Mannich multicomponent

Candeias NR, Montalbano F, Cal PMSD et al (2010) Boronic Acids and Esters in the Petasis-Borono Mannich Multicomponent Reaction. Chem Rev 110 6169-6193... 

SCHEME 11,1 Mannich multicomponent reaction for the synthesis of spirocyclic compounds. 

To fully use the advantages afforded by multicomponent reaction systems in solid-phase organic synthesis, strategies in which each component is immobilized on the resin must be devised. In this way, individual components can be explored in terms of diversity without the restrictions imposed by immobilization. We have described solid-phase Mannich reactions1 of a resin-bound alkyne (see chapter 5), and we show here that the diversity of products using this chemistry can be enhanced when a different component of the reaction system is immobilized. Specifically, a secondary amine, piperazine, is bound to a resin and then treated with... 

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. 

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... 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

Multicomponent Reactions Using Preformed Intermediates 4.1 The Mannich Reaction... 

An analogous non-electrochemical Ni(0)-catalysed process, exploited in a Mannich/ Reformatsky multicomponent process58, will be discussed in Section III (equation 41). In the third study, the a-bromoester Id is simply electrolysed in the presence of a carbonyl compound in DMF/THF in a 1 2 ratio using both indium and zinc rods as sacrificial anodes. While aldehydes afford the expected 3-hydroxyesters in high yield, aliphatic, aromatic and cyclic ketones, with the exception of acetone, directly afford /3-lactones,... 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

The first part of this chapter deals with the effects of high pressure on cycloaddition reactions, particularly the Diels-Alder reaction, which is the most important cycloaddition reaction. The second part will illustrate applications of pressure to nucleophilic substitutions, condensations and other reactions (miscellaneous reactions), such as Mannich, Heck, ene, SeAr, Wittig, Horner-Wadsworth Emmons and multicomponent Strecker reactions. 

Multicomponent reactions, although fashionable these days, have in fact a long history. Indeed, many important reactions such as the Strecker amino acid synthesis (1850)[6], the Hantsch dihydropyridine synthesis (1882) [7], the Biginelli dihydropyrimidine synthesis (1891)[8], the Mannich reaction (1912) [9], and the isocyanide-based Passerini reactions (1921) (Scheme 5.1) [10], among others, are all... 

For organic synthesis and biosynthesis the Mannich reaction (he most important multicomponent reaction. The Mannich reaction is an a-aminoalkylation (4) -i- (43) + HX <-> (40) -i- X + H2O -> (44) -I- H2O, where the anion X is a carbanion. Ugi was curious to find out whether or not a carbanionlike isocyanide is capable of undergoing a Mannich reaction , and the relevant experiments were conducted by his doctoral student Cornelius Steinbriickner. 

Scheme 7.19. Mannich-type multicomponent synthesis of propargylamines.

This reaction was first reported by Robinson in 1917 and subsequently improved by Schopf in 1935. It is an ingenious one-pot multicomponent synthesis of tropinone from succindialdehyde, acetonedicarboxylic acid and methylamine in aqueous solution involving a double Mannich Reaction This reaction is thus known as the Robinson tropinone synthesis," Robinson synthesis, " Robinson-Schopf reaction,Robinson-Schopf condensation, or Robinson condensation." It has been reported that the Robinson tropinone synthesis can take place without any racemization at the stereogenic center adjacent to the aldehyde group, as demonstrated by the formation of L-a/to-teloidinone from D-tartaraldehyde, and c-a/to-teloidinone from i-tartaraldehyde respectively." ... 

Phosphonate monomers of type 1 were made from the reaction of allyl glycidyl ether with hydroxy-functionalized phosphonic acid. To obtain azo-phosphonated products (type 2), multicomponent reactions (amine-, aldehyde/ketone-, or phosphorus-containing compounds) such as the Kabachnick-Fields," Mannich," or Moedritzer ° reactions, were used. These reactions generated in a selective way the a-aminoallq lphosphonate products. 

In the intensively studied field of multicomponent reactions (MCRs), one can highlight several interesting cascades involving successive C-N and C-C bond formations. It is important to note that, although the majority of these sequences such as the Hantzsch, the Biginelli, or the Mannich reactions are known for more than one century, their organocatalytic enantioselective versions have been disclosed only very recently. 

Subsequently, a plethora of proline-catalyzed multicomponent Mannich reactions have been copiously and successfully developed as epitomized in Table 2.1. 

SCHEME 2.2 Plausible mechanism for the proline-catalyzed Mannich reaction. TABLE 2.1 Several proline-catalyzed multicomponent Mannich reactions... 

Besides the widely investigated proUne catalysis, other pyrrolidine derivatives have been considered in multicomponent Mannich reaction, as depicted in Scheme 2.4. In these works, the effects of either a carboxylic 17 or ester 18 moiety in position 5 on the pyrrolidine ring have been examined, achieving the desired class of products 19 with comparable enantiomeric and diastereomeric excesses (up to 98% ee, dr up to 94 6) [21]. 

A combination of Michael addition, Mannich reaction, and intramolecular condensation allowed Xu and coworkers to get a quite facile access to tetrahydropyridines 165 with C3 all-carbon quaternary stereocenters in moderate yields and good optical purity (up to 74% ee) [79], The developed organocatalytic enantioselective multicomponent cascade reaction relies on the catalytic ability of the simple (5)-proline (1) that quickly reacts with the intermediate A, generated in turn via a Knoevenagel reaction between the p-ketoester 91 and formaldehyde 65. The resnlting iminium ion B undergoes the nucleophilic attack of a second moiety of p-ketoester 91 prodncing the Michael adduct D. Such intermediate enamine is then involved in the Mannich reaction with the imine E (dne to the in situ condensation between primary amine 51 and formaldehyde 65) to furnish the advanced intermediate F, which after an intramolecular condensation releases the (5)-proline (1), and the desired prodnct 165 (Scheme 2.52). 

G. Dagousset, F. Drouet, G. Masson, J. Zhu, Org. Lett. 2009, 11, 5546-5549. Chiral Brpnsted acid-catalyzed enantioselective multicomponent Mannich reaction synthesis of anti-1, 3-diamines using enecarbamates as nucleophiles. 

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