The Fourcomponent Reaction And Other Multicomponent Reactions Of The Isocyanides

Ivar Ugi and Birgit Werner

Institute of Organic Chemistry and Biochemistry, Technische Universität München, Germany


The usual syntheses of products from three or more educts require several preparative processes, and its intermediate or final product must be isolated and purified after each reaction. As the number of steps increase, the amounts of solvents and the preparative work grows, while the yields of products decrease and more and more solvents and by-products must be removed. In such reactions, scarcely all optimal aspects of green chemistry can be accomplished simultaneously.

Practically irreversible multicomponent reactions (MCRs), like the Ugi 4-component reaction (U-4CR), can usually fulfill all essential aspects of green chemistry. Their products can be formed directly, requiring minimal work by just mixing three to nine educts. Often minimal amounts of solvents are needed, and almost quantitative yields of pure products are frequently formed.

The chemistry of the isocyanide U-4CR was introduced in the late 1950s, but this reaction was relatively little used for more than three decades, only around 1995 almost suddenly it was recovered by the chemical industry.1

In the last few years the variability of educts and products of the U-4CR has essentially increased, so that by now the majority of new products have been prepared. The U-4CR allows the preparation of more different types of products than

Methods and Reagents for Green Chemistry: An Introduction, Edited by Pietro Tundo, Alvise Perosa, and Fulvio Zecchini

Copyright © 2007 John Wiley & Sons, Inc.

any other reaction. If such a product with desirable properties—a lead structure— is found, large amounts of related compounds can be prepared easily by the U-4CR and similar reactions.

It is barely possible to still find novel reactions of one or two components, whereas the chemistry of the MCRs is not yet exhausted. Still, many new combination of up to nine different types of MCR educts can form new types of products that can totally differ from the already known chemistry.1


Chemical reactions are in principle equilibria between one or two educts and products. In practice, the preferred preparative reactions proceed irreversibly. Syntheses of products from three or more educts are usually sequences of preparative steps, where after each reaction step its intermediate or final product must be isolated and purified while the yield decreases. Exceptions can be the reactions of three components on solid surfaces and also some MCRs with a-additions of intermediate cations and anions onto the isocyanides.1,2

Besides the usual chemistry, an increasing number of chemical compounds can be prepared by MCRs just by mixing more than two educts.3-5 Such processes do not proceed simultaneously, but they correspond to collections of subreactions, whose final steps form the products. Any product that can be prepared by an MCR whose last step is practically irreversible requires considerably less work and is obtained in a much higher yield than by any conventional multistep synthesis.

Three basic types of MCRs are now known.5 The MCRs of type I are collections of equilibrating subreactions. In type II the educts and intermediate products equilibrate, but their final products are irreversibly formed. The MCRs of type III correspond to sequences of practically irreversible reactions that proceed from the educts to the product.6

In 1960 Hellmann and Opitz7 introduced their a-Aminoalkylierung book, wherein they mentioned that the majority of the "name reactions" by MCRs belong together since they have in common their essential features. This collection of 3CRs can be considered as Hellmann-Opitz 3-component reactions, (HO-3CRs). They are either a-aminoalkylations of nucleophiles of MCR type I, or they form intermediate products that react with further bifunctional educts into heterocycles by 4CRs of type II. Their last step is always a ring closure that proceeds irreversibly.

This MCR chemistry began in 1850 when the Strecker reaction S-3CR8 of ammonia, aldehydes, and hydrogen cyanide was introduced. Since 1912 the Mannich reaction M-3CR9 of secondary amines, formaldehyde, and b-protonated ketones is used.

The MCRs of type II forming heterocycles begin with a-aminoalkylations of nucleophilic compounds, and subsequently these products react further with bifunctional educts whose last step is always an irreversible ring formation. Such reactions were introduced in 1882 by Hantzsch10 and by Radziszewski.11 Shortly after this Biginelli12 also entered a similar type of forming heterocycle by MCRs. In the 1920s Bucherer and Bergs13 began to produce hydantoin derivatives by BB-4CRs. This reaction begins with an S-3CR whose product then reacts with CO2 and forms irreversibly the hydantoin. The products of the S-3CR and of the BB-4CR can both be hydrolized into a-aminoacids, but the synthesis via the BB-4CR is used preferentially, since this leads to products of higher purity and with higher yields.

In the early Gatterman's preparative chemistry book,14 the one-pot synthesis of dihydropyridine derivatives like those formed by the Hantzsch reaction was one of practical laboratory exercises.

Schildberg and Fleckenstein observed that calciumantagonists can advantageously influence the peripheric vessels and those of the heart.15 With the 4-aryldihydropyridine-3,5-dicarboxylic esters 4 (Scheme 1.1) that have such effects, the first pharmaceutical products synthesized by Hantzsch reactions were independently introduced by the Bayer AG16 and Smith Cline & French.17

As the last classical MCR in the 1950s, Asinger18 introduced the 3CRs and 4CRs to form thiazole derivatives. It seems that these A-MCRs can belong to type I or to type II.

In preparative chemistry only a few MCRs of type III are known;6 however, in living cells, the collections of the biochemical compounds are formed by MCRs of type III. In that case the formation of the individual products proceeds by sub-reactions that are accelerated by the enzymes present in the suitable areas within the living cells. The resulting collections of products can be considered to be their libraries.

Multicomponent Reaction Type

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