Osmium arene activation

Fig. 7 Examples of ruthenium(II)-arene and osmium(II)-arene paullone complexes with high in vitro anticancer activity...

Protonation of 322 with tetrafluoroboric acid in diethyl ether gives the cyclohexadienyl derivative 325 in 70% yield. Treatment of 325 with lithium aluminum hydride yields the biscyclohexadienyl osmium(II) complex 326. Treatment of 322 with PMe3 at 60°C gives the hydridophenyl osmium-(II) complex 181, rather than the expected arene bistrimethylphosphine osmium(O) compound, via intramolecular C—H bond activation of the benzene ligand (192,193) (Scheme 38). Compound 181 as well as the analogous ruthenium complex (92) have also been obtained directly by cocondensation of osmium or ruthenium atoms with benzene and tri-methylphosphine (62) [Eq. (44)]. 

We have recently extended our interest to the analogous halfsandwich osmium-arene complexes and are exploring the chemical and biological properties of [Os(r 6-arene)(XY)Z]ra 1 complexes (Fig. 25) (105). Both the aqueous chemistry and the biological activity of osmium complexes have been little studied. Third-row transition metals are usually considered to be more inert than those of the first and second rows. Similar to the five orders of magnitude decrease in substitution rates of Pt(II) complexes compared to Pd(II), the [Os(ri6-arene)(L)X]"+ complexes were expected to display rather different kinetics than their Ru(II)-arene analogs. A few other reports on the anticancer activity of osmium-arene complexes have also appeared recently (106-108). 

In line with expectations of kinetic inertness for third-row transition metals, little interest has been vested in the development of osmium anticancer drugs, as ligand-exchange rates did not seem favorable on the timescale of cellular processes. Our work, however, shows that the kinetic lability of such complexes can be timed to such extent that anticancer activity comes within range. We have demonstrated how rational chemical design can thus be applied to osmium-arene complexes resulting in specific... 

A good example of how to tune a family of oganometallic complexes all the way from a lack of cytotoxic activity to IC50 values comparable to those of cisplatin and carboplatin is the newly developed series of osmium arene organometallic complexes. 

Novel picolinate derivatives have been synthesised that show hydrolysis rates intermediate between the slow values for the complexes with /V,/V-chelating ligands, and the rapidly-hydrolysing complexes with 0,0- or N,0- amino acidlike chelating ligands. For these organometallic osmium complexes, the hydrolysis rates fall into the range of the active ruthenium-arene relatives (Fig.l) [66]. 

Once the ruthenium or osmium arene organometallic complex is activated with the formation of the aqua species, [Ru/Os(r 6-arene)(OH2)(X)(Y)] (Chart 3), the metal becomes a potential centre for nucleophilic attack by biomolecules. The binding of Run/Osn arene complexes to nucleobases is of special interest, since DNA could be the ultimate target for this class of organometallic complexes. A number of studies have confirmed this postulate [86, 87] and investigated in detail such interactions [53, 54, 72, 88-93]. DNA interactions of Ru and Os arene complexes have recently been reviewed [94],... 

Arene ruthenium and osmium complexes play an increasingly important role in organometallic chemistry. They appear to be good starting materials for access to reactive arene metal hydrides or 16-electron metal(O) intermediates that have been used recently for carbon-hydrogen bond activation. Various methods of access to cyclopentadienyl, borane, and carborane arene ruthenium and osmium complexes have been reported. 

T/6-Arene ruthenium and osmium offer specific properties for the reactivity of arene ligand. The activation toward nucleophiles or electrophiles is controlled mainly by the oxidation state of the metal (II or 0). Recently, from classic organometallic arene ruthenium and osmium chemistry has grown an area making significant contributions to the chemistry of cyclo-phanes. These compounds are potential precursors of organometallic polymers which show interesting electrical properties and conductivity. 

The possibility of coordination of a two-electron ligand, in addition to arene, to the ruthenium or osmium atom provides a route to mixed metal or cluster compounds. Cocondensation of arene with ruthenium or osmium vapors has recently allowed access to new types of arene metal complexes and clusters. In addition, arene ruthenium and osmium appear to be useful and specific catalyst precursors, apart from classic hydrogenation, for carbon-hydrogen bond activation and activation of alkynes such compounds may become valuable reagents for organic syntheses. 

The osmylation of arenes (Ar) with osmium tetroxide is a particularly informative system with which to illustrate the close interrelationship between the thermal and photochemical activation of electron-transfer oxidation. For example, a colorless solution of osmium tetroxide in n-hexane or dichlorometbane upon exposure to benzene turns yellow instantaneously. With durene an orange coloration develops and a clear bright red solution results from hexamethylbenzene. The quantitative effects of the dramatic color changes are illustrated in Figure 3 by the spectral shifts of the electronic absorption bands that accompany the variations in aromatic conjugation and substituents. The progressive bathochromic shift parallels the decrease in the arene ionization potentials (/F) in the order benzene 9.23 eV naphthalene... 

Such dearomatization of the arene ligand activates it toward an electrophilic addition. Thus, osmium(ll) was used as a dearomatization agent for the direct 10/3-alkylation of /3-estradiol 70 (equation 29). When the tautomeric mixture 71 72 was placed in acidic methanol and reprecipitated, a 3 1 equilibrium ratio of the phenolic 71 and dienone 72 tautomers was observed . This intermolecular Michael addition to the C(10) position of the aromatic steroid was unprecedented. 

Most osmium complexes of phenols [26,44], anilines [24,45], and anisoles [23, 46,47] undergo electrophilic addition with a high regiochemical preference for para addition. While electrophilic additions to phenol complexes are typically carried out in the presence of an amine base catalyst, the other two classes generally require a mild Lewis or Bronsted acid to promote the reaction. The primary advantage of the less activated arenes is that the 4H-arenium species resulting from electrophilic addition are more reactive toward nucleophilic addition reactions (see below). 

The reactions outlined in the previous sections all utilized an arene with a heteroatom substituent that could stabilize the arenium intermediates resulting from electrophilic addition. Benzene, alkylated benzenes, and naphthalene are more difficult to activate because they lack this mode of stabilization. Osmium... 

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