Other Conjugate Addition Reactions

Piersanti and coworkers explored the effectiveness of a range of Lewis acids in promoting alkylation of indole by methyl a-acetamidoacrylate. This led not only to successful p-addition but also to a-addition (amidoalkylation, see Sect. 7). Ethylaluminum dichloride (two equiv.) and ZrCLt were the most effective in giving the p-adduct, while several soft Lewis acids, of which Bi(OTf)3 was most practical, gave the a-adducts. 1-Methylindole and several C-5 analogs showed the same selectivity [292]. 

A related reaction involves the use of aryl indole-3-carbinols with enamides. Under the influence of acid catalysts the carbinols generate electrophiles. The adducts hydrolyze to products that are the equivalent of conjugate addition to 1,3-diaryl propenones. These reactions can be done in up to 90% ee with chiral BINOL-phosphoric acid catalysts [293]. 

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Barbas developed this procedure further by introducing an asymmetric three-component Michael reaction that should be applicable to many other conjugate addition reactions. He used a Wittig olefmation to prepare, in situ, an a,P-unsatu-rated ketone that subsequently underwent a conjugate addition with malonates (Scheme 21) [94]. The rate of the conjugate addition process was observed to be considerably faster than the analogous reaction reported by Jprgensen which was attributed to the presence of triphenylphosphine oxide within the reaction mixture. 

Michael and other conjugate addition reactions, like the one we just saw in Scheme 6, are key steps in several indole syntheses. For example, Otera and colleagues developed... 

Related compounds have been generated from BocRNCH2SnR 3 and s-butyllithium/ CuCN which also added to conjugated ketones. Other amino-cuprates are known to give conjugate addition reactions... 

A variety of substrates has been used in this type of conjugate addition reaction with trialkyl phosphites, with assorted proton sources.361 384 Other types of trivalent phosphorus reagents without acidic (or conjugate base of acidic) sites have also been used successfully for this conjugate addition process, including triaryl phosphites (without dealkylation),369 phosphoramidites,385 389 phospho-nites,363 380 390 and phosphinites.360 380... 

As with other reactions, silyl esters of phosphorus acids constitute an important and useful category of reagents for conjugate addition reactions. With aldehydes, ketones, and esters, the silyl ester linkage is transferred to the carbonyl oxygen, facilitating the completion of the reaction, generating the free carbonyl or ester upon workup with a protic solvent (Equation 3.25). 

Feringa and co-workers described the tandem addition-aldol cyclization protocol leading to the formation of 6,6-, 6,7-, and 6,8-annulated bicyclic systems (Scheme 68).39 Using Cu(n)-29 as catalyst and functionalized organozinc reagents as nucleophiles, the conjugate addition reaction followed by aldol cyclization can offer highly enantioselec-tive annulation products (up to 98% ee). This method can be used in the synthesis of carbocyclic compounds, such as steroids, terpenes, and other natural products. 

This work was initiated in 1988 when Villacorta et al.71a reported the asymmetric conjugate addition of a Grignard reagent to 2-cyclohexenone. This study showed that 1,4-adducts with 4-14% ee were obtained in the presence of aminotroponeimine copper complex.713 Enhanced results (74% ee) were obtained by adding HMPA or silyl halides.71b Several other copper complexes were also used for inducing asymmetric conjugate addition reactions. Moderate results were obtained in most cases when THF was used as the solvent and HMPA as the additive. 

Other types of conjugate additions with chiral thioureas were also explored by Connon. P-Substituted nitro-olefms were used in the conjugate addition reaction with dimethyl chloromalonate 115 to generate chiral, functionalized nitrocyclopro-panes [73]. Utility of the nitrocyclopropanes was demonstrated in the one-step modification towards other functionalized chiral building blocks (Scheme 24). 

The simple addition and the conjugate addition reactions compete with each other. Figure 11-23 shows an example of a reaction with both the simple addition and the conjugate addition products. In this reaction, an increase in the size of the alkyl group on the Grignard reagent leads to an increase in the yield of the conjugate addition product, while substitution on the C=C leads to an increase in the yield of the simple addition product. 

Phosphine-complexed cuprates, formed from copper(I) iodide, 1 mol equiv. of RtLi, and 2-5 mol equiv. of tri-n-butylphosphine, show good reactivity in conjugate addition reactions with enones (Table l).39 The hazards surrounding the use of excess Bun3P, and the availability of other methodologies lower the popularity of this method, but efficiency can be realized with this methodology. 

The other important feature ofthis conjugate addition reaction is that the two carbonyl groups in the product are reasonably far apart while the newly formed bond is in the middle of the molecule. This means that Michael addition can be a convergent route to the product—a feature that usually maximizes synthetic efficiency. 

Diesters (malonates and substituted derivatives) combine three useful features in conjugate addition reactions they form stable enolate anions that undergo clean conjugate addition if required, one of the ester groups can be removed by hydrolysis and decarboxylation and, finally, the remaining acid or ester is ideal for conversion into other functional groups,... 

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. 

While such transition-state models have helped us to rationalize the patterns of selectivity observed in other reactions of 2-acyl- 1,3-dithiane 1-oxide substrates, such clear trends are not found in conjugate addition reactions (Table 3). One simple explanation for the poorer levels of stereoselectivity may be bond rotation within the acyl substituent, allowing the enone moiety to attain conformations other than those shown in 17 and 18. 

Some of the other reactions in which N. 0-acetals have been used as chiral auxiliaries include conjugate addition reactions,172 eyelopropanation,211 addition of nucleophiles to cyclic ketones212 and Diels-Alder reactions213... 

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