Multicomponent condensation reactions

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. 

Sridhar and co-workers [192] have described a microwave-promoted synthesis of 2-aminothiophenes 146 by reaction of a ketone with a nitrile and elemental sulfur using KF-alumina as a base via multicomponent condensation reaction. This method offers an efficient and convenient modification to the Gewald reaction replacing organic base with KF-alumina (Scheme 111). 

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. 

A similar example to obtain imidazoline carboxylic acids 1422 from a palladium-catalyzed multicomponent condensation reaction employs an imine 1420, an acid chloride 1421 and CO (Scheme 367). The reaction is also believed to proceed through a putative miinchnone intermediate <2001AGE3228>. 

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. 

TheBiginelli dihydropyrimidine synthesis o is another relevant multicomponent condensation reaction that has been recently adapted to the solid phase by Wipf et to prepare a small library... 

In a number of multicomponent condensation reactions, TMSCl has also been utilized to improve the yield or efficacy of the desired product, or is directly incorporated into the final molecules. Examples include the synthesis of Al-aryl-3-arylamino acids from a three-coir onent reaction of phenols, glyoxylates, and anilines, preparation of 2,4,5-trisubstituted oxazoles, or 4-cyanooxazoles, and the three-component BigmeUi reaction... 

Christinat N, To J, Schu C, Scopelliti R, Severin K (2009) Synthesis of moleeular nanostructures by multicomponent condensation reactions in a ball rrrill. J Am Chem Soe... 

Pascu M, RuggiA, ScopelhtiR, Severin K. Synthesis of borasiloxane-based macrocycles by multicomponent condensation reactions in solution or in a ball miU. Chem Commun 2013 49 45-7. 

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)... 

Acridines and their derivatives have potential applications in dyes, malarials, and cancer chemotherapy. An FSG-immobilized Hf(N(S02C8Fi7)2)2 catalyzed a one-pot multicomponent condensation reaction to afford acridine derivatives in good yield (Scheme 7.15) [25]. The fluorous catalyst was recycled three times by simple filtration. 

---