Multicomponent chemistry

Multicomponent reactions in which three or more components build a single product have attracted much interest for several years. Because most of these reactions tolerate a wide range of building block combinations they are frequently used for combinatorial purposes. 

The first solid-phase application toward the Ugi four-component condensation generating an acylamino amide library was reported in 1999. Amino-functionalized PEG-polystyrene (TentaGel S RAM) was used as the solid support [52]. A set of three aldehydes, three carboxylic acids, and two isonitriles was used for generation of the 18-member library. 

Very recently, a polymer-supported construct for quantifying the reactivity of monomers involving multicomponent Ugi strategies was reported [53]. The authors investigated the Ugi four-component condensation of a set of aldehydes, acids, and isonitriles. The amine compound used was bound to a specially modified Rink amide polystyrene resin bearing an ionization leveler and bromine functionality as a mass splitter for accurate analysis by positive electrospray ionization mass spectrometry. The microwave-assisted experiment was performed with a set of ten carboxylic acids, hydrocinnamaldehyde, and cyclohexyl isonitrile in DCM- 

Another valuable multicomponent reaction is the Gewald synthesis leading to 2-acyl-3-aminothiophenes these are of current interest because they are commercially used as dyes or conducting polymers and have much pharmaceutical potential. 

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Domling, A. (2002) Recent Advances in Isocyanide-Based Multicomponent Chemistry. Current Opinion in Chemical Biology, 6, 306-313. 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Yehia NAM, Antuch W, Beck B, Hess S, Schauer Vukasinovic V, Ahnstetter M, Eurer P, Herdtweck E, Domling A (2004) Novel nonpeptidic inhibitors of HIV-1 protease obtained via a new multicomponent chemistry strategy. Bioorg Med Chem Lett 14 3121-3125... 

Abstract In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity. 

Fig. 4 Frontier orbitals of the isocyanide, explaining the reactivity of this important functional group in multicomponent chemistry...

For all these reasons we are convinced that we will see many more exciting examples of the application of microwave irradiation to multicomponent chemistry in the near future. 

Pyrroles are the core unit of a wide variety of natural products [76]. Although many methods are available for the synthesis of these species, most are multi-step procedures resulting in low yields [77, 78]. However, Hantzsch made another important contribution to the progress of multicomponent chemistry. In his procedure pyrroles were successfully prepared from primary amines, j8-ketoesters, and a-halo-genated j5-ketoesters [79]. Only a few other one-step procedures have been reported for pyrroles but, because of to long reaction times and insufficient scope of substitution at the ring, these are not very satisfactory [80, 81]. 

C. O. Kappe, QSAR Comb. Sci. 2003, 22, 630-645. The generation of dihydropyrimidine libraries utilizing Biginelh multicomponent chemistry. 

Domling A (2002) Recent advances in isocyanide-based multicomponent chemistry. Curr Opin Chem Biol 6 306... 

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