Michael-Mannich reaction sequence

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). ... 

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. 

Further extension of the reaction pool of Schilf bases 138 was achieved by their reaction with tran -l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene) to give 2-substituted 5,6-didehydro-piperidin-4-ones 164 [135,136] (Scheme 10.54). The reaction is considered to be a sequence of an initial Mannich reaction between the imine and the silyl enol ether, followed by an intramolecular Michael addition and subsequent elimination of methanol. If the reaction was terminated by dilute ammonium chloride solution, then the Mannich bases 163 could be isolated and further transformed to the dehydropiperidinones 164 by treatment with dilute hydrochloric acid. This result proved that the reaction pathway is not a concerted hetero Diels-Alder type process between the electron-rich diene and the activated imine. The use of hydrogen chloride as a terminating agent resulted in exclusive isolation of the piperidine derivatives 164 formed with... 

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. 

A Mannich/Michael reaction sequence was used by Waldman for the formation of several piperidone derivatives. The reaction of 285 with 286 in the presence of a... 

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... 

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. 

A great deal of attention has been given to asymmetric Mannich reactions, some of which can be applied to the preparation of bridged piperidine systems. Among them, we will mention Carter s preparation of compound 130 from diaryl imines and 2-cyclohexenone in the presence of a modified proline catalyst via an asymmetric Mannich-Michael domino sequence (Scheme 3.39) [88]. 

However, diastereoselective transformations like this are not to be discussed within this monograph, as they do not fulfill the criteria of asymmetric synthesis, according to Marckwald s definition (in today s language) this would mean [...] those reactions, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation [35]. Thus, diastereoselective conversions not included for that reason in this book are, for example, aldol additions, Mannich reactions, and Michael additions of enolates to ketones, imines, and cx,P-unsaturated carbonyl compounds, respectively, with any chiral skeleton. For such stereoselective enolate reactions that are not asymmetric syntheses, the reader is referred to the literature, which treated this topic in a comprehensive manner [36]. 

The zinc chloride-mediated reaction of galactosyl imine 338 (R = Pr) with Danishefsky s diene 345 followed by acid treatment led to the diastereoselective formation of cyclic enaminone 346 in a domino Mannich-Michael sequence. The pure diastereomer 346, isolated in 81% yield, was converted into (5)-coniine, again under recovery of the reusable tetra-pivaloyl galactose 341 (Scheme 4.76) [170b, 173]. Later, the use of polymer-bound galactosyl imines for Mannich reactions and other transformations was reported [174]. 

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

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

In a sequence that is the equivalent of an oxocarbenium-induced C-C bondforming reactirai, McQuade and coworkers have used organic catalysts to carry out the coupling of 2-hydroxy tetrahydrofuran 48 with methyl ketones 49 to give 2-alkyl furans (Scheme 15) [13]. Mechanistically the reaction is proposed to proceed through the addition of a thiourea-stabiUzed enolate from the reaction of 49 with 51 to an iminium intermediate that comes from the condensation of 48 with proline catalyst 50. Hydrolysis and Michael cyclization or displacement of the ammonium ion subsequent to the Mannich reaction gives the observed product 52. 

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). 

The compounds obtained by the replacement of ring sulfur by carbon, as in the case of penicillins, show somewhat improved antibiotic properties. A free radical— based route has been described for the conversion of fermentation derived cephalosporins to their carbocyclic derivatives. The first step in this sequence consists of the condensation of the cephalosporin sulfone (36-1) with formaldehyde and dimethyla-mine the initial product from the Mannich-like reaction consists of the exomethylene derivative at the position adjacent to the activating sulfone. The product is treated in situ with phenylselenol to give the Michael adduct (36-2). This fragments with an extmsion of sulfur dioxide when heated with the free radical initiator AIBN in the presence of tributyltin hydride the reaction can be envisaged as leading to the... 

The forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

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]. 

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]. 

In accordance with the generally accepted mechanism ofthe MBH reaction, the aza MBH reaction involves, formally, a sequence of Michael addition, Mannich type reaction, and (3 elimination. A commonly accepted mechanism is depicted in Scheme 13.2. A reversible conjugate addition of the nucleophilic catalyst to the Michael acceptor generates an enolate, which can intercept the acylimine to afford the second zvdtterionic intermediate. A proton shift from the a carbon atom to the P amide followed by P elimination then affords the aza M BH adduct with concurrent regeneration of the catalyst [5]. 

Usually, the reaction involves an electron-rich diene and an imine activated with an electron-withdrawing group. Mechanistically, it is suggested that the aza Diels-Alder reaction is a Mannich-Michael sequence when using electron-rich dienes. Diverse asymmetric versions of this reaction have been developed involving a chiral imine or a catalytic amount of a chiral Lewis acid. ... 

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