Michael/enamine formation intramolecular condensation

Scheme 7.37 Enantioselective synthesis of 1,4-dihydropyridines by one-pot Michael/ enamine formation/intramolecular condensation reaction.

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

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