Multi-component reactions isocyanides

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

Ugi, L, Werner, B., Domling, A. (2003) The Chemistry of Isocyanides, Their Multi-Component Reactions and Their Libraries. Molecules, 8, 53-66. 

They produced an 18-member library of a-acylamino amides, in acceptable to high yields and purity, from a variety of isocyanides, aldehydes and carboxylic acids by using an amino-functionalised TentaGel resin (TentaGel S RAM). The developed procedure represents a rapid and efficient way of synthesising a-acylamino amides, simplifying the tedious purifications, which can usually accompany multi-component reactions. 

Domling, A. and Ugi, I., Multicomponent reactions with isocyanides, Angew. Chem., Int. Ed. Engl., 2000, 39, 3168-3210 Weber, L., Illgen, K. and Almsttetter, M., Discovery of new multi component reactions with combinatorial methods, Synlett, 1999, 3, 366-374. 

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. and Ugi, I., Multi-component reactions with isocyanides, Angew. Chem., Int. Ed. Engl, 2000, 39, 3169. 

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

Several protocols using multi-component reactions to prepare multisubstituted furans were reported. One procedure was that using acetylenedicarboxylate, isocyanides, triphenylphosphine and an aromatic carboxylic acid <07SL1610>. The others include the reaction of acetylenedicarboxylate, isocyanides and nicotinic acid <07S2637>, of dibenzoylacetylene, amines and diketene <07T8083>, of alkyl isocyanides, aromatic aldehydes and 3-cyanoacetyl indoles <07TL8987>, and of naphthoquinone, isocyanides and aldehydes <07T10269>. 

Another novel multi-component reaction involving the synthesis of 4//-pyrido[ 1,2-ajpyrimidines 52, a motif found in many bioactive molecules, was reported by Adib et al. <07T11135 07TL4195>. The reaction involves the formation of a reactive 1 1 zwitterionic intermediate resulting from the addition of isocyanides 53 to dialkyl acetylenedicarboxylates 54 followed by trapping with A-(2-pyridyl)amidcs 55. 

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

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. 

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. 

Ugi, I., Domiing, A. Multi-component reactions (MCRs) of isocyanides and their chemical libraries. Combinatorial Chemistry 2000, 287-302. 

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. 

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

Ugi multi-component reactions of an amine, aldehyde, carboxylic acid and isocyanide (or the three-component variant with preformed imines) involve a Mumm rearrangement of an imidate in the final step, often considered the stereoselective step. However, experimental and computational evidence for kinetic control has now been reported in Ugi reactions of a o-pentose-derived pyrroline (52). The selective step is the formation of the imidate by the addition of isocyanide to the intermediate iminium ion, with the conformation of the latter determined by its substitution pattern. 

A few months after announcement of the discovery, Passerini sent a second note to the Italian Chemical Society, concerning this multi-component reaction. To ensure that the above-mentioned reaction could be regarded as a general reaction, he repeated it with different isocyanides and ketones. Surprisingly, the product he... 

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]. 

For this multi-component reaction (MCR [28]) proceeding without the need for a further catalyst, a mechanism is suggested which involves primary attack of the isocyanide to the triple bond of DMAD followed by 1,3-dipolar cycloaddition of the resulting dipole 87 to the aldehyde C=0 group (87 88) subsequent (l,5)-H-shift in 88 complements formation of the aminofuran system 86. 

Several multi-component domino reactions for the preparation of libraries have been developed in the last years.141 One of the first examples in solution is a four-component reaction described by Ugi et al. in which a carbocyclic acid 5, an aldehyde 6 and an isocyanide 7 are condensed in presence of methanol to give amino acids 8 (scheme 2).151... 

A supported [1.3.2]oxazaphosphoHdine has been used for the conversion of isothiocyanates to isocyanides and their subsequent incorporation in Ugi multi-component couphngs (Scheme 2.7). The reaction was slow to proceed when heated under conventional heat bath conditions and led to low yields, following decompo-... 

Isocyanides have attracted much attention in synthetic organic chemistry, and have led to the development of a variety of useful synthetic transformations [1]. In particular, carbon-carbon bond forming reactions using isocyanides as key reagents have been extensively studied during the past 50 years, as they allow the realization of useful multi-component assembly reactions, such as the Ugi and Passerini reactions [2]. These have once again been highlighted in recent years with the development of combinatorial chemistry. The characteristic reactions of isocyanides are mostly ascribed to the unique reactivity of the isocyano carbon atom, which can be represented by a divalent, carbene-like electronic structure (Scheme 1). In this respect,... 

The Ugi reaction is a multi-component organic chemistry reaction (Scheme 7.12), which includes the participation of either a ketone or an aldehyde, an amine, an isocyanide, and a carboxylic acid to form a bis-amide [50]. The particular case shown in Scheme 7.12 corresponds to the study carried out by Buet al. [51]. First, the imine formation is carried out by the reaction between the aldehyde compounds and the amine. Then, the carbon atom of the synthesized imine is attacked by the nucleophilic carbon atom of the isocianide, which yields an adduct as reaction product. In other pathway, the oxygen atom of a carboxylic acid is added to the previous product, and a new adduct is obtained. After an internal rearrangement of the latter molecular structure, a diamide compound is obtained. It is known that for a successful reaction a pH of 3.6 should be used in the reaction media [52]. This important reaction has been often used to prepare hydrophobically modified alginates [52,53]. 

A new multi-component Ugi-Smiles coupling reaction of heteroaromatic phenols (pyridines and pyrimidines) 151 with carbonyl compounds 152, amines 153 and isocyanides 154 involves a Smiles rearrangement to form a library of heterocyclic scaffolds 155. The first Ugi-Smiles conversion of thiols 156 was also performed. The reaction of 156 with a carbonyl compound, an amine and an isocyanide afforded the desired product 157 at 80 °C. 

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). 

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