Three-component Mannich

Related to the Mannich three-component reaction is the Petasis or boronic-Mannich reaction, which involves the reaction between an aldehyde, an amine, and a boronic acid. 

On the other hand, Zhao s group achieved remarkable results with bifunctional cinchona alkaloid and thiourea catalysts [35], which, over the years, have been broadly employed as catalysts in Mannich reaction. Indeed, as Brpnsted bases, the preferred bifunctional catalyst 46 can lead to the Mannich three-component product 47 with extranely high diastereo- and... 

In 2003, Portlock and coworkers [53a] demonstrated that the Petasis borono Mannich (three-component) condensation can be performed in tandem with the Ugi (four-component) condensation to provide access to six-dimensional libraries of compounds with application in the drug discovery area. 

The Mannich condensation has traditionally been carried out in the presence of water as a three-component condensation involving a carbonyl compound (or related carbon nucleophile), formaldehyde, and a primary or secondary amine. The initial step is a condensation between the latter two reactants to form a mono- or dialkyl(methylene)ammonium ion which subsequently serves as the electrophilic partner in the reaction. With unsymmetrical ketones aminomethylation generally occurs at both positions to give mixtures of isomeric 3-amino ketones. The ratio of the isomers depends strongly on the structure of the ketone, and the more highly branched (3-amino ketone usually predominates. 

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... 

Tropinone is a structural component of several alkaloids, including atropine. The synthesis is based on a double Mannich process with iminium ions as intermediates. The Mannich reaction in itself is a three-component domino process, which is one of the first domino reactions developed by humankind. 

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... 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

The Mannich reaction is a three component reaction in which an imine, that was formed from the condensation of an amine with an aldehyde, reacts with a component containing at least one hydrogen atom of pronounced reactivity. It is possible to immobilize every Mannich partner on sohd supports. In combinatorial chemistry the Mannich reaction has been used for the generation of different h-braries (Scheme 3.26). 

Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction. 

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... 

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

Although imines are less electrophilic than carbonyl compounds, they are also more readily activated by acids or hydrogen bonding. For this reason, Mannich reactions are often faster than the corresponding aldol reactions. It is not even necessary to use preformed imines. In a typical three-component Mannich reaction, the acceptor imine is generated from an aromatic or otherwise protected primary amine. 

The easiest way to perform a Mannich reaction is to use an excess of the ketone donor and an aldehyde-amine pair to form the required imine in situ. This three-component Mannich protocol is, however, mostly restricted to aromatic amines (Scheme 24). 

When performing a Mannich reaction in its initial three-component design, the selectivity is sometimes difficult to obtain due to the competition with the side processes, primarily the auto-aldol condensation [52, 80], A common solution for this problem is the pre-formation of an imine or the enolate, or both and thus the sequential (indirect) performance of the reaction (Scheme 35) [52],... 

List B (2000) The direct catalytic asymmetric three-component Mannich reaction. J Am Chem Soc 122(38) 9336-9337... 

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

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... 

Mukund Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2004,126,718) a powerful three-component coupling, combining an a,(5-unsaturated amide 9, a hydroxylamine 10, and an aldehyde 11. The hydroxylamine condenses with the aldehyde to give the nitrone, which then adds in a dipolar sense to the unsaturated ester. The reaction proceeds with high diastereocontrol, and the absolute configuration is set by the chiral Cu catalyst. As the amide 9 can be prepared by condensation of a phosphonacetate with another aldehyde, the product 12 can be seen as the product of a four-component coupling, chirally-controlled aldol addition and Mannich condensation on a starting acetamide. 

Albert S.C. Chun of the Hong Kong Polytechnic University reports (J. Org. Chem. 68 1589, 2003) two important transformations. The three-component (Mannich) condensation of 10 with 11 and 12 proceeds with high diastereoselectivity, to give the amino alcohol 13. Hydroboration of the alkyne 14 followed by transmetalation of the intermediate vinyl borane gives a zinc species, which under catalysis by the easily-prepared 3-naphthol 13 adds to aromatic and branched aldehydes with high . The product allylic alcohols are useful intermediates for organic synthesis. 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

In origin, the Mannich reaction is a three-component reaction between an eno-lizable CH-acidic carbonyl compound, an amine, and an aldehyde producing / -aminocarbonyl compounds. Such direct Mannich reactions can encompass severe selectivity problems since both the aldehyde and the CH-acidic substrate can often act as either nucleophile or electrophile. Aldol addition and condensation reactions can be additional competing processes. Therefore preformed electrophiles (imines, iminium salts, hydrazones) or nucleophiles (enolates, enamines, enol ethers), or both, are often used, which allows the assignment of a specific role to each car-... 

Shibasaki et al. described the first direct three-component catalytic enantioselec-tive Mannich reaction [3], wherein propiophenone 1, paraformaldehyde 2 and pyrrolidine 3 were reacted using (R)-LaLi tris(binaphthoxide) [(R)-LLB, 4] as catalyst to form Mannich product 5 with 64% ee and in 16% yield (Scheme 9.2). 

Scheme 9.2. (R)-LaLi3tris(binaphthoxide)-catalyzed enantioselective three-component Mannich reaction.

List and coworkers discovered the first efficient catalytic asymmetric three-component Mannich reaction. In this proline-catalyzed Mannich reaction between ketones, aldehydes, and amines (typically p-anisidine, 6), Mannich products are formed in up to >99% ee and up to 96% yield (Scheme 9.3) [4],... 

The proline-catalyzed three-component Mannich reaction is proposed to proceed through the reaction of enamine a, formed by the reaction of the ketone with pro-... 

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). 

Scheme 9.7. Enantioselective three-component cross-Mannich reaction of two different aldehydes.

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,...

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... 

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