PASSERINI Condensation

Schme 9.2. Passerini condensation involving protected a-aminoaldehydes. 

While enantiomerically pure a-substituted isocyanoacetates have been used in Passerini condensation without significant racemization [4-6], the same class of compounds is believed to be configurationally unstable under the conditions of U-4CRs [7]. However, one notable exception is the reaction shown in Scheme 1.1, where L-isoleucine-derived isocyanide 2 has been condensed without such problems with pyrroline 1 [8]. The bulkiness of this isocyanide or the use of a preformed cyclic imine, thus avoiding the presence of free amine in solution, may be the reasons for the absence of racemization. 

PASSERINI Condensation 289 PATERNO BUCHI 2+2 Cydoaddition 290 PAYNE Rearrangement 290 Pauson 201... 

Although maybe Passerini condensation has been less successful in its application for preparing biologically relevant molecules in comparison with the Ugi reaction, mainly because in the Passerini reaction there are only three variables that can be introduced, thus limiting the application of intramolecular versions to prepare heterocycles, we reflect here two attractive examples. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. 

In this chapter we focus only on post-condensation transformations that follow classical Ugi or Passerini reactions (including the intramolecular ones) and that lead to heterocycles. Therefore, we will not report the many examples of postcondensation reactions applied to non-conventional Ugi or Passerini scaffolds generated by variants of these venerable reactions. Also post-IMCR transformations that involve the inclusion, in the final cyclic system, of sub-structures not initially present in the starting component will be overlooked. 

The amide (typically a tertiary one) or the ester derived from the carboxylic acid component in classical Ugi and Passerini reactions can undergo nucleophilic S Ac by various nucleophiles [54], These post-condensation reactions, however, do not... 

Marcaccini S, Torroba T (2005) Post-condensation transformations of the Passerini and Ugi reactions. In Zhu J, Bienayme H (eds) Multicomponent reactions. Wiley-VCH, Weinheim, pp 33-75... 

The Passerini reaction is a condensation between a carbonyl, a carboxylic acid and an isocyanide to form an ot-acyloxycarboxamide (Scheme 1) [5],... 

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. It is generally accepted that the reaction proceeds through intermediate 6, which rearranges to the product. The way this intermediate is formed is more debated. A possibility is a concerted non-ionic mechanism involving transition state 5. Since the simultaneous union of three molecules is not a very likely process, another possibility is a stepwise mechanism, with the intermediacy of a loosely bonded adduct 4 between the carbonyl compound and the carboxylic acid [2], Since all three... 

The power of the Passerini and Ugi reactions in constructing polyfunctional molecules has been well appreciated since the early studies. The classical Passerini and Ugi reactions afford a-acyloxy carboxamides and a-acylamino amides respectively, that can be easily manipulated by post-condensation reactions, generating molecular diversity for drug discovery and natural product synthesis [22], This strategy has been widely applied to the synthesis of natural peptides and open-chain peptide mimetics covered in this section. 

Furans, Pyrroles, and Indoles by Passerini-3CR or Ugi-4CR and Knoevenagel Condensation... 

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