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

protocols for the synthesis of novel 1-substituted 7-cyano-2,3-diphenylindo lizines from the corresponding indolizinol have been developed, and the com pounds' abilities to act as antioxidants, i.e. to inhibit lipid peroxidatio n in vitro, have been examined. 1-Bromo-7-cyano-2,3-diphenylindolizine 9 re adily participates in Pd-catalysed coupling reactions with organotin, organ ozinc, and organoboron reagents. Similar treatment of the corresponding ind olizinyl triflate 6, on the other hand, resulted only in partial cleavage o f the triflate back to the indolizinol, except in reaction with 1-ethoxyeth enyl(tributyl)tin. Here, the unexpected acetal (1-ethoxyethoxy)indolizine 1 0 was formed. The structure of 10 was determined by single-crystal X-ray di ffraction 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 l ipid peroxidation in vitro was examined. Lipid peroxidation of boiled rat l iver microsomes was induced by ascorbic acid/FeSO4 and peroxidation was det ermined by measuring the material reactive to thiobarbituric acid. In parti cular, the indolizinyl acetate 4 and the triflate 6 appear to be highly act ive antioxidants, with IC50 values below 1 mum in the bioassay.