Multicomponent Mannich reactions

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... 

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

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-... 

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. 

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. 

Organoboron compounds have gained special attention and importance in the last years due to their use in different processes, but one of the most important and efficient protocols is the multicomponent Petasis-borono-Mannich (PBM) reaction [17-19]. In this approach, an amine, an aldehyde, and a boronic acid react to give access to a new amine... 

See, for instances (a) S. Santra, R R. Andreana, Org. Lett. 2007, 9, 5035-5038. A one-pot, microwave-influenced synthesis of diverse small molecules by multicomponent reaction cascades, (b) M. Presset, Y. Coquerel, J. Rodriguez, Org. Lett. 2009, 11, 5706-5709. Microwave-assisted domino and multi-component reactions with cyclic acyUcetenes expeditious syntheses of oxazinones and oxazindiones. (c) W.-J. Hao, B. Jiang, S.-J. Tu, X.-D. Cao, S.-S. Wu, S. Yan, X.-H. Zhang, Z.-G. Han, F. Shi, Org. Biomol. Chem. 2009, 7,1410-1414. A new mild base-catalyzed Mannich reaction of hetero-arylamines in water highly efficient stereoselective synthesis of 3-aminoketones under microwave heating, (d) P. Nun, J. Martinez, F. Lamaty, Synthesis 2010, 2063-2068. Microwave-assisted neat procedure for the Petasis reaction. 

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

Keywords Indoles, aldehydes, secondary amines, L-Proline, solvent-free, room temperature, one-pot multicomponent reaction, Mannich-type reaction, 3-amino alkylated indoles... 

Kumar, A., Gupta, M. K., and Kumar, M. (2012). L-Proline catalysed multicomponent synthesis of 3-amino aUcylated indoles via a Mannich-type reaction under solvent-free conditions. Green Chem, 24, 290-295. 

Keywords Aromatic aldehydes, p-keto esters, amines, bismuth nitrate, ethanol, room temperature, homogeneous catalysis, tandem reaction, one-pot synthesis, multicomponent reaction (MCR), Mannich reaction, functionalized piperidines... 

It is interesting that three multicomponent reactions were broadly used over 150 years, known as name reactions according to their inventors Strecker synthesis of amino acids [3], Hantsch synthesis of 1,4-dihydropyrimidines [4] and particularly the imjxjrtant Mannich reaction [5]. 

Despite the chemical complexity of multicomponent reactions (MCRs), the dawn of MCRs was fairly early in the history of organic chemistry. The first MCR was the so-called Strecker reaction discovered in 1850 [1, 2], which generates amino acids via a three-component reactiOTi between amines, aldehydes (or ketones), and hydrogen cyanide (Scheme 1). Since then, organic chemists have devoted much effort to the discovery of additional MCRs. Thus, we now can find a number of MCRs, including the Biginelli reaction [3], the Gewald reaction [4], the van Leusen three-component reaction [5], the Hantzsch reaction [6], the Mannich reaction [7], the Kabachnik-Fields reaction [8, 9], the Passerini reaction [10], the Ugi reaction [11, 12] and numerous variations thereof [13]. 

Multicomponent reactions (MCRs) have attracted much attention in the past decade because of advantages such as high atom economy, simple procedure, and high efficiency. [1] Because of their ability to generate complex structures economically and efficiently [2], numerous MCRs have been developed and widely studied, such as the Cu-catalyzed three-component reactions [3-6], Mannich reactions [7, 8], Passerini reactions [9, 10], and A3-coupling reactions [11]. Of these, multicomponent alkyne reactions have become quite popular recently and abundant literature has been published regarding the various MCRs of alkynes with all sorts of reactants [12, 13]. 

The ion pair [emim][Pro] efficiently catalyzed multicomponent reactions of carbonyl compounds. In the presence of this catalyst a three-component Mannich... 

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