Mannich-type three-component coupling

Three-component coupling reaction of a-enones, silyl enolates, and aldehydes by successive Mukaiyama-Michael and aldol reactions is a powerful method for stereoselective construction of highly functionahzed molecules valuable as synthetic intermediates of natural compounds [231c]. Kobayashi et al. recently reported the synthesis of y-acyl-d-lactams from ketene silyl thioacetals, a,/l-urisalu-rated thioesters, and imines via successive SbCl5-Sn(OTf)2-catalyzed Mukaiyama-Michael and Sc(OTf)3-catalyzed Mannich-type reactions (Scheme 10.87) [241]. 

The effectiveness of lanthanide Lewis acid in Mannich-type reaction was further highlighted by three-component coupling reaction of aldehydes, amines, and enol silyl ethers [7]. With MS 4A or MgS04 as dehydrating agent, 5-10 mol% ofYb(OTf)3 worked well to afford corresponding -amino ketone and esters in good to excellent yield (Table 13.3). It should be noted that the present reaction conditions were... 

Considering the water tolerance of lanthanide Lewis acids, a logical extension of the above-mentioned three-component coupling reaction is the reaction in aqueous media. Kobayashi et al. reported Mannich-type reaction of aldehydes, aniline derivative, and methyl enol ethers with 10mol% of Yb(OTf)3 in THF/H2O solvent system (Table 13.4) [8]. Applicability of commercially available aqueous formaldehyde and chloroacetaldehyde solution is of particular importance from the synthetic point of view (entries 1-3). A wide variety of aldehydes were transformed... 

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