Domino Mannich/aza-Michael

In contrast to aldol reactions, the major diastereoisomer formed in the Mannich reaction has syn configuration, because the orientation of the imine is opposite to that of the carbonyl in the transition state (figure C in Scheme 6.5). Carter et al. reported an organocatalysed domino Mannich-aza-Michael reaction for accessing nitrogen-containing [2.2.2]-bicyclic scaffolds promoted by 15e, in a highly enantioselective and diastereoselective manner (eqn. (3) in Scheme 6.5). 

A domino Mannich/aza-Michael reaction was applied to the synthesis of 2,5-cis-configured polysubstituted pyrrolidines from y-malonate-substituted a,P-unsaturated esters with N-protected arylaldimines [117]. In this report, bifunctional thioureas were trialed with the Takemoto catalyst, being the most efficient with respect to yield as well as enantiomeric and diastereomeric excess. In a separate approach, the Garcia-Tellado group approached the pyrrole ring system 234, beginning with a tertiary skipped diyne 233 and a primary amine (Scheme 7.50). 

Scheme 10.17 Synthesis of pyrrolidines through domino Mannich/aza-Michael reaction.

In parallel, Akiyama used the same type of catalysts for highly enantioselective indirect Mannich-type reactions [8]. His group also disclosed that these chiral phosphoric acid derivatives can catalyse the aza-Diels-Alder reaction with high stereoselectivity [75]. In addition, chiral-phosphoric acids can mediate similar transformations as the proline-catalyzed domino Mannich/aza-Michael reactions with high enantioselectivity [76]. 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

As additional examples, we can first note the use of silylated serine or threonine for the addition of 2-phenylpropanal to vinylsulfone, giving the corresponding adduct in good yields (85-90%) but low ee (44-45%). As a second example, an aza-Michael reaction has been described with the ethyl methyl imidazolium salt of glycine as a catalyst. As a last example, the interest in tert-leucine can be noticed as it could act as a cocatalyst with a pyrrolidine bearing a thiopyridine. The ion-pair catalyst catalysed the domino oxa-Michael-Mannich reaction of salicylic aldehydes with cyclohex-2-enones. ... 

The aza-Morita-Baylis-HiUman reaction is known to be a useful and atom-economical C-C bond-forming reaction of electron-deficient alkenes with imines usually catalyzed by Lewis bases [202]. It formally involves a sequence of reactions including a Michael addition, a Mannich reaction, a proton transfer, and a retro-Michael reaction ( -elimination). Although there are many reports in the field of the enantioselective aza-Morita-Baylis-Hilhnan reaction, only rare examples of asymmetric domino reactions initiated by this reaction have been reported. In 2010, Sasai et al. [203] developed the first organocatalyzed asymmetric domino aza-Morita-Baylis-Hillman/aza-Michael reaction of a,p-unsaturated carbonyl compounds with N-tosylimines, allowing an easy access to chiral cis-1,3-disubstituted isoindolines as single diastereomers. The process was induced by a Hg-BINOL-derived catalyst and provided these products in high yields and enantioselectivities, as shown in Scheme 10.18. 

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