Ugi condensation reaction

Keung W, Bakir F, Patron AP, Rogers D, Priest CD, Darmohusodo V (2004) Novel alpha-amino amidine synthesis via scandium(III) triflate mediated 3CC Ugi condensation reaction. Tetrahedron Lett 45(4) 733-737... 

Figure 5.7. Comparisons of the 3D four-point pharmacophore fingerprints exhibited by several sets [MDDR database of 62,000 biologically active compounds, a corporate registry database of 100,000 compormds used for screening, 100,000 compounds from combinatorial libraries (from a four-com-poilent Ugi condensation reaction), and 14,000 compound random subsets (MDDR, corporate) or indlividual libraries]. The four-point potential pharmacophores were calculated using 10 distance range bins and the standard six pharmacophore features.

For 4 cyclen-containing carboxylic acids, 18 amines, 17 aldehydes, and 5 isocyanides were used to build the library. For 3 cyclen-containing amines, 18 carboxylic acids, 17 aldehydes, and 5 isocyanides were utilized to construct the library. In total, therefore, 7500 combinations of the four components were employed for the Ugi reaction. As each Ugi condensation reaction produces a stereogenic carbon atom, the total number of catalyst candidates prepared in this study was 15,000. The number of compounds to be placed in one reaction vessel was adjusted to produce 9 different combinations and, consequently, 18 catalyst candidates in each vessel. 

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. 

Scheme 2.2-48 MW-assisted three-component Ugi condensation reaction.

A. T. Khan, R. S. Basha, M. Lai, M. H. Mir, RSCAdv. 2012, 2, 5506-5509. Formation of unexpected a-amino amidine through three-component Ugi condensation reaction. 

Scheme 6.184 Ugi-type three-component condensation reactions.

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]. 

The amide (typically a tertiary one) or the ester derived from the carboxylic acid component in classical Ugi and Passerini reactions can undergo nucleophilic S Ac by various nucleophiles [54], These post-condensation reactions, however, do not... 

C=N bond formation has also been achieved starting from two additional carbonyl functions properly installed in an Ugi component. Cyclization has been accomplished in this case through a Paal-Knorr reaction of the dicarbonyl compound generated by the Ugi condensation, leading to pyrazinones [107]. 

Zhang W, Tempest P (2004) Highly efficient microwave-assisted fluorous Ugi and post-condensation reactions for benzimidazoles and quinoxalinones. Tetrahedron Lett 45 6757-6760... 

Cheng et al. describes an efficient solution phase and solid phase synthesis of 2-oxopiperazines [29]. These reactions involve a novel Ugi condensation-A-acylimi-nium condensation reaction (Scheme 9). A carboxylic acid 50, an aldehyde 51,... 

Multicomponent reactions have recently become one of the favored methods to prepare pharmacologically important compounds. Ugi condensations with O-protected hydroxylamines have been successfully performed in THE using ZnCl2 as activating agent (Scheme 56). This synthetic strategy opens up the route to a very convergent assembly of internal hydroxamic acid derivatives (A-acyl-A-hydroxypeptides 109)" . 

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. 

The enantiomerically pure 3-thiazoline 50, obtained via Asinger reaction using a galactose-derived chiral auxiliary, was successfully submitted to an Ugi condensation affording the trans adduct 51 with good stereoselectivity, as reported in Scheme 1.19 [56],... 

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. 

The power of the Passerini and Ugi reactions in constructing polyfunctional molecules has been well appreciated since the early studies. The classical Passerini and Ugi reactions afford a-acyloxy carboxamides and a-acylamino amides respectively, that can be easily manipulated by post-condensation reactions, generating molecular diversity for drug discovery and natural product synthesis [22], This strategy has been widely applied to the synthesis of natural peptides and open-chain peptide mimetics covered in this section. 

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. 

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