Disubstituted enone

Conjugate addition [2] to Midiael acceptors is die most important and usefid reaction in orgatiocopper diemistiy, and die reaction is ofien used as die key step in die syndiesis of numerous natural and unnatural products. Perhaps one of die most efficient methods for die syndiesis of quaternary carbon centers is organo-copper-mediated conjugate addidon to /, / -disubstituted enones. 

Zinc-copper compounds readily undergo Michael addition reactions in the presence of TMSCl, selectively affording 1,4-adducts [7, 34, 41, 42]. In the case of yS-disubstituted enones, the 1,4-addition proceeds well in the presence of BF3 OEt2 (Scheme 2.43) [89]. 

With a,p-disubstituted enuiies an unexpected mode of stereocontrol was evidenced [365, 366]. Syn products (7) were obtained by addition of the lithium enethiolate of methyl dithioacetate to an a,3-disubstituted enone via diastereoselective auto-protonation of the intermediate enolate generated in the 1,4 addition. 

Metzner reports that lithium dithioenolates, which are softer nucleophiles than the corresponding carbonyl enolates, add kinetically in a 1,4-mode exclusively to ot, 3-enones and the diastereoselectivity preferences are similar to that for ester enolate additions.l43a d Typically, kinetic deprotonation of dithioesters affords predominantly the (Z)-enethiolate (170) which is opposite to that for esters 139 thus, with ( )-enones, anti adducts (172) are obtained. In contrast, the addition of methyl dithioacetate to ot,P-disubstituted enones affords predominantly syn adducts (174 and 175) which is a consequence of intramolecular protonation of the resultant enolate (Scheme 68).143e... 

Benzaldehyde (entry 3) and the hindered iso-butyraldehyde (entry 2) give the lowest yields. Sakurai and Hosomi next extended the addition of allylsilane 1 to enones 8 [7]. In the presence of TiCU, the 1,4-adduct 9 is obtained in good yields (Scheme 13.3). It is interesting to note that allylcuprates are less selective than allylsilanes and that / ,/ -disubstituted enones react efficiently, leading to ketones bearing a quaternary carbon center at the / position (entry 3). 

Besides simple enones and enals, less reactive Michael acceptors like /3,/3-disubstituted enones, as well as a,/3-unsaturated esters, thioesters, and nitriles, can also be transformed into the 1,4-addition products by this procedure.44,44a,46,46a The conjugate addition of a-aminoalkylcuprates to allenic or acetylenic Michael acceptors has been utilized extensively in the synthesis of heterocyclic products.46-49 For instance, addition of the cuprate, formed from cyclic carbamate 53 by deprotonation and transmetallation, to alkyl-substituted allenic esters proceeded with high stereoselectivity to afford the adducts 54 with good yield (Scheme 12).46,46a 47 Treatment with phenol and chlorotrimethylsilane effected a smooth Boc deprotection and lactam formation. In contrast, the corresponding reaction with acetylenic esters46,46a or ketones48 invariably produced an E Z-mixture of addition products 56. This poor stereoselectivity could be circumvented by the use of (E)- or (Z)-3-iodo-2-enoates instead of acetylenic esters,49 but turned out to be irrelevant for the subsequent deprotection/cyclization to the pyrroles 57 since this step took place with concomitant E/Z-isomerization. 

If the 1,5-diearbonyl compound is required, then an aqueous work-up with either acid or base cleaves the silicon-oxygen bond in the product but the value of silyl enol ethers is that they can undergo synthetically useful reactions other than just hydrolysis. Addition of the silyl enol ether derived from aeetophenone (PhCOMe) to a disubstituted enone promoted by titanium tetrachloride is very rapid and gives the diketone product in good yield even though a quaternary carbon atom is created in the conjugate addition, This is a typical example of this very powerful class of conjugate addition reactions. 

It has been found that 1-substituted (trimeLhylsilyl)allenes are more efficient as the three-carbon component than the corresponding unsubstiluted allene and further substitution of the allene at the terminus allows a direct and stereoselective route to highly substituted cyclopentanes. However, for a sterically demanding acceptor such as /i./f-disubstituted enones. terminally substituted allenes fail to react. 

The addition is sensitive to steric effects in the acceptor with a / ,/J-disubstituted enone being unreactive under the reaction conditions. Alkyl substitution in the donor is better tolerated, with 2-substituted allylFp complexes exhibiting reasonable reactivity. 

One limitation is that addition of the cuprate to 3, 3-disubstituted enones is markedly inhibited. 

Hindered 3,/3-disubstituted enones such as 3-methylcyclohex-2-enone and (CH3)2C=CHC0CH3 are not useful for this reaction. Also, the corresponding... 

At -50°C in the presence of catalytic methylcopper and HMPA, diisobutylaluminium hydride will selectively reduce enones, including 3,3-disubstituted enones, in a 1,4- sense to give good yields of saturated ketones. Unfortunately HMPA apears to be essential to the success of the reaction and it could not be replaced by other dipolar aprotic solvents. The method may also be... 

Hindered /3,j3-disubstituted enones such as 3-methylcyclohex-2-enone and (CH3)jC=CHCOCH3 are not useful for this reaction. Also, the corresponding salt (C6HsS)3CNa gives significantly lower yields of ortho thioesters. a, 3-Un-saturated aldehydes react with (1) to give products of 1,2-addition. 

Methylquinoline is formed from aniline and but-2-enal (crotonaldehyde), whereas 4-methylquino-line is obtained from methyl vinyl ketone the 1,2-dihydroquinoline 85 is the end product when 4-methylpent-3-en-2-one (mesityl oxide), a terminally disubstituted enone, is used. 

Conjugate addition of an ethyl acetate group. The reagent undergoes Michael addition to enones the adducts are decarboxylated when warmed in acetic acid. The reaction is limited to disubstituted enones. ... 

Of course, the nucleophilic ring-opening can also occur in an intramolecular fashion, as demonstrated by the Payne rearrangement of the epoxyalcohol 75 to form the corresponding secondary alcohol (76). Dess-Martin oxidation of the latter provided expoxyketone 77 formally derived from P-disubstituted enones, which are difficult to access directly in an enantioselective fashion <01JCS(P1)1109>. 

Mukaiyama—Michael reactions This reaction involves addition of silyl ketene acetals to enones in the presence of a Lewis acid to form 1,5-keto esters (13,306-307 15,15). Surprisingly, a /3, j8-disubstituted enone (1) in the presence of various Lewis acid catalysts reacts more rapidly with the disubstituted silyl ketene acetal 2a than with the unhindered silyl ketene acetal 2b, to form the hindered adduct 3 with two adjacent quaternary carbon atoms. Similar results obtain with Bu2Sn(OTf)2 and TiCU. The result is hardly consistent with a nucleophilic reaction, but suggests that the reaction involves... 

As mentioned earlier, the increase in the in HTW and SCW produces equivalent quantities of and OH and therefore the increase in the observed rate of reaction could also arise from base catalysis. Eckert et al. observed base catalysis in HTW in the Claisen-Schmidt condensation of benzaldehyde and 2-butanone. The product outcome of this reaction under normal aqueous conditions depends upon whether the reaction is acid or base catalysed in acid catalysis a monosubstituted enone is formed whereas the base-catalysed route yields a disubstituted enone as the favoured product (Scheme 3.6). The disubstituted enone was found to be the dominant product for the Claisen-Schmidt condensation in HTW indicating base catalysis as the dominant pathway in HTW. 

Scheme 7.78 NHC-catalyzed asymmetric formal Diels-Alder reaction of a-chloroaldehydes with a,p-disubstituted enones reported hy Kobayashi.

The first examples of CM reactions of strained exocyclic enones have been reported by Howell et CM reactions of a-methylene-p-lactone 437, which was easily prepared from readily accessible MBH adducts, proceeded with high efficiency and diastereoselectivity. The unexpected predominant (Z)-stereo-chemistries of products 438 were observed, which was in contrast to the acquired high (jE)-selectivity in the usual CM reactions of a,p-unsaturated carbonyl compounds, including 1,1-disubstituted enones, with simple alkenes. The obtained reaction outcomes were remarkable because of the strain inherent in the systems and the ring-opened MBH precursors did not undergo CM under similar conditions (Scheme 3.194). 

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