Additions to Enones

Diethylalkynylalanes effect conjugate addition of acetylenic units to simple a/S-unsaturated ketones this reaction is limited to cisoid enones, suggesting intramolecular delivery of the alkynyl group in a six-membered transition state such as (145) transoid enones give products of 1,2-addition. The conjugate addition of lithium divinyl copper to a/3-unsaturated ketones affords a route to the y5-unsaturated homologues.  

Nagata has described a method for effecting overall conjugate hydro-cyanation of a/3-unsaturated aldehydes normally, organoaluminium cyanides 

Tronchet, J. Tronchet, and A. Birkh user, Helv. Chim. Acta, 1970, 53, 1489. 

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Like other carbon-carbon bond forming reactions organocuprate addition to enones is a powerful tool m organic synthesis... 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

Although the methodology described so far produces <5-oxo esters via diastereoselective enolate additions to enones, the same product may be obtained via an alternate sequence, i.e., addition of ketone or aldehyde enolates to a,j3-unsaturated esters or amides. Enolates of ketones are known to react with a,/ -unsaturated esters to give the Michael adducts50, however, the study of simple diastcrcoselectivity has, so far, been limited to special cases (MIMIRC reactions, Section 1.5.2.4.4.). 

Closely related to enolate additions to enones is the diastereoselective 1,4-addition of lithium enolates of esters, thioesters and amides to a,/ -unsaturated esters. These reactions provide syn-or ar /-2,3-disubstituted glutarates (pentanedioates). 

The ( )-trimethylsilylenolates of A-methylephedrine propanoates are useful as chiral propanoate equivalents in the titanium(IV) chloride catalyzed addition to enones. Although diastereoselec-tivities are high, this method suffers from low yields due to excessive polymerization190. 

Other routes you might have suggested include cyanide addition to enones, e.g. (3i), alkane... 

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). 

Recently, Li and co-workers also reported the Rh-catalyzed arylstannane addition to enones in water under reflux.139 The addition of KOH helps the reaction to proceed smoothly (Scheme 50). A tentative mechanism was proposed for the Rh-catalyzed conjugated addition of phenyltin trichloride under basic conditions (Scheme 51). Later, this kind of reaction was found to work even in water at 50 °C. 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

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... 

The anions (BuLi) of 1 and 2 undergo enantioselective 1,4-addition to enones. Ozonolysis of the adducts provides optically active keto aldehydes in 70-75% ee. 

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. 

Tab. 6.2. HMPT = Results of diastereoselective cuprate additions to enone hexamethylphosphoric triamide). 95 (TMS = trimethylsilyl,...

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).

Another highlight of these additions was a systematic investigation of the use of alkylseleno- and alkyltelluro groups as non-transferable ligands of alkyl higher-order cyanocuprates [(RY)Cu(CN)R Li2, Y=Se, Te] in addition to enones. The following example is illustrative. 

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