Silyl conjugate addition

Notwithstanding the extremely rich and diverse reactivity presented above, all the examples presented thus far feature the addition of an NHC catalyst onto an sp carbon. Several reactions have been developed in the last ten years describing the activation of heteroatom o bonds by NHCs [8cj. The concept can be well illustrated by the recent work of Hoveyda and coworkers, who reported boryl and silyl conjugate additions to a,P-unsaturated carbonyls (Scheme 18.35) [124]. In both cases, addition of the NHC onto a trivalent boron atom activated the B-heteroatom bond. The use of Cj-symmetric imidazolinium salt 169 in the sUyl conjugate addition led to P-silyl ketones, esters, and aldehydes in good to high enantioselectivity. 

Scheme 18.35 Botyl and silyl conjugate additions, according to Hoveyda and coworkers.

Allylsilanes in which the silyl group is at the more substituted end of the allyl system have been prepared by a reaction sequence involving the conjugate addition of silylcuprates to a, jS-unsat-urated esters followed by reduction and dehydration via selenoxide elimination38. 

The role of the trimethylsilyl group is to stabilize the enolate formed in the conjugate addition. The silyl group is then removed during the dehydration step. Methyl 1-trimethylsilylvinyl ketone can be used under aprotic conditions that are compatible with regiospecific methods for enolate generation. The direction of annulation of unsymmetrical ketones can therefore be controlled by the method of enolate formation. 

The scope of the conjugate addition reaction can be further expanded by use of Lewis acids in conjunction with enolate equivalents, especially silyl enol ethers and silyl ketene acetals. The adduct is stabilized by a new bond to the Lewis acid and products are formed from the adduct. 

Several examples of conjugate addition of carbanions carried out under aprotic conditions are given in Scheme 2.24. The reactions are typically quenched by addition of a proton source to neutralize the enolate. It is also possible to trap the adduct by silylation or, as we will see in Section 2.6.2, to carry out a tandem alkylation. Lithium enolates preformed by reaction with LDA in THF react with enones to give 1,4-diketones (Entries 1 and 2). Entries 3 and 4 involve addition of ester enolates to enones. The reaction in Entry 3 gives the 1,2-addition product at —78°C but isomerizes to the 1,4-product at 25° C. Esters of 1,5-dicarboxylic acids are obtained by addition of ester enolates to a,(3-unsaturated esters (Entry 5). Entries 6 to 8 show cases of... 

Conditions for effecting conjugate addition of neutral enolate equivalents such as silyl enol ethers in the presence of Lewis acids have been developed and are called Mukaiyama-Michael reactions. Trimethylsilyl enol ethers can be caused to react with electrophilic alkenes by use of TiCl4. These reactions proceed rapidly even at -78° C.308... 

Silyl ketene acetals also undergo conjugate addition. For example, Mg(C104)2 and LiC104 catalyze addition of silyl ketene acetals to enones. 

A number of other chiral catalysts can promote enantioselective conjugate additions of silyl enol ethers, silyl ketene acetals, and related compounds. For example, an oxazaborolidinone derived from allothreonine achieves high enantioselectivity in additions of silyl thioketene acetals.323 The optimal conditions for this reaction also include a hindered phenol and an ether additive. 

Entry 6 is an example of application of the chiral diazaborolidine enolate method (see p. 572). Entry 7 involves generation of the silyl ketene acetal by silylation after conjugate addition of the enolate of 3-methylbutanoyloxazolidinone to allyl 3,3,3-trifluoroprop-2-enoate. A palladium catalyst improved the yield in the rearrangement... 

In the synthesis shown in Scheme 13.15, racemates of both erythro- and threo-juvabione were synthesized by parallel routes. The isomeric intermediates were obtained in greater than 10 1 selectivity by choice of the E- or Z-silanes used for conjugate addition to cyclohexenone (Michael-Mukaiyama reaction). Further optimization of the stereoselectivity was achieved by the choice of the silyl substituents. The observed stereoselectivity is consistent with synclinal TSs for the addition of the crotyl silane reagents. 

A recent synthesis of P-D lactone (Scheme 13.51) used an enantioselective catalytic approach. A conjugate addition of a silyl ketene acetal derived from an unsaturated ester gave an unsaturated lactone intermediate. The catalyst is CuF-(S )-tol-BINAP.30 The catalytic cycle for the reaction is shown below. 

This reaction is extended to the intramolecular ring closure of the intermediate radical 224 with olefinic or trimethylsilylacetylenic side chains [121]. Cu(BF4)2 is also effective as an oxidant (Scheme 89) [122]. Conjugate addition of Grignard reagents to 2-eyclopenten-l-one followed by cyclopropanation of the resulting silyl enol ethers gives the substituted cyclopropyl silyl ethers, which are oxidized to 4-substituted-2-cyclohexen-l-ones according to the above-mentioned method [123]. (Scheme 88 and 89)... 

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). 

Silyl esters of trivalent phosphorus acids have been used successfully in conjugate addition reactions using acrylates,393 395 nitriles,394 amides,396 397 ketones and aldehydes,398-404 and nitro compounds.387... 

Silylation of Products of Conjugated Addition of Nucleophiles to a-Nitroolefins Nitroalkane anions can be generated not only by deprotonation of nitroalkanes (various modifications of these process were considered above) but also by the conjugated addition of nucleophiles 56 to a-nitroalkenes (42) (Scheme 3.56, Table 3.2). 

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. 

Such dideoxynucleosides as CNT (306) and the potent anti-HIV drug ddC (307) have been obtained (280), respectively, from the butenolide 248 and from its saturated analogue. Thus, conjugate addition of cyanide to 248, followed by reduction of the lactone group, acetylation of HO-1, and coupling with silylated thymine, afforded, after deprotection, compound 306. 

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