Synthesis of 1-substituted 7-cyano-2,3-diphenylindolizines and evaluation of antioxidant properties

O.B. Ystby, B. Dalhus, L.L. Gundersen, F. Rise, A. Bast, G.R.M.M. Haenen

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Protocols for the synthesis of novel 1-substituted 7-cyano-2,3-diphenylindolizines from the corresponding indolizinol have been developed, and the compounds’ abilities to act as antioxidants, i.e. To inhibit lipid peroxidation in vitro, have been examined. 1-bromo-7-cyano-2,3-diphenylindolizine 9 readily participates in pd-catalysed coupling reactions with organotin, organozinc, and organoboron reagents. Similar treatment of the corresponding indolizinyl triflate 6, on the other hand, resulted only in partial cleavage of the triflate back to the indolizinol, except in reaction with 1-ethoxyethenyl(tributyl)tin. Here, the unexpected acetal (1-ethoxyethoxy)indolizine 10 was formed. The structure of 10 was determined by single-crystal x-ray diffraction methods at 150 k. An alternative strategy for the introduction of substituents at c-1 is by lithiation of the bromide 9 followed by reaction with electrophiles. The ability of the indolizine derivatives to inhibit lipid peroxidation in vitro was examined. Lipid peroxidation of boiled rat liver microsomes was induced by ascorbic acid/feso4 and peroxidation was determined by measuring the material reactive to thiobarbituric acid. In particular, the indolizinyl acetate 4 and the triflate 6 appear to be highly active antioxidants, with ic50 values below 1 µm in the bioassay.
Original languageEnglish
Pages (from-to)3763-3770
Number of pages9
JournalEuropean Journal of Organic Chemistry
Publication statusPublished - 1 Jan 2000


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