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Ugi Reaction

The Ugi reaction (Scheme 1) is an isonitrile-based MCR that provides a rapid route for the preparation of a-aminoacyl amide derivatives. The Ugi 4 component condensation of an amine, oxo compound, carboxylic acid and an isocyanide is the most documented and versatile MCR.

Ugi Reaction

Scheme 1.

Combined with combinatorial chemistry, Musonda et al. describe using the Ugi MCR to develop a library of novel compounds to screen against known antimalrial pharmacophores. The library consisted of aminoquinoline containing a-aminoacyl amides that were used in structure-activity relationship (SAR) studies. This approach allowed them to synthesize a number of compounds in very few reaction steps and screen them rapidly.1

The Ugi reaction can be coupled with a post condensation reaction to increase the number of possible pharmacologically important scaffolds. An example is the Heck reaction. Umkehrer et al. recently demonstrated that the Ugi/Heck combination works well for high-throughput combinatorial library production of indol- 2-ones having four points of diversity. This scaffold is of interest because it has shown biological effect as antitumor(1) and tyrosine kinase(2) inhibitor activity.2

Ugi Reaction

Figure 1.

Ugi Reaction

Figure 2.

Materials
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1.
Musonda CC, Taylor D, Lehman J, Gut J, Rosenthal PJ, Chibale K. 2004. Application of multi-component reactions to antimalarial drug discovery. Part 1: Parallel synthesis and antiplasmodial activity of new 4-aminoquinoline Ugi adducts. Bioorganic & Medicinal Chemistry Letters. 14(15):3901-3905. https://doi.org/10.1016/j.bmcl.2004.05.063
2.
Umkehrer M, Kalinski C, Kolb J, Burdack C. 2006. A new and versatile one-pot synthesis of indol-2-ones by a novel Ugi-four-component-Heck reaction. Tetrahedron Letters. 47(14):2391-2393. https://doi.org/10.1016/j.tetlet.2006.01.149