Titanocenes

Titanocene dichloride, [TiIV(q5-C5H5)2Cl2], will be remembered in the history of metal-based drugs as a pioneer in the field of organometallic complexes with anticancer activity. 

Ultimately, formulation problems as a result of rapid hydrolysis, i.e. instability, halted further evaluation of the drug [2, 20]. In addition, the efficacy rates of titanocene dichloride in Phase II clinical trials in patients with metastatic renalcell carcinoma and metastatic breast cancer were too low to support further development [21, 22]. 

Although the progress of titanocene into the clinic has been hampered by the complicated characterisation of its metabolites [17, 20], the discovery of its cytotoxic activity has triggered the search for titanocene derivatives and other metallocenes ([M(Cp)2Cl2], where M is, e.g. V, Mo) that show similar or better antineoplastic activity [23-26] whilst controlling aqueous activity [3, 20, 27]. 

Similarly, McGowan et al. have synthesised a number of new ionic titanocene organometallic complexes (e.g. 4), which exhibit cytotoxicity against different human tumour cell lines including a cisplatin-resistant cell line [34]. 

Although hydrolysis may play an important role in the activation of titanocene derivatives as tumour inhibitors, few studies as yet support this postulate. 

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The full ab-initio molecular dynamics simulation revealed the insertion of ethylene into the Zr-C bond, leading to propyl formation. The dynamics simulations showed that this first step in ethylene polymerisation is extremely fast. Figure 2 shows the distance between the carbon atoms in ethylene and between an ethylene carbon and the methyl carbon, from which it follows that the insertion time is only about 170 fs. This observation suggests the absence of any significant barrier of activation at this stage of the polymerisation process, and for this catalyst. The absence or very small value of a barrier for insertion of ethylene into a bis-cyclopentadienyl titanocene or zirconocene has also been confirmed by static quantum simulations reported independently... 

Fig. 1. The structure of the ethylene-zirconocene complex (SiH2Cp2)ZrCHj-C2H4. The corresponding titanocene has basically the same structure, except that the Ti-C distances are obviously different from the Zr-C distances.

Fig. 2. Time-evolution of the methyl/ethyl C-C distances for both the zirconocene and the corresponding titanocene catalyst. The two curves starting at around 3.2 A represent the distance between the methyl carbon atom and the nearest-by ethylene carbon atom in the zirconocene-ethylene and the titanocene-ethylene complex, respectively. The two curves starting at around 1.35 A reflect the ethylene internal C-C bond lengths in the two complexes.

Thickness of the laminar layer is deterrnined both by the need to reproduce fine detail in the object and by the penetration depth of the actinic laser light into the monomer bath (21,76). There is thus a trade-off between precision of detail in the model and time required for stereohthography, ie, the number of layers that have to be written, and an optimum Light-absorbing initiator concentration in the monomer bath corresponding to the chosen layer thickness. Titanocene-based initiators, eg, bis-perfluorophenyltitanocene has been recommended for this apphcation (77). Mechanistic aspects of the photochemistry of titanocenes and mechanisms of photoinitiation have been reviewed (76). 

Photolysis of Cp2TiAr2 in benzene solution yields titanocene and a variety of aryl products derived both intra- and intermolecularly (293—297). Dimethyl titan ocene photolyzed in hydrocarbons yields methane, but the hydrogen is derived from the other methyl group and from the cyclopentadienyl rings, as demonstrated by deuteration. Photolysis in the presence of diphenylacetylene yields the dimeric titanocycle (28) and a titanomethylation product [65090-11-1]. 

Reductive ring opening of epoxides in radical reactions in presence of titanocenes as electron transfer catalysts 98SL801. 

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

The titanocene dichloride complexes derived from the camphor- and pinene-annulated ligands 126 and 127 were tested as enantioselective hydrogenation catalyst and using 2-phenylbutene as substrate 2-phenylbutane was obtained with ee up to 34% [148, 149]. 

In a reaction closely related to the latter, pyranylidene derivatives are obtained by the intermolecular radical coupling of alkynyl- or alkenylcarbene complexes and epoxides. Good diastereoselectivities are observed when cyclic epoxides are used. Moreover, the best results are reached by the generation of the alkyl radical using titanocene monochloride dimer [90] (Scheme 43). 

Mit Titanocen-dichlorid/Natrium werden dagegen Alkane und als Nebenprodukte A1 kohole erhalten1 (Vorsicht Der bei der Aufarbeitungentstehende graue Niederschlag aus Titan-Polymeren ist an der Luft selbstentziindlich). 

Das Reduktionspaar Titanocen-dichlorid/Natrium in Benzol ist zur Reduktion von Carbonsaure-estern zu Alkanen hervorragend geeignet4 ... 

Oxirane werden ebenfalls durch Titanocen-dichlorid/Natrium in Benzol zu Alkanen und Alkoholen (Nebenprodukt) reduziert (vgl. a.S.547) ... 

The reagent titanocene dichloride reduces carboxylic esters in a different manner from that of 10-86, 19-36, or 19-38. The products are the alkane RCH3 and the alcohol R OH. The mechanism probably involves an alkene intermediate. Aromatic acids can be reduced to methylbenzenes by a procedure involving refluxing first with trichlorosilane in MeCN, then with tripropylamine added, and finally with KOH and MeOH (after removal of the MeCN). The following sequence has been suggested ... 

Though the usual product of epoxide reductions is the alcohol (10-85), epoxides are reduced all the way to the alkane by titanocene dichloride and Et3SiH-BH3. ... 

Reduction of carboxylic esters with titanocene dichloride... 

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