Prolinol silyl ethers Mannich reactions

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

On the other hand, diaryl prolinol silyl ethers have been applied as orga-nocatalysts for the asymmetric Mannich reaction of acetaldehyde with N-benzoyl-, iV-Boc- and iV-Ts-imines in the presence of para-aiirobtnzoic acid in THF. The generated (3-amino aldehyde products were isolated in good to high yields and excellent enantioselectivities (95-98% ee) after conversion into the corresponding alcohols by reduction with L1A1H4 (Scheme 3.10). 

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

One year later, the same group achieved the four-component conpling of enals, protecting hydroxylamine (A -methoxycarbmate), aryamines, and acetone by a combination of (5)-prolinol silyl ether and (5)-proline [18], affording orthogonally protected 1,3-diamine motif efficiently with excellent stereochemical control (Scheme 9.17). Mechanistically, the reaction proceeds via a (S)-prolinol silyl ether-catalyzed aza-Michael addition of protected hydroxylamines to a,p-unsaturated enals followed by an (S)-proline-promoted Mannich reaction of the p-amino aldehyde... 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

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