Synthesis and Antiproliferative Effects of [3]Ferrocenophane Transposition Products and Pinacols Obtained from McMurry Cross-Coupling Reactions

We here report the synthesis and antiproliferative activities of two new series of ferrocenophanes obtained from McMurry cross-coupling reactions of [3]ferrocenophan-1-one with benzophenone, 4-hydroxybenzophenone, 4,4′-dihydroxybenzophenone, and 4,4′-diacetylaminobenzophenone. In addition to the main formation of olefins at reflux, tetrahedral transposition products, resulting from a pinacolic rearrangement, were also isolated in about 10% yields. Lowering the temperature of the reaction to 0 °C allowed the isolation of pinacols, which could be transformed into transposition compounds in good yields. Three ferrocenophane compounds have been characterized by X-ray crystallography: 1-(p-hydroxyphenyl)-1-phenyl-2-oxo[4]ferrocenophane (7b), 1,1-diphenyl-2-oxo[4]ferrocenophane (7c), and 1-hydroxy-1-[1-hydroxy-1-[3]ferrocenophanyl][3]ferrocenophane (12) crystallize in monoclinic P21/n, triclinic P1̅, and monoclinic P21/c space groups, respectively. The antiproliferative effects on hormone-independent breast cancer cells (MDA-MB-231) of the transposition compounds are generally lower than those of their corresponding butene analogues (IC50 values in micromolar versus nanomolar range). In contrast and quite surprisingly, the pinacol complexes are significantly cytotoxic (IC50 in the nanomolar range), among the most cytotoxic ferrocene compounds prepared so far. This antiproliferative activity may be linked to their oxidative cleavage.