Michael reactions additions, enones

Finally, it should also be pointed out that enantioselective Michael reactions to enones under PTC conditions do not exclusively rely on the use of chiral ammonium salts as catalysts and, for example, chiral phosphonium salts can also be successfully employed in this context. This is the case of binaphthyl-containing phosphonium salt 110, which was demonstrated to be an outstanding catalyst in the conjugate addition of oxindoles to enones under PTC conditions (Scheme 5.20). The Michael adducts were obtained in excellent yields and enantioselectivities for a wide variety of differently substituted 3-aryl oxindoles tested as Michael donors. Remarkably, the high acidity of the 3-aryloxindoles employed as Michael donors allowed the use of a very mild base such as potassium benzoate for the activation of the nucleophile. 

In 2008, Deng and coworker developed the first highly enantioselective aza-Michael reaction to enones [106]. In this work they used 9-amino cinchona alkaloid 33 as catalyst and TFA as additive. The reaction between Boc-protected N-benzyUiydroxylamine (115) and enones under these conditions renders the final... 

The first enantioselective organocatalytic oxo-Michael reaction to enones was reported by Falck [109]. Falck developed the intramolecular addition of boronic acids hemiesters to enones catalyzed by thiourea catalysts. Alkyl, aryl, and heteroaryl y-hydroxy enones react with phenylboronic acid to furnish the corresponding boronic hemiesters 118, which after oxidative cleavage of the resulting dioxaboro-lane renders the chiral 1,2 diols 119 in excellent yields and enantioselectivities (Scheme 33.34). 

Despite the great interest in chiral phosphines and the success in the phospha-Michael addition to enals, only one example of an organocatalytic phospha-Michael reaction to enones can be found in the Uterature. 

The Michael reaction involving addition to carbon-carbon double bonds containing an electron-withdrawing group is catalysed by base. A variety of heterogeneous bases which can be reused are known, including alumina, KF on alumina and phenolates supported on silica, the last having proved particularly effective for addition of /3-keto esters to enones (Scheme 1.7). 

Ye and co-workers have shown that NHC 67 can catalyse the aza-Morita-Bay-lis-Hillman reaction of enones 66 and N-tosyl imines 63, presumably via initial NHC conjugate addition to the enone to generate an azolium enolate 68 [18]. A related conjugate addition approach has been exploited by Fu and co-workers, with tautomerisation of the initial enolate 72 derived from NHC conjugate addition to 70 giving 73, with subsequent cyclisation resulting in the umpolung of Michael acceptors (Scheme 12.13) [19]. 

On the other hand, the enantioselective 1,4-addition of carbanions such as enolates to linear enones is an interesting challenge, since relatively few efficient methods exist for these transformations. The Michael reaction of p-dicarbonyl compounds with a,p-unsaturated ketones can be catalysed by a number of transition-metal compounds. The asymmetric version of this reaction has been performed using chiral diol, diamine, and diphosphine ligands. In the past few years, bidentate and polydentate thioethers have begun to be considered as chiral ligands for this reaction. As an example, Christoffers et al. have developed the synthesis of several S/O-bidentate and S/O/S-tridentate thioether... 

This finding is also in agreement with another three-component Michael/aldol addition reaction reported by Shibasaki and coworkers [14]. Here, as a catalyst the chiral AlLibis[(S)-binaphthoxide] complex (ALB) (2-37) was used. Such hetero-bimetallic compounds show both Bronsted basicity and Lewis acidity, and can catalyze aldol [15] and Michael/aldol [14, 16] processes. Reaction of cyclopentenone 2-29b, aldehyde 2-35, and dibenzyl methylmalonate (2-36) at r.t. in the presence of 5 mol% of 2-37 led to 3-hydroxy ketones 2-38 as a mixture of diastereomers in 84% yield. Transformation of 2-38 by a mesylation/elimination sequence afforded 2-39 with 92 % ee recrystallization gave enantiopure 2-39, which was used in the synthesis of ll-deoxy-PGFla (2-40) (Scheme 2.8). The transition states 2-41 and 2-42 illustrate the stereochemical result (Scheme 2.9). The coordination of the enone to the aluminum not only results in its activation, but also fixes its position for the Michael addition, as demonstrated in TS-2-41. It is of importance that the following aldol reaction of 2-42 is faster than a protonation of the enolate moiety. 

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

Tan and co-workers reported the Michael reactions of di-thiomalonates and P-keto-thioesters to a range of acceptors, including maleimides, cyclic enones, furanones and acyclic dioxobutenes [129]. Unlike dimethyl malonate, additions with acidic thioesters proceeded in higher yields, and overall better enantioselectivities (Scheme 74). 

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). 

Treatment with a base results in the ehmination of the alcohol at the 5 position by what is in effect a reverse Michael reaction to give the enone (19-1). The additional... 

The absolute course of the intramolecular Michael reaction can also be mediated by organo catalysts. Benjamin List of the Max-Planck-Institut, Miilheim, has shown (Angew. Chem. Int. Ed. 2004, 43, 3958) that 9 is particularly effective. Michael addition followed by intramolecular aldol condensation gives the Irons bicyclic enone 11 in high . 

Michael reaction with exocycHc ,(S-enones Conjugate addition of secondary amines to a,/ -enones proceeds readily unless the enonc is cxocyclic. in "Such a case the reaction is very slow unless alumina is added as catalyst. Thus the reaction of 1 and diethylamine in the presence of alumina proceeds in 2 hours to give 2 quantitatively. 

Michael reaction. In the presence of (C6H5)3CC104, silyl enol ethers undergo Michael addition to a,p-enones. The adducts can be isolated or rearranged to 1,5-diketones by base. The intermediates cannot be isolated from reactions catalyzed by TiCl4 or CsF. 

Complex LSB 9 is readily prepared either by the reaction of La(0 Pr)3 with 3 equiv. of B1NOL followed by the addition of NaO Bu (3 equiv.) or by the reaction of LaCl nfLO with sodium binaphthoxide. The complex 9 is stable to oxygen and moisture and has been proven to be effective in the catalytic Michael reaction of various enones with either malonates or p-keto esters. The Michael adducts with up to 92% ee were obtained in almost quantitative yield. Typical results with malonates are summarized in Table 8D.1 (Ln = lanthanide) [18], In general, the use of THF as solvent gave the best results except for the case of the LSB-catalyzed reaction of rmns-chalcone with dimethyl malonate, wherein the use of toluene was essential to give the adduct with good enantiomeric excess. The effects of the central metal (La, Pr, and Gd) on asymmetric induction were also examined in the same reaction, and LSB was found to be the best catalyst. 

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. 

When subjected to the action of propanethiol under basic conditions (pH 9.2), jatrophone (2) undergoes a Michael reaction across its C8-C9 double bond, followed by facile transannular cyclization to give the tetracyclic diketone 3.2,9 The susceptibility of this enone part structure to conjugate addition has been proposed to constitute the event responsible for the pronounced biological activity of 2.9... 

The Michael reaction is the conjugate addition of a soft enolate, commonly derived from a P-dicarbonyl compound 24, to an acceptor-activated alkene such as enone 41a, resulting in a 1,5-dioxo constituted product 42 (Scheme 8.14) [52]. Traditionally, these reactions are catalyzed by Bronsted bases such as tertiary amines and alkali metal alkoxides and hydroxides. However, the strongly basic conditions are often a limiting factor since they can cause undesirable side- and subsequent reactions, such as aldol cyclizations and retro-Claisen-type decompositions. To address this issue, acid- [53] and metal-catalyzed [54] Michael reactions have been developed in order to carry out the reactions under milder conditions. 

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