Isocyanide-based multi-component reactions

Domling, A. (2000) The Discovery of New Isocyanide-Based Multi-Component Reactions. Current Opinion in Chemical Biology, 4, 318-323. 

Domling, A., The discovery of new isocyanide-based multi-component reactions, Curr. Opin. Chem. Biol, 2000, 4, 318-323 Domling A., and Ugi I.K., A new 5,6-dihydro 211 1,3-oxazine synthesis via Asigner-type condensation, Tetrahedron, 1993, 49, 9495-9500. 

Domling, A., The discovery of new isocyanide-based multi-component reactions, Curr. Opin. Chem. Biol, 2000, 4,318. 

Domling A (1998) Isocyanide based multi component reactions in combinatorial chemistry. Comb Chem High Throughput Screen 1 1-22... 

Hulme, C., Nixey, T. Rapid assembly of molecular diversity via exploitation of isocyanide-based multi-component reactions. Current Opinion in Drug Discovery Development 2003, 6, 921 -929. 

One of the best strategies for the synthesis of valuable pharmaceutical compounds and also for the rapid generation of molecular diversity is the use of isocyanide-based multi-component reactions (IMCRs) [3-8]. More specifically. 

In addition to isocyanide-based MCRs, a wealth of highly functionalized heterocycles can be obtained from 1,3-dicarbonyl, cyanomalonate and malononitrile based MCRs [19]. These easily accessible starting materials participate in a variety of multi-component reactions and have found numerous applications in drug discovery. 

Efficient, Isocyanide-Based Ugi Multi-component Reactions... 

It was only two years later that Passerini had an opportunity to return to this, his work he published two additional notes, more extensive and containing more details. He added, however, very little novel material he noted that the subclass of cyclic ketones were well-suited for multi-component reactions. His fourth and final note on the Passerini reaction was published in March 1924 [9]. In this work, Passerini unequivocally demonstrated that his reaction was a general reaction involving isocyanides, and aromatic aldehydes or ketones, in the presence of organic acids. Passerini regretted that, still examining the reaction mechanism, based on intermediate formation, he had failed to isolate it, although he referred to unspecified chemical and physical experiments by which he hoped to ascertain its existence. ... 

This organic reaction is the first multi-component reaction based on isocyanides it currently plays a central role in combinatorial chemistry. Recently S. E. Denmark and Y. Fans have developed an enantioselective catalyst for asymmetric Passerini reactions, whose reaction mechanism is not well understood even to this day [12]. 

The author explored the reaction chemistry of intermediates 2-6 with isocyanides. Isocyanides bearing less-bulky and bulky substituents led to mono- and bis (iminoacyl)-Zr intermediates, respectively. Upon hydrolysis, the isolated mono (iminoacyl)-Zr intermediates underwent intramolecular cyclization to afford tetra-substituted 5-azaindoles, while intramolecular cyclization of bis(iminoacyl)-Zr intermediates led to the formation of dihydropyrrolo[3,2-c]azepines. Based on the above results, the author developed zirconocene-mediated multi-component coupling of bis(alkynyl)silanes, nitriles, and isocyanides. The structure of a bis(imi-noacyl)-Zr intermediate, formed via insertion of two molecules of CyNC into the Zr-C bond, and structures of two dihydropyrrolo[3,2-c]azepines were characterized by single-crystal X-ray structural analysis (Scheme 2.9). 

---