100 years of isocyanide-based multicomponent reactions

In 1921 Mario Passerini (1891–1962), who was holding a chair of organic chemistry at the University of Florence (Italy), published a report [1] where he described the first multicomponent reaction based on the peculiar chemistry of isocyanides. Isocyanides (also called isonitriles) are indeed “stable carbenes”, having a carbon atom that can act both as nucleophile and electrophile. In the reaction named after him, isocyanides react with carbonyl compounds and carboxylic acids to afford α-acyloxyamides.

In 1921, the term “multicomponent reaction” was not already used, and probably Passerini was not fully aware of the importance of his discovery. Nowadays, we define a multicomponent reaction as a process where three or more substrates react to give a product that contains essential parts of all starting materials. It was Ivar Ugi who, about 40 years after Passerini's discovery, [2] first understood the potential of multicomponent reactions in “diversity-oriented synthesis” [3] and in combinatorial chemistry. Ugi published his well-known reaction in 1960, 39 years later than the first report by Passerini. In consideration of the mechanistic similarity of the two reactions, it is surprising that so much time passed between the two discoveries. [4] This may be due to the fact that Passerini published his work in Italian that was not at the time the leading scientific language. The work of Passerini was indeed completely neglected until the early '50 s. Moreover, the mechanism initially proposed by Passerini, which was later found wrong, may have misled other researchers to simply substitute the carbonyl component with an imine.

In any case, both Passerini and Ugi reactions turned into high popularity only in the '90 s, when pharmaceutical companies became increasingly interested in combinatorial chemistry. It was soon clear that multicomponent reactions are exceptionally useful in this context. This is particularly true for those, like Passerini and Ugi reactions, which combine in a single step three or four real diversity inputs, represented by easily available reagents. Since then, the number of publications on multicomponent reactions (MCR) has grown up exponentially, and several new MCRs have been discovered in the last 30 years. However, isocyanide-based MCRs continue to maintain a leading role.

They have evolved along four main paths: (a) single-component replacements have generated numerous variants of Passerini and Ugi reactions; (b) coupling the classical reactions with post-MCR reactions (especially cyclizations) or with pre-MCR processes has allowed to widely explore scaffold diversity, for example, giving access to a huge variety of heterocycles; (c) new isocyanide-based chemistry has been investigated leading to the discovery of completely new IMCRs; (d) diastereoselectivity [5] and enantioselectivity of IMCRs have been studied. In particular, the very challenging issue of develo** enantioselective catalytic Passerini [6] and Ugi reactions [7,