Abstract
Optimization of Radziszewski's four-component reaction employing a microwave-assisted protocol, led to a small library of 48 imidazoles with a success rate of 65% (conversion > 45%). All three diversity points of the four-component reaction were varied. Aromatic and aliphatic inputs were successfully implemented and mono-, di-, tri- and tetrasubstituted imidazoles with various substitution patterns were synthesized. Furthermore, unsymmetrical diketones could successfully be used which improved the intrinsic diversity of the method significantly. If the unsymmetrical diketone 1,2-phenylpropanedione (R1 and R2) was used two regioisomers were formed. Depending on the type of amine (R4) and aldehyde (R3) applied, regioselectivity was modest to good. Based on these results, a reaction mechanism is proposed.
Abbreviations
- MW:
-
microwave
- MCR:
-
multicomponent reaction
- EWG:
-
electron withdrawing group
References
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The isolated yield was determined by work-up via the following procedure. After the reaction, the reaction mixture was taken up in DCM. Water was added and the water layer was neutralized with Na2CO3. The layers were separated and the water layer was extracted twice more with DCM. The combined DCM layers were dried over Na2SO4 and reduced in vacuo. The crude mixture was analysed by 1H-NMR and was found to contain 71% of the expected imidazole 1. Flash chromatography with DCM as the eluent gave imidazole 1 in 70% yield and 95% purity.
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This was established by NOESY-NMR analysis.
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Gelens, E., Kanter, F.J.J.D., Schmitz, R.F. et al. Efficient library synthesis of imidazoles using a multicomponent reaction and microwave irradiation. Mol Divers 10, 17–22 (2006). https://doi.org/10.1007/s11030-006-8695-3
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DOI: https://doi.org/10.1007/s11030-006-8695-3