Mannich/Michael reaction pathway

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

In 2005, Cordova and coworkers described the first example of the enantioselective organocatalytic aza-hetero-Diels-Alder reaction [60]. The one-pot three-component direct aza-hetero-Diels-Alder reaction under the catalysis of prohne afforded the desired cycloadducts 135 with excellent chemo-, regjo-, and stereoselectivity (Scheme 38.39). This reaction was considered to proceed via a plausible Mannich-Michael reaction pathway. Recently, Wang and coworkers developed a chiral ionic liquid catalyst for this reaction to afford up to >99% ee [61]. 

The isolation of an intermediate revealed that the reaction proceeds via a tandem Mannich-Michael addition pathway. The zinc (II) chloride-promoted cascade reaction starts with a Mannich reaction. For a number of reactions, the Mannich-type intermediate can be isolated if the reaction is stopped by addition of diluted ammonium chloride solution [52,53]. 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

Earlier syntheses of arylquinolizidine alkaloids mainly utilized the pelletierine condensation to construct the basic skeleton, 4-aryl-2-quinolizidinone (11) (Scheme 1). Two mechanistic pathways, involving (a) initial aldol condensation of pelletierine (8) with an aromatic aldehyde followed by intramolecular Michael-type addition of the resulting enone 9 (6, 7) and (b) a Mannich-type reaction through 10 (8, 9), were proposed without any experimental evidence. Preparation and cyclization studies of the intermediate 9, however, gave conclusive evidence to show that the pelletierine condensation proceeded through pathway a (10). 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

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