Ugi-4-component reaction

Practically irreversible multicomponent reactions (MCRs), like the Ugi 4-component reaction (U-4CR), can usually fulfill aU essential aspects of green chemistry. Their products can be formed directly, requiring minimal work by just mixing three to nine educts. Often minimal amounts of solvents are needed, and almost quantitative yields of pure products are frequently formed. 

One way to gain fast access to complex stmctures are multicomponent reactions (MCRs), of which especially the isocyanide-based MCRs are suitable to introduce peptidic elements, as the isonitrile usually ends up as an amide after the reaction is complete. Here the Ugi-4 component reaction (Ugi CR) is the most suitable one as it introduces two amide bonds to form an M-alkylated dipeptide usually (Fig. 2). The Passerini-3CR produces a typical element of depsipeptides with ester and amide in succession, and the Staudinger-3CR results in p-lactams. The biggest unsolved problem in all these MCRs is, however, that it is stUl close to impossible to obtain products with defined stereochemistry. On the other hand, this resistance, particularly of the Ugi-reaction, to render diastereo- and enantioselective processes allows the easy and unbiased synthesis of libraries with all stereoisomers present, usually in close to equal amounts. 

Fig. 2 Selected multicomponent reactions (MCRs) producing peptidic substructures, with the Ugi-4 component reaction (Ugi-4CR) as most commonly used one...

Cyclo-addition [76] (nitriloxide - isoxazole alkene —> isoxazoline), 1,3-dipolar cyclo-addition (pyrrole), Ugi 4-components reaction [75], Aza-Wittig reaction, N-alkylation [77], Stille reaction [78], Heck reaction [74], Pd-cata yzed amina-tion with primary and secondary alkyl- or aryl- ... 

Multicomponent reactions can also be performed under fluorous-phase conditions as shown for the Ugi 4 component reaction [97]. To improve the efficiency of a recently reported Ugi-de-Boc cyclization strategy, a fluorous Boc group for amine protection was introduced and the Ugi multicomponent condensation was conducted under microwave irradiation conditions (Scheme 16.64). The desired fluorous condensation products were easily separated by fluorous solid-phase extraction (F-SPE) and deprotected by treatment with trifluoroacetic acid-tetrahydrofuran under the action of microwave irradiation. The resulting quinoxa-linones were purified by a second F-SPE to furnish the products in excellent purity. This method has also been used for benzimidazole synthesis, vdth benzoic acid as substrate. 

G. M. Chinigo, A. Breder, E. M. Carreira, Org. Lett. 2011,13, 78-81. Ugi-4-component reaction enabling rapid access to the core fragment of Massadine. 

Welsch, S. J., Umkehrer, M., Ross, G., Kolb, J., Burdack, C., Wessjohann, L. A. (2011). Pdll/IV catalyzed oxidative cyclization of 1,6-enynes derived by Ugi-4-component reaction. Tetrahedron Letters, 52, 6295-6297. 

The Ugi-4-component reaction has also been used to directly access diverse dibenzoazepine derivatives from suitably substituted biaryl derivatives (Scheme 7) [42]. In comparison to conventional heating, use of MW led to much reduction in the reaction time with significant improvement of the yield. This method should be particularly suited for library s5mthesis of such type of compounds. 

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