Robinson annulation with silyl vinyl ketones

One problem with the Robinson annulation is the reversible nature of the initial Michael addition. One solution is to use a conjugated system that is particularly prone to Michael addition and forms the product, essentially irreversibly. a-Silyl vinyl ketones have been shown to be powerful Michael acceptors.The lithium enolate of cyclohexanone reacted with conjugated ketone 559 to produce the Michael product. 560.304b jn this case, the initially formed Michael adduct was stabilized by the presence of the silyl group at the a-position, driving the reaction toward the product. Hydrolysis produced 561, which was converted to the Robinson product (562) in 80% overall yield by treatment with NaOMe/MeOH under the requisite thermodynamic conditions.304b Pq,. this sequential process is justified when compared with normal treatment... 

Conjugate addition reactions, including the Robinson annulation, which make use of reactive Michael acceptors such as methyl vinyl ketone, can suffer from low yields of the desired adduct. The basic conditions required for enolate formation can cause polymerization of the vinyl ketone. Further difficulties arise from the fact that the Michael adduct 42 and the original cyclohexanone have similar acidities and reactivities, such that competitive reaction of the product with the vinyl ketone can ensue. These problems can be minimized by the use of acidic conditions. Sulfuric acid is known to promote the conjugate addition and intramolecular aldol reaction of 2-methylcyclohexanone and methyl vinyl ketone in 55% yield. Alternatively, a silyl enol ether can be prepared from the ketone and treated with methyl vinyl ketone in the presence of a Lewis acid such as a lanthanide triflate" or boron tri fluoride etherate (BF3 OEt2) and a proton source to effect the conjugate addition (followed by base-promoted aldol closure). 

The use of a-silylated vinyl ketone is another approach to overcome drawbacks of the standard Robinson annulation conditions such as polymerization of the vinyl ketone. The a-silylated vinyl ketones are stable and can undergo Michael addition in standard aprotic conditions (conditions that induces polymerization for vinyl ketones), as well as protic conditions. Synthesis of the octalone 21 can be used as an example of this variation. The silylated ketone 20 reacts with lithium enolate 13 (generated by methyllithium from its corresponding enol silyl ether in THE) in /-butyl... 

Annulation. 3-Trimethylsilyl-3-buten-2-one has been employed as a methyl vinyl ketone homolog in an improved method for the annulation of ketones. Based on work by Stork and Ganem, who employed 3-triethylsilyl-3-buten-2-one as a Michael acceptor in the Robinson annulation reaction, Suzuki and co-workers prepared a functionalized bicyclic ketone via a silyl enol ether as shown in eq 1. In general, the annulation of 2-alkylcycloketones with methyl vinyl ketone and its homologs produces rather poor yields of the desired cyclized products. 

Dibutyltin bis(triflate), Bu2Sn(OTf)2, is a mild Lewis acid which catalyzes clean Michael addition of enol silyl ethers [148]. The new catalyst enables use of various labile acceptors such as methyl vinyl ketone and 2-cyclopentenone which do not undergo smooth reaction with conventional Lewis acids. A variety of enol silyl ethers are also employable and thus 2-(trimethylsiloxy)propene, the simplest of this class of compounds, can be used. The adducts of enol silyl ethers of cycloalkanones with vinyl ketones are readily cyclized to give the desired annulated enones free of isomers. Consequently, a practical version of the Robinson annulation has been realized. 

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