Mannich-Michael reactions

The tandem Michael-Mannich reactions serve to assemble a tetracyclic intermediate with the aspidosperma alkaloid skeleton from 3-indoleacetyl chloride in one step [138]. 

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. ... 

Scheme 2.38 Domino Michael/Mannich reaction of imino esters with nitroalkenes catalysed by an in situ generated imidazoline-aminophenol nickel catalyst.

Scheme 4.1 Domino Michael/Mannich reaction of imino esters with nitroalkenes.

In the same year, Xu et al developed an efficient example of asymmetric cooperative catalysis applied to a domino oxa-Michael-Mannich reaction of salicylaldehydes with cyclohexenones. The proeess was eatalysed by a combination of two chiral catalysts, such as a chiral pyrrolidine and amino acid D-tert-leucine. The authors assumed that there was protonation of the aromatic nitrogen atom of the pyrrolidine catalyst by u-te/t-leucine, which spontaneously led to the corresponding ion-pair assembly (Scheme 2.6). This self-assembled catalyst possessed dual activation centres, enabling the catalysis of the electrophilic and nucleophilic substrates simultaneously. The domino oxa-Michael-Mannich reaction provided a range of versatile chiral tetrahydroxanthenones in high yields and high to excellent enantioselectivities of up to 98% ee, as shown in Scheme 2.6. 

Scheme 2.6 Domino oxa-Michael-Mannich reaction catalysed by a combination of a chiral pyrrolidine and n-tert-leucine.

Scheme 11.25 Diastereoselective thia-Michael/Mannich reaction using chiral imines.

A one-pot synthesis of 1,3-diamines was described in 2009 by Cordova and coworkers [17]. An asymmetric cascade aza-Michael/Mannich reaction was developed using a combination of diphenylprolinol trimethylsilyl ether 5 and proline as catalysts (Scheme 12.13). The cascade was possible because of the complete difference in reactivity between chiral pyrrolidine 5 and proline in the separate reactions. The conjugate addition of a protected methoxyamine to hex-2-enal was coupled to a three-component Mannich reaction, giving direct access to orthogonally protected chiral diamine derivatives with excellent chemo and enantioselectivities (yield 60-62%, ee 98-99%). The use of l-Pto as a catalyst for the Mannich reaction afforded the 6yn-l,3-diamine 30 (dr > 19/1), while the use of the antipode D-proline gave the anti derivative 31 with similar levels of diastereoselectivity. 

The imidazoline-aminophenol-ligand complex (34) has been developed for the 3 + 2-cycloaddition reaction of methyleneindolinones (32) with iminoesters (33) to produce exo-spiro[pyrrolidin-3,3 -oxindole]s (35) as stable isomers. The reaction proceeds in a stepwise Michael-Mannich reaction sequence (Scheme 12). ... 

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