Passerini Multicomponent Reactions

The mechanism of the Passerini reaction was widely examined. A plausible mechanism that is consistent with experimental data is as follows First, the carbonyl compound and the carboxylic acid forms a hydrogen bonded adduct. Subsequently, the carbon atom of the isocyanide group attacks the electrophilic carbonyl carbon, and also reacts with the nucleophilic oxygen atom of the carboxylic acid. The resulting intermediate cannot be isolated as it rearranges to the more stable a-acyloxycarboxamide in an intramolecular transacylation. 

Banfi and co-workers utilized the Passerini three component reaction to prepare a 9600 member hit generation library of nor-statines. ° These compounds are potential transition state mimetics for the inhibitors of aspartyl proteases. The authors produced the library by starting out from eight A/-Boc-a-aminoaldehydes, twenty isocyanides and sixty carboxylic acids. The key Passerini reaction occurred under mild conditions. This transformation was followed by removal of the Boc protecting group and acyl transfer. Three representative examples of the library are shown. 

Bossio and co-workers developed a novel method for the synthesis of tetrasubstituted furan derivatives. The Passerini reaction between arylglyoxals, isocyanides, and cyanoacetic acids led to the formation of A/-substituted 3-aryl-2-cyanoacetoxy-3-oxopropionamides, which in the presence of amine bases underwent a Knoevenagei condensation providing A/-substituted 3-aryl-cyano-2,5-dihydro-5-oxofuran-2-carboxamides. 

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Passerini multicomponent reaction Condensation of isocyanides with carboxylic acids and carbonyl compounds to afford a-acyloxycarboxamides. 330... 

Banfi, L., Guanti, G., Riva, R. Passerini multicomponent reaction of protected a-amino aldehydes as a tool for combinatorial synthesis of enzyme inhibitors. Chem. Common. 2000, 985-986. 

In the second communication, Passerini also determined that the addition of hydrogen peroxide was unnecessary and, to an extent, deleterious as it mediated the decomposition of /7-isonitrileazobenzene. The formation of a-acyloxyamides from isonitriles, carboxylic acids and ketones or aldehydes subsequently became known as the Passerini reaction or the Passerini multicomponent reaction. The process is sometimes denoted as P-3CR according to Ugi s classification of multicomponent reactions (MCR). ... 

A. R. Kazemizadeh, A. Ramazani, J. Braz. Chem. Soc. 2009,20, 309-312. Passerini multicomponent reaction of indane-1,2, 3-trione an efficient route for the one pot synthesis of stericaUy congested 2,2-disuhstituted indane-l,3-dione derivatives. 

The renewed popularity of the Passerini multicomponent reaction is due to its apphcation in the preparation of polymers from renewable materials and pep-tidomimetics [14—17]. 

Sehlinger A, Kreye O, Meier MAR (2013) Tunable polymtax obtained from Passerini multicomponent reaction derived acrylate monomers. Macnunolecules 46(15) 6031-6037... 

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