Reactions multicomponent

Multicomponent reactions offer the possibility to introduce structural variations at more than two positions of a basic scaffold in a single step (for recent reviews, see [37]). In many cases at least some classes of components are commercially available in great numbers and reasonable structural diversity, e.g., in the case of the Ugi reaction, primary amines, aldehydes, and carboxylic acids. For these reasons, multicomponent reactions provide, at least in principle, one of the most economical tools for synthesizing large libraries. 

However, it must be borne in mind that multicomponent syntheses imply a number of reaction steps. Each of them may not only form the desired product, but also by-products to a larger or lesser extent. In addition, every one of the reagents may contribute its own impurities to the resulting reaction mixture. Both are expected to aggravate the purification problems. Therefore, much of the time that could principally be saved by using multicomponent reactions may have to be spent on finding appropriate reaction conditions and eventually on purification of the products (and perhaps even the starting materials). 

Some examples for the use of multicomponent reactions in combinatorial chemistry are given in Table 3.9. Multicomponent reactions have also been employed in the synthesis of rings (see Section 3.3.11). 

Components Product Presence of other functional groups Reference 

Multicomponent reactions are very attractive for the preparation of organic compounds since they are very efficient chemical procedures that allow production of highly elaborated compounds from raw materials with low levels of byproducts in an economical, energy-saving and intensified 

4-Dihydropyridines can be prepared via the three-eomponent coupling of cinnamaldehyde, aniline and p-keto esters under solvent-free conditions by means again of L-Pro as catalyst in the transformation. The three-component reaction of 1,3-indanedione, isatins and enamines as the nucleophiles is also possible in the presence of L-Pro for the one-pot synthesis of highly functionalised spirooxindoles derivatives. While only some examples are highlighted here, ° ° the possibilities of L-Pro in multicomponent reactions are tremendous. It has also shown good catalytie activity in classic multicomponent reactions such as Biginelli reactions and Hantzsch dihydropyridine synthesis. 

Compounds other than carbonyls could be activated by L-Pro. Thus, nitroalkanes react with aldehydes in a Henry-type reaction facilitated by L-Pro. After elimination of the catalyst and a water molecule, the resulting nitroalkene can react with several nucleophiles such as sodium azide, p-ketoesters or sulfur ylides.  

A number of aromatic compounds have been prepared by means of L-Pro catalysis in multicomponent reaetions. With this strategy, interesting substitution patterns in the aromatie ring could be achieved, which sometimes 

4 Synthesis of Aromatic Compounds. (Formal) Cycloaddition Reactions 

Even though the history of multicomponent reactions dates baek to the second half of the 19th century with the reactions of Strecker, Hantzsch, and Biginelli, it was only in recent decades with the work of Ugi that the concept of the multicomponent reaction has emerged as a powerful tool in synthetic 

1 Three-Component Couplings of Unsaturated Hydroearbons, Carbonyl Compounds and Derivatives, and Redueing Agents 

1 Reactions of 1,3-Dienes, Carbonyl Compounds, and Reducing Agents 

3 Reactions ofAlkynes, Aldehydes or Aldimines, and Reducing Agents 

Tilting of the N-aryl ring of U relative to the imidazolidine ring positioned the ortfto-eyelohexyl substituent anti to the backbone phenyl group and distal to nickel. This orientation then positioned the ort/zo-methyl substituent syn to the backbone phenyl group and proximal to nickel. It was the ortho-methyl substituent that thus dictated the selectivity of aldehyde binding according to this model. Oxidative cyclisation of U to metallacycle V then led to the formation of the final product. 

There are a few library concepts originating from synthetic feasibility considerations. Multicomponent reactions, click chemistry, and diversity-oriented synthesis will now be discussed in more detail. 

MCRs can be considered the cradle of combinatorial chemistry [56]. Other than the stepwise library synthesis described in the library design section above, MCRs have the advantage of the very short reaction sequence. This allows for the possibility to apply extreme cherry-picking of the desired products, resulting in very low matrix coverage and high structural diversity regarding the decoration of the scaffold. 

However, many MCRs result in a single type of scaffold structure, for example, the Biginelli reaction or the Hantzsch dihydropyridine synthesis, which clearly 

Abstract Some innovative S3mthetic methods in organic chemistry are concisely presented, multicomponent reactions, specifically the Ugi multicomponent reaction, parallel syntheses and combinatorial chemistry, mechanochemically promoted organic reactions, organic reactions promoted by microwave irradiation and syntheses in ionic liquids. Examples of chemoselective or as3mimetric syntheses completed by one of the presented specific methods are presented for the antihy-pertensive drug nifedipine, the alkaloid tropinone, the local anesthetic xylocaine and the HIV inhibitor tipranavir. 

This chapter is more informative then educative and to a certain extent departs from the main concept of this book. Familiarity with principles of less-known synthetic methods, though not correlated to retrosynthetic analysis, is expected to expand the imaginative capacity of synthetic organic chemists. 

Multicomponent reactions (MCRs) have long been known in laboratoiy praxis, but not recognized as a general concept. In the last decades their industrial utiUty has been recognized and multicomponent syntheses developed for large-scale 

Sunjic and V. Petrovic Perokovic, Organic Chemistry from Retrosynthesis to Asymmetric Synthesis, DOI 10.1007/978-3-319-29926-6 6 

Odom and coworkers have developed titanium pyrrole derivatives as highly efficient catalysts for multicomponent reactions. The processes involve the reaction between an alltyne, an isonitrile and a primary amine, giving rise to di-imine intermediates, which react in situ with either 

Titanium-catalysed multicomponent reactions for the formation of JV-heterocyclic rings. 

The reaction is quite effective under thermal conditions for terminal and internal allq nes with a variety of aliphatic and aromatic amines or aromatic hydrazines, giving moderate to good yields. 

Ashfeld and coworkers have developed titanocene/zinc-catalysed multi-component reactions of aromatic aldehydes with zinc acetylides generated in situ in the presence of phosphine. The eatalyst system has great potential for the synthesis of complex organie moleeules of pharmaeeutieal interest from inexpensive starting materials. 

One of the fundamental aspects in Green Chemistry is linked to the number of steps in organic synthesis as well as atom economy. Multicomponent reactions (MCR) are thus becoming a more and more important class of reactions since they allow combining several starting materials in usually a single compound and in a one-flask operation. 

Cu(l)-modified zeolites, especially Cu(I)-USY, proved to be very efficient catalyst in multicomponent reaction. Such catalysts allowed for an efficient, solvent-free synthesis of propargylamines from aldehydes, amines and terminal alkynes with high yields. 

Propargylic amines are high value building blocks in organic synthesis, and the corresponding stractural motif has been found in various natural products, and in compounds of pharmaceutical or phytoprotective relevance. They can be obtained by addition of alkynes to imines, bnt since imines are easily formed from aldehydes and amines. 

3-component versions are known, either as such or promoted by various transition metals. A few supported versions or versions based on heterogeneous catalysts have recently been described, but zeolite-catalyzed version has only been reported recently. 

The C—H bond activation characterized by H/D exchange with solid acids allows ranking solid acids by their activity and acidity. Moreover neopentane being a bulky probe is sensible to steric hindrance and confinement effect.  

Later on, the same group developed another three-component reaction of diazo compounds with anilines and 4-oxo-enolates based on their previous work [44], By controlling the addition sequence of the substrates, this three-component reaction could proceed through an aza-Michael addition/ylide generation/intramolecular aldol 

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E. V. Albano. On the universality classes of the discontinuous irreversible phase transitions of a multicomponent reaction system. J Phys A (Math Gen) 27 3751-3758, 1994. 

E. V. Albano. Irreversible phase transitions into non-unique absorbing states in a multicomponent reaction system. Physica A 274 426-434, 1995. 

A new multicomponent reaction of nitro compounds with isocyanides gives ct-oxyimi-noamides, which are important for dnig synthesis such as cephiilosporin and fi-lactamase inhibitor fEq 6 65 Multicomponent reactions using isocyanides fUgi reacdoni is re-... 

Microwave-Assisted Multicomponent Reactions for the Synthesis of Heterocycles... 

Keywords Heterocycles Multicomponent reactions Microwave Organic synthesis... 

A library of 800 substituted prolines of type 112 was described using a similar synthetic approach. The [3 + 2] cycloaddition occurred via a multicomponent reaction of a-amino esters, aldehydes, and maleimides (Scheme 38). 

Bagley MC, Lubinu MC (2006) Microwave-Assisted Multicomponent Reactions for the Synthesis of Heterocycles. 1 31-58... 

Mitchell, M. C., Spikmans, V., Bessoth, F., Manz, a., de Mello, A., Towards organic synthesis in microfluidic devices multicomponent reactions for the construction of compound libraries, in van den Berg, A., Olthuis, W., Bergveld,... 

Ugi, I. K., New aspects of natural and preparative of one-pot multicomponent reactions and their libraries, in Ehefeld,... 

Ugi, I. (1998) MCR. XXIII. The Highly Variable Multidisciplinary Preparative and Theoretical PossibUities of the Ugi Multicomponent Reactions in the Past, Now, and in the Future. Proceedings of the Estonian Academy of Science Chemistry, 47, 107-127. 

Lombardo, M. Trombini, C. (1998) One-Pot Multicomponent Reactions. In Seminars in Organic Synthesis XXIII Summer School A. Corbella , pp. 7-32. Societa Chimica Italiana, MUan. 

Ugi, I., Domling, A., Werner, B. (2000) Since 1995 the New Chemistry of Multicomponent Reactions and Their Libraries, Including Their Heterocyclic Chemistry. Journal of Heterocyclic Chemistry, 37, 647-658. 

Ugi, I. (2001) Recent Progress in the Chemistry of Multicomponent Reactions. Pure and Applied Chemistry, 73, 187-191. 

Simon, C., Constantieux, T, Rodriguez, J. (2004) Utilisation of 1,3-Dicarbonyl Derivatives in Multicomponent Reactions. European Journal of Organic Chemistry, 4957M 980. 

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

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