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Supplementary Methods from A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

Supplementary Figure 3 from A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

Supplementary Figure 4 from A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

Supplementary Figure 1 from A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

Supplementary Figure 2 from A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress Gene CHOP

In an effort to determine the thermochemistry of established organometallic transformation, the well documented reaction of alkynes with a palladacycle was investigated by isothermal titration calorimetry (ITC). Although the mechanism of the insertion of unsaturated substrates into the Pd−C bond of cyclopalladated compounds is known, no information is available so far about their thermochemistry. The enthalpies of the reactions of Ph−C≡C−Ph and MeOC(O)−C≡C(O)COMe with the bisacetonitrilo salt of the N,N-benzylamine palladacycle were determined by ITC in chlorobenzene after having optimized the conditions to ensure that only the double and a single insertion of alkynes were occurring respectively. The reaction energy profile established by DFT for the double insertion process involving Ph−C≡C−Ph confirmed earlier conclusions on the rate determining character of the first insertion. Further computations of reaction enthalpies reveal significant discrepancies between ITC and DFT-D/continuum solvation enthalpies, that are suspected to arise from an unexpected explicit noncovalent interaction of PhCl with the components of the reaction.

Ruthenium and osmium complexes have been shown to bypass several resistance mechanisms of platinum anticancer drugs, suggesting that they might represent therapeutic alternatives. However, the resistance mechanisms that may alter the cytotoxicity of ruthenium and osmium complexes have not been identified yet. Here we investigated the mechanisms governing the variability in the cytotoxicity of two ruthenium cyclometalated compounds and their osmium equivalents. We characterized their anticancer properties in vitro and in vivo, and we developed a 4-step approach to identify genes involved in their sensibility/resistance by correlating their cytotoxicity measures with transcriptomic data of 60 cancer cell lines. As previously observed for ruthenium complexes, we showed that osmium compounds target the endoplasmic reticulum stress pathway and that their activity was not hindered by mutation in the tumor suppressor gene TP53. Then, we identified multiple sensibility/resistance genes that correlated with the cytotoxicity of cyclometalated compounds. Docking and functional studies demonstrated that inhibition of some of these resistance mechanisms, namely ABCB1 export and EGFR expression, improved the activity of cyclometalated complexes. Interestingly, switching from ruthenium to osmium favored cytotoxicity while reducing sensibility to the ABCB1 export mechanism. In summary, this study represents the first comprehensive investigation of the resistance mechanisms that alter the biological activity of ruthenium or osmium complexes, and identifies some of the chemical determinants that are important for their activity.

International audience; Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960’s. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes. Then, they discovered that these organo-ruthenium/osmium complexes could act independently of DNA damage and bypass the requirement for the tumor suppressor gene TP53 to induce the endoplasmic reticulum (ER) stress pathway, which is an original cell death pathway. They showed that other types of ruthenium complexes—as well complexes with other metals (osmium, iron, platinum)—can induce this pathway as well. They also demonstrated that ruthenium complexes accumulate in the ER after entering the cell using passive and active mechanisms. These particular physico-chemical properties of the organometallic complexes designed by Dr. Pfeffer contribute to their ability to reduce tumor growth and angiogenesis. Taken together, the pioneering work of Dr. Michel Pfeffer over his career provides us with a legacy that we have yet to fully embrace.

Kinetically unstable heteroleptic trans-bispalladacycles were isolated by using hemichelation. Three structures of trans isomers and five of cis isomers were characterized by X-ray diffraction analysis. The ready trans-to-cis isomerization of such hemichelates that was monitored by variable temperature NMR experiments is facilitated dynamically because the Pd(ii) center can preserve its square planar coordination in a rather low lying transition state, which was localized by methods of the density functional theory. This process is not achievable in the isomerization of conventional homoleptic trans-bispalladacycles since it involves the preliminary partial chelate decoordination and an unfavorable high-lying planar trigonal coordinated - or Y-shaped-Pd(ii) transition state according to DFT investigations.

International audience; Targeting specific tumor metabolic needs represents an actively investigated therapeutic strategy to bypass tumor resistance mechanisms. In this study, we describe an original approach to impact the cancer metabolism by exploiting the redox properties of a ruthenium organometallic compound. This organometallic complex induced p53-independent cytotoxicity and reduced size and vascularization of patients-derived tumor explants that are resistant to platinum drugs. At the molecular level, the ruthenium complex altered redox enzyme activities and the intracellular redox state by increasing the NAD+/NADH ratio and ROS levels. Pathway analysis pointed to HIF-1 as a top deregulated metabolite pathway. Unlike cisplatin, treatment with the ruthenium complex decreased HIF1A protein levels and expression of HIF1A target genes. The rapid downregulation of HIF1A protein levels involved a direct interaction of the ruthenium compound with the redox enzyme PHD2, a HIF1A master regulator. HIF1A inhibition led to decreased angiogenesis in patient-derived xenografted using fragments of primary human colon tumors. Altogether, our results show that a ruthenium compound impacts metabolic pathways acting as anticancer agents in colon cancer via an original mechanism of action that affects redox enzymes differently than platinum-based drugs.

The two MeCN ligands in [Ru(2-C6H4-2'-Py-κC,N)(Phen, trans-C)(MeCN)2]PF6 (1), both trans to a sp(2) hybridized N atom, cannot be substituted by any other ligand. In contrast, the isomerized derivative [Ru(2-C6H4-2'-Py-κC,N)(Phen, cis-C)(MeCN)2]PF6 (2), in which one MeCN ligand is now trans to the C atom of the phenyl ring orthometalated to Ru, leads to fast and quantitative substitution reactions with several monodentate ligands. With PPh3, 2 affords [Ru(2-C6H4-2'-Py-κC,N)(Phen, cis-C)(PPh3)(MeCN)]PF6 (3), in which PPh3 is trans to the C σ bound to Ru. Compound 3 is not kinetically stable, because, under thermodynamic control, it leads to 4, in which the PPh3 is trans to a N atom of the Phen ligand. Dimethylsulfoxide (DMSO) can also substitute a MeCN ligand in 2, leading to 5, in which DMSO is coordinated to Ru via its S atom trans to the N atom of the Phen ligand, the isomer under thermodynamic control being the only compound observed. We also found evidence for the fast to very fast substitution of MeCN in 2 by water or a chloride anion by studying the electronic spectra of 2 in the presence of water or NBu4Cl, respectively. An isomerization related to that observed between 3 and 4 is also found for the known monophosphine derivative [Ru(2-C6H4-2'-Py-κC,N)(PPh3, trans-C)(MeCN)3]PF6 (10), in which the PPh3 is located trans to the C of the cyclometalated 2-phenylpyridine, since, upon treatment by refluxing MeCN, it leads to its isomer 11, [Ru(2-C6H4-2'-Py-κC,N)(PPh3, cis-C)(MeCN)3]PF6. Further substitutions are also observed on 11, whereby N^N chelates (N^N = 2,2'-bipyridine and phenanthroline) substitute two MeCN ligands, affording [Ru(2-C6H4-2'-Py-κC,N)(PPh3, cis-C)(N^N)(MeCN)]PF6 (12a and 12b). Altogether, the behavior of the obtained complexes by ligand substitution reactions can be rationalized by an antisymbiotic effect on the Ru center, trans to the C atom of the cyclometalated unit, leading to compounds having the least nucleophilic ligand trans to C whenever an isomerization, involving either a monodentate or a bidentate ligand, is possible.

International audience; Two novel cycloruthenated compounds, 2 and 3, derived from cycloruthenated 2-phenyl pyridine(Ru(PhPy)) have been synthesized by adding one equivalent of 2,20;60,200-terpyridine (terpy) to [Ru(2-C6H4-20-C5H4N-kC,N)(MeCN)4]PF6 in MeOH/MeCN (16:1) at reflux temperature as a mixture of 1:1 isomers. The structures of both compounds that were formed under kinetic and thermodynamic control respectively, differ by the position of the central pyridine unit of terpy that was found trans or cis to the C-Ru bond of the Ru(PhPy) unit for 2 and 3 respectively. Whereas 2 did not afford substitution reactions when treated with any ligand, the substitution by MeOH or H2O of the MeCN trans to C in 3 could be followed by UV-vis spectroscopy. Moreover, the reaction in MeOH between 3 and imidazoles afforded new cycloruthenated compounds, 6a and 6b whose cytotoxicities, together with that of 2 and 3, against HCT116 and AGS cancer cells were determined.

International audience; An upper rim, o-(diphenylphosphinyl)phenyl-substituted calix[4]arene has been prepared and its coordinative properties investigated. When heated in the presence of palladium, the new biarylphosphine undergoes conversion into two diastereomeric, calixarene-fused phospholes. In both, the P lone pair adopts a fixed orientation with respect to the calixarene core. The more hindered phosphole (8), i.e. the one with the endo-oriented lone pair (cone angle 150°–175°), forms complexes having their metal centre positioned very near the calixarene unit but outside the cavity, thus inducing an unusual chemical shift of one of the methylenic ArCH2Ar protons owing to interactions with the metal centre. As expected for dibenzophospholes, the complex [Rh(acac)(CO)·8], when combined with one equivalent of free 8, efficiently catalyses the hydroformylation of styrene, the catalytic system displaying high regioselectivity in favour of the branched aldehyde (b/l ratio up to 30). The optical and redox properties of the derivatives have also been investigated.

Ruthenium complexes are considered as potential replacements for platinum compounds in oncotherapy. Their clinical development is handicapped by a lack of consensus on their mode of action. In this study, we identify three histones (H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium compound (RDC11). Using purified histones, we confirmed an interaction between the ruthenium complex and histones that impacted on histone complex formation. A comparative study of the ruthenium complex versus cisplatin showed differential epigenetic modifications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modifications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures specific for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to specificities distinguishing the ruthenium complex from cisplatin. For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways. To further understand the role of HDACs in these regulations, we used suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin cytotoxicity while antagonizing the ruthenium complex activity. This study provides critical information for the characterization of signaling pathways differentiating both compounds, in particular, by the identification of a non-DNA direct target for an organoruthenium complex.

We warmly thank our co-workers whose names appear in the references.; International audience; Among the various applications of metal-based compounds, those that involve catalytic properties and biological activity have been the goals of quests by many research teams throughout the world. We mainly concentrate in this short review article on the anticancer properties of a certain class of organometallic ruthenium compounds: the cyclometalated derivatives that have been studied in the last decade. We emphasize the apparent contradiction between the known reactivity of the carbon–metal bonds in these species towards nucleophilic and electrophilic reagents and the fact that these bonds most probably survive the harsh reaction conditions that exist in most of the catalytic media and probably also in the biologic media. We focus on the mechanisms of action of the cycloruthenated molecules in terms of their anticancer properties and thus reveal some of the most recent findings on the potential modes of action of these compounds in cancer cells, which open new therapeutic perspectives.

Hemichelation is emerging as a new mode of coordination where non-covalent interactions crucially contribute to the cohesion of electron-unsaturated organometallic complexes. This study discloses an unprecedented demonstration of this concept to a Group 9 metal, that is, Rh(I). The syntheses of new 14-electron Rh(I) complexes were achieved by choosing the anti-[(η(6):η(6)-fluorenyl){Cr(CO)3}2] anion as the ambiphilic hemichelating ligand, which was treated with [{Rh(nbd)Cl}2] (nbd=norbornadiene) and [{Rh(CO)2Cl}2]. The new T-shaped Rh(I) hemichelates were characterized by analytical and structural methods. Investigations using the methods of the DFT and electron-density topology analysis (NCI region analysis, QTAIM theory) confirmed the closed-shell, non-covalent and attractive characters of the interaction between the Rh(I) center and the proximal Cr(CO)3 moiety. This study shows that, by appropriate tuning of the electronic properties of the ambiphilic ligand, truly coordination-unsaturated Rh(I) complexes can be synthesized in a manageable form.

The electronic spectra of 4 cyclometalated ruthenium compounds built up from cycloruthenated 2-phenylpyridine with monodentate and bidentate ligands, namely 1 [Ru(MeCN)2(phen)(PhPy)]1+ (RDC11), 2 [Ru(phen)2(PhPy)]1+ (RDC34), 3 [Ru(MeCN)2(PhPy)(dppz)]1+ (RDC11Z), 4 [Ru(bpy)(PhPy)(dppz)]1+ (RDCbpZ), the last two being newly synthesized, have been recorded and calculated together with that of 5 [Ru(bpy)2(dppz)]2+ (RDNbpZ). Recently synthesized variants of RDC34 where the phenylpyridine ligand is substituted with an electro-attractor or an electro-donor group, 6 [Ru(phen)2(NO2PhPy)]1+ RDC40 and 7 [Ru(phen)2(NH2PhPy)]1+ RDC41 respectively, and the dicationic reference complex [Ru (phen)2(bpy)]2+ (RDN34) have been investigated as well for comparison. The global structures of RDC34 and RDN34 are very similar despite of the substitution of one N atom by one C atom. As expected a shortening of the Ru–C bond as compared to the Ru–N bond is observed. The calculated structures of the investigated complexes point to a rather rigid structure whatever their environment. The introduction of a strong Ru–C bond has a minor effect on the coordination sphere around the metal atom keeping the other Ru–N bonds and bond angles similar, the only noticeable alteration being an increase of the Ru–N bond trans to the Ru–C bond. The experimental spectra are characterized by an intense band in the UV domain centered at 270 nm and corresponding to a strong intra-ligand (IL) absorption. Low-lying MLCT states contribute to a weak shoulder around 370 nm and to a large band between 550 nm and 400 nm. The tail of this band, towards 650 nm, is a characteristic of the cyclometalated complexes. This series of molecules, as other polypyridyl complexes, are characterized by a high density of excited states in the vis/UV energy domain, a large mixing between MLCT/IL and LLCT states in the upper part of the spectrum, and a significant sensitivity to the environment of the IL state localized on the dppz ligands.

Interactions between DNA and ruthenium organometallic compounds are studied by using visible light absorption and circular dichroism measurements. A titration technique allowing for the absolute determination of the advancement degree of the complexation, without any assumption about the number of complexation modes is developed. When DNA is in excess, complexation involves intercalation of one of the organometallic compound ligands between DNA base pairs. But, in the high complexation ratio limit, where organometallic compounds are in excess relative to the DNA base pairs, a new mode of interaction is observed, in which the organometallic compound interacts weakly with DNA. The weak interaction mode, moreover, develops when all the DNA intercalation sites are occupied. A regime is reached in which one DNA base pair is linked to more than one organometallic compound.

Cyclometalation of (2R,5R)-2,5-diphenylpyrrolidine (1) with [(η5-Cp*)MCl2]2 using NaOAc in CH2Cl2 at room temperature, followed by cationization with KPF6 in CH3CN, cleanly yielded the cationic cyclometalated amines 2a,b (a, M = Ir; b, M = Rh). This constituted an improvement with regard to another cyclometalation pathway, which had led to unwanted oxidation of the ligand to an imine. Compounds 2a,b were characterized by elemental analysis and X-ray diffraction of single crystals; the latter gave evidence of an R configuration of the metal center, and a λ envelope conformation of the five-membered metallacycle. Successful application of the NaOAc/CH2Cl2 methodology to the cycloiridation and cyclorhodation of the imidazolines 3–5 led to the neutral half-sandwich chloro complexes 6–8, which were completely characterized, with yields ranging from 44% to 82%. In these complexes, the labile NH proton was localized in a γ position with regard to the metal. From the enantiopure chiral ligands 4 and 5, both diast...

[Ru(N∧N)(MeCN)2(2-Ph-2′-Py)]PF6 (2-Ph-2′-Py = ortho-metalated 2-phenylpyridine, N∧N = phenanthroline, 2,2′-bipyridine), in which one of the nitrogens of the N∧N ligand is bound to Ru trans to the p...

A library of 29 organoosmium compounds has been built up with known and novel cyclometalated compounds obtained with C-N, N(∧)C(∧)N, and C(∧)N(∧)N ligands. All compounds have been tested for their in vitro cytotoxic properties against A172, a tumor cell line derived from a human glioblastoma, this affording a contrasted picture of the activities of the compounds gathered in this study. Some compounds displayed good to excellent activities, some of them showing IC50 in the nanomolar range. The level of activity was tentatively correlated to several physicochemical properties of the compounds such as their E(0)1/2(Os(III/II)) redox potential and their lipophilicity (log Po/w). A parallel with related ruthenium derivatives was tentatively proposed.

A Mn(I) tricarbonyl complex of a 1,3-diferrocenyl-1-oxopentadienyl ligand was synthesised adventitiously by what seems to be an in-situ aldol-like condensation of two acetylferrocene units promoted by benzyl-Mn(CO)5. X-ray structural analysis of this unexpected product confirms the η5 coordination of the 1,3-diferrocenyl-1-oxopentadienyl ligand to the Mn(CO)3 moiety. The nature of the metal-ligand bonding relationship was studied by theoretical calculations; it outlines the charge unbalance (polarisation) at the oxopentadienyl moiety as well as the lack of ketone character of the latter Mn-bound ligand.

The reaction of (2R,5R)-2,5-diphenylpyrrolidine (L1) with [(η5-C5Me5)MCl2]2 (M = Rh, Ir) in acetonitrile in the presence of KPF6 and NaOH at room temperature led to mixtures of two products, [(η5-C...

Cyclometallated platinum complexes of the monoanionic ligand 2-NMe2C6H4CH(SiR3)− (R = Me, Ph; dmat-SiR3−) have been synthesized via the reaction of the organolithium reagent with both [PtCl2(Et2S)2] and [PtCl2(Et2COD] (COD = 1,5-cyclooctadiene). The 1:1 reaction of Li(dmat-SiR3) with [PtCl2(Et2S)2] affords the mono-alkylated platinum complexes [PtCl(dmat-SiR3)Et2S]. The X-ray crystal structure of one of these (R = Me) was determined. The platinum centre has a square-planar geometry with a trans-C-Pt-Cl arrangement and the chelate dmat-SiMe3 ring has a conformation that places the bulky SiMe3 substituent out of the aryl ring plane. From the 2:1 reaction of Li(dmat-SiR3) with [PtCl2(Et2S)2] no stable organoplatinum compound could be isolated. However with [PtCl2(Et2S)2COD] this 2:1 reaction affords complexes of [Pt(dmat-SiR3)2COD] stoichiometry. These latter monomeric complexes contain one cyclometallated dmat-SiR3 ligand and a COD ligand that, after having undergone an addition of the second dmat-SiR3 ligand to one of its double bonds, is η2, η1−bound to the metal.

The “one-pot” generation of a tris-cationic homobimetallic racemic planar-chiral ruthenacyclic ruthenium sandwich complex from a reaction of the metal-free chelating ligand with the (η6-benzene)dic...

Various cycloruthenated complexes were used as homogeneous catalysts for the atom-transfer radical addition of polyhalogenated compounds to several olefinic substrates. Yields obtained through conventional or microwave heating could reach high values (up to 98% with CBrCl 3 and 88% with CCl 4 ).

The stereospecificity of ligand exchange at the Ir(III) centre of a cycloiridium arenetricarbonylchromium complex has been established experimentally by various analytical methods as well as by X-ray diffraction structural analysis and computational investigations. Two new cases of phenyl and methyl iridium(III) complexes have been prepared by reaction of (S(P)*,R(Ir)*-chlorido{2-[(tricarbonyl)(eta(6)-phenylene-kappaC(1'))chromium(0)]pyridine-kappaN}(pentamethylcyclopentadienyl)iridium(III) with PhMgBr and MeMgBr. The determining influence of electrostatic repulsion has been established by means of density functional theory at the Becke-Perdew/TZP(ZORA) level by using, among other means, energy partitioning analysis. It is also shown that the Cr(CO)(3) fragment is likely to ease the ionic cleavage of the Ir-Cl bond in chlorido cycloiridium tricarbonylchromium complexes in a way similar to that already established for the solvolysis of benzyl halide complexes, that is, through a direct interaction of the Cr(0) centre with the cationic Ir(III) centre.

The mechanism of asymmetric hydrogen transfer catalyzed by a ruthenacycle has been studied. Ruthenium-hydride intermediates have been characterized by 1H NMR and IR. These hydride complexes appeared as a diastereomeric mixture (de = 64%) responsible for the enantiomeric excess of the hydrogen transfer reaction (ee = 60%). Kinetic measurements have been performed as a function of substrate concentration and temperature. Michaelis−Menten kinetics were observed indicating substrate−catalyst complex formation (thermodynamic data for the complexation reaction: ΔG0 = −13 kJ mol−1 at 273 K, ΔH0 = −58 kJ mol−1, ΔS0 = −170 J K−1 mol−1). The complexation process is accomplished prior to an intracomplex chemical reaction. As the substrate is still bound to the catalyst, pericyclic hydrogen transfer is deduced with an activation energy Ea = 83 kJ mol−1. On the basis of these data, a mechanism is proposed for the overall hydrogen transfer reaction.

Exposure of various arylethynes to catalytic amounts of dimeric ruthenacycles containing the chloro(dicarbonyl)ruthenium [Ru(CO) 2 Cl] motif efficiently and selectively leads to the formation of (E)-1,4-diaryl-but-1-en-3-ynes that result from head-to-head C-C coupling.

A library of 19 cycloruthenated derivatives is constructed by making use of the well-known cyclometalation reaction. Their geometries are modified in a straightforward manner by addition of either mono- or bidentate ligands, such as bipyridine, phenanthroline, 1,2-bis(diphenylphosphanyl)ethane, dimethylphenylphosphane, triphenylphosphane, and 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (PTA) ligands, to cationic cycloruthenated centers. The antitumor properties of the compounds thus obtained are investigated in order to compare them with recently reported ruthenium complexes and cisplatin. IC50 values against mammalian cells (A-172, HCT-116, and RDM-4) are determined for the library compounds and some of them, such as those derived from orthoruthenated phenylpyridine and a bidentate N,N ligand, display activity of the same order of magnitude as cisplatin.

The cyclometalation of chiral secondary amines through ortho-metalation of an aryl group occurred readily with [(η6-benzene)RuCl2]2 in acetonitrile. Reasonable to good yields of the expected cationic products of the form [(η6-benzene)Ru(N−C)(NCMe)](PF6), in which N−C represents the cyclometalated ligands, were obtained with bis-(R)-phenylethylamine, bis-(R)-1-naphthylethylamine, and (2R,5R)-2,5-diphenylpyrrolidine. Variable proportions of the expected four diastereoisomers were found according to NMR studies. The stereochemistry of complexes was investigated by 2D NMR in solution and by X-ray diffraction of single crystals. The (S) configuration at the metal was generally associated with a δ conformation of the metallacycle, and conversely, the (R) configuration with the λ conformation.

The cyclometalation of chiral and achiral primary amines occurred readily with Ru(II), Rh(III), and Ir(III) derivatives. Thus, the metalation of (R)-1-phenylethylamine by [(η6-benzene)RuCl2]2, [(η5-Cp*)RhCl2]2, and [(η5-Cp*)IrCl2]2 was studied. Good yields of the expected cationic products in which the phenyl group was ortho-metalated were obtained for the rhodium and the ruthenium derivatives, whereas a mixture of products was formed in the case of the iridium complex. Benzylamine, (R)-1-phenylpropylamine, (R)-1-(1-naphthyl)ethylamine, and (R)-1-aminotetraline afforded also the cycloruthenation products whose general formula is [(η6-benzene)Ru(N−C)(NCMe)]PF6 where N−C represents the ortho-metalated ligands. Substitution of the acetonitrile ligand by PMe2Ph occurred readily on the ruthenium complexes, affording stable compounds that were characterized by X-ray diffraction studies on single crystals, thus ascertaining the existence of the cycloruthenated five-membered rings. Accurate analyses of the struct...

The cyclometallation of 2,5-diphenyl-1,3,4-oxadiazole with benzylpentacarbonylmanganese afforded the related mono- and binuclear complexes. The thermolytic coupling of 1,1-diphenyldiazomethane with monometallated 2,5-diphenyl-1,3,4-oxadiazole afforded substantial amounts of a new trihaptobenzylic complex. In the solid state, an X-ray diffraction analysis confirmed the coordination of manganese metal to one of the phenyl groups introduced by the 1,1-diphenyldiazomethane and to one of ligand’s nitrogen centre. In solution, this trihaptobenzylic complex displays a fluxionality which is assumed to be related to the equilibration of its helical Λ and Δ enantiomers.

We synthesized two organometallic diazepam-palladium(II) derivatives by C-H activation of diazepam (DZP) with palladium salts, i.e., PdCl2 and Pd(OAc)2 (OAc=acetate). Both compounds obtained are air stable and were isolated in good yields. The anticonvulsant potential of the complexes, labeled [(DZP)PdCl]2 and [(DZP)PdOAc]2, was evaluated through two animal models: pentylenetetrazole (PTZ)- and picrotoxin (PTX)-induced convulsions. The organometallic DZP-palladium(II) acetate complex, [(DZP)PdOAc]2, significantly increased (p

We have synthesized and fully characterized three chiral ligands with a rigid xanthene backbone having phosphorus and/or nitrogen donor atoms, viz. the diimine 5 and the iminophosphines 15a and 15b . When the imine functions were derived from (1 R )-camphor (compounds 5 and 15a ), their configuration was ( E ), whereas a dynamic mixture of ( Z ) and ( E ) isomers was observed in solution for the (1 S )-fenchone derivative 15b . Attempts to coordinate palladium (II) with these ligands have led to untractable mixtures. By contrast, we isolated in good yields the well-defined silver (I) complexes 18–20 , in which the ligands were bidentate, and the rhodium (III) complex 21 in which ligand 15a was tridentate. Complexes 18 , 19 and 21 were characterized by X-ray crystallography. A fluxionality of the silver complexes owed to conformational (flip-flop) equilibrium was revealed by VT-NMR analysis. The rhodium complex was not fluxional. In the silver complexes, the camphimine was in the ( E ) configuration as in the free ligand, whereas it had isomerized to ( Z ) in the rhodium complex. Pd-, Ag- or Rh-catalyzed reactions implemented with our ligands have in general led to good conversions but modest enantioselectivities (0–36%).

The reaction of a chiral terpenic 2-phenylpyridine with mercury (II) acetate afforded a new ortho -chloromercurated substrate, which was treated with [(η 6 -cymene)RuCl 2 ] 2 to afford two diastereomers of the corresponding half-sandwich cyclochlororuthenated terpenic ligand. The latter two complexes were successfully separated by conventional chromatography and their configurational stability investigated by 1 H NMR and CD spectroscopy. It was found that both isolated diastereomers displayed a fair configurational stability in CH 2 Cl 2 while when dissolved in MeOH they epimerize. It was shown that the rate of epimerization is rather slow in pure MeOH, whereas in the presence of an excess of Lewis acid such as HgCl 2 it was notably accelerated suggesting that the decoordination of the chloride from the Ru(II) center is a key step in the epimerization process.

The heat-promoted reaction of 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene with cyclomanganated 2-[tricarbonyl(η 6 -phenyl)chromium]pyridine afforded, upon departure of a molecule of CO, a new stable manganese alkylidene complex in which, according to X-ray diffraction analyses, the heterocyclic ligand is anti -facial with respect to the Cr(CO) 3 moiety. Similar heat-promoted reactions of unsymmetrically substituted diazoalkanes such as (Me 3 Si)(H)CN 2 , (Ph)(Me)CN 2 , (Ph)( t -Bu)CN 2 and (Ph)(FcCH 2 CH 2 )CN 2 , which are precursors of more electrophilic alkylidenes, with cyclomanganated 2-[tricarbonyl(η 6 -phenyl)chromium]pyridine derivatives afforded new syn -facial heterobimetallic benzyl complexes. The stereoselectivity of these reactions depends on the steric demand of the substituents at the diazoalkane. A phenyl substituent at the diazoalkane favors the formation of syn -facial heterobimetallic benzyl complexes with the Ph group in the endo position. Combining this “phenyl directing effect” to the steric effect operated by a bulky group at the phenyldiazoalkane, like noticed with (Ph)( t -Bu)CN 2 , led to total stereoselectivity. This study discloses four new X-ray structures of syn -facial Cr,Mn benzyl complexes, which all present the same short Cr-to-Mn distance of ca. 3.04 A.

Yellow cyclometalatated ruthenium (II) complexes [Ru(o-X-2-py)(MeCN)4]PF6 (1, X = C6H4 (a) or 4-MeC6H3 (b)) react readily with 1,10-phenanthroline (LL) in MeCN to give brownish-red species cis-[Ru(o-X-2-py)(LL)(MeCN)2]PF6 in high yields. The same reaction of the same complexes under the same conditions with 2,2′-bipyridine results in a significant color change from yellow to brownish-orange suggesting a formation of new species. Surprisingly, X-ray structural studies of these two complexes showed that they are structurally indistinguishable from the starting complexes 1. Referred to as complexes 4a,b, the new compounds are slightly more stable in the air though their spectral characteristics in solution are similar to 1a,b. The diffuse reflectance spectroscopy is so far the only technique that indicated differences between 1 and 4.

The thermolytic coupling of Ph(2)CN(2) and (t-Bu)(Ph)CN(2) with doubly cyclomanganated 2,5-diphenylpyrazine and 4,6-diphenylpyrimidine afforded substantial amounts of new triple decker compounds of either C(i) and C(2) symmetry respectively containing, in both series, two eta(3)-bonded Mn(CO)(3) fragments which intervene as scaffolds sustaining the helical non-conjugated triaryl backbone. The molecular structures of two pyrazine derivatives show a typical non-parallel stacking of the aromatic rings and the encapsulation of the central pyrazyl fragment with interplanar centroid-to-centroid distances of ca. 3.5 A. The stacking of the aromatics in the triple-decker pyrimidine derivatives has been assessed by (1)H NMR experiments at low temperature. All the triple-decker-type compounds are electroactive. Pyrimidine triple-deckers can reversibly be electrochemically reduced to the corresponding anions.

Cycloruthenated complexes obtained by direct C-H activation of enantiopure aromatic primary and secondary amines are efficient catalysts in asymmetric hydride transfer reaction. Reduction of acetophenone has been achieved rapidly with enantiomeric excesses (ee's) ranging from 38 to 89 %. The importance of Ru-C bond in the catalytic efficiency is highlighted.

[reaction: see text] Ruthenacycles obtained by cyclometalation of enantiopure aromatic primary or secondary amines with [(eta6-benzene)RuCl2]2 or with [(eta6-p-cymene)RuCl2]2 are efficient catalysts for asymmetric transfer hydrogenation (TOF up to 190 h(-1) at room temperature). Enantioselectivities in the transfer hydrogenation of acetophenone ranged from 38% to 89%. It is possible to prepare the catalysts in situ, which allows the use of high throughput experimentation.

Cyclometalated derivatives of ring-substituted N,N-dimethylbenzylamines with controlled redox potentials as potent mediators of bioelectrochemical electron transport are reported. The cycloruthenation of R1R2R3C6H2CH2NMe2 (R1, R2, R3 = H, Me, tBuO, MeO, NMe2, F, CF3, CN, NO2) by [(η6-C6H6)RuCl(μ-Cl)]2 in the presence of NaOH/KPF6 in acetonitrile or pivalonitrile affords cyclometalated complexes [(η6-C6H6)Ru(C6HR1R2R3-o-CH2NMe2)(RCN)]PF6 [R = Me (1) and R = CMe3 (2)] in good yields. Reactions of complexes 1 and 2 with 2,2′-bipyridine (bpy) in acetonitrile or pivalonitrile result in dissociation of η6-bound benzene and the formation of [Ru(C6HR1R2R3-o-CH2NMe2)(bpy)(RCN)2]PF6 [R = Me (3) and R = CMe3 (4)]. All new compounds have been fully characterized by mass spectrometry, 1H/13C NMR, and IR spectroscopy. An X-ray crystal structural investigation of complex 1 (R1/R2/R3 = H/H/H) and two complexes of type 3 (R1/R2/R3 = MeO/H/H, MeO/MeO/H) has been performed. Acetonitrile ligands of 3 are mutually cis and the σ-bound carbon is trans to one of the bpy nitrogens. Measured by the cyclic voltammetry in MeOH as solvent, the redox potentials of complexes 3 for the RuII/III feature cover the range 320–720 mV (versus Ag/AgCl) and correlate linearly with the Hammett ( σ p + + σ m ) constants. Complexes 3 mediate efficiently the electron transport between the active site of PQQ-dependent glucose dehydrogenase (PQQ = pyrroloquinoline quinone) and a glassy carbon electrode. Determined by cyclic voltammetry the second order rate constant for the oxidation of the reduced (by d -glucose) enzyme active site by RuIII derivative of 3 (R1/R2/R3 = H) (generated electrochemically) is as high as 4.8 × 107 M−1 s−1 at 25 °C and pH 7.

The reaction of racemic orthomercurated (η6-arene)tricarbonylchromium complexes with bis[(?6-cymene)ruthenium(II)dichloride] affords the corresponding dinuclear (Cr,Ru) products with moderate yields, which have been satisfactorily characterized by X-ray diffraction analysis. The synthesis of nonracemic orthomercurated (η6-arene)tricarbonylchromium complexes has been attempted starting from enantio-enriched homo- and heteroleptic Pd(II) bischelated complexes. Both enantiomers of ortho-mercurated 2-[tricarbonyl(?6-phenyl)chromium]pyridine have been synthesized by reaction of a heteroleptic Pd(II) bischelated with HgCl2. The two mercury(II) complexes were also submitted to a transmetalation reaction with bis[(?6-cymene)ruthenium(II)dichloride] and yielded the corresponding nonracemic (Cr, Ru) products, with enantiomeric excesses ranging from 82 to 89% as suggested by 1H NMR analyses in the presence of BINPHAT anion.

The thermolysis of various cyclomanganated arenes in the presence of 5-diazocyclopentadiene, 7-diazoindene or 9-diazofluorene afforded the corresponding arenes tethered with cymantrenyl, benzocymantrenyl or dibenzocymantrenyl groups in fair to good yields. This reaction implies a multi-facetted mechanism that consists of three steps: the insertion of an alkylidene moiety into a C−Mn bond, a CAr−C bond formation and several haptotropic ring-slippages. The coupling reaction has proven to be particularly efficient with Mn(CO)4 chelates derived from acetylarenes and nitrogen-containing heterocycles. In one case of a 2-phenyl-2-oxazoline complex, the coupling with 9-diazofluorene yields a new η1-dibenzocymantrene complex in which the Mn(CO)4 moiety is chelated and is part of a six-membered metallacycle. The results of this study are mainly supported by the molecular structures of nine new complexes obtained by X-ray diffraction analyses. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

A minilibrary of cationic N-heterocycles has been prepared and evaluated. The potential for the preparation was a result of the high versatility of palladium-mediated chemistry. The synthesis of the novel molecules was based on intramolecular quaternization of tertiary amine attached allylpalladium complexes. The steric and electronic factors of the reaction are discussed. The structures of the synthesized molecules made them candidates for precise biological and pharmacological evaluations. Of the various N-heterocyclic compounds, 2,2-dimethyl-3-methylenenaphtho[def]quinolizinium showed antibacterial activity at micromolar concentrations. This compound also proved to be a nanomolar competitive antagonist for the channel site of the nicotinic acetylcholine receptor. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Ethene has been reacted under mild conditions with the benzene cycloruthenated dimethyl(phenylmethyl)amine compounds [Ru(η6-C6H6){2-(CH2NMe2-κN)-C6H4-κC1}L]+ (1a, L = Cl-; 1b, L = NCMe), obtained via intramolecular C−H activation. The stoichiometric arylated olefin dimethyl((2-ethenylphenyl)methyl)amine (2) and/or new organometallic species resulting from the overall insertion of one carbon atom into the Ru−C bond, [Ru(η6-C6H6){1-(CHMe-κC)-2-(CH2NMe2-κN)-C6H4}L]+ (3a, L = Cl-; 3b, L = NCMe), have been obtained in varying proportions according to the reaction conditions and to the nature of the starting complex. The six-membered metallacycles were found as a single pair of enantiomers of RRuRC and SRuSC configurations, as established by 1H NOE experiments. In solution under an argon atmosphere, 3a rearranged to the more stable five-membered ruthenacycle [Ru(η6-C6H6){2-(CH2NMe2-κN)-3-Et-C6H3-κC1}Cl] (4a). Under ethene pressure, the intramolecular rearrangement is followed by a second ethene insertion into t...

Synthetic routes to neopentyl and trimethylsilylmethyl complexes of Pd(II) are reported, Pd(CH2EMe3)Ph(tmeda) [E = C (1), Si (3); tmeda = N,N,N',N'-tetramethylethylenediamine] and Pd(CH2EMe3)Ph(bpy) [E = C (2), Si (4); bpy = 2,2'-bipyridine]. Complexes 1 and 3 are formed on the reaction of PdIPh(tmeda) with LiCH2EMe3, and they react with bpy to give 2 and 4. Oxidative addition reactions of 8-(bromomethyl)quinoline (mqBr) with Pd(CH2EMe3)Ph(bpy) result in the formation of octahedral Pd(IV) complexes [Pd(mq)(CH2EMe3)Ph(bpy)]Br [E = C (5), Si (6)]. An X-ray structural analysis for 5, the first example of a stable cationic arylpalladium(IV) complex, shows a fac-PdC3N3 configuration with the neopentyl group trans to the quinoline nitrogen donor atom.