Tandem Mannich-Michael reaction

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

This methodology opens up an efficient stereoselective access to chiral piperidi-none derivatives 60 which have opposite configuration compared to compounds 46 obtained by the tandem Mannich-Michael reaction sequence described in Section 4.3.2. The high diasteroselectivity and regioselectivity in these reactions once again illustrate the stereodifferentiating potential of carbohydrates in the synthesis of chiral heterocyclic systems. 

A sequence of tandem-Mannich-Michael reactions and conjugate additions of organocuprates has been used for the synthesis of enantiomerically pure alkaloids such as (—)-dihydro-pinidine 193, the indolizidine alkaloid (5/, 8a/ )-gephyrotoxin 167B 194 and the decahydroquinoline alkaloid 4a- p/-pumiliotoxin C 195 (Figure 10.18) [150]. 

Kunz, H, Pfrengle, W, Carbohydrates as chiral templates stereoselective tandem Mannich-Michael reaction for the synthesis of piperidine alkaloids, Angew. Chem. Int. Ed., 28, 1067-1068, 1989. 

Using diene 288 and imine 289, the tandem Mannich/Michael reaction sequence afforded the vinylogous amide 290 in 66% yield (97TL2829). Imines derived from other aldehydes were also studied, providing derivatives of 290 in moderate yields... 

Lewis acid-catalyzed (EtAlCla, ZnClz) aza Diels-Alder reaction of imines derived from amino acid esters or carbohydrates with Danishefsky s diene provide precursors of chiral piperidine alkaloids. When using imines derived from 0-pivaloylated glycosylamines and ZnCl2 as Lewis acid, highly diastereoselective tandem-Mannich-Michael reactions are observed. The carbohydrate moiety is easily removed by treatment with HCl/MeOH. By employing galactopyranosylamine or arabinosylamine derivatives both enantiomeric series are readily available. 

Kirschbaum, S. and Waldmann, H. (1997) Construction of the tricyclic benzoquinolizine ring system by combination of a tandem Mannich-Michael reaction with a Heck reaction. Tetrahedron Lett., 38, 2829-32. 

A-Benzylimine [(24) derived from (R)-glyceraldehyde], undergoes a tandem Mannich-Michael reaction with Danishefsky s diene (25) to give cyclic enaminones (26)." " The diastereoselectivity of the reaction, and the effects of temperature, solvent. 

The isolation of an intermediate revealed that the reaction proceeds via a tandem Mannich-Michael addition pathway. The zinc (II) chloride-promoted cascade reaction starts with a Mannich reaction. For a number of reactions, the Mannich-type intermediate can be isolated if the reaction is stopped by addition of diluted ammonium chloride solution [52,53]. 

Murata, K., Kitazume, T. Study of the effect of fluorine atom(s)on fluoromethylated imines in the tandem Mannich-Michael-type reaction. 

Polyhaloalkyl-substituted chromones and 7-pyrones react with salicylaldehydes in the presence of piperidine to give a variety of fused 277-chromenes in good yields (Scheme 58) <2006JOC4538>. Although it is conceivable that this reaction could proceed through a Baylis-Hillman reaction pathway, studies of this reaction point to the mechanism being a tandem intramolecular oxa-Michael addition and subsequent Mannich condensation. 

The best catalyst for this transformation was AgSbFg (10 mol%), and (3-ketoesters, malonates, and silyl enol ethers have been used for the nucleophilic addition on the pyridinium intermediate DD. The dihydroisoquinolines 48 have been further used in several reactions in order to assemble the framework of various alkaloids. One example is given in the formation of dihydroisoquinoline 49, bearing a pendent a, 3-unsaturated ketone. Compound 49 can rearrange to the tetracycle 50 (related to the core structure of karachine, Scheme 5.23), using TMSOTf, via a tandem Michael addition-Mannich reaction process (intermediates EE and FF). 

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

Stereochemical control in the double conjugate addition Tandem Reactions as Polymerisation Terminated by Cyclisation The MIMIRC sequence with vinylphosphonium salts Tuning the MIMIRC sequence with different Michael acceptors Heterocycles by Tandem Conjugate Additions Tandem conjugate addition and Mannich reaction Tandem Conjugate Addition and Aldol Reaction... 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

Guo, S., Xie, Y, Hu, X., Xia, C., Huang, H. (2010). Diastereo- and enantioselective catalytic tandem Michael addition/Mannich reaction Access to chiral isoindohnones and azetidines with multiple stereocenters. Angewandte Chemie International Edition, 49, 2728-2731. 

Scheme 42.6 A Mannich/aza-Michael tandem reaction under an enamine/iminium ion activation sequence.

Huperzine B (2) exhibits a memory facilitating effect in mice and may be useful as an acetylcholinesterase inhibitor for the treatment of Alzheimer s disease (90-92). An efficient synthetic approach to huperzine B (2) has been established successfully. The tetracyclic intermediate 140 is constructed by means of a tandem Michael addition and an intramolecular Mannich cyclization using 139 and 6-methyl-3,4-dihydropyridin-2-one as the two reactants. Racemic huperzine B (2) is obtained via a reaction sequence of 12 steps in 6.6% overall yield (Scheme 17) (89). 

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