Acceptor-substituted dienes addition, regioselectivity

In contrast to these transformations, Michael additions of simple enolates to acceptor-substituted dienes often yield mixtures of 1,4- and 1,6-addition products27-30. For example, a 70 30 mixture of 1,4- and 1,6-adducts was isolated from the reaction of the lithium enolate of methyl propionate with methyl sorbate30. This problem can be solved by using the corresponding silyl ketene acetal in the presence of clay montmorillonite as acidic promoter under these conditions, almost exclusive formation of the 1,4-addition product (syn/anti mixture) was observed (equation ll)30. Highly regioselective 1,4-additions... 

Nucleophilic additions of amines to acceptor-substituted dienes were examined as early as 1950. Frankel and coworkers98 found that the reaction of 2,4-pentadienenitrile with various secondary amines proceeded regioselectively to furnish the 1,6-addition products (equation 29). In some cases, these could converted into the 2,4-diamino-substituted pen-tanenitriles by isomerization and 1,4-addition of a second molecule of amine. Analogous results were reported by other groups17,99 100 and extended to hydrazine as nucleophile101 and to vinylcyclobutenones48 and dienoates102-104 as Michael acceptors. 

Thanks to their ambident character, acceptor-substituted dienes can provide several isomeric products in copper-mediated Michael additions, therefore making it particular important to control not only the regioselectivity but also the stereoselectivity of these transformations (Scheme 4.1). 

Scheme 4.1. Regioselectivity in conjugate addition reactions to acceptor-substituted dienes.

The first example of a cuprate addition to an acceptor-substituted diene was reported by Naf et al. [9], who used lithium di-(Z)-l-heptenylcuprate in a Michael addition to dienoate 1 (Eq. 4.2). The reaction proceeded highly regioselectively, furnishing a 1 1 mixture of the two isomeric 1,6-adducts 2, which were converted into the Bartlett pear constituent ethyl (2 ,6Z)-2,6-dodecadienoate (3) by basic isomerization. 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

By far most of the reports on addition reactions of hetero-nucleophiles to activated dienes deal with sulfur-nucleophiles17,48,80,120-137, in particular in the synthesis of 7/3-sulfur-substituted steroids which, like their carbon-substituted counterparts (Section n.A), are of interest because of their ability to inhibit the biosynthesis of estrogens80,129-137. Early investigations17,120-122 concentrated on simple acyclic Michael acceptors like methyl sorbate and 2,4-pentadienenitrile. Bravo and coworkers120 observed the formation of a 3 1 mixture of the 1,6- and 1,4-adduct in the reaction of methyl sorbate with methanethiol in basic medium (equation 39). In contrast to this, 2,4-pentadienenitrile adds various thiols regioselectively at C-5, i.e. in a 1,6-fashion (equation 40)17,121,122, and the same is true for reactions of this substrate with hydrogen sulfide (equation 41), sodium bisulfite and ethyl thioglycolate17. 

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