Mannich Reactions of Acetaldehyde Donors

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]. 

Bronsted Acid Catalysis Including Hydrogen-Bond Catalysis 

Aldol Reactions in Bronsted Acid and Hydrogen-Bond Catalysis 

2 Mukaiyama Aldol Reactions in Bransted Acid Catalysis 

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It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

One year later, the List group reported Mannich reactions involving the use of acetaldehyde 2r as the Mannich donor, which due to its reactive nature, is a very difficult substrate. Albeit not in high yields, they showed that under carefully controlled conditions such Mannich reactions could proceed in excellent selectivity, even in case of the aliphatic Boc-protected imines 23i and j (Scheme 5.15) [22],... 

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