The reactions of [Ti(η5-Ind)(NMe2)2Me], [Ti(η5-Ind)(NMe2)Cl2], and [Zr(η5-Ind)(NMe2)2Cl] with 2,6-dimethylphenyl isocyanide (CN(2,6-Me2Ph)) and tert-butyl isocyanide (CN-t-Bu) have been investigated. For the first complex, insertion occurs exclusively into the Ti−C bond to give [Ti(η5-Ind)(NMe2)2{C(Me)N-t-Bu}] (1), which, according to DFT results, is due to the weakness of the Ti−CH3 bond when compared to Ti−NR2. [Ti(η5-Ind)(NMe2)Cl2] was found to react with 1 equiv of CN(2,6-Me2Ph) to yield [Ti(η5-Ind){C(NMe2)N(2,6-Me2Ph)}Cl2] (2). Two equivalents of 2,6-dimethylphenyl isocyanide reacts with [Zr(η5-Ind)(NMe2)2Cl] to give the double insertion compound [Zr(η5-Ind){C(NMe2)N(2,6-Me2Ph)}2Cl] (3). The same reaction performed with CN-t-Bu proceeds slowly and enabled the characterization, by NMR, of [Zr(η5-Ind)(NMe2){C(NMe2)N-t-Bu}Cl] (4) and [Zr(η5-Ind){C(NMe2)N-t-Bu}2Cl] (5). The molecular structures of 2 and 3 have been determined by X-ray diffraction. DFT calculations of the insertion of CNH in the zirconium nitrogen bonds of [Zr(η5-Ind)(NR2)2Cl] (R = H, Me) have been performed and show that the progressive stability of the insertion products accounts for the experimentally found double insertion product.

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Mechanochemistry is a powerful and environmentally friendly synthetic technique successfully employed in different fields of synthetic chemistry. Application spans from organic to inorganic chemistry including the synthesis of coordination compounds. Metal-organic frameworks (MOFs) are a class of compounds with numerous applications, from which we highlight herein their application in the pharmaceutical field (BioMOFs), whose importance has been growing and is now assuming a relevant and promising domain. The need to find cleaner, greener and more energy and material-efficient synthetic procedures led to the use of mechanochemistry into the synthesis of BioMOFs.

The incorporation of organometallic moieties into the structure of known active drugs to improve their therapeutic properties has gained considerable interest in recent years. The benzo- [b]thiophene derivative raloxifene is a selective estrogen receptor modulator (SERM) that has been found to decrease breast cancer risk in postmenopausal women compared to placebo. The current data suggest that, in the postmenopausal setting, raloxifene may have the benefits of the widely used tamoxifen with fewer side effects. As part of a program designed toward the synthesis and biological screening of organometallic benzo[b]thiophene derivatives inspired by the structure of raloxifene, we have prepared a series of 2-benzoyl-3-ferrocenylbenzo[b]thiophenes where the benzoyl sub- stituent contains terminal tertiary alkylamino groups, expected to ensure affinity to the estrogen receptor. The synthetic strategy and full characterization (NMR, MS, X-ray diffraction, cyclic voltammetry) of the new ferrocenylbenzo[b]thiophenes is reported herein. Moreover, the new 2- benzoyl-3-ferrocenylbenzo[b]thiophene derivatives were tested for their cytotoxic properties against several human tumor cell lines. All the test compounds showed considerable cytotoxic activity; among these, [3-ferrocenyl-6-methoxybenzo[b]thiophen-2-yl][4-(piperazin-1-yl)methyl- phenyl]methanone (compound 13) is of note, showing IC50 values in the low-micromolar range and more than 1 order of magnitude lower than those of the reference compound, cisplatin. In addition, chemosensitivity tests on resistant phenotypes indicated that compound 13 elicited no cross-resistance with cisplatin, besides not being a potential multidrug-resistant (MDR) substrate. Moreover, caspase-3 activation analyses revealed that 13 induced a caspase-3-dependent apoptotic cell-death mechanism. Taken together, these data suggest that the new 2-benzoyl-3- ferrocenylbenzo[b]thiophenes, in particular compound 13, have potentially useful antitumor properties

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