Arene ruthenium complexes with phosphinoferrocene amino acid conjugates: Synthesis, characterization and cytotoxicity

Article abstract of DOI:10.1016/j.jorganchem.2012.10.009

A series of heterodinuclear p-cymene ruthenium ferrocene complexes, [(η⁶-p-MeC₆H₄Prⁱ)RuCl ₂(Ph₂PfcCONHRCO₂Me-κP)] (R = (S)-Me: 6, R = (S)-CHMe₂: 7, R = (S)-CH₂OMe: 8, R = (S)-CH ₂SMe: 9, R = (S)-CH₂CH₂CO₂Me: 10) have been synthesized from p-cymene ruthenium dichloride dimer and phosphinoferrocene ligands bearing carboxamide substituents derived from amino acids, Ph₂PfcCONHRCO₂Me (R = (S)-Me: 1, R = (S)-CHMe ₂: 2, R = (S)-CH₂OMe: 3, R = (S)-CH₂SMe: 4, R = (S)-CH₂CH₂CO₂Me: 5, fc = ferrocene-1,1′- diyl). All new compounds, 3-10, were fully characterized by elemental analysis, multinuclear NMR and IR spectroscopy and electrospray ionisation mass spectrometry, and their electrochemical properties were studied by cyclic voltammetry at a platinum disc electrode. The cytotoxicity of 6-10 was studied on human ovarian cancer cells. The related glycine derivatives [(η⁶-arene)RuCl₂(Ph₂PfcCONHCH ₂CO₂Me-κP)] (arene = C₆H₆: 11a, arene = p-MeC₆H₄Prⁱ: 11b, arene = C ₆Me₆: 11c), [(η⁶-arene)RuCl(MeCN)(Ph ₂PfcCONHCH₂CO₂Me-κP)][PF₆] (arene = C₆H₆: 12a, arene = p-MeC₆H ₄Prⁱ: 12b, arene = C₆Me₆: 12c), [(η⁶-arene)Ru(MeCN)₂(Ph₂PfcCONHCH ₂CO₂Me-κP)][PF₆]₂ (arene = C₆H₆: 13a, arene = p-MeC₆H₄Pr ⁱ: 13b, arene = C₆Me₆: 13c) and [(η⁶-p-MeC₆H₄Prⁱ)RuCl ₂(Ph₂PfcCONHCH₂CONH₂-κP)] (14), which we reported recently, were also included in the cytotoxicity study. The arene ruthenium ferrocene complexes show moderate to good in vitro anticancer activity towards human ovarian cancer cells, the IC₅₀ values of the most active derivative 13c being 4.1 ± 0.8 μM for the A2780 cell line and 6.9 ± 0.01 μM for the cisplatin-resistant derivative A2780cisR.

Full text of DOI:10.1016/j.jorganchem.2012.10.009

Journal of Organometallic Chemistry 723 (2013) 233e238
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Arene ruthenium complexes with phosphinoferrocene amino acid conjugates:
Synthesis, characterization and cytotoxicity
a
,
,
b
,
c
c
Jirí Tauchman b, Georg Süss-Fink a , Petr Stepnicka
, Oliver Zava , Paul J. Dyson
ꢀ
*
**
ꢀ
ꢀ
ꢀ
a Institut de Chimie, Université de Neuchâtel, Avenue de Bellevaux 51, CH-2000 Neuchâtel, Switzerland
b Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 2030, CZ-12840 Prague 2, Czech Republic
c Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
a r t i c l e i n f o
a b s t r a c t
h
6-p-MeC6H4Pri)RuCl2(Ph2Pfc-
Article history:
A series of heterodinuclear p-cymene ruthenium ferrocene complexes, [(
Received 6 September 2012
Received in revised form
27 September 2012
CONHRCO2Me-
k
P)] (R ¼ (S)-Me: 6, R ¼ (S)-CHMe2: 7, R ¼ (S)-CH2OMe: 8, R ¼ (S)-CH2SMe: 9, R ¼ (S)-
CH2CH2CO2Me: 10) have been synthesized from p-cymene ruthenium dichloride dimer and phosphi-
noferrocene ligands bearing carboxamide substituents derived from amino acids, Ph2PfcCONHRCO2Me
(R ¼ (S)-Me: 1, R ¼ (S)-CHMe2: 2, R ¼ (S)-CH2OMe: 3, R ¼ (S)-CH2SMe: 4, R ¼ (S)-CH2CH2CO2Me: 5,
fc ¼ ferrocene-1,10-diyl). All new compounds, 3e10, were fully characterized by elemental analysis,
multinuclear NMR and IR spectroscopy and electrospray ionisation mass spectrometry, and their elec-
trochemical properties were studied by cyclic voltammetry at a platinum disc electrode. The cytotoxicity
Accepted 2 October 2012
Keywords:
Ruthenium complexes
Ferrocene ligands
Amino acids
Cytotoxicity
Electrochemistry
of 6e10 was studied on human ovarian cancer cells. The related glycine derivatives [(h
6-arene)
RuCl2(Ph2PfcCONHCH2CO2Me-
[(
k
P)] (arene ¼ C6H6: 11a, arene ¼ p-MeC6H4Pri: 11b, arene ¼ C6Me6: 11c),
h
6-arene)RuCl(MeCN)(Ph2PfcCONHCH2CO2Me-
k
P)][PF6] (arene ¼ C6H6: 12a, arene ¼ p-MeC6H4Pri: 12b,
arene ¼ C6Me6: 12c), [(
h
6-arene)Ru(MeCN)2(Ph2PfcCONHCH2CO2Me-
k
P)][PF6]2 (arene ¼ C6H6: 13a,
arene ¼ p-MeC6H4Pri: 13b, arene ¼ C6Me6: 13c) and [(
h
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH2CONH2-
k
P)] (14), which we reported recently, were also included in the cytotoxicity study. The arene ruthenium
ferrocene complexes show moderate to good in vitro anticancer activity towards human ovarian cancer
cells, the IC50 values of the most active derivative 13c being 4.1 ꢀ 0.8 M for the A2780 cell line and
6.9 ꢀ 0.01 M for the cisplatin-resistant derivative A2780cisR.
m
m
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
ruthenium anticancer agents and the current understanding of
their mode of action is summarised in several review articles [5e9].
In addition to half-sandwich arene ruthenium compounds,
ferrocene compounds show excellent anticancer properties inhib-
iting the development of tumors in vivo [10]. It has been shown that
tethering biologically active groups to the ferrocenyl unit increases
their potency, possibly due to the combined action of the organic
molecule with Fenton chemistry of the Fe-centre [11]. Ferrocene
has also been covalently linked to both platinum [12-13] and gold
[14] centres in order to achieve enhanced effects between the two
active metals. In addition, ferrocenoyl pyridine arene ruthenium
complexes have been prepared and studied for in vitro anticancer
activity [15].
Arene ruthenium compounds such as the prototype complexes
[(p-PriC6H4Me)RuCl2(pta)]
(pta¼1,3,5-triaza-7-phosphatricyclo
[3.3.1.1.3.7]decane (termed RAPTA-C) [1] and [(C6H5Ph)RuCl(en)]þ
(en¼1,2-ethylenediamine) [2] have antitumoral and/or anti-
metastatic properties in vitro and in vivo. The anticancer potential of
these types of compounds has been partially explained by their
dual character, with the hydrogen bonding capacity of the pta or en
ligands counterbalanced by the lipophilicity of the arene ligand [3],
while the mechanism of cytotoxic action is thought to involve
hydrolysis of the RueCl bond followed by reaction with the
biomolecular target or targets [4]. The underlying design of arene
In general, iron compounds are well tolerated in vivo, and
similarly, ruthenium compounds exhibit low general toxicity
compared to their platinum counterparts, which is probably due to
two main reasons. First, ruthenium compounds specifically accu-
mulate in rapidly dividing cells, such as in tumors, due to possible
HSA transport [16] or the ability of ruthenium(III) to mimic iron in
* Corresponding author. Tel.: þ41 (0) 32 718 2405; fax: þ41 (0) 32 718 2511.
** Corresponding author. Tel.: þ420 221 951 260; fax: þ420 221 951 253.
E-mail addresses: georg.suess-fink@unine.ch (G. Süss-Fink), stepnic@natur.cuni.cz
ꢀ
ꢀ
ꢀ
(P. Stepnicka).
0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2012.10.009

234
J. Tauchman et al. / Journal of Organometallic Chemistry 723 (2013) 233e238
binding to transferrin [17], the protein which delivers iron to cells,
and transferrin receptors are over-expressed in cancer cells [18].
Second, the majority of ruthenium drugs comprise ruthenium in
the þ3 oxidation state and it has been proposed that in this
oxidation state ruthenium is less active and is reduced in vivo to
more active ruthenium(II) complexes, a process favored in the
hypoxic environment of a tumor [18]. However, it should be noted
that ruthenium(II) compounds also exhibit a low general toxicity
and, since cancer cells can also become oxidizing at certain stages of
their growth cycle, oxidation of the ruthenium cannot be excluded
[19].
pendants. In addition to the signals of the amino acid side chain, the
characteristic resonance of the NH group is observed as a CH-
coupled doublet at dH 6.5e6.6 ppm, while those of the methyl
esters groups are seen as singlets at dH ca. 3.75 ppm and dC 52e
53 ppm. The 31P{1H} NMR spectra display
a singlet at dP
ca. ꢁ18 ppm. The positive-ion ESI mass spectra show the pseudo-
molecular ions [M þ K]þ, [M þ Na]þ and [M þ H]þ. The presence of
the amide and ester groups is clearly manifested in the IR spectra
via strong bands due to nCO at ca. 1740 cmꢁ1 and by amide I (1638e
1651 cmꢁ1) and amide II vibrations (1518e1533 cmꢁ1).
The phosphinoferrocene amides, 1e5, react with p-cymene
ruthenium dichloride dimer in chloroform to give the corre-
As part of our ongoing studies focused on the chemistry of
phosphinoferrocene carboxamides [20] prepared by amidation of
ferrocene phosphinocarboxylic acids with amino acid esters
sponding p-cymene ruthenium complexes [(
RuCl2(Ph2PfcCONHRCO2Me-
P)] (R ¼ (S)-Me: 6, R ¼ (S)-CHMe2: 7,
h
6-p-MeC6H4Pri)
k
[21,22], we recently described the synthesis of
h
6-arene ruthenium
R ¼ (S)-CH2OMe: 8, R ¼ (S)-CH2SMe: 9, R ¼ (S)-CH2CH2CO2Me: 10)
in high yield (Scheme 2). Complexes 6e10 are red, air-stable solids,
which can be purified by column chromatography on silica.
Compounds 6e10 were fully characterized by 1H and 31P{1H}
NMR and IR spectroscopy, ESI mass spectroscopy and satisfactory
elemental analysis. The 1H NMR spectra of 6e10 are similar to those
of the corresponding free ligands but also contain additional signals
due to the coordinated p-cymene (a pair of AA0BB0 type doublets in
the range dH ¼ 4.8e5.3 ppm). The 31P{1H} NMR spectra show
a single resonance close to dP þ18 ppm, while the positive-ion ESI
mass spectra display ions attributable to [M þ Na]þ and [M ꢁ Cl]þ.
As for the ligands 1e5, the IR spectra oꢁf 1the complexes 6e10 also
complexes containing phosphinoferroceneeglycine conjugates as
P-monodentate ligands and established their catalytic potential for
the oxidation of secondary alcohols to ketones with tert-butyl
hydroperoxide [23]. Considering the successful applications of
ruthenium complexes as anticancer agents and the fact that the
amino acid residue in our ligands typically remains uncoordinated
and can thus serve as a directing group in biological systems, we
decided to evaluate cytotoxicity of these compounds. To this end,
we extended the series of the known heterobimetallic FeeRu
complexes [(h
6-arene)RuCln(MeCN)2ꢁn(Ph2PfcCONHCH(R)CO2Me-
k
P)](2ꢁn)þ (R ¼ H, n ¼ 0e2) [23] by other (chiral) derivatives
(R ¼ Me, CHMe2, CH2OMe, CH2SMe, CH2CH2CO2Me, n ¼ 2) and
studied their antiproliferative effects on A2870 and A2870cisR
human ovarian cancer cell lines.
exhibit strong bands at ca. 1740 cm
(carbonyl) and 1638e
1651 cmꢁ1 (amide I) and 1518e1533 cmꢁ1 (amide II).
The heterodinuclear p-cymene ruthenium ferrocene complexes
6e10 have been studied by cyclic voltammetry at a Pt disc electrode
in acetonitrile. Representative cyclic voltammograms are shown in
Fig. 1 and the pertinent data are presented in Table 1. In line with
their glycine analogues studied earlier [23], complexes 6e10
undergo two successive oxidations. The first redox process occur-
ring at ca. 0.27 V versus the ferrocene/ferrocenium reference is
a reversible, one-electron oxidation attributable to the oxidation of
the ferrocene moiety to the corresponding ferrocenium. The
following oxidation at ca. 0.86 V is electrochemically irreversible
and can be assigned to oxidation occurring at the Ru(II) centre, very
likely multi-electron in nature.
2. Results and discussion
The new phosphinoferrocene amino acid conjugates
Ph2PfcCONHRCO2Me (R ¼ (S)-CH2OMe: 3, R ¼ (S)-CH2SMe: 4,
R ¼ (S)-CH2CH2CO2Me: 5, fc ¼ ferrocene-1,10-diyl) were obtained by
amide coupling reactions of 10-(diphenylphosphino)ferrocene-1-
carboxylic acid (Hdpf) [27] and the corresponding amino acid
esters in the presence of 1-hydroxybenzotriazole and 1-[3-(dime-
thylamino)propyl]-3-ethylcarbodiimide as peptide coupling
reagents (Scheme 1), by analogy to the known derivatives 1
(R ¼ (S)-Me) and 2 (R ¼ (S)-CHMe2), described earlier [21,22].
Compounds 3e5 were characterized by multinuclear (1H, 31P
{1H}, 13C{1H}) NMR and IR spectroscopy, and high-resolution mass
spectroscopy. The 1H and 13C{1H} NMR spectra display the char-
acteristic signals of the 10-(diphenylphosphino)ferrocene-1-yl
moiety, possessing a stereogenic centre (namely eight signals due
to diastereotopic ferrocene protons and a multiplet of the phos-
phine phenyl groups) as well as the signals of the carboxamide
The in vitro anticancer activity of the p-cymene ruthenium
complexes 6e10 containing phosphinoferrocene chiral amino acid
conjugates has been studied on the human ovarian cancer cell lines
A2780 and A2780cisR, the latter having acquired resistance to
cisplatin. The related glycine derivatives [(h
6-arene)RuCl2(Ph2Pfc-
CONHCH2CO2Me-
arene
CO2Me-
k
P)] (arene ¼ C6H6: 11a, arene ¼ p-MeC6H4Pri: 11b,
¼
C6Me6: 11c), [(h
6-arene)RuCl(MeCN)(Ph2PfcCONHCH2
-
k
P)][PF6] (arene ¼ C6H6: 12a, arene ¼ p-MeC6H4Pri: 12b,
PPh2
PPh2
[H3NCH(R)CO2Me]Cl/NEt3
HOBt/EDC
Fe
Fe
H
N
CO2Me
CO2H
R
O
(Hdpf)
R
3
4
5
(S)-CH2OMe
(S)-CH2SMe
(S)-CH2CH2CO2Me
Scheme 1. Synthesis of the new phosphinoferrocene amides 3e5. HOBt ¼ 1-hydroxybenzotriazole, EDC ¼ 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide.

J. Tauchman et al. / Journal of Organometallic Chemistry 723 (2013) 233e238
235
PPh2
i
Ru
[(p-MeC6H4Pr )RuCl2]2
P
Fe
Cl
H
N
Ph
CO2Me
2 Cl
Fe
H
CO2Me
N
R
O
R
O
R
R
1
2
3
4
5
(S)-Me
6
7
(S)-Me
(S)-CHMe2
(S)-CHMe2
(S)-CH2OMe
(S)-CH2SMe
(S)-CH2CH2CO2Me
8
(S)-CH2OMe
9
(S)-CH2SMe
10
(S)-CH2CH2CO2Me
Scheme 2. Synthesis of the heterodinuclear p-cymene ruthenium ferrocene complexes 6e10.
arene
CO2Me-
¼
C6Me6: 12c), [(
h
6-arene)Ru(MeCN)2(Ph2PfcCONHCH2
The cytotoxicity of the neutral dichloro complexes bearing the
simplest glycine-based ligand and various arene donors increases
significantly (IC50: 11c < 11b < 11a) upon increasing the number of
alkyl substituents at the Ru-bound arene for both cell lines and,
hence, correlates with the redox potentials of both the Fe(II/III) and
Ru(II/III) couples. A similar trend is seen also for the dicationic
complexes 13aec, whereas the IC50 values of 12aec suggest
a different trend (IC50: 12c < 12a < 12b).
-
k
P)][PF6]2 (arene ¼ C6H6: 13a, arene ¼ p-MeC6H4Pri: 13b,
arene ¼ C6Me6: 13c) and [(
h
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH2
-
CONH2-kP)] (14), reported recently [23], were also included in the
cytotoxicity study, see Scheme 3 and Table 1.
The IC50 cell survival rates for A2780 and A2780cisR cancer cells
are summarized in Table 1, together with the Fe(II)/Fe(III) and
Ru(II)/Ru(III) redox potentials. Most compounds show only
moderate cytotoxicities, only 7, 12c and 13c approach that of
The variation of the amino acid pendant, that is to say R in the
cisplatin in the A2789 cell line (IC50 1.6
m
M for A2780 and 8.6
mM for
neutral complexes of the type [(
CONHCHRCO2Me- P)] also influences the cytotoxicity, albeit less
h
6-p-cymene)RuCl2(Ph2Pfc-
A2780 [15]). There is no clear-cut correlation between redox
potentials and cytotoxicities, suggesting that catalytic glutathione
oxidation, assumed for some other cytotoxic arene ruthenium
complexes [24e26], in particular for dinuclear trithiolato deriva-
tives [25,26] is not involved.
k
obviously. From the results in Table 1, one can conclude that simple
alkyl groups increase the cytoxicity (decrease IC50) towards both
types of the cancer cells. Compounds possessing functional
substituents (R ¼ CH2OMe, CH2SMe, and CH2CH2CO2Me), however,
cause higher IC50 values. Finally, the bis-amide complex 14 is the
least cytotoxic (highest IC50 values) in this series, which implies
that the group attached to the O-terminus of the amino acid chain
plays a significant role in determining the biological activity.
Table 1
Electrochemical and cytotoxicity data for human ovarian cancer cell lines of the
arene ruthenium phosphinoferrocene amino acid conjugates 6e14.
Data
Eꢂ0 [V]a
IC50
[
mM]
Compound
FeII/III
RuII/III
A2780
A2780cisR
6
7
8
9
0.270
0.265
0.265
0.275
0.860
0.860
0.860
0.865
0.865
0.935b
0.850b
0.710b
n.o.b
16.5 ꢀ 1.6
7.8 ꢀ 0.1
50.2 ꢀ 6.7
42.5 ꢀ 2.5
41.3 ꢀ 0.7
35.4 ꢀ 6.7
17.4 ꢀ 3.2
8.7 ꢀ 0.1
32.3 ꢀ 1.1
48.9 ꢀ 4
31 ꢀ 8.8
14.5 ꢀ 0.02
50.3 ꢀ 11.3
48.6 ꢀ 15.7
42.6 ꢀ 7.9
30.2 ꢀ 11.7
14.4 ꢀ 4
10
0.270
11a
11b
11c
12a
12b
12c
13a
13b
13c
14
0.315b
0.285b
0.245b
0.430b
0.410b
0.385b
0.540b
0.530b
0.510b
0.260b
7.6 ꢀ 1.2
32 ꢀ 13.6
53.6 ꢀ 12.7
11.9 ꢀ 1.5
20.9 ꢀ 4.2
5.9 ꢀ 0.6
n.o.b
n.o.b
7.5 ꢀ 1
n.o.b
22 ꢀ 7.9
n.o.b
12.2 ꢀ 2
n.o.b
4.1 ꢀ 0.8
98.3 ꢀ 19.4
6.9 ꢀ 0.01
118.5 ꢀ 4.5
0.850b
a
The potentials are given relative to the ferrocene/ferrocenium couple.
Eꢂ0 ¼ ½(Epa þ Epc), where Epa (Epc) denote the anodic (cathodic) peak potential in
cyclic voltammetry.
Fig. 1. A partial (top) and full (bottom) cyclic voltammogram of 9 as recorded in
acetonitrile at a Pt disc electrode (scan rate: 200 mV sꢁ1). The partial voltammogram is
b
shifted by þ4
mA to avoid overlaps.
Data from reference [23]; n.o. ¼ not observed.

236
J. Tauchman et al. / Journal of Organometallic Chemistry 723 (2013) 233e238
[PF6]
[PF6]2
arene
arene
arene
Ru
Ru
Ru
NCMe
Cl
P
P
P
NCMe
Cl
Ph2
Ph2
Cl
NCMe
Ph2
H
Fe
Fe
Fe
C(O)Y
O
C
O
C
N
H
NHCH2CO2Me
NHCH2CO2Me
O
arene
Y
arene
arene
11a
11b
11c
14
C6H6
p-MeC6H4Pr
C6Me6
OMe
12a
12b
12c
C6H6
p-MeC6H4Pr
C6Me6
13a
13b
13c
C6H6
p-MeC6H4Pr
C6Me6
i
i
i
i
OMe
OMe
NH2
p-MeC6H4Pr
Scheme 3. Arene ruthenium phosphinoferrocene glycine conjugates [23] included in this study.
3. Experimental
3.4. Cell culture and cell growth
3.1. Materials
Human A2780 and A2780cisR ovarian carcinoma cell lines were
obtained from the European Centre of Cell Cultures (ECACC, Salis-
bury, UK) and maintained in culture as described by the provider.
The cells were routinely grown in RPMI 1640 medium containing
10% fetal calf serum (FCS) and antibiotics at 37 ꢂC and 6% CO2. For
the evaluation of growth inhibition tests, the cells were seeded in
96-well plates (Costar, Integra Biosciences, Cambridge, USA) and
grown for 24 h in complete medium. Compounds 6e13 and rHSA
solutions were diluted directly in culture medium to the required
concentration and added to the cell culture for 72 h incubation. The
MTT (MTT ¼ 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) test was performed for the last 2 h without changing the
culture medium and was performed in triplicate. Briefly, following
drug exposure, MTT (Sigma) was added to the cells at the final
concentration of 0.2 mg/mL and incubated for 2 h, then the culture
medium was aspirated and the violet formazan precipitate dis-
solved in 0.1 N HCl in 2-propanol. The optical density was quanti-
fied at 540 nm using a multiwell plate reader (iEMS Reader MF,
Labsystems, US), and the percentage of surviving cells was calcu-
lated from the ratio of absorbance of treated to untreated cells. The
IC50 values for the inhibition of cell growth were determined by
fitting the plot of the percentage of surviving cells against the drug
concentration using a sigmoidal function (Origin v7.5).
The syntheses were performed in a nitrogen atmosphere with
exclusion of direct day light. The starting materials [(
6-p-
h
MeC6H4Pri)RuCl2]2 [28], Hdpf [27], ligands 1 and 2 [21,22] and the
glycine-derived complexes 11e14 [23] were prepared according to
literature procedures. Amino acid methyl ester hydrochlorides, (S)-
[H3NCH(CH2EMe)CO2Me]Cl (E ¼ O, S) were obtained upon reacting
the respective amino acid with thionyl chloride in dry methanol
[29]. Chloroform and dichloromethane were dried by standing over
CaH2 and distilled under nitrogen. Methanol was distilled from
MeONa. Other chemicals and solvents used for crystallizations and
in chromatography were used without further purification.
3.2. Spectroscopy
NMR spectra were recorded on a Bruker AMX 400 MHz spec-
trometer (1H, 400.13 MHz; 13C{1H}, 100.62 MHz; and 31P{1H},
161.98 MHz) at 296 K. Chemical shifts (
the residual peak of the solvent (CDCl3, dH ¼ 7.26; dC ¼ 77.16) or to
external 85% aqueous H3PO4
ded with a PerkineElmer FTIR 1720-X spectrometer using KBr
pellets. Electrospray ionization (ESI) mass spectra were obtained in
positive-ion mode with an LCQ Finnigan mass spectrometer.
Optical rotations were determined with an Autopol III (Rudolph
Research) automatic polarimeter at room temperature.
d/ppm) are given relative to
(
dP ¼ 0). Infrared spectra were recor-
3.5. General procedure for the synthesis of the phosphinoferrocene
amides 3e5
3.3. Electrochemistry
A suspension of Hdpf (414 mg, 1.00 mmol) and 1-
hydroxybenzotriazole monohydrate (184 mg, 1.20 mmol) in
dichloromethane (10 mL) was cooled in an ice bath and treated with
neat 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.21 mL,
1.20 mmol). The resultant mixture was stirred at 0 ꢂC for 15 min,
whereupon the solids dissolved to give a clear orange-red solution.
A solution of the corresponding amino acid methyl ester hydro-
chloride [H3NCH(R)CO2Me]Cl (1.30 mmol) and triethylamine
(0.20 mL, 1.40 mmol) in dichloromethane (20 mL) was introduced,
and the cooling bath was removed. The reaction mixture was stirred
overnight at room temperature and then washed successively with
10% aqueous citric acid (50 mL), saturated aqueous NaHCO3
(2 ꢃ 50 mL), and brine (50 mL). The organic phase was separated,
dried over MgSO4 and evaporated under vacuum. The orange oily
residue was purified by column chromatography (silica gel,
Electrochemical measurements were performed with a multi-
purpose potentiostat mAUTOLAB III (EcoChemie) at room temper-
ature (ca. 25 ꢂC) using a standard Metrohm three-electrode cell
equipped with a platinum disc (2 mm diameter) as the working
electrode, platinum sheet auxiliary electrode, and double-junction
Ag/AgCl (3 M KCl) reference electrode. Samples were dissolved in
acetonitrile (SigmaeAldrich, absolute) to give solutions containing
ca. 1 mM of the analyte and 0.1 M [Bu4N][PF6] (Fluka, purissimum
for electrochemistry). The solutions were deaerated by bubbling
with argon before the measurement and then kept under an argon
blanket. The potentials are given relative to ferrocene/ferrocenium
reference. The redox potential of the ferrocene/ferrocenium couple
was 0.425 V vs. Ag/AgCl (3 M KCl).

J. Tauchman et al. / Journal of Organometallic Chemistry 723 (2013) 233e238
237
dichloromethane/methanol, 50:1 v/v). A single orange band was
collected and evaporated to afford the analytically pure amide.
138.47 (d, 1JPC ¼ 8 Hz, Cipso PPh2), 170.18 (CONH), 172.55 (CO2Me),
173.81 (CO2Me); the signal due to CeP of fc was not found. 31P{1H}
NMR (CDCl3):
d
ꢁ17.6 (s). IR (KBr): nNH 3415 s, nCO 1741 vs, amide I
3.5.1. (S)-Ph2PfcCONHCH(CH2OMe)CO2Me (3)
1630 vs, amide II 1533 vs cmꢁ1. MS (ESIþ): m/z 610 ([M þ K]þ), 594
([M þ Na]þ), 572 ([M þ H]þ). HRMS (ESIþ) calc. for C30H31O5NPFe
[M þ H]þ 572.1284, found 572.1283.
Orange solid. Yield: 493 mg (93%). [
NMR (CDCl3):
a
]
¼ ꢁ3 (c ¼ 0.5, CHCl3). 1H
D
2
d
3.35 (s, 3H, CH2OMe), 3.69 (dd, JHH ¼ 9.5 Hz,
3JHH ¼ 3.4 Hz, 1H, CH2OMe), 3.77 (s, 3H, CO2Me), 3.88 (dd,
2JHH ¼ 9.5 Hz, 3JHH ¼ 3.4 Hz, 1H, CH2OMe), 4.15 (unresolved dq, 1H,
fc), 4.22 (m, 3H, fc), 4.47 (dt, J z2.4, 1.1 Hz, 1H, fc), 4.49 (dt, J z2.4,
1.2 Hz, 1H, fc), 4.58 (dt, J z2.5, 1.4 Hz, 1H, fc), 4.65 (dt, J z2.5, 1.4 Hz,
1H, fc), 4.86 (dt, 3JHH ¼ 8.3, 3.4 Hz, 1H, NHCH), 6.54 (d, 3JHH ¼ 8.3 Hz,
3.6. General procedure for the synthesis of the arene ruthenium
complexes 6e10
A solution of 0.2 mmol of the appropriate ligands 1e5 in CHCl3
1H, NHCH), 7.28e7.43 (m, 15H, PPh2). 13C{1H} NMR (CDCl3):
d
52.58
(5 mL) was added to 61 mg (0.1 mmol) of solid [(h
6-p-cymene)
(OMe), 52.72 (OMe), 59.41 (NHCH), 69.32 (CH fc), 69.78 (CH fc),
72.13 (CH fc), 72.18 (CH fc), 72.48 (OCH2), 73.32 (2ꢃ d, JPC ¼ 4 Hz, CH
fc), 74.44 (d, JPC ¼ 14 Hz, CH fc), 74.63 (d, JPC ¼ 14 Hz, CH fc), 75.89
RuCl2]2, which dissolved rapidly in this mixture. After stirring the
solution at room temperature for 3 h, the solvent was evaporated
under vacuum, and the residue was purified by column chroma-
tography on silica gel using chloroform/acetone (5:1 v/v) as the
eluent. The products were isolated by evaporation and dried under
vacuum. The elemental analyses showed all compounds to contain
a small amount of chloroform (between 0.35 and 0.80 equivalents),
which could not be removed even under high vacuum.
3
(CeCONH fc), 128.39 (2ꢃ d, JPC ¼ 7 Hz, CH PPh2), 128.85 (2ꢃ CH
2
2
PPh2), 133.49 (d, JPC ¼ 6 Hz, CH PPh2), 133.69 (d, JPC ¼ 6 Hz, CH
PPh2), 138.49 (d, 1JPC ¼ 2 Hz, Cipso PPh2), 138.57 (d, 1JPC ¼ 2 Hz, Cipso
PPh2), 169.79 (CONH), 171.05 (CO2Me); the signal due to CeP of fc
was not found probably due to overlaps. 31P{1H} NMR (CDCl3):
d
ꢁ17.6 (s). IR (KBr): nNH 3414 vs, nCO 1745 s, amide I 1638 vs, amide
II 1522 vs cmꢁ1. MS (ESIþ): m/z 568 ([M þ K]þ), 552 ([M þ Na]þ),
530 ([M þ H]þ). HRMS (ESIþ) calc. for C28H29O4NPFe [M þ H]þ
530.1178, found 530.1177.
3.6.1. (S)-[(h kP)]
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH(CO2Me)Me-
(6)
Red solid. Yield: 155 mg (96 %). [
a
]
¼ þ79 (c ¼ 0.5, CHCl3). 1H
D
3
NMR (CDCl3):
d
0.99 (d, JHH ¼ 6.9 Hz, 3H, CHMe2), 1.00 (d,
3.5.2. (S)-Ph2PfcCONHCH(CH2SMe)CO2Me (4)
Orange solid. Yield: 475 mg (87 %). [
NMR (CDCl3):
3JHH ¼ 6.9 Hz, 3H, CHMe2), 1.59 (d, 3JHH ¼ 7.4 Hz, 3H, CHMe), 1.72 (s,
a
]
¼ ꢁ3 (c ¼ 0.5, CHCl3). 1H
3H,
h
6-C6H4Me), 2.52 (sept, 3JHH ¼ 6.9 Hz,1H, CHMe2), 2.96 (br s,1H,
D
2
d
2.12 (s, 3H, CH2SMe), 3.00 (dd, JHH ¼ 13.9 Hz,
fc), 3.62 (dt, J z2.4,1.2 Hz,1H, fc), 3.78 (s, 3H, OMe), 4.40 (dt, J z2.4,
1.2 Hz, 1H, fc), 4.46 (dq, J z2.5, 1.3 Hz, 1H, fc), 4.47 (m, 2H, fc), 4.53
(dq, J z3.6, 1.2 Hz, 1H, fc), 4.61 (pent, 3JHH ¼ 7.4 Hz, 1H, NHCH), 4.86
3JHH ¼ 6.0 Hz, 1H, CH2SMe), 3.05 (dd, 2JHH ¼ 13.9 Hz, 3JHH ¼ 5.0 Hz,
1H, CH2SMe), 3.76 (s, 3H, CO2Me), 4.18 (br s, 1H, fc), 4.23 (m, 3H, fc),
4.48 (dt, J z2.4, 1.2 Hz, 1H, fc), 4.50 (dt, J z2.4, 1.2 Hz, 1H, fc), 4.60
(dt, J z2.5, 1.3 Hz, 1H, fc), 4.64 (dt, J z2.6, 1.3 Hz, 1H, fc), 4.91 (ddd,
3JHH ¼ 5.0, 6.0, 7.6 Hz, 1H, NHCH), 6.61 (d, 3JHH ¼ 7.6 Hz, 1H, NHCH),
(br s, 1H, fc), 4.99 (d, JHH ¼ 6.0 Hz, 1H,
h
6-C6H4), 5.14 (d, JHH ¼ 6.1 Hz,
3
1H,
h
6-C6H4), 5.23 (m, 2H,
h
6-C6H4), 7.59 (d, JHH ¼ 7.4 Hz, 1H,
NHCH), 7.36e7.47 (m, 6H, PPh2), 7.69e7.77 (m, 2H, PPh2), 7.85e7.94
7.30e7.44 (m,10H, PPh2). 13C{1H} NMR (CDCl3):
d
16.15 (SMe), 36.56
(m, 2H, PPh2). 31P{1H} NMR (CDCl3):
d 17.6 (s). IR (KBr): nNH 3415 s,
(SCH2), 51.42 (NHCH), 52.73 (OMe), 69.55 (CH fc), 69.72 (CH fc),
72.13 (2ꢃ CH fc), 73.23 (d, JPC ¼ 3 Hz, CH fc), 73.34 (d, JPC ¼ 4 Hz, CH
fc), 74.43 (d, JPC ¼ 13 Hz, CH fc), 74.63 (d, JPC ¼ 14 Hz, CH fc), 75.88
(CeCONH fc), 128.41 (2ꢃ d, 3JPC ¼ 7 Hz, CH PPh2), 128.89 (CH PPh2),
nCO 1740 s, amide I 1638 vs, amide II 1527 vs cmꢁ1. MS (ESIþ): m/z
828 ([M
þ
Na]þ), 770 ([M
ꢁ
Cl]þ). Anal. Calc. for
C37H40NO3PCl2FeRu$0.7 CHCl3: C 50.93, H 4.61, N 1.58. Found: C
50.80, H 4.56, N 1.45.
2
128.93 (CH PPh2), 133.50 (d, JPC ¼ 9 Hz, CH PPh2), 133.70 (d,
2JPC ¼ 9 Hz, CH PPh2), 138.28 (d, 1JPC ¼ 8 Hz, Cipso PPh2), 138.43 (d,
1JPC ¼ 8 Hz, Cipso PPh2), 169.95 (CONH), 171.72 (CO2Me); the signal
3.6.2. (S)-[(
P)] (7)
h
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH(CHMe2)CO2Me-
k
due to CeP of fc was not found. 31P{1H} NMR (CDCl3):
d
ꢁ17.6 (s). IR
Red solid. Yield: 150 mg (90 %). [
a]
¼ þ52 (c ¼ 0.5, CHCl3). 1H
D
(KBr): nNH 3415 s, nCO 1744 s, amide I 1637 vs, amide II 1529 vs cmꢁ1
.
NMR (CDCl3):
d
0.99 (d, 3JHH ¼ 6.9 Hz, 3H,
h
6-C6H4CHMe2), 1.01 (d,
MS (ESIþ): m/z 584 ([M þ K]þ), 568 ([M þ Na]þ), 546 ([M þ H]þ).
HRMS (ESIþ) calc. for C28H29O3NPSFe [M þ H]þ 546.0950, found
546.0949.
3JHH ¼ 7.0 Hz, 6H, CHCHMe2), 1.03 (d, JHH ¼ 6.9 Hz, 3H, h6
-
3
3
C6H4CHMe2), 1.69 (s, 3H,
h
6-C6H4Me), 2.33 (d of sept, JHH ¼ 6.9,
3
6.5 Hz, 1H, CHCHMe2), 2.60 (sept, JHH
¼
6.9 Hz, 1H, h6
-
C6H4CHMe2), 3.21 (br s, 1H, fc), 3.77 (s, 3H, OMe), 3.78 (dt, J z2.6,
3.5.3. (S)-Ph2PfcCONHCH(CH2CH2CO2Me)CO2Me (5)
1.3 Hz, 1H, fc), 4.38 (m, 2H, fc), 4.46 (m, 3H, fc), 4.49 (dd, 3JHH ¼ 8.6,
Orange solid. Yield: 531 mg (93 %). [
a]
¼ ꢁ11 (c ¼ 0.5, CHCl3).
6.5 Hz, 1H, NHCH), 4.82 (br s, 1H, fc), 4.98 (d, JHH ¼ 6.1 Hz, 1H, h6
-
D
1H NMR (CDCl3):
d
2.09 (ddt, 2JHH ¼ 14.3 Hz, 3JHH ¼ 7.2, 8.3 Hz, 1H,
C6H4), 5.17 (d, JHH ¼ 6.1 Hz,1H,
h h
6-C6H4), 5.25 (m, 2H, 6-C6H4), 6.72
2
3
CH2CH2CO2Me), 2.26 (ddt, JHH ¼ 14.2 Hz, JHH ¼ 4.8, 7.2 Hz, 1H,
(d, 3JHH ¼ 8.6 Hz, 1H, NHCH), 7.37e7.50 (m, 6H, PPh2), 7.72e7.82 (m,
2
3
CH2CH2CO2Me), 2.45 (dt, JHH ¼ 17.1 Hz, JHH ¼ 7.3 Hz, 1H,
2H, PPh2), 7.84e7.93 (m, 2H, PPh2). 31P{1H} NMR (CDCl3):
d 18.1 (s).
2
3
CH2CH2CO2Me), 2.50 (dt, JHH ¼ 17.1 Hz, JHH ¼ 7.3 Hz, 1H,
CH2CH2CO2Me), 3.65 (s, 3H, CH2CO2Me), 3.73 (s, 3H, CHCO2Me), 4.11
(br s, 1H, fc), 4.22 (m, 2H, fc), 4.25 (br s, 1H, fc), 4.46 (dt, J z2.4,
1.1 Hz, 1H, fc), 4.49 (dt, J z2.4, 1.2 Hz, 1H, fc), 4.59 (dt, J z2.4, 1.2 Hz,
1H, fc), 4.66 (dt, J z2.4,1.3 Hz,1H, fc), 4.69 (dt, 3JHH ¼ 4.7, 8.2 Hz,1H,
NHCH), 6.63 (d, 3JHH ¼ 7.7 Hz, 1H, NHCH), 7.28e7.44 (m, 10H, PPh2).
IR (KBr): nNH 3419 s, nCO 1736 vs, amide I 1638 vs, amide II 1518 vs
cmꢁ1. MS (ESIþ): m/z 856 ([M þ Na]þ), 798 ([M ꢁ Cl]þ). Anal. Calc.
for C39H44NO3PCl2FeRu$0.7 CHCl3: C 51.99, H 4.91, N 1.53. Found: C
52.02, H 4.80, N 1.52.
3.6.3. (S)-[(
CO2Me- P)] (8)
h
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH(CH2OMe)
13C{1H} NMR (CDCl3):
d
27.10 (CHCH2), 30.49 (CH2CO2Me), 51.97
k
(NHCH), 52.05 (OMe), 52.60 (OMe), 69.47 (CH fc), 69.64 (CH fc),
72.06 (CH fc), 72.12 (CH fc), 73.11 (d, JPC ¼ 3 Hz, CH fc), 73.24 (d,
JPC ¼ 4 Hz, CH fc), 74.34 (d, JPC ¼ 13 Hz, CH fc), 74.56 (d, JPC ¼ 14 Hz,
Red solid. Yield 157 mg (94 %). [
a]
¼ þ26 (c ¼ 0.5, CHCl3). 1H
D
NMR (CDCl3):
d
0.96 (d, 3JHH ¼ 6.9 Hz, 6H,
h
6-C6H4CHMe2), 1.76 (s,
3H,
h
6-C6H4Me), 2.54 (sept, 3JHH ¼ 6.9 Hz, 1H,
h
6-C6H4CHMe2), 3.38
3
CH fc), 75.89 (CeCONH fc), 128.40 (2ꢃ d, JPC ¼ 7 Hz, CH PPh2),
(s, 3H, CH2OMe), 3.52 (dt, J z2.5, 1.4 Hz 1H, fc), 3.69 (dd,
128.87 (CH PPh2), 128.91 (CH PPh2), 133.50 (d, 2JPC ¼ 8 Hz, CH PPh2),
133.69 (d, 2JPC ¼ 8 Hz, CH PPh2), 138.26 (d, 1JPC ¼ 8 Hz, Cipso PPh2),
2JHH ¼ 9.6 Hz, JHH ¼ 3.7 Hz, 1H, CH2OMe), 3.72 (dt, J z2.6, 1.3 Hz
3
2
3
1H, fc), 3.78 (s, 3H, CO2Me), 3.91 (dd, JHH ¼ 9.6 Hz, JHH ¼ 4.4 Hz,

238
J. Tauchman et al. / Journal of Organometallic Chemistry 723 (2013) 233e238
1H, CH2OMe), 4.27 (dt, J z2.5, 1.2 Hz, 1H, fc), 4.30 (dt, J z2.6, 1.3 Hz,
1H, fc), 4.44 (dq, J z2.4, 1.3 Hz, 1H, fc), 4.48 (dq, J z2.4, 1.2 Hz, 1H,
fc), 4.53 (dq, J z2.5, 1.3 Hz, 1H, fc), 4.73 (dq, J z2.5, 1.2 Hz, 1H, fc),
the Swiss National Science Foundation (project no 200020-
143254). A generous loan of ruthenium chloride hydrate from the
Johnson Matthey Technology Centre is gratefully acknowledged.
4.80 (dt, 3JHH ¼ 8.3, 4.1 Hz, 1H, NHCH), 5.08 (d, JHH ¼ 6.1 Hz, 1H, h6
-
C6H4), 5.13 (d, JHH ¼ 6.1 Hz, 1H,
h
6-C6H4), 5.16 (d, JHH ¼ 6.3 Hz, 1H,
References
h
6-C6H4), 5.19 (d, JHH ¼ 6.2 Hz, 1H,
h
6-C6H4), 6.76 (d, 3JHH ¼ 8.3 Hz,
1H, NHCH), 7.38e7.49 (m, 6H, PPh2), 7.77e7.91 (m, 4H, PPh2). 31P
[1] C.S. Allardyce, P.J. Dyson, D.J. Ellis, S.L. Heath, Chem. Commun. (2001)
1396e1397.
[2] R.E. Morris, R.E. Aird, P.d.S. Murdoch, H. Chen, J. Cummings, N.D. Hughes,
S. Pearsons, A. Parkin, G. Boyd, D.I. Jodrell, P.J. Sadler, J. Med. Chem. 44 (2001)
3616e3621.
{1H} NMR (CDCl3):
d 18.3 (s). IR (KBr): nNH 3418 s, nCO 1744 s, amide I
1651 vs, amide II 1524 vs cmꢁ1. MS (ESIþ): m/z 858 ([M þ Na]þ), 800
([M ꢁ Cl]þ). Anal. Calc. for C38H42NO4PCl2FeRu$0.45 CHCl3: C 51.93,
H 4.81, N 1.58. Found: C 51.86, H 4.74, N 1.49.
[3] P.J. Dyson, Chimia 61 (2007) 698e703.
[4] S.J. Dougan, P.J. Sadler, Chimia 61 (2007) 704e715;
C. Scolaro, A.B. Chaplin, C.G. Hartinger, A. Bergamo, M. Cocchietto,
B.K. Keppler, G. Sava, P.J. Dyson, Dalton Trans. (2007) 5065e5072.
[5] W.H. Ang, P.J. Dyson, Eur. J. Inorg. Chem. (2006) 4003e4018.
[6] C.G. Hartinger, P.J. Dyson, Chem. Soc. Rev. 38 (2009) 391e401.
[7] M. Melchart, P.J. Sadler, in: G. Jaouen (Ed.), Bioorganometallics, Wiley-VCH,
Weinheim, 2006, p. 39.
[8] L. Ronconi, P.J. Sadler, Coord. Chem. Rev. 251 (2007) 1633e1648.
[9] G. Süss-Fink, Dalton Trans. 39 (2010) 1673e1688.
[10] L.-V. Popova, V.N. Babin, Y.A. Belousov, Y.S. Nekrasov, A.E. Snegireva,
N.P. Borodina, G.M. Shaposhnikova, O.B. Bychenko, P.M. Raevskii, Appl.
Organomet. Chem. 7 (1993) 85e94;
3.6.4. (S)-[(
CO2Me- P)] (9)
h
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH(CH2SMe)
k
Red solid. Yield: 158 mg (93%). [
a
]
¼ þ36 (c ¼ 0.5, CHCl3). 1H
D
NMR (CDCl3):
d
0.98 (d, 3JHH ¼ 6.9 Hz, 3H,
h
6-C6H4CHMe2), 1.01 (d,
3JHH ¼ 7.0 Hz, 3H,
h
6-C6H4CHMe2), 1.73 (s, 3H,
h
6-C6H4Me), 2.17 (s,
3H, CH2SMe), 2.57 (sept, 3JHH ¼ 7.0 Hz, 1H,
h
6-C6H4CHMe2), 3.10 (d,
3JHH ¼ 1.0 Hz, 1H, CH2SMe), 3.12 (d, 3JHH ¼ 2.4 Hz, 1H, CH2SMe), 3.22
(virtual q, J z1.8 Hz,1H, fc), 3.63 (virtual q, J z1.8 Hz,1H, fc), 3.80 (s,
3H, CO2Me), 4.40 (virtual t, J z1.9 Hz, 1H, fc), 4.50 (m, 3H, fc), 4.79
P. Köpf-Maier, H. Köpf, E.W. Neuse, J. Cancer Res. Clin. 108 (1984) 336e340;
M. Görmen, P. Pigeon, S. Top, E.A. Hillard, M. Huché, C.G. Hartinger, F. de
Montigny, M.-A. Plamont, A. Vessières, G. Jaouen, ChemMedChem 5 (2010)
2039e2050.
(m, 1H of NHCH and 1H of fc), 5.04 (d, JHH ¼ 6.0 Hz, 1H,
h
6-C6H4),
5.18 (m, 3H,
h
6-C6H4), 7.20 (d, 3JHH ¼ 8.1 Hz, 1H, NHCH), 7.37e7.49
(m, 6H, PPh2), 7.72e7.80 (m, 2H, PPh2), 7.84e7.92 (m, 2H, PPh2). 31
P
[11] E. Hillard, A. Vessieres, F. Le Bideau, D. Plazuk, D. Spera, M. Huché, G. Jaouen,
ChemMedChem 1 (2006) 551e559. and references cited therein.
[12] W. Henderson, S.R. Alley, Inorg. Chim. Acta 322 (2001) 106e112.
[13] A. Rosenfeld, J. Blum, D. Gibson, A. Ramu, Inorg. Chim. Acta 201 (1992)
219e221.
{1H} NMR (CDCl3):
d 17.9 (s). IR (KBr): nNH 3311 m, nCO 1739 vs,
amide I 1651 vs, amide II 1525 vs cmꢁ1. MS (ESIþ): m/z 874
([M
þ
Na]þ), 816 ([M
ꢁ
Cl]þ). Anal. Calc. for
[14] M. Viotte, B. Gautheron, M.M. Kubicki, I.E. Nifant’ev, S.P. Fricker, Met.-based
Drugs 2 (1995) 311e326.
C38H42NO3PSCl2FeRu$0.8 CHCl3: C 49.20, H 4.55, N 1.48. Found: C
49.23, H 4.57, N 1.39.
ꢀ
ꢀ
ꢀ
[15] M. Auzias, B. Therrien, G. Süss-Fink, P. Stepnicka, Wee Han Ang, P.J. Dyson,
Inorg. Chem. 47 (2008) 578e583.
3.6.5. (S)-[(
CO2Me- P)] (10)
Red solid. Yield: 163 mg (93%). [
h
6-p-MeC6H4Pri)RuCl2(Ph2PfcCONHCH(CH2CH2CO2Me)
[16] A.K. Bytzek, K. Boeck, S. Hann, B.K. Keppler, C.G. Hartinger, G. Koellensperger,
Metallomics 3 (2011) 1049e1055.
[17] M. Pongratz, P. Schluga, M.A. Jakupec, V.B. Arion, C.G. Hartinger, G. Allmaier,
B.K. Keppler, J. Anal. At. Spectrom. 19 (2004) 46e51.
[18] L. Messori, F. Gonzales Vilchez, R. Vilaplana, F. Piccioli, E. Alessio, B.K. Keppler,
Met.-based Drugs 7 (2000) 335e342;
k
a
]
¼ þ77 (c ¼ 0.5, CHCl3). 1H
D
3
NMR (CDCl3):
3H,
d
1.05 (d, JHH ¼ 7.0 Hz, 6H,
h
6-C6H4CHMe2), 1.70 (s,
h
6-C6H4Me), 2.33 (m, 2H, CH2), 2.54 (m, 2H of CH2 and 1H of h6
-
A.R. Timerbaev, C.G. Hartinger, S.S. Aleksenko, B.K. Keppler, Chem. Rev. 106
(2006) 2224e2248;
C.G. Hartinger, W.H. Ang, A. Casini, L. Messori, B.K. Keppler, P.J. Dyson, J. Anal.
At. Spectrom. 22 (2007) 960e967;
K. Polec-Pawlak, J.K. Abramski, O. Semenova, C.G. Hartinger, A.R. Timerbaev,
B.K. Keppler, M. Jarosz, Electrophoresis 27 (2006) 1128e1135;
M.J. Clarke, S. Bitler, D. Rennert, M. Buchbinder, A.D. Kelman, J. Inorg. Biochem.
12 (1980) 79e87;
P. Schluga, C.G. Hartinger, A. Egger, E. Reisner, M. Galanski, M.A. Jakupec,
B.K. Keppler, Dalton Trans. 14 (2006) 1796e1802.
C6H4CHMe2), 2.92 (br s, 1H, fc), 3.68 (s, 3H, CH2CO2Me), 3.70
(unresolved dt, 1H, fc), 3.79 (s, 3H, CHCO2Me), 4.37 (unresolved dq,
1H, fc), 4.47 (dt, J z 2.5, 1.3 Hz, 1H, fc), 4.51 (m, 2H, fc), 4.55 (m, 1H
fc), 4.57 (m, 1H, NHCH), 4.81 (d, JHH ¼ 5.9 Hz, 1H,
h
6-C6H4), 4.89 (br
s,1H, fc), 5.15 (d, JHH ¼ 5.9 Hz,1H,
h
6-C6H4), 5.23 (d, JHH ¼ 6.0 Hz,1H,
h
6-C6H4) 5.31 (d, JHH ¼ 6.0 Hz, 1H,
h
6-C6H4), 7.36e7.45 (m, 6H,
3
PPh2), 7.48 (d, JHH ¼ 8.1 Hz, 1H, NHCH), 7.68e7.76 (m, 2H, PPh2),
7.85e7.93 (m, 2H, PPh2). 31P{1H} NMR (CDCl3):
d 17.6 (s). IR (KBr):
[19] P.J. Dyson, G. Sava, Dalton Trans. (2006) 1929e1933.
[20] For a general review on the chemistry of phosphine-carboxamides, see:
nNH 3415 s, nCO 1737 vs, amide I 1650 vs, amide II 1524 vs cmꢁ1. MS
(ESIþ): m/z 900 ([M þ Na]þ), 842 ([M ꢁ Cl]þ). Anal. Calc. for
C40H44NO5PCl2FeRu$0.35 CHCl3: C 52.71, H 4.86, N 1.52. Found: C
52.65, H 4.75, N 1.42.
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P. Stepnicka Chem. Soc. Rev. 41 (2012) 4273e4305.
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Acknowledgements
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Results presented in this paper were obtained within a cooper-
ation supported by the bilateral Swiss-Czech Scientific Exchange
Program (Sciex) NMS-CH (project no. 10.133) and are a part of the
long-term research plan of the Faculty of Science, Charles Univer-
sity in Prague supported by the Ministry of Education, Youth and
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