Mannich-type three-component reactions

In parallel to the bismuth(III)-catalyzed three-component allylation reaction, we have reported the corresponding three-component bismuth(III)-catalyzed Mannich-type reaction. A major merit of the three-component reaction is indeed that many unique structures can be afforded rapidly when three or more reactants are combined in a single step to afford new compounds. The development of an efficient bismuth-catalyzed Mannich-type three-component reaction that combines an aldehyde, an amine, and a silyl enolate to give compounds with a (3-amino carbonyl core... 

In another study by Dondoni et al. [17] the synthesis of C-glycosyl-/ -aminoesters as single diastereomers is achieved via a Mannich-type three-component reaction of /Minked C-galactosyl or C-ribosyl formaldehyde, p-methoxybenzyl amine and ketene silyl acetals using catalytic amounts of InCfi (Scheme 9.8). 

The required aldehyde precursor 186 was obtained by a Sn(II)-catalyzed asymmetric aldol reaction [90]. It was then mixed in one pot with o-methoxy aniline 187 and enol ether 188 to afford the key /7-amino ketone 189 in a 2 1 diastereomeric ratio through a Mannich-type three-component reaction. This reaction was performed in an aqueous medium and the use of a surfactant such as dodecyl sulfate (DS) was essential. The diastereomeric mixture 189 was treated with HF and the... 

In the solid phase, Sc(OTf)3 also effectively catalyzed Mannich-type three-component reactions of aldehydes, amines, and PSSEEs to afford polymer-supported /3-amino thioesters (Eq. 22). Reductive cleavage from the supports gave the amino alcohols in good to high yields [85b]. /3-Amino acid and /3-lactam libraries are also constructed according by this method (Eq. 23). 

Mannich-type three-component reaction as the key steps (Scheme 30) [290, 291]. 

Scheme 7.25 Mannich-type three-component reaction catalysed by chiral phosphoric acid catalysis and rhodium catalysis.

Kob1996b Kobayashi, S., Moriwaki, M., Akiyama, R, Suzuki, S. and Hachiya, I., Parallel Synthesis Using Mannich-type Three-Component Reactions and Field Synthesis for the Construction of an Amino Alcohol Library, Tetrahedron Lett., 37 (1996) 7783-7786. 

Recently, Xu et al. describled a highly enantioselective Mannich-type three-component reaction of diazoacetophenones 315, alcohols 311, and imines 148 under the cocatalysis of Rh COAc) and phosphoric acid 5 m (Scheme 2.86). In the presence of RhjCOAc), diazoacetophenones and alcohols formed oxonium ylides to serve as the enol equivalents of a-alkoxyl aryl ketones, which then underwent Mannich-type reaction with phosphoric acid-activated imines to produce enantioenriched p-amino-a-hydroxyl ketone products 316 [119],... 

SCHEME 2.87 Synthetic applications of a dual catalytic asymmetric Mannich of type three-component reaction. 

Sydnonimines and sydnones can be readily synthesized in a three-component reaction of the Mannich type (Scheme 13) (71CCC2640), for example to prepare 3-lV-hydroxy- (78) or 3-N-amino- (79) substituted sydnonimines (70CPB128, 70JHC123, 71T4449). 

The Hf(OTf)4-catalyzed Mannich-type reaction of imine with enol silyl ethers has been used as a means of access to 8-amino carbonyl compounds (Eq. 21) [23] this also was extended to a three-component reaction (Eq. 22). 

Alder, cyanation, allylation, Michael reaction, and Friedel-Crafts acylation). The same catalyst was also effective in three-component reactions such as Mannich-type reactions, Strecker, and quinoline-forming reactions. The polymer catalyst was recovered and reused many times without loss of activity (Eq. 31). 

In the presence of catalytic amounts of Sc(OTf)3 and SDS, three-component Mannich-type reactions of aldehydes, amines, and silyl enol ethers proceeded smoothly in micellar systems to afford the corresponding-amino ketones or esters in high yields (Scheme 3.48). Yb(OTf)3 and Cu(OTf)2 also worked well in this system.Furthermore, three-component reactions of aldehydes, amines, and allyltributylstannane proceeded smoothly in water to afford the corresponding homoallylic amines in high yields (Scheme 3.49). ... 

Disconnection of TM 2.17a requires new knowledge. This stmcture corresponds to the Mannich base since the terf-amino group is present in the fl-posilion to the strong electron-withdrawing nitro group. The retra-Mannich type disconnection of two bonds leads to simple starting materials, piperidine, formaldehyde and 2-nitropropane. In the same scheme are proposed reaction conditions for the synthesis of TM 2.17. More details on the Mannich reaction are presented in Sects. 4. 4.2 and 6.1. Here it suffices to mention that this three-component reaction affords P-amino carbonyl compounds known as Mannich bases. 

On the other hand, Kobayashi has developed a Bronsted acid-combined catalyst for aqueous Mannich-type reactions. Three-component Mannich-type reactions of aldehydes, amines, and ketones (e.g., benzaldehyde, p-anisidinc. and cyclohexanone) were efficiently... 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

Quite recently, not only Lewis adds, but also Bronsted adds were found to be effedive catalysts for the three-component Mannich-type reactions in water with the aid of a surfadant. For example, Akiyama and co-workers1301 have reported that a combination of HBF4 and SDS is effedive for the readions of aldehydes, amines, and silyl enolates. We have found that dodecylbenzenesulfonic add (DBSA), a Bronsted add with a surfadant moiety, also catalyzes the reactions in water.1311 Furthermore, DBSA can be used for the dired Mannich-type reactions of aldehydes, amines, and ketones, without using silyl enolates as nucleophilic components (Eq. 8).1321... 

Bismuth-Mediated Three-Component Mannich-Type Reaction. 88... 

Scheme 12.26. Syntheses offebrifugine and isofebrifugine using a three-component Mannich-type reaction, by Kobayashi and co-workers [89] TBS = t-butyldi methyl si ly I, Bn = benzyl,...

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

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