Ugi multicomponent condensation reaction

Main, M., Snaith, J.S., Meloni, M.M., etal. (2008) Using the Ugi multicomponent condensation reaction to prepare families of chromophore appended azamacrocycles and their complexes. Chemical Communications, 5212. 

Bu, H., Kj0niksen, A.L., Knudsen, K.D., Nystrom, B. Rheological and structural properties of aqueous alginate during gelation via the Ugi multicomponent condensation reaction. Biomacromolecules 5, 1470-1479 (2004)... 

Furthermore, multicomponent reactions can also be performed under fluorous-phase conditions, as shown for the Ugi four-component reaction [96], To improve the efficiency of a recently reported Ugi/de-Boc/cyclization strategy, Zhang and Tempest introduced a fluorous Boc group for amine protection and carried out the Ugi multicomponent condensation under microwave irradiation (Scheme 7.84). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid/tet-rahydrofuran under microwave irradiation. The resulting quinoxalinones were purified by a second F-SPE to furnish the products in excellent purity. This methodology was also applied in a benzimidazole synthesis, employing benzoic acid as a substrate. 

Several groups have pioneered the use of such multicomponent condensation reaction (MCR) technologies, including those led by Ugi, Bienayme, Domling, and Weber, spawning new chemically driven companies that have rapidly built up their own internal corporate collections. One particular branch of MCR methodologies, namely postcondensation modifications (or secondary reactions) of IMCRs (isocyanide - based multicomponent reactions), forms the basis of this chapter. 

Ideal reactions for solution-phase parallel synthesis are those that are kinetically and thermodynamically favored, are tolerant of diverse functionality, and have a broad range of reactant tolerance. In this approach, capture resins and extraction procedures are often used for preliminary purification. The solution-phase reaction conditions must be validated in terms of scope and optimal reaction conditions over the range of reactants. Two common strategies for solution libraries involve derivatization of preformed functionalized scaffolds and multicomponent condensation reactions, for example, the Ugi reaction, the Passerini reaction, and the formation of hydroxyamininimides from an ester, a hydrazine, and an epoxide. 

The catalyst for cleavage of peptide deformylase was searched with a library of catalyst candidates synthesized by the Ugi reaction (Scheme 2) (134). In this multicomponent condensation reaction, the mixture of a carboxylic acid, an amine, an aldehyde, and an isocyanide produces an iV-acyl amino acid amide. The catalyst candidates, therefore, are iV-acylamino acid amides containing various polar and nonpolar pendants as well as the Co(III) complex of cyclen. The Co(III) complex of cyclen (135) was chosen as the proteolytic center in view of the results described in Section V.A. Cyclen with three secondary amines protected with ferf-butyloxycarbonyl (t-boc) groups was incorporated in either the carboxyl or the amine component of the Ugi reaction. Later, the t-boc groups were removed and Co(III) ion was inserted to the cyclen portion. 

By exploiting the Co(III) complex of cyclen as the essential part of the catalyst candidates for cleavage of angiotensin I or II, two kinds of chemical libraries of the catalyst candidates were constructed by using multicomponent condensation reactions. Members of the first chemical hbrary were synthesized according to Scheme 3 by the Ugi condensation reaction (134). Members of the second chemical library were synthesized according to Scheme 4 by a variation (141) of the Ugi condensation. 

After every reaction step, the product can be extracted from the organic phase with fluorinated solvents. Excess reagents remain in the organic phase and can be easily removed. The strategy has also been successfully used in a Ugi multicomponent-type reaction condensing derivatised benzoic acid 31 with amines, aldehydes and isonitriles as shown in Scheme 3.3.2. The reaction was carried out in TFE and products 32 were isolated by liquid-liquid extraction. After cleavage of the fluorinated chain with TBAF followed by another extraction, the desired products 33 were isolated in good to excellent yields and with purities >80% (determined by GC). 

The four component Ugi reaction is a condensation between a carboxylic acid, a ketone or an aldehyde, an amine and an isonitrile. Basically each of the reaction components can be attached to the resin. The Ugi reaction is employed for the synthesis of small molecule combinatorial libraries on solid supports. Recently a novel resin bound isonitrile has been used in the Ugi multicomponent reaction for synthesizing diversity libraries of diketopiperazines and benzodiazepindiones (Scheme 3.25) [285]. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Isonitriles can otherwise attain tetravalent respectability by participating in cyclization reactions, - and in multicomponent condensations such as the Passerini (3-component) and Ugi (4-component) re-actions. Nitrilium-type intermediates are implicated in many of Aese processes. These isonitrile reactions of major synthetic importance are discussed in detail elsewhere in this compendium. 

Heterocyclic chemistry has been a major beneficiary of MW-expedited solvent-lfee chemistry utilizing mineral supported reagents. It has been exploited for parallel synthesis, a strategy that is adaptable for multicomponent reactions, such as Ugi " and Biginelli reactions " , for rapid assembly of a library of compoimds. A representative multi-component condensation reaction to create a small-molecule library of imidazo[l,2-a]pyridines, imidazo[l,2-a] pyrazines, and imidazo[l,2-a]pyrimidines is depicted in Scheme 3. 

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... 

Multicomponent condensations such as the Ugi reaction [44] and the Big-inelli condensation [45] are especially useful for the creation of diverse chemical libraries on the solid phase. Four-component condensations have been reviewed by Mjalli and Toyonaga [46] for the synthesis on the solid phase of small-ring heterocycles [47]. For example, the one-pot condensation of an amine (derived from amino acids) and an aldehyde, followed by the addition of an isocyanide and a carboxylic acid, provides a dipeptidomimetic iV-alky 1-A-acyl- a-amino amide 10 that can serve as a useful starting point for the synthesis of imidazoles 11 and pyrroles 12, which are pharmaceutically useful compounds (Fig. 4). 

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. ... 

Wessjohann LA, Tran TFT, Westermann B (2008) Method for producing condensation products from n-substituted glycine derivatives (peptoids) by sequential Ugi-multicomponent reactions. Patent WO 2008/022800... 

A further small tweaking of the reaction conditions involves great changes a further new cascade channel is breaking. This is accomplished by modulation of the nucleophilicity of the activated methylene compounds applied. When used with isocyanoacetate 87 instead of cyanoacetates 86 as a methylene-activated component, an Ugi-like multicomponent cascade reaction is observed. This reaction was first detected by deployment of ethyl isocyanoacetate 87 in reactions of ribose and proline. In these experiments, proline—once the catalyst in the Knoevenagel condensation/ketalization/oxa-Michael cascade reactions—is directly incorporated into the product. As a result of that, seven-membered lactone 89 is formed. This sharp difference is demonstrated in Scheme 2.18 [40]. 

A combination of a multicomponent Ugi transformation and an intramolecular Diels-Alder reaction has been developed by Paulvannan [13]. Hence, condensation of the resin-bound (acid-labile ArgoGel-Rink resin) amine 10-37 with a tenfold... 

---