Ugi-type multicomponent reactions

The IBX-mediated oxidative Ugi-type multicomponent reaction of tetrahydroisoquinoUne with isocyanides and carboxylic acids affords the nitrogen- and carbon-functionalized tetrahydroisoquinolines 867 in good to excellent yields [1184]. Likewise, the three-component Passerini reaction of an alcohol, carboxylic acid and an isonitrile in the presence of IBX affords the corresponding a-acyloxy carboxamides 868 in generally high yields (Scheme 3.347) [1185]. 

S. K. Guchait, C. Madaan, Org. Biomol. Chem. 2010, 8, 3631-3634. Towards molecular diversity dealkylation of tert-butyl amine in Ugi-type multicomponent reaction product establishes fcrt-butyl isocyanide as a useful convertible isonitrile. 

T. Ngouansavanh, 1. Zhu, Angew. Chem. Int. Ed. 2007, 46, 5775-5778. IBX-mediated oxidative Ugi-type multicomponent reactions application to the N and Cl functionalization of tetrahydroisoquinoline. 

Y. Su, M. J. Bouma, L. Alcaraz, M. Stocks, M. Furber, G. Masson, J. Zhu, Chem.-Eur. J. 2012, 18, 12624-12627. Organocatalytic enantioselective one-pot four-component Ugi-type multicomponent reaction for the synthesis of epoxy-tetrahydropyrrolo [3,4-h]pyridin-5 -ones. 

S.K. Guchhait, C. Madaan, An efficient, regioselective, versatile synthesis of N-fused 2- and 3-aininoimidazoles via Ugi-type multicomponent reaction mediated by zirconium(tV) chloride in polyethylene glycol-400, Synlett (2009) 628-632. 

Guchhait and Madaan (2010) reported a novel microwave-assisted one-pot novel tandem de-tert-butylation of tert-butyl amine in an Ugi-type multicomponent reaction product. Tert-butyl isocyanide has been explored as a useful convertible isonitrile for the first time affording access to molecular diversity of pharmaceutically important polycyclic N-fused imidazo-heterocycles. 

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

Further investigation of this Ugi-type cascade reaction and optimization revealed a broad application of this multicomponent cascade. This transformation works without any catalyst or reagent at room temperature. For shortening reaction times and increasing yields, catalytic amounts of tertiary amines and working in boiling methanol proved to be the most successful conditions. These reaction conditions do not only influence the selectivity of the reaction but also increase the yield slightly in much shorter reaction time. 

A further extension of the MAO-N-catalyzed desymmetrization of bicyclic meso-pyrrolidines was also reported in which the formed imine was coupled with the Ugj-type multicomponent reaction (MCR) to access highly substitute prolyl peptides and derivates diereof. The so-obtained products are applicable in meicinal chemistry as well as organocatalysis as proline analogues [141]. Subsequently, this combination (desymmetrization and Ugi-type MCR) [142] has also led to the development of an efficient synthesis of the peptide-based hepatitis C protease inhibitor telaprevir through coupling of the A -pyrroline with the fragments 1 and 2 (Scheme 2.39) [143]. 

The synthesis of a small library of very large (up to 60-membered) steroid/ peptide hybrid macrocycles has been achieved using double and fourfold Ugi reactions. This type of compound has not previously been described in literature. Neither have multicomponent reactions been used so far to form directly macrocycles of this size. In fact, synthetic macrocycles of this size with this structural complexity are very rare. 

Finally, in the most complex multicomponent reaction involving isocyanides, the 7-CC proposed by Ugi in 1993 [93], a moderate diastereoselectivity, leading to a 2 1 mixture of epimeric thiazolidines 109 was observed. The reaction is a combination between an Asinger condensation, involving an a-mercaptoaldehyde (generated from the a-bromoaldehyde and SH ) and an Ugi-type 4-CC with a monoalkyl car-boxylate as acid component (Scheme 1.38). Although the relative configuration of the major stereoisomer was not demonstrated, it is probably trans, in line with the results of Ugi condensation with chiral thiazolines, reported above in Scheme 1.19. 

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-... 

This multigeneration strategy for the synthesis of pyrimidines combines efficiently a novel cyclocondensation reaction using the highly reactive acetylenic ketones 153215,218 to build the pyrimidine skeleton, with a multicomponent reaction, and a multidirectional cleavage procedure. The Ugi four component reaction is especially useful in the context of building peptidomimetic-derived combinatorial libraries as it affords directly dipeptide analogues of type 159. 

Finally, other reactions can be performed directly using water as a solvent. Ugi s four components reaction, for example, provides an expedient access to peptidic scaffolds starting from an isocyanide, an amine, an aldehyde and a carboxylic acid. However, in competition to Ugi s reaction, Passerini ester formation often pollutes the reaction mixture and it is of great interest to perform this type of highly complex transformation in supported versions. Indeed, when an ammonium chloride supported aldehyde, similar to those used in Grieco s multicomponent reactions, are dissolved in water in the presence of an amine, the imine formation occurs within 15 min and isocyanide and acid can subsequently be added to the mixture. After 24 h at room temperature, amides were isolated in high yield with no other purification than washing with diethyl ether [135] (Fig. 44). 

Furthermore, multicomponent reactions, as represented by Ugi reaction and Biginelli reaction, are attractive strategies for the selective construction of complex organic molecules from several simple starting materials in a single operation. Recently, Wang and Zhu et al. reported asymmetric synthesis of 5-(l-hydroxyalkyl)tetrazoles 60 from aldehydes, isocyanide, and hydrazoic acid via chiral salen-organoaluminum complex 59 catalyzed asymmetric Passerlni-type reaction (Scheme 43) [76]. 

Ddmling and coworkers adapted a four-component Ugi-type reaction sequence to the synthesis of highly substituted 3-pyrrolin-2-ones (Scheme 104 20040L39). The combination of aUyl isocyanide (395), primary amine 396, a-phosphonoacetic acid 397, and a-ketoaldehyde 398 gives the 5-carboxamido-3-pyrrolin-2-one 399. The two-step process involves an Ugi multicomponent reaction followed by an intramolecular Homer/ Wadsworth/Emmons cycHzation. 

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. 

Other reactions, in which carbenium ion addition to an isocyanide is the key step, are the Passerini and Ugi reactions and reactions of similar type. These multicomponent transformations have recently been reviewed The Passerini reaction starts from an isocyanide, a carbonyl compound and a carboxylic acid. 

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). 

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