Conjugated iminium species

Class rv processes are those which do not clearly fall into the first three categories. An example of this is the MacMillan synthesis of (-)-flustramine B 198 where an indole reacts asymmetrically with a conjugated iminium species and an appending and already present side chain cyclizes onto the resulting C=N bond (Scheme 1.45) [63]. 

Pyrrolidin-2-yltetrazole has been found to be a versatile organocatalyst for the asymmetric conjugate addition of nitroalkanes to enones.45 Using this catalyst, this transformation requires short reaction times, tolerates a broad substrate scope, and possibly proceeds via generation of an iminium species. 

In a related process, Dixon and co-woricers reported a cascade process with the same chiral phosphoric acid in the reaction between tryptamine 134 and enol lactone 133 (Scheme 1.33) [43]. In this reaction, it is postulated that the primary amine of the tryptamine ring-opens the lactone which is then followed by chiral Brpnsted acid catalyzed dehydrative cyclization to give an N-acyliminium ion intermediate 136. Presumably as with the other reactions of this class described above, there is an association between the conjugate base of the chiral acid and the acyl iminium species, allowing the subsequent cyclization onto the indole to be asymmetrically controlled and generate enanliopure product 137. 

A computational study of the two possible mechanisms for the asymmetric epoxidation of conjugated aldehydes with H2O2, catalysed by chiral pyrrolidine derivatives lacking proton donor groups, indicates that the more probable route is via formation of an iminium intermediate rather than the general base-catalysed mechanism. The oxidant H2O2 acts as a co-catalyst in the initial formation of the iminium species. The epoxide... 

Protonation to the conjugate acid (iminium cation) increases the potential of the itnine to act as an electrophile (compare carbonyl see Section 7.1), and this is followed by nucleophilic attack of water. The protonated product is in equilibrium with the other mono-protonated species in which the nitrogen carries the charge. We shall meet this mechanistic feature from time to time, and it is usually represented in a mechanism simply by putting H+, +H+ over the equilibrium arrows. Do not interpret this as an internal transfer of a proton such transfer would not be possible, and it is necessary to have solvent to supply and remove protons. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

Figure 15.20 shows the multistep mechanism of the [4+2]-cycloaddition between 1-(dimethylamino)-l,3-butadiene and cis-dicyanoethenedicarboxylic acid diester. The reaction proceeds via an intermediate, which must be zwitterion conformer B. The anionic moiety of this zwitterion is well stabilized because it represents the conjugate base of a carbon-acidic compound (Section 13.1.2). The cationic moiety of zwitterion B also is well stabilized. It is an iminium ion (i.e., a species with valence electron octet) rather than a carbenium ion (which is a species with valence electron sextet). Moreover, the iminium ion is stabilized by conjugation to a C=C double bond. 

Because azlactone enolates can be generated under very mild conditions, these species were applied to chiral secondary amine f-16-catalyzed conjugate addition to enals, which proceeded via iminium activation (Scheme 23) [40]. Variable... 

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