Multicomponent Synthesis on a Diiron Platform of Stable Ferrabenzenes with Promising Anticancer Activity

Despite extensive research on metallabenzenes, ferrabenzenes have remained elusive, with only a single example reported to date, discovered accidentally. In this work, we present a reproducible, room-temperature reaction on a diiron bis-cyclopentadienyl platform, providing access to a class of four substituted ferrabenzenes (5a-c), stabilized by η6-coordination to a second iron fragment. This synthesis involves a one-pot double C─C coupling of iminium, carbene (from a diazo compound), and carbon monoxide moieties, yielding ferra-cyclohexadienone derivatives (4a-c), followed by O-alkylation with alkyl triflates. Experimental and computational studies enabled the proposal of a plausible reaction mechanism. Combined X-ray crystallography, nuclear magnetic resonance (NMR), and computational data support the aromatic character of the ferrabenzene ring in compounds 5a-c and, to a lesser extent, in their precursors 4a-c. Complexes 4a-c and 5a-c were further characterized by IR spectroscopy, mass spectrometry, and IR spectroelectrochemistry. A selection of ferrabenzenes (5a, 5b, 5aEt) revealed physicochemical properties suitable for biological applications, including permanent air stability, adequate aqueous solubility and stability, and balanced hydrophilic/lipophilic profile. These compounds exhibited potent cytotoxicity in vitro against three cancer cell lines, with 5aEt standing out for its pronounced activity, attributed to disruption of cell redox homeostasis, and marked selectivity compared to two noncancerous cell lines.