Classical Passerini Reactions

While chiral isocyanides such as a-substituted isocyanoacetates also usually react with low stereoselectivity, the specially designed, camphor-derived, isonitrile 11 

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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... 

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

In the classic Passerini reaction (P-3CR), an a-acyloxy carboxamide is formed from the reaction of an isocyanide, an aldehyde (or ketone), and a carboxylic acid. The... 

Synthesis of Heterocycles Through Classical Ugi and Passerini Reactions... 

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. 

In the discussion of the various examples, we will concentrate more on the secondary transformations than on the Ugi or Passerini reaction themselves, which are in most cases carried out under standard conditions (alcoholic solvents for the Ugi and apolar solvents for the Passerini). Classical IMCRs are well known to be, in most cases, poorly diastereoselective and thus the stereochemical aspect, aheady described in a previous review [13], will be mostly ignored in this chapter. 

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... 

Besides numerous applications of a-acidic isocyanides in classical IMCRs, such as the Ugi and Passerini reaction, the presence of an a-acidic proton enables other reaction paths and, subsequently, the development of novel MCRs. Here we focus on novel MCRs involving a-acidic isonitriles that have been described in literature since 1998. 

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. 

The realization that this was a new type of compound, isomeric to the nitriles, and the elaboration of the classical methods for the preparation of isocyanides, the alkylation method and the carbylamine method by Gautier and Hofmann, initiated an active period of isocyanide chemistry that ended by the turn of the century with Nef s investigations on the reactions of the formally divalent carbon atom in the isocyanides. - TTie discovery of the Passerini reaction in 1921 led to a brief renaissance of isocyanide chemistry. 

The mechanism of Passerini reactions promoted by a Lewis acid has not been as extensively studied as the mechanism of the classic reaction. However, two precepts in regard to the component substitution should be noted. First, metal and metalloid-based Lewis acids are typically much more powerful acids than common carboxylic acids and second, as a consequence, nucleophiles (i.e., Lewis bases) will be both lower in strength and concentration under these conditions. Most of the differences in mechanism are inferred from indirect evidence, relying upon insight about the origins of observed products and side reactions, all of which logically proceed from a nitrilium intermediate. 

With regard to the carbonyl component, the low nucleophilicity of isonitriles means that only the more active carbonyl substrates give Passerini products in good yields. Formaldehyde, aldehydes, and unhindered or activated ketones all have participated in successful Passerini reactions. On the contrary, a,P unsaturated aldehydes and ketones fail to give good yields of Passerini products under classical conditions, but the more strongly acidic mineral acid-based or Lewis acid-based protocols can result in good yields of the desired products. 

SCHEME 8.1 The classical Passerini three-component reaction. 

Classical Passerini and Ugi reactions are the most common MCRs on water. One early example of these reactions was reported by Pirrung and Sarma that clearly demonstrated a significant enhancement in the reaction rate and efficiency of the reaction on water compared to the same reaction in an organic solvent (Scheme 11.23) [73]. 

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