has not been already considered. 

There is also an interesting example of an enantioselective thiourea-catalyzed oxa-Michael reaction using enones as Michael acceptors in which phe-nylboronic acid was employed as hydroxyl anion equivalent (Scheme 4.64) The authors demonstrated that amine bases were able to activate these kinds of reagents by complexation, thus becoming effective reagents for the transfer of the OH group to the Michael acceptor. The reaction had to proceed in an intramolecular way and, for this reason, y-hydroxy-a,(3-unsaturated ketones had to be employed as substrates. In the enantioselective version, 71b was identified as a very efficient catalyst, providing a series of (3,y-dihydroxy ketones in excellent yields and enantioselectivities, after oxidative work-up. The process consists of the initial reaction of the boronic add first with the y-hydroxy... 

Continuing with the use of cinchona alkaloid-based quaternary ammonium salts as catalysts, phenyl vinyl sulfones have also been employed as Michael acceptors in the reaction with glycine imines using cinchonidinium salt 103a as catalyst both in solution or in a solid-supported version (Scheme 5.33), furnishing similar results to those provided by the corresponding vinyl ketones and acrylates shown in Schemes 5.8 and 5.23. ... 

Highly substituted cyclohexanes and cyclopentanes have been prepared by means of a cascade process involving the use of a nitroalkene as Michael acceptor and an a-substituted p-ketoester incorporating a lateral p-substituent with a terminal methyl ketone moiety at the convenient position, ready to... 

Many a, -unsaturated ketones (p-quinones, in particular) add diazomethane to give diazoline adducts (26). The bonding processes at both ends involve soft-soft interactions. As Michael acceptors, p-benzoquinone and its sul-fonylimine derivatives react with enamines to afford dihydrobenzofurans (64) and indolic compounds (65), respectively. 

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