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Asymmetric 1,4‐Michael Addition Reactions Catalyzed by a Cinchona Alkaloid Derived Primary Amine: A Theoretical Investigation of the Reaction Mechanism and Enantioselectivity
Author(s) -
Su Zhishan,
Lee Hai Whang,
Kim Chan Kyung
Publication year - 2013
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201201152
Subject(s) - chemistry , iminium , quinuclidine , malononitrile , cinchona , michael reaction , protonation , moiety , tertiary amine , organocatalysis , organic chemistry , medicinal chemistry , catalysis , enantioselective synthesis , ion
Abstract The mechanism and enantioselectivity of the asymmetric 1,4‐Michael addition of malononitrile to unsaturated aryl ketones catalyzed by a cinchona alkaloid derived primary amine have been investigated by DFT and ONIOM methods. The calculations indicated that three continuous stages are involved in the overall reaction: 1) The formation of a (ket)iminium intermediate, 2) an addition reaction between the iminium and malononitrile, and 3 ) hydrolysis and regeneration of the catalyst. The proton from an acidic additive plays an important role in the formation of the key ketiminium ion intermediate in which the protonated tertiary amine of the alkaloid not only activates the carbonyl substrate through hydrogen bonding, but also facilitates the condensation of the primary amine catalyst by participating in the formation of water molecules. The calculations also indicated that steric interactions between the aromatic substituent, the quinoline ring, and the alkene moiety of the unsaturated ketone force the key ketiminium ion intermediate to adopt a preferred conformation to achieve more accessible Re ‐face attack of the substrate. These results are in good agreement with experimental observations.