The Passerini Reaction

Banfi, Luca; Riva, Renata


Isocyanides are a very special class of organic compounds, which may behave as acyl anion equivalents. However, with very few exceptions, isocyanides do not react with carbonyl compounds in the absence of an acid. In this chapter, all reactions of a carbonyl compound or an acetal with an isocyanide are considered. These are processes that frequently, but not invariably, result in the incorporation of an acid residue in the final product. In the classic Passerini reaction, discovered in 1921 by Mario Passerini, the acid is always a carboxylic acid and the products alpha-acyloxy amides. A more recent variation, which is often referred to as the Passerini reaction as well, employs a variety of mineral (H+) or Lewis acids (LA) to afford alpha-hydroxy amides. These compounds may also be formed in the presence of carboxylic acids such as formic acid or trifluoracetic acid. Interactions of isocyanides with carbonyl compounds and some protic or Lewis acids can also lead to a large variety of products other than alpha-hydroxy amides, including several heterocyclic systems. These Passerini-type reactions are discussed. Acetals can also react with isocyanides in the presence of Lewis acids. The usual products are alpha-alkoxy amides.

The classic Passerini reaction is one of the oldest multicomponent reactions and is the first based on isocyanides to be discovered. This method is experiencing a growing interest. Its scope has been expanded by employing bifunctional substrates able to undergo secondary reactions. In this way, a larger variety of products can be synthesized and complex biologically active substances can be accessed quickly. Modifications that form products different from alpha-acyloxy amides or alpha-hydroxy amides, especially those leading to heterocycles, may find useful applications in synthesis.