Michael Friedel-Crafts domino reactions

Scheme 10.40 Four-component domino Friedel-Crafts/Michael/Michael/aldol condensation reaction.

Enders et al. [75] developed a synthesis of polyfunctionalized 3-(cyclohex-enylmethyl)-indoles 125 via a quadruple domino Friedel-Crafts-type Michael-Michael-aldol condensation reaction, in 2010. This cascade sequence is initiated by a Friedel-Crafts reaction of indole (126) by an iminium activation mode to the enal, followed sequentially by an enamine- and an iminium-mediated Michael addition. After an intramolecular aldol-condensation, four C-C bonds are formed and the domino product is constructed bearing three contiguous stereogenic centers (Scheme 10.34). 

D. Enders, C. Wang, M. Mukanova, A. Greb, Chem. Commun. 2010, 46, 2447-2449. Organocatalytic asymmetric synthesis of polyfunctionalized 3-(cyclohexenyhnethyl)-indoles via a quadruple domino Friedel-Crafts-type/Michael/Michaehaldol condensation reaction. 

Later, You et al. investigated relay catalysis consisting of a combination of the same ruthenium catalyst and a closely related chiral BINOL-derived phosphoric acid. As shown in Scheme 7.42, the use of this catalyst system in an asymmetric domino intramolecular Friedel-Crafts-type-aza-Michael reaction allowed a range of chiral fused indoles to be achieved in high yields and moderate to high enantioselectivities from the corresponding enones and indolyl olefins. 

Scheme 7.42 Domino intramolecular Friedel-Crafts-type-aza-Michael reaction catalysed by chiral phosphoric acid catalysis and ruthenium catalysis.

A similar organocatalytic quadruple domino Friedel-Crafts/Michael/Michael/ aldol condensation reaction initiated by Friedel-Crafts reaction of indole to acrolein was also developed by Enders et al. [48], as well as a microwave-assisted qnadruple cascade organocatalytic Michael/Henry condensation/Michael/aldol condensation anploying acetaldehyde and nitroalkenes as substrates [49]. 

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