Aminocatalyzed Biginelli Reactions

Although L-proline and its corresponding hydrochloride derivative have been nsed as catalysts in the Biginelli reaction, the resulting DHPMs were found to be racemic [48], In contrast, Juaristi and coworkers described the application of a chiral bicyclic diamine 36 as organocatalysts in the enantioselective Biginelli reaction, affording the expected DHPMs 37 

A plausible transition state (TS) to explain the origin of the activation and the asymmetric induction through a dualactivation mode by the catalyst has been envisioned by the authors (Fig. 9.3). The synergic effect provided by the involvement of both an achiral Brpnsted add and the chiral secondary amine 38 as the catalytic systan in this multicomponent process was crucial for the success of this reaction since neither by themselves could catalyze the formation of DHPM efficiently. Thus, the acid additive could be involved in the formation of 

Further achievements have also been reached in the aminocatalysis field using the same class of chiral amine catalysts by other research groups [52]. In this sense, Zhao, Wang, and coworkers developed a new 5-(pyrrolidin-2-yl) tetrazole derivative 42 as an active catalyst in this MCR 

A dual-activation way is invoked based on the similar widely accepted catalytic mode of activation for L-proline catalyst. In this context, the acidic tetrazole moiety activates the electrophilic imine by a hydrogen-bonding interaction, and the pyrrolidine moiety would activate the nucleophilic P-ketoester via formation of an enamine intermediate. The stereochemistry of the acidic tetrazole moiety seems to be crucial for the stereoselectivity in the final products. This 

FIGURE 94 Proposed oiganocatalytic mechanism using catalyst 42. 

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