Isonitriles and multicomponent reactions

The first isonitriles were obtained by Lieke in 1859 and synthesized and identified by Hoffman and Gautier less than ten years later. These compounds, isomers of nitriles with a divalent terminal carbon, remained mere laboratory curiosities for many years. Despite the theoretical interest and strong synthetic potential of these unusually valent carbon derivatives, the unpleasant odor of the simplest compounds probably deterred most chemists from investigating their properties. For decades, therefore, isonitriles remained associated with the Hoffman carbylamine reaction used as a characteristic test for primary amines. In 1921, Passerini described the first three-component coupling between carboxylic acids, carbonyl derivatives and isonitriles, but this work went unrecognized during the first half of the twentieth century. The extension to imines was not discovered until almost forty years later by Ugi, and represents the first relatively efficient and general four-component reaction.

However, the Ugi reaction only really came into use in the early 1980s, when very few isonitriles were commercially available. The initial impetus came from the pharmaceutical industry, which associated the multicomponent nature of these couplings with the possibility of rapidly creating large libraries of compounds for biological screening. Numerous industrial teams have seized on this reaction and transformed it into a highly effective tool for the preparation of biologically active heterocyclic structures (heterocyclic pharmacophores such as pyrazines, indoles, imidazoles...). Multicomponent reactions involving isonitriles are now standard tools in pharmaceutical research.

More recently, the advent of green chemistry and the need to design chemical processes that are more in tune with societal expectations are shedding new light on these fields. Reducing the use of organic solvents and optimizing synthesis routes have always been major concerns for industrialists, for reasons of cost optimization. Today, however, these concerns are joined by more important issues in terms of communication and, above all, maintaining industrial activities close to urban areas. Industrial and academic organic synthesis is therefore increasingly structured around the concepts of atom and step savings. Among the most successful examples of these new principles is the use of isonitriles in multicomponent reactions: the great structural diversity accessible in a single step means that complex substrates can be synthesized in a very limited number of steps. In terms of green chemistry, the most characteristic features of multicomponent reactions involving isonitriles remain the use of particularly concentrated media (water can even be used as a solvent) with, as the only by-product, a single molecule of...