Ketone enone, conjugate addition

This is a fairly difficult problem because it is not obvious at the outset which of the two possible enolates of benzyl ethyl ketone undergoes conjugate addition to the o,/3-unsaturated ketone. A good idea here is to work backward from the final product—in effect, do a ret-rosynthetic analysis. The first step is to recognize that the enone arises by dehydration of a /Thydroxy ketone. 

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

Vinylcyclopropanation of Enones. Conjugate addition of sulfur-stabilized aUyl carbanions to a. -unsaturated ketones produces enolates that cyclize to vinylcyclopropyl ketones upon treatment with nearly one equivalent of (CuOTf)2-C6H6, i.e. 1.9 equivalents of Cu (eq 68). ... 

Reduction of a conjugated enone to a saturated ketone requires the addition of two electrons and two protons. As in the case of the Birch reduction of aromatic compounds, the exact order of these additions has been the subject of study and speculation. Barton proposed that two electrons add initially giving a dicarbanion of the structure (49) which then is protonated rapidly at the / -position by ammonia, forming the enolate salt (50) of the saturated ketone. Stork later suggested that the radical-anion (51), a one electron... 

Conjugate addition of methyl magnesium iodide in the presence of cuprous chloride to the enone (91) leads to the la-methyl product mesterolone (92) Although this is the thermodynamically unfavored axially disposed product, no possibility for isomerization exists in this case, since the ketone is once removed from this center. In an interesting synthesis of an oxa steroid, the enone (91) is first oxidized with lead tetraacetate the carbon at the 2 position is lost, affording the acid aldehyde. Reduction of this intermediate, also shown in the lactol form, with sodium borohydride affords the steroid lactone oxandrolone... 

Combination of nickel bromide (or nickel acetylacetonate) and A. A -dibutylnorephcdrinc catalyzed the enantioselective conjugate addition of dialkylzincs to a./Tunsaturated ketones to afford optically active //-substituted ketones in up to ca. 50% ee53. Use of the nickel(II) bipyridyl-chiral ligand complex in acetonitrile/toluenc as an in situ prepared catalyst system afforded the //-substituted ketones 2, from aryl-substituted enones 1, in up to 90% ee54. 

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). 

The Michael addition of nitroalkanes to a,P-unsaturated ketones followed by the Nef reaction has been extensively used as a method for the conjugated addition of acyl anions to enones (see Section 6.1, Nef Reaction). This strategy is one of the best methods for the preparation of 1,4-dicarbonyl compounds.156a h Various natural products have been prepared via this route.157 For example, r/.v-jasmone is prepared from readily available materials, as shown in Scheme 4.19.156f... 

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

Enones have also served as latent enols in the hydroalkoxylation process. For example, an Au(m) catalyst has been used to effect the conjugate addition of alcohols (or other nucleophiles) to a,/ -unsaturated ketones, thereby triggering a hydroalkoxylation pathway of the resulting enol to furnish furans as products. (Equation (98)). 

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... 

Conjugate addition of RN02 to enones. Primary nitroalkanes and a, (3-enones when activated by alumina form conjugate addition products that are oxidized in situ by alkaline hydrogen peroxide to 1,4-diketones. A similar reaction of nitromethane with a vinyl ketone provides 1,4,7-triketones. 

Addition of RJCuLi to bridgehead enones.1 Ordinarily organocuprates do not react with a bridgehead halide. However, they can undergo conjugate addition to bridgehead enones generated in situ from p-bromo ketones with potassium t-butoxide or lithium 2,6-di-r-butyl-4-methylphenoxide (6,95). 

Conjugate additions to a, j5-unsaturated ketones and esters are the most important cuprate reactions. Kinetic studies by Krauss and Smith on Me2CuLi and a variety of ketones revealed the following kinetic characteristics (Eq. 10.5), first order both in cuprate dimer and in the enone [60]. 

Photochemical irradiation of a,-unsaturated ketones in the presence of Mc3SiOP(OR)2 (R = Me, Et) gave phosphonosilylation products of 1,4-conjugate additions which are hydrolysed to the phosphono ketones (165). The envisaged initiation step is electron transfer to the triplet excited state of the enone to generate a radical ion pair. 

The first organocatalyzed conjugate addition of a-substituted p-ketoester to a,P-unsaturated ketones was presented by Deng et al. [42] (Scheme 3). Although traditional Cinchona alkaloids were efficient catalysts for conjugate addition of carbon nucleophiles to nitroalkenes and sulfones, replacement of the C(9)-OH with an ester group (Q-7b) showed great improvement in stereoselectivity. The reaction is applicable to a variety of cyclic and acyclic enones (16,18). 

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

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