Direct vinylogous Mannich reaction

In this review we will attempt to highlight the most important contributions toward the realization of a catalytic, enantioselective, vinylogous Mannich reaction and show the current state of the art. This chapter is organized in such a way that vinylogous Mannich reactions of preformed silyl dienolates in Mukaiyama type reactions will be discussed first followed by direct vinylogous Mannich reactions of unmodified substrates. 

Direct Vinylogous Mannich Reactions of Unmodified Substrates... 

Scheme S.11 Organocatalytic, direct, vinylogous Mannich reaction of a,a dicyanoalkenes 48...

Propose a transition state for the direct vinylogous Mannich reaction with the bifunctional thiourea catalyst 51 reported by Chen and his group that accounts for the observed relative and absolute configurations of the products (Scheme 5.11). 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

Aromatic and heteroaromatic aldimines were effectively converted into vinylogous Mannich products 31 with complete y regioselectivity and with typically 80 90% ee. The reaction could easily be run in a three component fashion, starting directly from an aldehyde, para anisidine, and silyl dienolate 30 obviating the need to prepare the imine in a separate reaction. In contrast to most other protocols that required a salicyl imine moiety in the substrate for selectivity issues, here the amine component within the imine could just be a phenyl group or any para substituted phenyl group. 

As shown in Fig. 8, the Ni2-lb complex was applicable to broad range of catalytic asymmetric reactions under simple proton transfer conditions [19-30]. As donors in direct Mannich-type reactions, not only a-nitroacetates, but also malonates, p-keto esters [22], p-keto phosphonates [23], and a-ketoaniUdes [24] gave excellent enantioselectivity and diastereoselectivity. It is noteworthy that the Ni2-lb complex also promoted vinylogous direct catalytic asymmetric Mannich-type reaction of an a,p-unsaturated y-butyrolactam, giving synthetically versatile functionalized a,p-unsaturated y-butyrolactam in 99% ee [25]. Because the Ni2-lb... 

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