Michael addition of enols, to enones

Selective formation of 1,5-dicarbonyl compounds by 1,4-addition (Michael addition) of enolates to enones is facilitated by the use of enol silyl ethers as enolate equivalents [37]. The reaction is catalyzed by... 

The hindered aluminum tris(2,6-diphenylphenoxide) is an effective promoter of Michael additions of enolates to enones.89... 

Diketones are accessible via a number routes, for example by Michael addition of enolate to enone (or precursor Mannich base " ) or by ozonolysis of a cyclopentene precursor. They react with ammonia, with loss of two mole equivalents of water to produce cychc bis-enamines, i.e. 1,4-dihydro-pyridines, which are generally unstable, but can be easily and efficiently dehydrogenated to the aromatic heterocycle. 

Once you understand the mechanisms, concentrate on the synthetic applications of the process. Focus on the carbon-carbon bond-forming examples, with particular emphasis on the Michael addition, the 1,4-addition of enolates to enones or enals. The combination Michael addition-aldol condensation provides a powerful means of synthesis of six-membered rings, the Robinson annulation. Don t worry about all these people s names learn the retrosynthetic analysis for compounds containing six-membered rings. 

Michael addition.2 This triflate is an effective catalyst for Michael addition of enol silyl ethers to a,P-enones such as methyl vinyl ketone to provide adducts in 60-75% yield, equation (I). This variation is useful in Robinson annelations. 

Dibutyltin bis(triflate), Bu2Sn(OTf)2, is a mild Lewis acid which catalyzes clean Michael addition of enol silyl ethers [148]. The new catalyst enables use of various labile acceptors such as methyl vinyl ketone and 2-cyclopentenone which do not undergo smooth reaction with conventional Lewis acids. A variety of enol silyl ethers are also employable and thus 2-(trimethylsiloxy)propene, the simplest of this class of compounds, can be used. The adducts of enol silyl ethers of cycloalkanones with vinyl ketones are readily cyclized to give the desired annulated enones free of isomers. Consequently, a practical version of the Robinson annulation has been realized. 

Another example of organocatalytic Michael addition apphed in total synthesis is that J0rgensen and co-workers [38] developed an asymmetric total synthesis of (/ )-warfarin (104) in 2003 as shown in Scheme 17.17. The key Michael addition of enol 101 to enone 102 was catalyzed by chiral diamine 103 to afford (/ )-warfarin (104) in... 

Carbon nucleophiles enols and enolates The direct Michael addition of enol acetates R CH=C(OAc)R to enones R CH=C(R )COR" has been attained using a combination of the Lewis acidic catalysts InCl3 and Me3SiCl, which generate stable enol-form intermedites4 ... 

Conjugate addition of allylsilanes to enones results in regiospe-cific introduction of the allyl group (eq 34). The reaction can be intramolecular (eq 35). TiCU or SnCU activates nitro alkenes for Michael addition with silyl enol ethers or ketene silyl acetals. The silyl nitronate product is hydrolyzed to a 1,4-diketone or -y-keto ester (eq 36). ... 

In the Michael addition of achiral enolates and achiral Michael acceptors the basic general problem of simple diastereoselection (see Section D.1.5.1.3.2.), as described in Section 1.5.2.3.2. is applicable. Thus, the intermolecular 1,4-addition of achiral metal enolates to enones, a.jS-unsat-urated esters, and thioamides, results in the formation of racemic syn-1,2 and/or anti-3,4 adducts. 

When chiral enolates or chiral Michael acceptors are used, for instance, when stereogenic centers are present in the substrate or when X or Y are chiral auxiliaries, both simple and induced diastereoselectivity is observed. This results, in principle, in the formation of four diastereomers 1 -4. The diastereoselectivity in the Michael addition of lithium enolates to enones can be rationalized by consideration of chelated transition states A-D372. 

Four different orientations are possible when the enantiofaces of (E)- and (Z)-enolates and an ( )-enone combine via a closed transition state, in which the olefinic moieties of the donor and the acceptor are in a syn arrangement. It should be emphasized that, a further four enan-tiomorphous orientations of A-D are possible leading to the enantiomers 2 and 3. On the basis of extensive studies of Michael additions of the lithium enolates of esters (X = OR) and ketones (X = R) to enones (Y = R) it has been concluded ... 

The reactions of the lithium enolates of substituted 2-cyclohexenones and 2-cyclopentenones with ( )-l-nitropropene give a mixture of syn- and ami-products3. The lithium enolate of 3,5,5-trimethyl-2-cyclohexenone gives a mixture of the syn- and //-3.5,5-trimethyl-6-(l-methyl-2-nitroethyl)-2-cyclohexcnoncs in modest diastereoselection when the reaction mixture is quenched with acetic acid after. 30 minutes at —78 =C. When the reaction mixture is heated to reflux, tricyclic products are obtained resulting from intramolecular Michael addition of the intermediate nitronate ion to the enone moiety. 

Key features of the cyclopropanation include the ylide acting as a mild base to isomerize the 1,2-dioxines into cis-y-hydroxy enones, followed by Michael addition of the ylide and last by cyclization of the intermediate enolate [35]. It must be noted that the trans-y-hydroxyenones do not give the cyclopropanation. 

Domino transformations combining two consecutive anionic steps exist in several variants, but the majority of these reactions is initiated by a Michael addition [1]. Due to the attack of a nucleophile at the 4-position of usually an enone, a reactive enolate is formed which can easily be trapped in a second anionic reaction by, for example, another n,(5-urisalurated carbonyl compound, an aldehyde, a ketone, an inline, an ester, or an alkyl halide (Scheme 2.1). Accordingly, numerous examples of Michael/Michael, Michael/aldol, Michael/Dieckmann, as well as Michael/SN-type sequences have been found in the literature. These reactions can be considered as very reliable domino processes, and are undoubtedly of great value to today s synthetic chemist... 

Rhodium(i) complexes are excellent catalysts for the 1,4-addition of aryl- or 1-alkenylboron, -silicon, and -tin compounds to a,/3-unsaturated carbonyl compounds. In contrast, there are few reports on the palladium(n) complex-catalyzed 1,4-addition to enones126,126a for the easy formation of C-bound enolate, which will result in /3-hydride elimination product of Heck reaction. Previously, Cacchi et al. described the palladium(n)-catalyzed Michael addition of ArHgCl or SnAr4 to enones in acidic water.127 Recently, Miyaura and co-workers reported the 1,4-addition of arylboronic acids and boroxines to a,/3-unsaturated carbonyl compounds. A cationic palladium(n) complex [Pd(dppe)(PhCN)2](SbF6)2 was found to be an excellent catalyst for this reaction (dppe = l,2-bis(diphenyl-phosphine)ethane Scheme 42).128... 

Michael additions of ketone enolates. The stereochemistry of Michael additions of lithium enolates of ketones to a,(3-enones is controlled by the geometry of the enolate. Addition of (Z)-enolates results in anti-products with high diaster-eoselectivity, which is not changed by addition of HMPT. Reaction of (E)-enolates is less stereoselective but tends to favor syn-selectivity, which can be enhanced by addition of HMPT. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

Michael addition of tin(II) dienolates.1 The tin(II) dienolates of (3,y-enones undergo y-selective addition to acyclic ot,(3-enones to give frans-l,7-enediones. If the reaction is carried out at high dilution, the intermediate tin(II) enolate can undergo an intramolecular aldol cyclization to give a cyclohexenol. 

The titanium(IV) chloride-catalyzed conjugate addition of enol silyl ethers (182) to (184) and (189 Scheme 30), and silyl ketene acetals, (191) to (194), to ot, 3-enones is die key feature in various synthetic strategies (Mukaiyama-Michael) (Scheme 31).78 79 In contrast to the earlier described enolate addition... 

In the first attempts to use a chiral a-sulfinyi ester enolate as donor in Michael additions to a -un-saturated esters, only low selectivities were observed.185 186 Better results are obtained when the a-lithio sulfoxide (174), a chiral acyl anion equivalent, is employed. Conjugate addition of (174) to cyclopent-enone derivatives occurs with reasonably high degrees of asymmetric induction, as exemplified by the preparation of the 11-deoxy prostanoid (175 Scheme 63).187 188 Chiral oxosulfonium ylides and chiral li-thiosulfoximines can be used for the preparation of optically active cyclopropane derivatives (up to 49% ee) from a, -unsaturated carbonyl compounds.189... 

The stability of an a-silyl carbanion is responsible for the unproved synthetic utility of the Stork annulation over other annulations195,196. These reactions involve the Michael addition of an enolate ion to an enone, and in the absence of a a-silyl substituent suffer drawbacks due to the reversibility of the Michael reaction. However, the addition of enolate ions to a-trimethylsilylvinyl ketones is not reversible, owing to a-silicon stabilization of the canonical form 152 shown in equation 122. 

Selective and efficient Michael additions of heterocyclic enamines (e.g. indoles, pyrroles, and pyrazoles) to enones can be catalysed by ZrCU (2 mol%).150 Michael addition of a - cy an o k e t e n e -. V,. S - ac et al s (RS)2C=CHCN to enones R CH=CHCOR2 can be promoted by TiCl4.151 Addition of the lithium enolate, generated from (2S,5S)- (g) c -l,3-dioxolan-4-one, which in turn was prepared from (S)-mandelic acid and pival-aldehyde, to several 2-arylidene-1,3-diketones, gives the Michael adducts in good yields and diastereoselectivities.152... 

Mukaiyama-Michael reaction1 (13, 339-340 14, 344-345). The conjugate addition of enol silyl ethers of optically active ketones to a,(i-enones catalyzed by trityl perchlorate can proceed with high diastereoselectivity. Thus the (Z)-enol silyl ether (2) of the ketone (R)-l reacts with enone 3 to give the 1,5-ketone 4 with high... 

Michael addition to a., -enoates- Aluminum ion-exchanged montmorillonite (Al-Mont1) is a very effective catalyst for Michael addition of silyl ketene acetals or silyl enol ethers to a,(3-enoates. In fact this heterogeneous catalyst is more effective than Lewis acids, which are generally required in a stoichiometric amount. It also facilitates Michael addition to a,p-enones.2 Examples ... 

Enantioselective Michael additions.1 The addition of tin(II) enolates to enones can proceed enantioselectively when activated by trimethylsilyl triflate and in the presence of a chiral diamine such as 1. 

A new curcuminoid, cyclocurcumin, possessing nematocidal activity, was isolated from the mother liquor by repeated purification as a yellow gum (Kiuchi et al, 1993). It had the same molecular formula as curcumin, but differed in structure by an intramolecular Michael addition of the enol-oxygen to the enone group. The chemical structures of these components are given in Fig. 6.2. 

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