Ugi four-component condensation reaction

Chucholowski A, Heinrich D, Mathys B, Muller C, Generation of benzodiazepine and benzodiazocine libraries through resin capture of Ugi-four component condensation reaction products, Book of Abstracts, 214th ACS National Meeting, Las Vegas, September 7-11, American Chemical Society, Washington, 1997. 

Condensation reactions are one of the most frequently used approaches to prepare pyridinones. A novel synthesis of pyridine-2(l//)-thiones has been described using arylmethylenecyanothioacetamides and dimedone <97T 17441, 97JCR(S)200>. A Ugi four-component condensation reaction between cinnamaldehyde, benzoylformic acid, an isocyanide and an amine affords an amide intermediate that upon addition of base cyclizes to the 1,6-... 

From the perspective of diversity-oriented synthesis and the rapid constructirai of complex ring systems, the A C pathway may offer the most promising approach. As an example, an Ugi four-component condensation reaction was used as the key step to constmct 146 (Scheme 39). Conversion of 140 to the corresponding diazoimide 146 followed by rhodium(II)-catalyzed intramolecular dipolar cycloaddition then afforded the hexacyclic product 147 in 57% yield (two steps) in a highly stereocontrolled manner. 

The Passerini synthesis is one of the oldest and most important multicomponent reactions (chronologically preceded by the reaction of Biginelli [1] and followed by the equally well-known Ugi four-component condensation reaction [2], currently widely studied for its originality in terms of application and mechanism). Surprisingly, little information is available regarding its discoverer, the Florentine chemist Mario Passerini. The reasons for the lack of a biography of this scientist can be traced, in part, to Passerini s reserved nature, reserved to the point of erroneously being perceived as shadowy. ... 

If ammonia or an amine is also added to the mixture (in which case the reaction is known as the Ugi reaction, or the Ugi four-component condensation, abbreviated 4... 

P., Warrington, B., Wong, S., A microreactor device for the Ugi four component condensation (4CC) reaction, in Ramsey,... 

Multicomponent reactions (MCR), in which three or more reactions combine to give a single product, have lately received much attention. The Ugi four-component condensation in which an amine, an aldehyde or ketone, a carboxylic acid, and an isocyanide combine to yield an ot-acylamino amide, is particularly interesting, because... 

Trifilenkov AS, Ilyin AP, Kysil VM, Sandulenko YB, Ivachtchenko AV (2007) One-pot tandem complexity-generating reaction based on Ugi four component condensation and intramolecular cyclization. Tetrahedron Lett 48 2563-2567... 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Multi-component reactions where three or more components build a single product have received considerable interest for several years. Since most of these reactions tolerate a wide range of building block combinations, these types of reactions are frequently applied for combinatorial purposes. A solid-phase application towards the Ugi four component condensation (Ugi-4CC) generating a 18-member acylamino amide library appeared in 199939. The acylamino amide library was synthesised using amino-functionalised PEG-polystyrene (TentaGel S RAM) as the solid support. (Scheme 7.22). 

The Ugi four-component condensation (U-4CC) between an aldehyde, an amine, a carboxylic acid and an isocyanide allows the rapid preparation of a-aminoacyl amide derivatives. The Ugi Reaction products can exemplify a wide variety of substitution patterns, and constitute peptidomimetics that have potential pharmaceutical applications. This reaction is thus very important for generating compound libraries for screening purposes. 

Pauson-Khand cycloaddition Pictet-Spengler reaction Ugi four-component condensation Wittig reaction (and Homer-Emmons condensation)... 

Figure 3-11 four-component Ugi reaction reported by Keating and Armstrong. A combinatorial mixture of the intermediate cyclohexenyl amide can be split into several portions, and each can be further reacted to give a variety of products, all of which will be combinatorial. (Reaction redrawn from description from Keating. T. A., and Armstrong. R. W Molecular diversity via a convertible isocyanide in the Ugi four-component condensation J. Am. Chem. Soc. 117 7842-7843. 1995.)... 

Ugi reaction Also called the Ugi four-component condensation (4CC) in which an isonitrile is treated with a carboxylic acid and an aldehyde or a ketone in the presence of ammonia or an amine to give a bis-amide. Related to the Passerini reaction. 

To achieve maximum efficiency, the synthesis pathways in DOS should be not more than three to five steps. To achieve skeletal complexity in DOS, it is critical to identify and to implement complexity-generating reactions that rapidly and efficiently generate complex molecular skeletons. For example, Schreiber et al. used tandem Ugi four component condensation-Diels-Alder reaction to generate complexity (Figure 9.3). 

As mentioned above, fhe second PASP strategy for purifying a crude reaction mixture after a synfhesis is to separate fhe desired product by selective covalent derivatization with a functionalized resin followed by filtration and rinsing. After fhe formation of the product in solution, it reacts selectively wifh a solid support while impurities and unreacted substrate remain in solution and are washed away. This resin-capture concept has been demonstrated in fhe context of fhe Ugi four-component condensation [51]. After the condensation, fhe reactivity of fhe enam-ide allowed fhe specific reaction with Wang resin under anhydrous acidic conditions. The resin was washed wifh methanol and dichloromefhane and fhe subsequent cleavage was performed with trifluoroacetic add in dichloromefhane. The final carboxyhc adds were characterized without further purification and were found to be > 95 % pure. 

Dihydro thiazoles have been applied as the imine components in the synthesis of oligopeptides based on the Ugi four components condensation (4CC) reaction <94S6I9>. 

A very versatile application of the Ugi reaction has been reported by Keating and Armstrong [42]. They use cyclohexenyl isonitrile (1) as a universal isocyanide in an Ugi four-component condensation. The other components are varied. The reaction products, 2-acylamino-alkanoic acid amides of generic structure 2, can undergo a number of further reactions leading in parts to new types of structures and increased diversity (Scheme 3.4). If a resin with free alcoholic groups is used the acylaminoacyl moiety can be bound to the solid phase before it is subjected to further modifications (resin capture). 

G Gokel, G Luedke, I Ugi. Four-component condensations and related reactions. In I Ugi ed. Isonitrile Chemistry. New York Academic Press, 1971, pp. 145-199. 

Scheme 1.8.5.1) or, in the case of a secondary amine 5, can rearrange to give imide 6. Both products constitute the thermodynamically most stable species in the reaction mixture. Many variations of the Ugi four component condensation (Ugi-4CC) have been published and a short compilation is depicted in Figure 1.8JJ. 

Based on a four component condensation reaction (the Ugi reaction ), Mjalli et developed a solid-phase protocol for the synthesis of tetrasubstituted imidazoles. Because of the limited number of commercially available isocyanides, the selected strategy started with the generation of an isocyanide component tethered to Wang resin. 

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