Conjugate addition to enones

Other bonds that merit attention are those connecting C(7) through C(ll). These could be formed by one of the many methods for the synthesis of ketones. Bond disconnections at carbonyl centers can involve the 0=C-C(a) (acylation, organometallic addition), the C(a)-C((3) bond (enolate alkylation, aldol addition), or C((3)-C(7) bond (conjugate addition to enone). 

Whereas, the sulfur ylide 9 undergoes conjugate addition to enones thereby precluding 1,2-cyclopentyl annulation, the organolithium 37a undergoes clean carbonyl addition. Cyclopentenone participates smoothly in this sequence (Eq. 88)81>. 

In total, over the past six years, the chelating P,N-ligands have shown considerable promise in a variety of enantioselective processes, including transfer-hydrogenation and hydrosilylation of ketones, hydroboration of alkenes, conjugate addition to enones and Lewis-acid catalysed Diels-Alder reactions, in addition to those described above.128,341 It is anticipated that this list will continue to grow, and... 

Organoaluminum reagents have been used in the copper-catalyzed conjugate addition to enones with some success. Iwata and co-workers (182) demonstrated that dimethoxyphenyl oxazoline (247) provides modest selectivities in the copper-catalyzed conjugate addition of trimethylaluminum to 3,4,4-trimethylcyclohexadi-enone to provide the adduct in 68% ee, Eq. 145. The use of TBSOTf is crucial to attain high conversion and selectivity in this process. Woodward and co-workers (183) subsequently reported that a Cu(I) complex of thiocarbamate 248 provides modest facial discrimination in the addition of trimethylaluminum to a linear enone to afford 245b in 51% ee, Eq. 146. The authors note that this catalyst system decomposes under the reaction conditions at ambient temperature. 

One of the first synthetic applications of organoboranes in radical chemistry is the conjugate addition to enones (Scheme 23, Eq. 23a) and enals reported by Brown [58-61]. Addition to -substituted enones and enals are not spontaneous and initiation with the oxygen [62], diacetyl peroxide [63], or under irradiation [63] is necessary (Eq. 23b). A serious drawback of this strategy is that only one of the three alkyl groups is efficiently transferred, so the method is restricted to trialkylboranes derived from the hydroboration of easily available and cheap alkenes. To overcome this limitation B-alkylboracyclanes have been used but this approach was not successful for the generation of tertiary alkyl radicals [64,65]. 

Tandem processes mediated by triethylborane involving conjugate addition to enones followed by aldol reaction are reported (Scheme 52, Eq. 52a). More recently, a tandem process involving addition of an isopropyl radical to an o ,/3-unsaturated oxime ether afforded an azaenolate intermediate that reacts with benzaldehyde in the presence of trimethylaluminum. The aldol product cyclizes to afford an isopropyl substituted y-bulyroloaclonc in 61% overall yield (Scheme 52) [116]. In these reactions, triethylborane is acting as a chain transfer reagent that delivers a boron enolate or azaenolate necessary for the aldolization process. 

Scheme 6.21. Lewis acid-promoted diastereoselective conjugate addition to enone 98 (Bn = benzyl).

The use of vinyl epoxides as substrates in enantioselective copper-catalyzed reactions, on the other hand, has met with more success. An interesting chiral ligand effect on Cu(OTf)2-catalyzed reactions between cyclic vinyloxiranes and dialkylzinc reagents was noted by Feringa et al. [51]. The 2,2 -binaphthyl phosphorus amidite ligands 32 and 43 (Fig. 8.5), which have been successfully used in copper-catalyzed enantioselective conjugate additions to enones [37], allowed kinetic resolution of racemic cyclic vinyloxiranes (Scheme 8.26). 

Scheme 10.14. Various proposed mechanisms for MesSiCI acceleration of conjugate additions to enones (X = Me3SiCI).

Notes Catalyst for polymerization and dimerization of alkynes and alkenes. Has been used for catalyzing conjugate additions to enones. Useful as a Lewis acid. 

Most main group organometallic compounds undergo nucleophilic reactions with carbonyl groups, whereas 1,4-conjugate addition to enones... 

ArSCu(RMgX)n. These heterocuprates are more useful than lithium dialkyl-cuprates for conjugate addition to enones.5 They are also useful for conjugate addition to the less reactive cinnamates and crotonates.6 Yields are markedly improved by use of 2-methoxyphenylthio as the ligand in additions to the crotonates. 

Ligands functioning as acyl anion equivalents also proceed efficiently in the conjugate addition to enones, producing the -substituted product in high yield (equation 54).1,3 Removal of the protecting group results in the free keto unit, and provides an alternative to the direct acylation (vide supra).37,38... 

Mixed homocuprates.7 Mixed cuprates (1) in which the nontransferable ligand is an a-sulfonyl carbanion are easily prepared from dimethyl sulfone or methyl phenyl sulfone (equation I), and are effective for conjugate addition to enones and for a synthesis of ketones from acid chlorides. 

Ryu, I. Nakahira, H. Ikebe, M. Sonoda, N. Yamato, S.-Y. Komatsu, M. Chelation-aided generation of ketone a,/1-dianions and their use as copper ate complexes. Unprecedented enolate intervention in the conjugate addition to enones./. Am. Chem. Soc. 2000, 122,1219-1220. 

Enantioselective addition (C H Zn with enones.1 In the presence of (1S,2R)-1 (1 equiv.), diethylzinc undergoes conjugate addition to enones to form (R)-P-ethyl ketones in 81-94% ee. Use of catalytic amounts of 1 decreases the enantioselectivity to 60-80% ee. 

Normally, the nucleophile or the Michael acceptor needs to be activated in the Michael additions. To achieve this activation, either the nucleophile is deprotonated with strong bases or the acceptor is activated in the presence of Lewis acid catalysts under much milder conditions. Recently, important advances have been made with Lewis acid catalysts and these developments continue. Four possible mechanisms are suggested for the catalyst action in conjugate additions to enones under nonbasic conditions [38]. First is the... 

Conjugate addition to enones gives enolates regiospecifically... 

Although we did not talk in detail about them at that time, you will recall from Chapter 10 that conjugate addition to enones generates first an enolate, which is usually protonated in the work-up. But, again, more fruitful things can be done with the enolate under the right conditions. 

See page 1571, Section 2 for analogous conjugate addition to enones. 

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