Multicomponent reactions have become increasingly popular as tools for the rapid generation of small-molecule libraries. However, to ensure sufficient molecular diversity and complexity, there is a continuous need for novel reactions. Although serendipity has always played an important role in the discovery of novel (multicomponent) reactions, rational design strategies have become much more important over the past decade. In this Review, we present an overview of general strategies that allow the design of novel multicomponent reactions. The challenges and opportunities for the future will be discussed.

Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity

Multicomponent reactions: advanced tools for sustainable organic synthesis

Heterocycles constitute the largest and the most diverse family of organic compounds Among them, aromatic heterocycles represent structural motifs found in a great number of biologically active natural and synthetic compounds, drugs, and agrochemicals Moreover, aromatic heterocycles are widely used for synthesis of dyes and polymeric materials of high value 1 There are numerous reports on employment of aromatic heterocycles as intermediates in organic synthesis 2

Although, a variety of highly efficient methodologies for synthesis of aromatic heterocycles and their derivatives have been reported in the past, the development of novel methodologies is in cuntinious demand Particlularly, development of new synthetic approaches toward heterocycles, aiming at achieving greater levels of molecular complexity and better functional group compatibilities in a convergent and atom economical fashions from readily accessible starting materials and under mild reaction conditions, is one of a major research endeavor in modern synthetic organic chemistry Transition metal-catalyzed transformations, which often help to meet the above criteria, are among the most attractive synthetic tools

Several excellent reviews dealing with transition metal-catalyzed synthesis of heterocyclic compounds have been published in literature during recent years Many of them highlighted the use of a particular transition metal, such as gold,3 silver,4 palladium,5 copper,6 cobalt,7 ruthenium,8 iron,9 mercury,10 rare-earth metals,11 and others Another array of reviews described the use of a specific kind of transformation, for instance, intramolecular nucleophilic attack of heteroatom at multiple C–C bonds,12 Sonogashira reaction,13 cycloaddition reactions,14 cycloisomerization reactions,15 C–H bond activation processes,16 metathesis reactions,17 etc Reviews devoted to an application of a particular type of starting materials have also been published Thus, for example, applications of isocyanides,18 diazocompounds,19 or azides20 have been discussed In addition, a significant attention was given to transition metal-catalyzed multicomponent syntheses of heterocycles21 Finally, syntheses of heterocycles featuring formation of intermediates, such as nitrenes,22 vinylidenes,23 carbenes, and carbenoids24 have also been reviewed

The main focus of the present review is a transition metal-catalyzed synthesis of aromatic monocyclic heterocycles The organization of the review is rather classical and is based on a heterocycle, categorized in the following order: (a) ring size of heterocycle, (b) number of heteroatoms, (c) type of heterocycle, and (d) a class of transformation involved A brief mechanistic discussion is given to provide information about a possible reaction pathway when necessary The review mostly discusses recent literature, starting from 200425 until the end of 2011, however, some earlier parent transformations are discussed when needed

Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles

Multicomponent reactions (MCRs) receive increasing attention because they address both diversity and complexity in organic synthesis. Thus, in principle diverse sets of relatively complex structures can be generated from simple starting materials in a single reaction step. The ever increasing need for optically pure compounds for pharmaceutical and agricultural applications as well as for catalysis promotes the development of asymmetric multicomponent reactions. In recent years, asymmetric multicomponent reactions have been applied to the total synthesis of various enantiopure natural products and commercial drugs, reducing the number of required reaction steps significantly. Although many developments in diastereoselective MCRs have been reported, the field of catalytic enantioselective MCRs has just started to blossom. This critical review describes developments in both diastereoselective and catalytic enantioselective multicomponent reactions since 2004. Significantly broadened scopes, new techniques, more environmentally benign methods and entirely novel MCRs reflect the increasingly inventive paths that synthetic chemist follow in this field. Until recently, enantioselective transition metal-catalyzed MCRs represented the majority of catalytic enantioselective MCRs. However, metal contamination is highly undesirable for drug synthesis. The emergence of organocatalysis greatly influences the quest for new asymmetric MCRs.

Recent developments in asymmetric multicomponent reactions.

As valuable C1 building blocks, isocyanides represent an important class of reactive species and synthons. During the past decades, exhaustive efforts have been devoted to the discovery of highly efficient reactions involving isocyanide on the basis of the development of the Passerini and Ugi reactions. Several types of reactions involving isocyanides have been reported, such as nucleophilic attack, electrophilic addition, imidoylation reactions, and oxidation etc. In this review, recent progress in isocyanide insertion chemistry is presented. Among all isocyanide insertions, two catalytic systems have been developed, that is, Lewis (Bronsted) acid-catalyzed isocyanide insertions and transition-metal-enabled isocyanide insertions, respectively. This review is hence written in the sequence of Lewis (Bronsted) acid-catalyzed isocyanide insertion and transitional metal-enabled isocyanide insertion, where isocyanide insertion into heteroatom–hydrogen bonds, carbon–halogen bonds, carbon–hydrogen bonds, and metal carbenes are summarized.

Recent advances in isocyanide insertion chemistry

Mehrkomponentenreaktionen haben sich zu sehr populA¤ren Hilfsmitteln\nfA¼r die schnelle Erzeugung von Bibliotheken niedermolekularer organischer\nVerbindungen entwickelt. Um dabei auch genA¼gend molekulare DiversitA¤t\nund KomplexitA¤t sicherzustellen, gibt es einen kontinuierlichen\nBedarf an neuen Reaktionen. Auch wenn der Zufall immer eine wichtige\nRolle in der Entdeckung neuer (Mehrkomponenten-)Reaktionen gespielt\nhat, so ist die Bedeutung gezielter Entwicklungsstrategien im letzten\nJahrzehnt bestA¤ndig gestiegen. Hier prA¤sentieren wir einen allgemeinen\nAœberblick zu Strategien bei der Entwicklung neuer Mehrkomponentenreaktionen.\nDabei werden Herausforderungen und Chancen fA¼r die Zukunft diskutiert.

Mehrkomponentenreaktionen als Weg zu molekularer Komplexität und Diversität

A Novel Three-Component Reaction toward Dihydrooxazolopyridines

Diastereoselective Multicomponent Synthesis of Dihydropyridones with an Isocyanide Functionality

Highly functionalized and conformationally constrained depsipeptides based on a dihydropyridin-2-one core are prepared by the combination of a four- and a three-component reaction. The synthesis combines a one-pot Horner-Wadsworth-Emmons/cyclocondensation sequence leading to isonitrile-functionalized DHP-2-ones with an isonitrile-based Passerini multicomponent reaction (MCR). Substituents could be independently varied at six different positions. The two MCRs could also be performed as a one-pot procedure, simplifying the protocol and leading to a new and highly variable six-component process.

Rachel Scheffelaar

Papers

Multicomponent Reaction Design in the Quest for Molecular Complexity and Diversity

Mehrkomponentenreaktionen als Weg zu molekularer Komplexität und Diversität

A Novel Three-Component Reaction toward Dihydrooxazolopyridines

Diastereoselective Multicomponent Synthesis of Dihydropyridones with an Isocyanide Functionality

A Flexible Six-Component Reaction To Access Constrained Depsipeptides Based on a Dihydropyridinone Core