Passerini reaction heterocycles

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. 

Xia, Q., Ganem, B. Metal-Promoted Variants of the Passerini Reaction Leading to Functionalized Heterocycles. Org. Lett. 2002, 4, 1631-1634. 

The Passerini reaction and the Ugi reaction provide a-acyloxyamides and a-acet-amidoamides, respectively. Naturally, these reactions have been applied in the synthesis of peptides and cyclopeptides/cyclodepsipeptides [91]. Recently, the application of these reactions in the synthesis of heterocycles was reported. One of the most notable examples is Fukuyama and co-workers total synthesis of ecteinascidin 743 (Et 743) (148), a complex natural product recently commercialized as an anticancer drug (Scheme 5.46) [92]. Thus, reaction of the amine 149, the amino acid 150, 4-methoxyphenyl isocyanide (151) and acetaldehyde afforded the corresponding Ugi adduct 152 in 90% yield. After a series chemical transformations, 152 was ultimately converted to Et 743. The connection between the structure of Et 743 and the peptidic nature of Ugi adduct is not obvious, but with the deep insight of an experienced synthetic chemist, the non-trivial link can be drawn and be put into practice [93, 94]. 

This reaction was first reported by Hofmann in 1868. It is the synthesis of isonitriles (also known as isocyanides) from primary amines and chloroform in the presence of alkali and is known as the Hofmann isonitrile synthesis, Hofmann carbylamine reaction, or Hofmann carbylamine synthesis. This reaction has been used to test the presence of primary amines from the order of isocyanides. Alternatively, the isonitriles can be prepared by means of the treatment of formamide of primary amines with toluenesulfonyl chloride" or phosphorus oxychloride (POCls)." Currently, the isonitriles have gained much attention in organic synthesis because of their application as versatile building blocks for heterocycles and in multicomponent reactions to generate combinatorial libraries, such as that in the Passerini reaction and Ugi reaction ... 

Recent developments in solvent-free multicomponent reactions A perfect synergy for eco-compatible organic synthesis 12RCA4547. Synthesis of fimctional heterocycles via tandem reaction 13YZ879. Synthetic applications of Passerini reaction 12COC418. 

The particularly mild conditions of Passerini reactions, and the corresponding broad functional group tolerance, has meant that many reactive functionalities can remain unprotected on the component substrates and then utilized in a secondary reaction as a tandem or domino reaction sequence. Notably, this facet has led to the extensive use of the Passerini reaction for the construction of numerous functionalized furans, oxazoles, tetrazoles, P-lactams, butenolides and other complex heterocycles. 

The Passerini reaction has also been utilized as a method for the homologation of heterocyclic carboxaldehydes. Studies by Weinreb and coworkers, directed toward the synthesis of amphimedine, have used a Passerini reaction for the homologation of the methoxypyridine derivative 65 with methyl isocyanide and acetic acid in methanol to give 66 in 77% yield. 

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. 

Nerdinger, S., Beck, B. New heterocycle synthesis by using bifunctional reactants in multicomponent reaction chemistry the use of arylglyoxals and cinnamaldehyde in the Ugi-4CR and Passerini-3CR. Chemtracts 200Z, 16, 233-237. 

Potentially useful heterocyclic libraries can also be prepared by the application of solution-phase combinatorial chemistry. Although multiple reactions in solution have often been complicated by the difficulties with liquid-liquid extractions the introduction of solid scavengers and equipment to automate these extraction processes allows hundreds of reactions to be managed simultaneously. A typical example is a series of aminothiazole derivatives which has been prepared starting from acyclic precursors (Scheme 3.9). Naturally one-pot multicomponent condensations such as the Ugi (library 84) [332], Passerini or Biginelli reactions present one of the simplest... 

Carbonyl compounds and imines are the electrophilic partner of isocyanides in the Passerini-3CR and the Ugi-4CR, respectively. Other highly electrophilic multiple bonds, such as in dimethyl acetylenedicarboxylate (DMAD), are also known to react with isocyanides. The initially formed 1 1 zwitterionic species having carbanion, carbene character can undergo further reaction with DMAD and isocyanides in different molar ratios, leading to a variety of heterocyclic systems (Scheme 5.32) [69]. 

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