ThePasserini Reaction

Abstract

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.

Asymmetric Isocyanide‐Based MCRs

“…On the contrary, a-alkoxy substituted aldehydes do not racemize. In the classical Passerini reaction [11], an isocyanide is condensed with a carbonyl compound and a carboxylic acid to afford a-acyloxyamides 7 (Scheme 1.2). When the carbonyl compound is prochiral, a new stereogenic center is generated.…”

Groebke–Blackburn–Bienaymé multicomponent reaction: emerging chemistry for drug discovery

“…This involves the reaction of an isocyanide with a carboxylic acid and an aldehyde or ketone to give α- [9,10]). This reaction was further expanded by Ugi and Steinbrückner in 1961 by using amines to give a dipeptide-like backbone ( Fig.…”

Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct

“…Since one stereogenic center is generated in this transformation, the ability to control the stereochemical outcome would expand significantly its synthetic utilities.H owever,t he development of ac atalytic, enantioselective Ugi reaction remains an unsolved problem in spite of the progress recorded in the field of asymmetric Passerini reactions, [4][5][6][7][8][9] ac losely related three-component condensation of an aldehyde,carboxylic acid, and isonitrile. [10] Our group [11] and that of Maruoka [12] have independently reported chiral phosphoric acid (CPA) and chiral dicarboxylic acid catalyzed Ugi-type three-component reactions in which the transient nitrilium intermediate was trapped by an internal carboxamide function (Scheme 1a,b). Very recently, Wulff and co-workers described ac hiral BOROX-catalyzed reaction of aldehydes,s econdary amines,a nd isonitriles for the synthesis of enantioenriched a-aminoacetamides (Scheme 1c).…”