Iminium-Activated Sequential Reactions

SCHEME 1.46 Cascade Michael-aldol condensation reactions. 

In the process, activation of a,P-unsaturated aldehydes by a chiral organocatalyst produces iminiums which trigger a Michael-aldol cascade process to afford intermediates which undergo spontaneous dehydration to give oc,p-unsaturated aldehydes 129. 

The extension of this strategy to 2-mercaptobenzaldehyde and a, 3-unsaturated ketones [72], 2-mercaptoacetophenones [73], salicylaldehydes [74], 2-amino benzal-dehydes [75], 2-(nitromethyl)benzaldehyde [76], and 2-(( )-2-nitrovinyl)phenol [77] has been disclosed. 

SCHEME 1.48 Enantioselective oxa-Michael/Michael cascade reactions with alkynals. 

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Design of iminium-enamine cascade reactions Iminium-activated Diels-Alder reactions Iminium-activated sequential [4h-2] reactions Iminium-activated [3-h2] reactions Iminium-activated sequential [3-1-2] reactions Iminium-activated [2h-1] reactions... 

This dual enamine/iminium activation profile in cascade Michael/aldol reactions can also be found even in some early reports, mostly focused on the self-dimerization of enals catalyzed by proline or analogues derived thereof, which generally proceeded with low enantioselect vities. There is not a clear and definitive mechanistic pathway confirmed for these reactions, although the most widely accepted proposal for the dimerization of enals (Scheme 7.4) ° involved sequential activation of one molecule of the substrate as a dienamine (Michael donor) and another molecule as iminium ion (Michael acceptor). 

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). 

In an effort to develop new cascade reactions, Zhang et al. envisioned that a linear aldehyde can also be genaated in situ via an extra iminium catalysis from an ot,p-unsaturated aldehyde prior to the triple cascade reaction. Therefore, there would be a possibility of extending the triple cascade reactions to four-component cascade reactions. Based on this design, a four-component quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michael addition of alcohol to acrolein in moderate yield (about 50%), excellent diastereoselectivities (>20 1), and excellent enantioselectivities (>99% ee) was accomplished (Scheme 1.33) [47]. 

SCHEME U3 Four-component cascade reactions through iminium-enamine-iminium-enamine sequential activation. 

Three-component reactions can be designed by incorporating suitable nucleophiles and electrophiles into iminium-activated systems (Scheme 1.40a). Furthermore, cyclic structures can be constructed if these nucleophiles and electrophiles can be incorporated into the same molecule as 111 (Scheme 1.40b). In fact, [2-i-l], [3-1-2], sequential [4-1-2], and Diels-Alder reactions have been developed, depending on the distance between nucleophilic and electrophilic positions of 111 to fnmish diverse cyclic structures. 

Sequential Iminium-Enamine Catalysis. Directed Electrostatic Activation. A comparison of the standard catalytic cycles for enamine activation (Scheme 2.1) and for iminium ion activation (Scheme 2.12) show that iminium catalysis proceeds, after the addition of the nucleophile, via an ( )-enamine. In the presence of a suitable electrophile, this enamine gives rise to an iminium ion that after hydrolysis can give rise to an a,p-diftmctionalyzed carbonyl (Scheme 2.13) [85]. Scheme 2.13 also shows that when using a chiral 2-substituted pyrrohdine or an imidazolidinone as the catalyst, the sequential apphcation of the steric model for Michael addition to iminium ions (Figure 2.15) and of the steric model for electrophilic attack to enamines (Figure 2.IB) predicts the absolute stereochemistry of the major isomer obtained in the reaction. 

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