Michael acceptors, base catalyzed

In this example, the /3-diketone 2-methyJ-l,3-cyclopentanedione is used to generate the enolate ion required for Michael reaction and an aryl-substituted a,/3-unsaturated ketone is used as the acceptor. Base-catalyzed Michael reaction between the two partners yields an intermediate triketone, which then cyclizes in an intramolecular aldol condensation to give a Robinson annulation product. Several further transformations are required to complete the synthesis of estrone. 

Michael additions. Conjugate addition of / -dicarbonyl compounds to various Michael acceptors is catalyzed efficiently by Ni(acac),. Yields arc usually higher than those obtained with traditional bases. 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

What product would you obtain from a base-catalyzed Michael reaction of 2,4-pentanedione with each of the following a,/3-unsaturated acceptors ... 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

The stereoselective formation of carbon-carbon bonds is an important problem in organic chemistry. The Baylis-Hillman-reaction allows the direct preparation of oc-methylene-/ -hydroxycarbonyl compounds by base-catalyzed reaction of a,/ -unsaturated carbonyl compounds with aldehydes [1-3]. The first step of this reaction involves nucleophilic attack of the catalyst onto the Michael-acceptor 1 under formation of the zwitterionic intermediate 2. Subsequently, this intermediate reacts in the rate-determing step of the Baylis-Hillman-reaction with the aldehyde 3 under formation of the alcoholate 4 (Scheme 1). The product 5... 

The development of efficient, asymmetric versions of the Baylis-Hillman-reaction for the synthesis of enantiomerically pure a-methylene-/ -hydroxycarbonyl and related compounds is still a rewarding issue. Interesting recent approaches for the solution of this problem include the use of chiral Michael acceptors or aldehyde/aldimine components. The use of stoichiometric or catalytic amounts of chiral base is also of great current importance. Besides the development of an asymmetric version of the Baylis-Hillman-reaction, alternative reaction sequences giving nonracemic Baylis-Hillman-adducts have attracted considerable attention. Likewise, the recently reported Palladium-catalyzed deracemization of Baylis-Hillman-adducts appears to be promising. Besides stereoselectivity, the low rate and chemical yields often observed in Baylis-Hillman reactions remain important issues to be carefully addressed in all future studies. 

According to Figure 13.44, ketones often do not engage in base-catalyzed aldol additions because of a lack of driving force. Hence, ketones also are less suitable electrophiles than aldehydes in aldol condensations. However, for ketones, too, the elimination step is irreversible and they can therefore form a,/i-unsaturated carbonyl compounds. It is not always possible to isolate the a,/3-unsaturated carbonyl compounds thus formed. If the 0-/1 atom is not sterically hindered, these products can act as electrophiles and add any residual ketone enolate the f/,/1-unsaturated carbonyl compound acts as a Michael acceptor in this case (Section 13.6.1). 

Phenol complexes of [Os] display pronounced reactivity toward Michael acceptors under very mild conditions. The reactivity is due, in part, to the acidity of the hydroxyl proton, which can be easily removed to generate an extended enolate. Reactions of [Os]-phenol complexes are therefore typically catalyzed using amine bases rather than Lewis acids. The regio-chemistry of addition to C4-substituted phenol complexes is dependent upon the reaction conditions. Reactions that proceed under kinetic control typically lead to addition of the electrophile at C4. In reactions that are under thermodynamic control, the electrophile is added at C2. These C2-selective reactions have, in some cases, allowed the isolation of o-quinone methide complexes. As with other [Os] systems, electrophilic additions to phenol complexes occur anti to the face involved in metal coordination. 

However, an encouraging result was obtained very recently for the 1,4-conjugate addition of dialkyl zinc to a variety of Michael acceptors catalyzed by copper. Alexakis, Roland and coworkers have investigated the addition of diethyl zinc to cycloheptenone and observed an enantiomeric excess of 93% (95% yield) in the presence of Cu(OAc)2 and the silver carbene derivative of imidazolium 1 (Scheme 3) [10]. Silver carbene complexes are efficient transfer agents to copper(II) and therefore the potentially harmful use of a base to generate the catalytic species is avoided. 

Implied in the stoichiometry of their preparation is the full equivalent of transition metal relative to substrate. Indeed, to this day, cuprates tend to be used in excess in most smaller scale reactions. Over the past decade, however, there has been a noticeable shift toward development of methodology catalytic in Cu(I). The rationale behind the emphasis is in line with the times that is, environmental concerns have come to the fore, placing implied limits on the extent of transition metal usage. Therefore, notwithstanding favorable economic factors associated with copper, it being a base rather than precious metal, much effort has been devoted toward copper-catalyzed reactions, including cross-couplings to arrive at C-N, C-O, and C-H, in addition to C-C bonds. Moreover, tremendous strides have been made in asymmetric versions of perhaps the most fundamental of cuprate reactions 1,4-additions to Michael acceptors. 

The enone 3 was further functionalized via tandem reaction by Michael addition of methanol to the conjugate system at C-5, followed by base catalyzed nitromethane addition to the keto function at C-2 and base catalyzed (TMG -tetramethylguanidine) mesylation/elimination with the formation of new a-nitroenone as depicted in Scheme 7. The intermediate a-nitroenone functionalized at C-2 as a conjugate system is indeed an excellent Michael acceptor of reactive nucleophiles, including 1-thio-P-D-glucose. The conjugate addition of this reactive thiol was performed in the same fashion as before (2, 3) with the stereoselective formation of the first representative example of highly functionalized and previously unknown class of C-nitro-5-thiodisaccharide derivatives. 

Dimethyluracils substituted in the 5-position, preferably with electron-withdrawing groups, react as Michael acceptors with 6-aminouracils. By a base-catalyzed ring transformation, the C—C —C unit bearing the electron-withdrawing substituent builds up the C5-C6-C7 part of the final pyrido[2,3-t/]pyrimidine-2,4,7(1//,37/,8//)-trione 21.240,241... 

A series of chiral triazolium salts have been reacted with a base to form the corresponding chiral carbenes, which was shown to catalyze the Stetter reaction efficiently and to provide 1,4-dicarbonyl products in high yields and enantioselectivities (eq 33). A survey of common bases identified KHMDS as providing an optimal balance between the yield and selectivity in this reaction. The reaction is sensitive to the nature of the Michael acceptor while electron deficient -alkenes provided the desired product in good yields and enantioselectivities, no reaction was observed in the case of Z-alkenes. ... 

This reaction was first reported by Mukaiyama et al. in 1974. It is a Lewis acid-catalyzed Michael conjugate addition of silyl enol ether to o ,/3-unsaturated compounds. Therefore, it is generally referred to as the Mukaiyama-Michael reaction. Because this reaction is essentially a conjugate addition, it is also known as the Mukaiyama-Michael addition or Mukaiyama-Michael conjugate addition. This reaction is a mechanistic complement for the base-catalyzed Michael addition, j and often occurs at much milder conditions and affords superior regioselectivity. s Besides silyl enol ether, silyl ketene acetals are also suitable nucleophiles in this reaction.For the hindered ketene silyl acetals, the Lewis acid actually mediates the electron transfer from the nucleophiles to o ,/3-unsaturated carbonyl molecules.On the other hand, the Q ,j8-unsaturated compounds, such as 3-crotonoyl-2-oxazolidinone, alkylidene malonates, and a-acyl-a,/3-unsaturated phosphonates are often applied as the Michael acceptors. It has been found that the enantioselectivity is very sensitive to the reactant structures —for example, Q -acyl-Q ,j8-unsaturated phosphonates especially prefers the unique syn- vs anft-diastereoselectivity in this reaction. In addition,... 

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... 

The enantioselective phase-transfer catalyzed Michael addition of A-(diphenyl-methylene)glycine fert-butyl ester to several Michael acceptors such as methyl acrylate, cyclohex-2-enone and ethyl vinyl ketone was initially studied by Corey et al. employing 0(9)-aUyl-Af-9-anlhraceny]melhylcinchonidimum bromide (173) (Fig. 2.24) as catalyst and cesium hydroxide as base [272]. Different studies followed this pioneering woik, presenting diverse modifications over the standard procedure such as the employment of non-ionic bases [273], variations of the nucleophile functionality [274], and using new chiral phase-transfer catalysts, the most attention paid to this latter feature. For instance, catalyst 173 was successfully employed in the enantioselective synthesis of any of the isotopomers of different natural and unnatural amino acids... 

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