Mannich Reactions in Enamine Catalysis

Mannich Reactions in Enamine Catalysis 28.2.2.1 Antf-Selective Mannich Reactions 

Chiral 3-amino carbonyl compounds and 1,2-amino alcohols are among the most valuable building blocks for asymmetric synthesis and catalysis. Efficient enanti-oselective syntheses of these compounds were reported from 2000 to 2006 using enamine-based organocatalysts. For example, Mannich reactions employing aliphatic aldehyde as a donor with a-imino glyoxylate as an acceptor provide syn-adducts (74) as the major product with excellent enantiomeric excess in the presence of (S)-proline (13) as a catalyst (Table 28.5, entry 1) [41]. When the ketone is employed as a donor, the sy -isomer is obtained with excellent diastereo-and enantioselectivities (entry 2) [42]. 

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Scheme 28.2 Aldol and Mannich reactions in enamine catalysis.

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

Hydroxyacetone 96 is a reagent in an even more remarkable reaction the asymmetric direct three-component Mannich reaction. It is combined with an aromatic amine 98 and the inevitable isobutyraldehyde 89 with proline catalysis to give a very high yield of a compound 99 that might have been made by an asymmetric amino-hydroxylation. The proline enamine of hydroxyacetone, must react with the imine salt formed from the amine and isobutyraldehyde. This is a formidable organisation in the asymmetric step. 

Abstract The organocatalytic asymmetric Mannich reaction and the related aza-Morita-Baylis-Hillman have been reviewed. The activities in this field have been snbdivided based on the types of catalysts that have been ntilized, which includes catalysis by enamine-forming chiral amines, chiral Br0nsted bases, chiral Brpnsted acids, and phase-transfer catalysts. 

These findings were extended to a set of very useful cascade reactions by the MacMiUan group [111]. In a first series 1,4-hydride additions were combined with aminations, oxidations, or Mannich reactions (Scheme 4.30). The hydride transfer was catalyzed by imidazoHdinone 9, whereas subsequent functionalization was realized by enamine catalysis through the deployment of proline. Depending on the chirality of proline used, optically pure anti- or syu-configured products 84-86 were isolated. 

In terms of enamine and iminium ion catalysis, an intramolecular cascade conjugate addition/Mannich reaction was shown to be effectively catalyzed by 36 [108]. The reaction involves the construction of a tetracycUc structure from the indoyl methyl enone shown in Scheme 6.53. The highest enantioselectivities were obtained with addition of nitrobenzoic acid and with ethyl acetate as the solvent... 

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]. 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

In 2007, Ding and Wn reported a cascade reaction combining enamine and Ag catalysis for the synthesis of 1,2-dihydroisoquinoline derivatives [42]. Initially, the nncleophilic enamine derived from the ketone and proUne attacked the imine that arose from the aldehyde and the amine, forming the Mannich base 140, which then participated in a hydroamination reaction toward pendant alkyne to build the final prodnct (Scheme 9.46). 

Following immediately the initial efforts on primary amino acids catalyzed aldol reactions, the application of primary amine acid in Mannich reaction has also been attempted. Cordova reported that simple primary amino acids and their derivatives could catalyze the asymmetric Mannich reactions of ketones with comparable results to those obtained in the catalysis of proline[28]. Later, Barbas [29] and Lu [30] independently reported that L-Trp or 0-protected L-Thr could catalyze anti-selective asymmetric Mannich reactions of a-hydroxyacetones with eiflier preformed or in-situ generated imines. The preference of anii-diastereoselectivity was ascribed to the formation of a Z-enamine, with the assistance of an intramolecular H-bond (Scheme 5.15). 

An example of a cascade reaction combining enamine and silver catalysis for synthesis of 1,2-dihydroisoquinoline derivatives is shown in Fig. 8.26. In the first step, nucleophilic enamine formed from the ketone and proline reacts with the imine, which is generated from the aldehyde and the amine. As a result, the Mannich base is formed, which then undergoes a hydroamination reaction in the presence of silver catalyst. 

Nitroethene is sufficiently electrophilic to substitute indole without the need for acid catalysis. Despite this, it has been shown that siUca-gel-supported CeCl3.7H20/NaI brings about such reactions at room temperature under solvent-free conditions or, to take another solvent extreme, the reaction occurs in water with a catalytic amount of a heteropoly acid (H3PWi204o). The employment of 2-dimethylamino-l-nitroethene in trifluoroacetic acid leads to 2-(indol-3-yl)nitroethene - the reactive species is the protonated enamine and the process is similar to a Mannich condensation (20.1.1.9). The use of 3-trimethylsilyl-indoles, with tpxo-substitution of the silicon, is an alternative means for effecting alkylation, avoiding the need for acid catalysis. 

The term aminocatalysis has been coined [4] to designate reactions catalyzed by secondary and primary amines, taking place via enamine and iminium ion intermediates. The field of asymmetric aminocatalysis, initiated both by Hajos and Parrish [5] and by Eder, Sauer, and Wiechert [6] in 1971, has experienced a tremendous renaissance in the past decade [7], triggered by the simultaneous discovery of proline-catalyzed intermolecular aldol [8] and Mannich [9] reactions and of asymmetric Diels-Alder reactions catalyzed by chiral imidazolidinones [10]. Asymmetric enamine and iminium catalysis have been influential in creating the field of asymmetric organocatalysis [11], and probably for this reason aminocatalytic processes have been the object of the majority of mechanistic smdies in organocatalysis. 

In conclusion, Kappe s group demonstrated the absence of any differences between conventional and microwave heating in proline-catalyzed Mannich and aldol reactions as well as no evidence for specific or non-thermal microwave effects. In all cases, in contrast to the previous literature reports, the results obtained with microwave irradiation could be reproduced by conventional heating at the same reaction temperature and time in an oil bath. The differences observed in previous publications could be a result of incorrect temperature measurements [36]. After Kappe s [35] publication several articles appeared in the literature concerning the application of microwaves in asymmetric organocatalysis, mostly in aldol and Michael type reactions operating via enamine as well as iminium catalysis. 

The enamine (/dienamine)-iminium cycle-specific cascade catalysis is an important constituent of amine-catalyzed cascade reactions [10]. This strategy has been explored extensively and also applied to natural product synthesis. One such example is the total synthesis of dihydrocorynantheol, which was first isolated from the bark of Aspidosperma marcgravianum in 1967 [29]. This indole alkaloid is a member of the corynantheine and was found to exhibit antiparasitic, antiviral, or analgetic activities, which have attracted considerable attention from the synthetic community. Among those reported total syntheses, Itoh et al. developed a Mannich-Michael cascade reaction catalyzed by L-proline 52 for the total synthesis of ent-dihydrocorynantheol 54 (Scheme 3.8) [30], The cascade reaction of 3-ethyl-3-buten-2-one 51 with dihydro-P-carboline 50 catalyzed by 30mol% of (S)-proline afforded the tetracyclic core structure 53 in 85% yield. Excellent stereoselectivity was achieved in this cascade reaction (99% enantiomeric excess and almost complete diastereomeric control). Therefore, this organocascade reaction could lead expeditiously to construction of the core structure, which enabled the authors to accomplish the total synthesis of enl-dihydrocorynantheol 54 in just five steps. 

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