Organometallic Ruthenium and Osmium Compounds

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CHEMISTRY & BIODIVERSITY – Vol. 9 (2012)

Organometallic Ruthenium and Osmium Compounds of Pyridin-2- and -4ones as Potential Anticancer Agents by Helena Henke a ) b ), Wolfgang Kandioller a ), Muhammad Hanif c ), Bernhard K. Keppler a ) b ), and Christian G. Hartinger* a ) b ) d ) a

) University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, AT-1090 Vienna b ) University of Vienna, Research Platform Translational Cancer Therapy Research, Waehringer Str. 42, AT-1090 Vienna c ) Department of Chemistry, COMSATS Institute of Information Technology Abbottabad Campus, University Road, Abbottabad-22060, Pakistan d ) The University of Auckland, School of Chemical Sciences, Symonds Str. 23, 1010 Auckland, New Zealand (e-mail: [email protected])

Organometallic RuII compounds are among the most widely studied anticancer agents. Functionalizing metal centers with biomolecule-derived ligands has been shown to be a promising strategy to improve the antiproliferative activity of metal-based chemotherapeutics. Herein, the synthesis of a series of novel 3-hydroxypyridin-2-one-derived ligands and their MII(h6-p-cymene) half-sandwich complexes (M ¼ Ru, Os) is described. The compounds were characterized by 1D- and 2D-NMR spectroscopy, and elemental analysis.

Introduction. – Due to the severe side effects of chemotherapeutics and their use limited to a few types of tumors, the search for new compounds with tumor-inhibiting properties is crucial. New drugs need to have improved selectivity and activity, and should exhibit less side-effects as compared to established chemotherapeutics [1 – 5]. In the field of medicinal inorganic chemistry, non-platinum anticancer agents based on ruthenium and gallium have demonstrated great promise in clinical trials and could be an alternative fulfilling afore-mentioned criteria for novel chemotherapeutics [6]. With the emergence of organometallic Ru compounds, research has been redirected to compounds designed to exhibit biological properties based on more selective interaction with target molecules [7]. In an initial development stage, researchers aimed to attach biologically active ligand systems to the metal center. This approach resulted in the preparation of [Ru(h6-C6H6 )Cl2(metronidazole)] with metronidazole, being a well-known anti-infective agent [8], and a series of compounds with various enzyme inhibitors as ligands or structural elements like ethacrynic acid, paullones, and staurosporine [7]. In recent years, we have explored the use of (thio)pyridinone (including pyranone) ligand systems derived from the biomolecule maltol in the development of anticancer agents [4] [9] [10]. Hydroxypyridinones are of high interest in medicinal inorganic chemistry [4] [11]. Selected examples include their application as antidiabetic [12 – 15], antibacterial [16 – 18], and antiviral agents [18], as Na þ - and Li þ -receptors [19 – 21], for treatment of iron-overload disease [11] and, potentially, of neurodegenerative 2012 Verlag Helvetica Chimica Acta AG, Zrich


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disorders [22], as matrix metalloprotein [23 – 25] and anthrax lethal factor inhibitors [17] [18], magnetic resonance imaging (MRI) contrast agents [26] [27], and as anticancer drugs [28 – 30]. One of the most important examples is the presence in the anticancer agent tris(maltolato)gallium(III) which has been undergoing clinical trials in order to improve the bioavailability of GaIII and to prevent the hydrolysis of the drug [28] [29] [31]. We have reported a series of mono- and polynuclear Ru and Os complexes derived from maltol as the central building block to exhibit biological activity based on varying chemical properties, such as cross-linking of DNA duplexes and of DNA and proteins by dinuclear compounds [32], and potential to overcome drug resistance [33]. In case of mononuclear compounds, the increased stability of thiopyranones over pyranones is noteworthy, accompanied by a change in selectivity of cytotoxicity in cancer cells [34] [35]. Herein, we report on the preparation and characterization of an extended series of maltol-based organometallic Ru and Os complexes aiming at compounds functionalized on the pyridinone moiety in order to alter their stability in aqueous solution and their biological properties. Results and Discussion. – RuIIpyranone complexes have been shown to undergo aquation of the chloride ligand upon dissolution in H2O, followed by the formation of dimeric tris(hydroxido)-bridged Ru complexes [4] [34 – 37]. Since pyridinones are known to form more stable complexes than pyranones (the stability decreases in the order 3-hydroxypyridin-4-one > 3-hydroxypyridin-2-one > 1-hydroxypyridin-2-one [38]) and in order to functionalize RuII compounds at the ligand, a series of pyridinone ligands were synthesized. The most general approach to convert hydroxypyranones into hydroxypyridinones involves the protection of the OH group with a Bn moiety and reaction with the primary amine at a pH value of ca. 12, followed by hydrogenation to cleave the protecting group (Scheme 1) [38]. Scheme 1. Synthesis of 3-Hydroxypyridin-4(1H)-ones

a) BnBr. b) RNH2 , pH 12. c) H2 , Pd/C.

A straightforward approach for the synthesis of pyridin-2(1H)-one ligands is the Nalkylation of 2,3-dihydroxypyridine [39] [40], and it was applied to prepare 4a – 4c (Scheme 2). Compound 1 was obtained by N-alkylation of 2,3-dihydroxypyridine with BrCH2COOEt (77%), followed by protection of the OH group of 1 with BnCl under alkaline conditions via an SN2 reaction, yielding ethyl [3-(benzyloxy)-2-oxopyridin1(2H)-yl]acetate (2) in high yield (83%) after aqueous workup [41]. In the next step of the ligand synthesis, the ester moiety was converted with the appropriate amine into the corresponding amides 3a – 3c. Therefore, ester 2 was hydrolyzed under alkaline

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Scheme 2. Preparation of the Pyridin-2(1H)-one Complexes (cym ¼ h6-cymene; M ¼ Ru, Os; X ¼ Cl, Br, I; 4-MMP ¼ 4-methylmorpholine)

conditions, and the obtained carboxylic acid was activated with 2-(1H-benzotriazol-1yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) to form the reactive O-acylN,N,N’,N’-tetramethyluronium intermediate. This active ester was reacted with the respective amines (a: propylamine; b: 4-(morpholin-4-yl)aniline; c: 4-phenylaniline) to yield the desired amides after aqueous workup. To obtain ligands 4a and 4b, the protecting group was removed by catalytic hydrogenation using H2 gas and Pd on activated charcoal as catalyst. In case of 4c, the Bn group was removed under acidic conditions. Both methods resulted in similar yields, however, the catalytic hydrogenation was much faster than cleavage under acidic conditions. The characterization of the compounds was carried out by 1H-,13C{1H}- and 2DNMR spectroscopy. The 1H-NMR spectra of 4a – 4c displayed several features confirming the nature of the compounds: the NH H-atom signals of the amides appeared as a singlet at ca. 10 ppm, and the OH H-atoms were assigned to signals at ca. 9 ppm, indicating successful cleavage of the Bn group (Fig.). Furthermore, the lack of signals assignable to the aromatic H-atoms and the CH2 group of the Bn moiety is a clear indication of successful preparation of the desired ligands. 13C{1H}-NMR Spectroscopy confirmed the observations mentioned above, and 1H,13C-HSQC and HMBC were used for unambiguous assignments of the peaks.


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Figure. Reaction monitoring of the conversion of 3b to 4b by 1H-NMR spectroscopy

Complexes 5 were prepared by deprotonation of the ligands with MeONa and subsequent addition of the dimeric precursor [Ru(h6-p-cymene)X(m-X)]2 (X ¼ Cl, Br, I; Scheme 2). The mixture was stirred for a minimum of 3 h at room temperature, and purification was achieved by precipitation from CH2Cl2 with Et2O to yield the chlorido complexes in ca. 60% yield. Replacement of the Cl ligand with either Br or I led to much lower yields of the complexes. For comparison purposes, also complexes of 3hydroxy-1,2-dimethylpyridin-4(1H)-ones were prepared to yield RuII- and OsII(h6-pcymene) complexes (6 – 8; Scheme 3) employing the same procedure as described for 5. Scheme 3. Synthesis of the (h6-p-cymene)3-hydroxy-1,2-dimethylpyridin-4(1H)-oneMII Complexes 6 – 8

The complexes were characterized by 1H- and 13C{1H}-NMR spectroscopy, melting point, and elemental analysis. Most of the complexes decomposed at temperatures

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> 2008, and the elemental analysis data were in good agreement with the calculated values. NMR Experiments were carried out in (D4 )MeOH or CDCl3 because of higher stability of the complexes than in (D6 )DMSO. The NMR spectra of 5bCl and 5bI revealed that the H-atoms of the NCH2CO group were not equivalent. The signals of the aromatic H-atoms of the p-cymene appeared in the range of 5.3 – 5.6 ppm, which is comparable to related O,O-chelated RuIIpyridinone complexes [42]. The Me2CH signal appeared as a multiplet at ca. 3 ppm, and those of the Me H-atoms of the iPr group were detected in the lower ppm range. Chemical shifts of the coordinated ligands are similar to those found in the spectra for the free ligands. The 13C-NMR signals of 5bCl, which are representative of the p-cymene signals, were observed as follows: those of the CH groups were at ca. 80 (C(2)/C(6)), 78 (C(3)/C(5)), and 31 ppm (C(7)), of the two quaternary C-atoms at 100 (C(1)) and 95 ppm (C(4)), and of the Me groups at 23 (C(8)/C(9)) and 19 ppm (C(10)). The same 2D methods were applied to unambiguously assign the NMR signals of the ligands. Conclusions and Outlook. – Developing new tumor-inhibiting drugs is very important, due to the steady increase of the number of cancer patients and limitations of currently applied chemotherapeutics. Compounds with new modes of action are urgently needed hoping to find a successful way to cure cancer. A relatively new class of compounds involves the use of hydroxypyridinone ligands coordinated to metal centers. These ligands are of great interest for medicinal chemists, as pyridinones are already applied in various areas of medicine. Here, we reported on new derivatives of pyridinone Ru and Os complexes. A series of novel ligands was prepared in order to extend the number of derivatives of this type of compounds. By modifying not only the coordination sphere of the metal center but also the ligand, the pharmacological properties of the anticancer agent can be modulated. Therefore, pyridin-2-(1H)-one-based ligands were modified at the amide functionality with Pr, 1,1’-biphenyl-4-yl, and 4-(morpholin-4-yl)phenyl residues. The corresponding RuII(h6-p-cymene) complexes with different halido leaving groups (chlorido, bromido, and iodido) were synthesized and characterized, as were pyridin-4(1H)-one complexes for comparison purposes. The preparation of these complexes provides the basis to include them in further biological testing as well as to study their drug-like properties, in order to pinpoint the influence of modification at various sites of the complexes, and to gaining more insight on the biological properties of these compounds. We thank the Johanna Mahlke geb. Obermann-Stiftung, the Higher Education Commission of Pakistan, the Austrian Exchange Service (AD), the Hochschuljubilumsstiftung Vienna, COST D39, and CM0902, and the Austrian Science Fund for financial support.

Experimental Part General. The chemicals of anal. grade were purchased from commercial providers. Dry solvents were produced following standard procedures. Bis[dichlorido(h6-p-cymene)ruthenium(II)] [43] [44], bis[dibromido(h6-p-cymene)ruthenium(II)], bis[(h6-p-cymene)diiodidoruthenium(II)] [45], bis[dichlorido(h6-p-cymene)osmium(II)] [46], the precursors 1 and 2 [41], and 6 [47] were synthesized according


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to literature procedures. M.p. Bchi B-540 apparatus. 1H- (500.10 MHz) and 13C{1H}- (125.75 MHz) as well as the 2D-NMR spectra (in gradient-enhanced mode): Bruker FT-NMR Avance IIITM 500 MHz spectrometer; at 258; abbreviations for assignments: amide, R of the amide moity; Cym, p-cymene; Ph, phenyl group (incl. substituents); Pyr, pyridin-2(1H)-one or pyridin-4(1H)-one moiety. Elemental analyses: Microanalytical Laboratory, University of Vienna, on a PerkinElmer 2400 CHN Elemental Analyzer. Syntheses. Amide Formation: General Procedure (GP). 4-Methylmorpholine (4-MMP; 2 equiv.) was added to a soln. of ethyl [3-(benzyloxy)-2-oxopyridin-1(2H)-yl]acetate (2; (1 equiv.) and 2-(1Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; 1.05 equiv.) in dry DMF (50 ml) under Ar, and the mixture was stirred at r.t. for 20 min. Subsequently, the appropriate amine was added, and the mixture was stirred for another 18 h at r.t. The solvent was removed under vacuum, and the residue was dissolved in CH2Cl2 and washed with 5% aq. HCl (2 ), 5% aq. NaOH (3 ), and H2O (2 ). The solvent was removed on a rotary evaporator, and the crude product was recrystallized from 96% EtOH [48]. Complexation. The ligand (1 equiv.) was deprotonated by MeONa (1.1 equiv.) in MeOH. Subsequently, the corresponding dimer [M(h6-p-cymene)X(m-X)]2 (M ¼ Ru, Os, X ¼ Cl, Br, I; 0.9 equiv.) was dissolved in CH2Cl2 and added in one portion. The mixture was stirred at r.t. for 3 h. Then, the solvent was removed under reduced pressure, the residue was extracted with CH2Cl2 and filtered, and the soln. was concentrated to a volume of ca. 2 – 3 ml. Et2O was added until precipitation occurred, and the pure product was isolated by filtration. 2-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-N-propylacetamide; 3a). The reaction was performed according to GP, using 2 ( ¼ [3-(benzyloxy)-2-oxopyridin-1(2H)-yl]acetic acid; 4.00 g, 15.4 mmol), TBTU ( ¼ O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate; 5.28 g, 16.4 mmol), 4-MMP ( 3.12 g, 30.8 mmol) , and PrNH2 (0.91 g, 15.1 mmol) . Yield : 4.02 g (87%). 1H-NMR (500.10 MHz, (D4 )MeOH): 7.48 (d, J ¼ 7.3, 2 H, Ph); 7.30 – 7.40 (m, 3 H, Ph); 7.18 (dd, J ¼ 1.5, 6.5, 1 H, Pyr); 6.99 (dd, J ¼ 1.5, 6.5, 1 Hm, Pyr); 6.28 (t, J ¼ 8.0, 1 H, Pyr); 5.12 (s, CH2O); 4.66 (s, CH2N); 3.19 (t, J ¼ 7.1, CH2 , amide); 1.54 – 1.59 (m, CH2 , amide); 0.96 (t, J ¼ 7.4, Me). 2-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-N-[4-(morpholin-4-yl)phenyl]acetamide; 3b). The reaction was performed according to the General Procedure, using 2 (1.94 g, 7.5 mmol), TBTU (2.60 g, 8.0 mmol), 4-MMP (1.52 g, 15.0 mmol), and 4-(morpholin-4-yl)aniline (1.34 g, 7.5 mmol). Yield: 2.10 g (67%). M.p. 211 – 2128. 1H-NMR (500.10 MHz, (D6 )DMSO): 10.11 (s, NH); 7.39 – 7.46 (m, 6 H, Ph); 7.27 (dd, J ¼ 1.5, 7.0, 1 H, Pyr); 6.95 (dd, J ¼ 1.5, 7.6, 1 H, Pyr); 6.91 (d, J ¼ 7.0, 2 H, Ph); 6.15 (t, J ¼ 7.1, 1 H, Pyr); 5.03 (s, CH2O); 4.72 (s, NCH2CO), 3.73 (t, J ¼ 5, 2 CH2O); 3.05 (t, J ¼ 5.0, 2 CH2 ). 13C{1H}-NMR (125.75 MHz, CDCl3 ): 165.4 (C¼O); 157.6 (C¼O); 148.3 (COBn); 147.7 (CN); 137.1 (C); 132.0 (arom. CH); 131.6 (CN); 128.9 (arom. CH); 128.4 (arom. CH); 128.39 (arom. CH); 120.5 (arom. CH); 116.3 (arom. CH); 115.9 (arom. CH); 103.9 (arom. CH); 70.3 (OCH2Ph); 66.6 (CH2O, Morph.); 52.3 (NCH2CO); 49.3 (CH2N, Morph.). 2-[3-(Benzyloxy)-2-oxopyridin-1(2H)-yl]-N-(1,1’-biphenyl-4-yl)acetamide; 3c). The reaction was performed according to GP, using 2 (1.40 g, 5.4 mmol), TBTU (1.80 g, 5.6 mmol), 4-MMP (1.10 g, 10.9 mmol), and 4-phenylaniline (0.91 g, 5.4 mmol). Yield: 1.60 g (70%). M.p. 203 – 2048. 1H-NMR (500.10 MHz, (D6 )DMSO): 8.69 (t, J ¼ 5.5, NH); 7.60 – 7.70 (m, 4 H, Ph); 7.30 – 7.50 (m, 10 H, Ph); 7.25 (d, J ¼ 6.6, 1 H, Pyr); 6.94 (d, J ¼ 7.5, 1 H, Pyr); 6.14 (t, J ¼ 7.0, 1 H, Pyr); 5.02 (s, CH2O); 4.63 (s, NCH2CO). 13 C{1H}-NMR (125.75 MHz, CDCl3 ): 167.4 (C¼O); 157.6 (C¼O); 148.4 (COBn); 140.4 (C); 139 – 3 (C); 138.9 (C); 137.1 (C); 132.0 (arom. CH); 129.4 (arom. CH); 128.9 (arom. CH); 128.45 (arom. CH); 128.36 (arom. CH); 127.8 (arom. CH); 127.1 (arom. CH); 116.2 (arom. CH); 103.9 (arom. CH); 70.3 (CH2O); 51.8 (NCH2CO). 2-(3-Hydroxy-2-oxopyridin-1(2H)-yl)-N-propylacetamide (4a). Compound 3a (1.1 g, 3.7 mmol) was dissolved in MeOH, and 10% Pd/C (0.2 g) was added. The soln. was put into an autoclave, and the apparatus was purged with Ar and evacuated (3 ). H2 at a pressure of 10 – 15 bar was applied, and the soln. was stirred overnight at r.t. Then, the soln. was filtered through Celite to remove the catalyst, and the solvent was removed under reduced pressure. Recrystallization from EtOH yielded the pure product. Yield: 0.50 g (77%). M.p. 209 – 2118. 1H-NMR (500.10 MHz, (D6 )DMSO): 8.93 (s, OH); 8.11 (t, J ¼ 5.4,

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NH); 7.06 (d, J ¼ 6.5, 1 H, Pyr); 6.70 (d, J ¼ 7.5, 1 H, Pyr); 6.07 (t, J ¼ 7.0, 1 Hm, Pyr); 4.53 (s, NCH2CO), 3.04 (q, J ¼ 7.0, CH2 , amide); 1.37 – 1.43 (m, CH2 , amide); 0.86 (t, J ¼ 7.2, Me). 2-(3-Hydroxy-2-oxopyridin-1(2H)-yl)-N-[4-(morpholin-4-yl)phenyl]acetamide (4b). Compound 3b (2.00 g, 4.8 mmol) was dissolved in AcOH, and 10% Pd/C (0.50 g) was added. The soln. was put into an autoclave, and the apparatus was purged with Ar and evacuated (3 ). H2 at a pressure of 10 – 15 bar was applied and the soln. was stirred overnight at r.t. Then, the soln. was filtered through Celite to remove the catalyst, and the solvent was removed under reduced pressure. Recrystallization from EtOH yielded the pure product. Yield: 1.10 g (70%). M.p. 246 – 2478. 1H-NMR (500.10 MHz, (D6 )DMSO): 10.10 (s, NH); 8.99 (s, OH); 7.45 (d, J ¼ 9.0, 2 H, Ph); 7.14 (dd, J ¼ 1.4, 6.8, 1 H, Pyr); 6.91 (d, J ¼ 9.0, 2 H, Ph); 6.74 (dd, J ¼ 1.5, J ¼ 7.2, 1 H, Pyr); 6.11 (t, J ¼ 7.0, 1 H, Pyr); 4.73 (s, NCH2CO); 3.73 (t, J ¼ 5, CH2O); 3.05 (t, J ¼ 5, CH2N). 13C{1H}-NMR (125.75 MHz, CDCl3 ): 165.4 (C¼O); 158.4 (C¼O); 147.7 (COH); 147.1 (CN); 131.5 (CN); 130.1 (arom. CH); 120.5 (arom. CH); 120.5 (arom. CH); 115.9 (arom. CH); 115.6 (arom. CH); 105.1 (arom. CH); 66.6 (CH2O, Morph.): 52.2 (NCH2CO); 49.3 (CH2N). N-(1,1’-Biphenyl-4-yl)-2-(3-hydroxy-2-oxopyridin-1(2H)-yl)acetamide (4c). Compound 3c (1.60 g, 3.90 mmol) was dissolved in HCl/AcOH 1 : 1 (250 ml) and stirred at r.t. for 3 – 4 d. The mixture was concentrated, the residue was suspended in MeOH, and the solvent was removed (3 ). Recrystallization from EtOH gave the pure product. Yield: 0.90 g (72%). M.p. 236 – 2378. 1H-NMR (500.10 MHz, (D6 )DMSO): 9.00 (s, OH); 8.69 (t, J ¼ 6.0, NH); 7.60 – 7.70 (m, 4 H, Ph); 7.45 – 7.50 (m, 2 H, Ph); 7.25 – 7.35 (m, 3 H, Ph); 7.12 (dd, J ¼ 1.7, 6.9, 1 H, Pyr); 6.72 (dd, J ¼ 1.7, 7.2, 1 H, Pyr); 6.10 (t, J ¼ 7.0, 1 H, Pyr); 4.64 (s, NCH2CO). 13C{1H}-NMR (125.75 MHz, CDCl3 ): 167.3 (C¼O); 158.4 (C¼O); 147.1 (CO); 140.4 (C); 139.3 (C); 138.9 (C); 130.0 (arom. CH); 129.4 (arom. CH); 128.4 (arom. CH); 127.8 (arom. CH); 127.1 (arom. CH); 115.4 (arom. CH); 105.2 (arom. CH); 51.8 (NCH2CO). [Chlorido(h6-p-cymene)(N-{[ ( propylamino)carbonyl]methyl}-3-oxo-kO-pyridin-2(1H)-onatokO)ruthenium(II)] (5aCl ). The reaction was performed according to GP1, using 4a (101 mg, 0.48 mmol), MeONa (32 mg, 0.59 mmol), and [RuCl(m-Cl)(h6-p-cymene)]2 (123 mg, 0.20 mmol). Yield: 115 mg (60%). M.p. 137 – 1428. 1H-NMR (500.10 MHz, (D4 )MeOH): 8.18 (br. s, NH); 6.83 (br. s, 1 H, Pyr); 6.71 (br. s, 1 H, Pyr); 6.39 (br. s, 1 H, Pyr); 5.67 (br. s, 2 H, Cym); 5.45 (br. s, 2 H, Cym); 4.7 – 5.0 (1 H of NCH2CO, overlapped with solvent signal); 4.66 (s, 1 H of NCH2CO); 3.20 – 3.30 (m, CH2 , amide); 2.90 – 2.98 (m, Me2CH); 2.27 (s, Me, Cym); 1.54 – 1.64 (m, Me2CH); 1.28 – 1.34 (m, CH2 , amide); 0.97 (t, J ¼ 8.0, Me, amide). Anal. calc. for C20H27ClN2O3Ru · 0.25 CH2Cl2 (501.20): C 48.53, H 5.53, N 5.59; found: C 48.31, H 5.22, N 5.94. [(h6-p-Cymene)iodido(N-{[(propylamino)carbonyl]methyl}-3-oxo-kO-pyridin-2(1H)-onato-kO)ruthenium(II)] (5aI ). The reaction was performed according to GP, using 4a (70 mg, 0.33 mmol), MeONa (24 mg, 0.44 mmol), and [RuI(m-I)(h6-p-cymene)]2 (120 mg, 0.12 mmol). Yield: 15 mg (11%). 1H-NMR (500.10 MHz, (D4 )MeOH): 6.81 (br. s, 1 H, Pyr); 6.65 (br. s, 1 H, Pyr); 6.35 (br. s, 1 H, Pyr); 5.69 (br. s, 2 H, Cym); 5.47 (br. s, 2 H, Cym); 4.7 – 5.0 (1 H of NCH2CO, overlapped with solvent signal); 4.66 (s, 1 H of NCH2CO); 3.10 – 3.20 (m, MeCH2 ); 2.90 – 2.98 (m, Me2CH); 2.27 (s, Me, Cym); 1.55 – 1.65 (m, MeCH2CH2 ); 1.28 – 1.34 (m, Me2CH); 0.97 (t, J ¼ 7.0, MeCH2CH2 ). Anal. calc. for C20H27IN2O3Ru · 0.25 CH2Cl2 (592.65): C 41.04, H 4.68, N 4.73; found: C 41.08, H 4.47, N 4.46. [Chlorido(h6-p-cymene)(N-{[ (4-(morpholin-4-yl)anilino)carbonyl]methyl}-3-oxo-kO)-pyridin2(1)-onato-kO)ruthenium(II)] (5bCl ). The reaction was performed according to GP1, using 4b (145 mg, 0.44 mmol), MeONa (32 mg, 0.59 mmol), and [RuCl(m-Cl)(h6-p-cymene)]2 (123 mg, 0.20 mmol). Yield: 155 mg (64%). M.p. 241 – 2448 (dec.). 1H-NMR (500.10 MHz, CDCl3 ): 8.06 (s, NH); 7.60 (d, J ¼ 8.9, 2 H, Ph); 6.85 (d, J ¼ 8.9, 2 H, Ph); 6.69 (d, J ¼ 7.7, 1 H, Pyr); 6.52 (d, J ¼ 6.1, 1 H, Pyr); 6.29 – 6.33 (m, 1 H, Pyr); 5.55 (t, J ¼ 5.2, 2 H, Cym); 5.25 – 5.30 (m, 2 H, Cym); 5.22 (d, J ¼ 15.1, 1 H, of NCH2CO); 4.35 (d, J ¼ 15.1, 1 H, of NCH2CO); 3.86 (t, J ¼ 7.0, 2 CH2O); 3.05 (t, J ¼ 7.0, 2 CH2N); 2.90 – 2.98 (m, Me2CH); 2.32 (s, Me); 1.28 – 1.34 (m, Me2CH). 13C{1H}-NMR (125.75 MHz, CDCl3 ): 166.1 (C¼O); 163.9 (C¼O); 161.2 (CO); 148.4 (CN); 130.3 (CN); 122.1 (arom. CH); 120.8 (arom. CH); 118.0 (arom. CH); 115.9 (arom. CH); 113.8 (arom. CH); 99.5 (MeC, Cym); 95.0 (Me2CC); 80.1 (CH, Cym); 80.0 (CH, Cym); 78.2 (CH, Cym); 77.7 (CH, Cym); 66.9 (CH2O), 54.4 (NCH2CO); 49.7 (CH2N); 31.2 (Me2CH, Cym); 22.5 (1 C, Me2CH); 22.3 (1 C, Me2CH); 18.5 (Me, Cym). Anal. calc. for C27H32ClN3O4Ru (599.08): C 54.13, H 5.38, N 7.01; found: C 54.18, H 5.24, N 7.04.


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[Bromido(h6-p-cymene)(N-{[ (4-(morpholin-4-yl)anilino)carbonyl]methyl}-3-oxo-kO-pyridin2(1H)-onato-kO)ruthenium(II)] (5bBr ). The reaction was performed according to GP1, using 4b (109 mg, 0.33 mmol) , MeONa (24 mg, 0.44 mmol), and [RuBr(m-Br)(h6-p-cymene)]2 (106 mg, 0.15 mmol). Yield: 67 mg (39%). 1H-NMR (500.10 MHz, CDCl3 ): 7.99 (s, NH); 7.59 (d, J ¼ 8.9, 2 H, Ph); 6.85 (d, J ¼ 8.9, 2 H, Ph); 6.69 (d, J ¼ 7.7, 1 H, Pyr); 6.52 (d, J ¼ 6.1, 1 H, Pyr); 6.28 – 6.32 (m, 1 H, Pyr); 5.55 (t, J ¼ 5.2, 2 H, Cym); 5.32 (dd, J ¼ 3.6, 5.3, 2 H, Cym); 5.22 (d, J ¼ 15.0, 1 H, NCH2CO); 4.32 (d, J ¼ 15.0, 1 H, NCH2CO); 2.92 – 2.95 (m, Me2CH); 2.32 (s, Me, Cym); 1.30 – 1.40 (m, Me2CH). Anal. calc. for C27H32BrN3O4Ru · 0.05 CH2Cl2 (647.78): C 50.15, H 4.99, N 6.49; found: C 49.86, H 4.78, N 6.81. [(h6-p-Cymene)iodido(N-{[(4-(morpholin-4-yl)anilino)carbonyl]methyl}-3-oxo-kO-pyridin-2(1H)onato-kO)ruthenium(II)] (5bI ). The reaction was performed according to GP, using 4b (109 mg, 0.33 mmol), MeONa (24 mg, 0.44 mmol), and [RuI(m-I)(h6-p-cymene)]2 (120 mg, 0.12 mmol). Yield: 86 mg (51%). 1H-NMR (500.10 MHz, CDCl3 ): 8.07 (s, NH); 7.55 – 7.65 (m, 2 H, Ph); 6.86 (d, J ¼ 8.5, 2 H, Ph); 6.70 (t, J ¼ 7.7, 1 H, Pyr); 6.59 (d, J ¼ 6.2, 1 H, Pyr); 6.29 – 6.36 (m, 1 H, Pyr); 5.55 – 5.70 (m, 2 H, Cym); 5.33 – 5.40 (m, 2 H, Cym); 5.31 – 5.33 (m, 1 H, NCH2CO); 4.74 (s, 1 H, NCH2CO); 2.94 – 2.99 (m, Me2CH); 2.36 (s, Me, Cym); 1.28 – 1.36 (m, Me2CH, Cym). Anal. calc. for C27H32IN3O4Ru · 0.5 H2O (699.54): C 46.32, H 4.82, N 6.00; found: C 46.33, H 4.38, N 6.24. [Chlorido(h6-p-cymene)(N-{[(1,1’-biphenyl-4-ylamino)carbonyl]methyl}-3-oxo-kO-pyridin-2(1H)onato-kO)ruthenium(II)] (5cCl ). The reaction was performed according to GP, using 4c (130 mg, 0.44 mmol), MeONa (32 mg, 0.60 mmol), and [RuCl(m-Cl)(h6-p-cymene)]2 (123 mg, 0.20 mmol). Yield: 153 mg (65%). M.p. 122 – 1268 (decomp.). 1H-NMR (500.10 MHz, CDCl3 ): 7.52 – 7.60 (m, 5 H, Ph); 7.41 – 7.48 (m, 4 H, Ph); 6.69 (d, J ¼ 7.4, 1 H, Pyr); 6.48 (d, J ¼ 6.1, 1 H, Pyr); 6.29 (dd, J ¼ 7.0, 14.4, 1 H, Pyr); 5.55 (t, J ¼ 5.2, 2 H, Cym); 5.32 (dd, J ¼ 3.6, 5.3, 2 H, Cym); 5.20 (d, J ¼ 15.0, 1 H, NCH2CO); 4.76 (d, J ¼ 15.0, 1 H, NCH2CO); 2.87 – 2.96 (m, Me2CH); 2.32 (s, Me, Cym); 1.28 – 1.34 (m, Me2CH). 13C{1H}-NMR (125.75 MHz, CDCl3 ): 166.6 (C¼O); 165.8 (C¼O); 140.4 (CO); 136.5 (C); 128.7 (arom. CH); 127.6 (arom. CH); 127.1 (arom. CH); 120.8 (arom. CH); 118.0 (arom. CH); 114.7 (arom. CH); 113.8 (arom. CH); 107.7 (arom. CH); 101.3 (MeC, Cym); 95.1 (iPrC); 81.3 (C, Cym); 80.5 (C, Cym); 54.4 (NCH2CO); 30.5 (Me2CH); 22.5 (1 C, Me2CH); 22.3 (1 C, Me2CH); 18.5 (Me, Cym). Anal. calc. for C29H29ClN2O3Ru (590.08): C 59.03, H 4.95, N 4.75; found: C 58.63, H 5.04, N 4.55. [Bromido(h6-p-cymene)(1,2-dimethyl-3-oxo-kO-pyridin-4(1H)-onato-kO)ruthenium(II)} (7). The reaction was performed according to GP, using 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (92 mg, 0.66 mmol), MeONa (39 mg, 0.72 mmol), and [RuBr(m-Br)(h6-p-cymene)]2 (237 mg, 0.30 mmol). Yield: 20 mg (7%). 1H-NMR (500.10 MHz, CDCl3 ): 6.92 (d, J ¼ 6.8, 1 H, Pyr); 6.41 (d, J ¼ 6.8, 1 H, Pyr); 5.39 – 5.52 (m, 4 H, Cym); 3.62 (s, MeN); 2.92 – 3.02 (m, Me2CH); 2.44 (s, Me); 2.35 (s, Me); 1.28 – 1.33 (m, Me2CH, Cym). 13C{1H}-NMR (125.75 MHz, CDCl3 ): 173.7 (C¼O); 159.0 (CO); 134.7 (MeC, Pyr); 133.8 (CH, Pyr); 108.7 (CH, Pyr); 98.8 (C, Cym); 95.4 (C, Cym); 79.1 (CH, Cym); 77.7 (CH, Cym); 41.6 (MeN); 31.0 (Me2CH, Cym); 21.2 (Me2CH); 17.3 (Me, Cym); 10.6 (Me, Pyr). Anal. calc. for C17H22BrNO2Ru (453.34): C 45.04, H 4.89, N 3.09; found: C 44.80, H 4.67, N 3.07. {Chlorido(h6-p-cymene)[1,2-dimethyl-3-oxo-kO-pyridin-4(1H)-onato-kO]osmium(II)} (8). The reaction was performed according to GP, using 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (61 mg, 0.40 mmol), MeONa (27 mg, 0.50 mmol), and [OsCl(m-Cl)(h6-p-cymene)]2 (158 mg, 0.20 mmol). Yield: 21 mg (11%). 1H-NMR (500.10 MHz, CDCl3 ): 6.99 (d, J ¼ 6.5, 1 H, Pyr); 6.51 (d, J ¼ 6.5, 1 H, Pyr); 6.00 (d, J ¼ 5.5, 1 H, Cym); 5.93 (d, J ¼ 5.5, 1 H, Cym); 5.78 (d, J ¼ 5.5, 1 H, Cym); 5.73 (d, J ¼ 5.5, 1 H, Cym); 3.67 (s, MeN); 2.70 – 2.78 (m, Me2CH); 2.45 (s, Me), 2.37 (s, Me), 1.24 – 1.27 (m, Me2CH). Anal. calc. for C17H22ClNO2Os (498.05): C 41.00, H 4.45, N: 2.81; found: C 40.64, H 4.18, N 2.94.

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