Mannich products of kojic acid and N-heterocycles and their Ru(II)-arene complexes: Synthesis, characterization and stability

Article abstract of DOI:10.1016/j.jorganchem.2010.01.007

Ru(II)-η⁶-p-cymene compounds bearing pyrone-derived ligands, which were obtained by Mannich reaction with piperidine and related analogues, have been synthesized. The compounds were characterized by NMR spectroscopy, mass spectrometry, thermogr

Full text of DOI:10.1016/j.jorganchem.2010.01.007

Journal of Organometallic Chemistry 695 (2010) 875–881
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Mannich products of kojic acid and N-heterocycles and their Ru(II)–arene
complexes: Synthesis, characterization and stability
Johanna H. Kasser , Wolfgang Kandioller , Christian G. Hartinger a,*, Alexey A. Nazarov a,b,
a
a
a
b
a,c
Vladimir B. Arion , Paul J. Dyson , Bernhard K. Keppler
a
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
Research Platform Translational Cancer Therapy Research, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria
b
c
a r t i c l e i n f o
a b s t r a c t
Ru(II)–g
6-p-cymene compounds bearing pyrone-derived ligands, which were obtained by Mannich reac-
Article history:
Received 26 November 2009
Received in revised form 18 December 2009
Accepted 5 January 2010
tion with piperidine and related analogues, have been synthesized. The compounds were characterized
by NMR spectroscopy, mass spectrometry, thermogravimetric analysis and in the case of 2-(2,6-
dimethyl-morpholin-4-ylmethyl)-3-hydroxy-6-hydroxymethyl-pyran-4-one by X-ray diffraction analy-
sis. The chlorido complexes are prone to aquation in aqueous solution which results in the formation
of dimers. Dimer formation can be inhibited by in situ replacement of the chlorido ligand by imidazole
Available online 11 January 2010
Dedicated to Professor Richard H. Fish on
the occasion of his 70th birthday.
1
yielding compounds which are significantly more stable in water, as demonstrated by H NMR
spectroscopy.
Keywords:
Kojic acid
Ó 2010 Elsevier B.V. All rights reserved.
Mannich reaction
Ruthenium(II)–arene complexes
Stability studies
Synthesis
1
. Introduction
Severe side effects, high toxicity and limited activity of plati-
mors in vivo [17,18]. The most widely developed compounds
are cationic ethylenediamine (en) and RAPTA compounds [8–
10,19]. The replacement of the chelating en moiety by O,S-con-
taining bidentate ligands results in compounds which are signifi-
cantly less active, at least in human tumor cell lines [20]. The
lower potency to inhibit cell proliferation of, for example, malto-
lato complexes was related to the formation of stable dinuclear
num anticancer agents have led to the development of new me-
tal-containing chemotherapeutics [1]. Ruthenium compounds are
considered to be promising alternatives with complementary
activity, i.e., in tumors that do not respond to platinum drugs,
and moreover, exhibit a lower general toxicity.
+
6
2 2 3
[Ru (cym) (OH) ] species (cym = g -p-cymene) in aqueous solu-
Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]
KP1019) and imidazolium trans-[tetrachlorido(S-dimethyl sulfox-
tion, as demonstrated by electrospray ionization mass spectrom-
etry (ESI-MS) [20]. Replacement of pyronato by thiopyronato and
pyridinonato ligands stabilizes the compounds and cytotoxicities
(
ide)(1H-imidazole)ruthenate(III)] (NAMI-A) entered clinical trials
in recent years [2–4]. Protein binding after intravenous administra-
tion and activation by reduction in the tumor cell appear to be
essential steps in the mode of action of these and related Ru(III)
complexes [5–7].
More recently, organometallic Ru(II)–arene compounds (see
Fig. 1 for some examples of mono- and polynuclear compounds)
were identified as promising anticancer agents [8–10]. They exhi-
bit activity in different tumor models compared to the established
platinum-based anticancer agents and some are even active in
platinum resistant cell lines [11–16] and against metastatic tu-
in the low
lM range were obtained [21–24]. However, more re-
cently pyrone compounds were reported that do not undergo
the described dimer formation but also do not exhibit antiprolif-
erative activity [25]. This behavior was related to the decomposi-
tion of the compounds by reaction with biological nucleophiles,
e.g., those present in the medium used for cultivating human tu-
mor cell lines [25].
Kojic acid, or 5-hydroxy-2-hydroxymethyl-4H-pyran-4-one, is a
bioactive c-pyrone derivative produced by many species of Asper-
gillus and Penicillium [26]. The chelating properties of such pyrones
to transition metal ions, e.g., Ru(II/III), Fe(III), Cu(II), [27–31] make
them interesting ligands. Complexes of pyrones with vanadium
and zinc have already been developed as insulin mimics and
*
Corresponding author. Tel.: +43 1 4277 52609; fax: +43 1 4277 9526.
E-mail address: christian.hartinger@univie.ac.at (C.G. Hartinger).
0
022-328X/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.01.007

8
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J.H. Kasser et al. / Journal of Organometallic Chemistry 695 (2010) 875–881
2.2. General procedure for the reaction of kojic acid with secondary
amines and formaldehyde ꢀ synthesis of 1a–1f
Ru
O
NH
Cl
O
Cl
NH
Cl
Cl
The secondary amine (4.5 mmol) and 35% aqueous formalde-
hyde solution (0.44 mL, 5.5 mmol) were dissolved in MeOH
(30 mL) and heated to 65 °C. Kojic acid (0.78 g, 5.5 mmol) was
added to the refluxing solution and the reaction mixture was
cooled under stirring to room temperature. If no precipitation oc-
curred, the reaction mixture was concentrated under reduced pres-
sure and stored at 4 °C overnight. In any case the resulting
N
Ru
Cl
NH Cl
NH
N
Ru
S
Cl
Cl
N
(
N
N
H
N
H
Cl
N
CH3
)12
HN
O
CH
3
O
Cl
O
Ru
KP1019
NAMI-A
PyrRu212
2
precipitate was filtered, washed with Et O and dried in vacuo.
2
4
.2.1. 3-Hydroxy-6-hydroxymethyl-2-[(piperidin-1-yl)methyl]-pyran-
(1H)-one 1a
The reaction was performed according to the general procedure,
Ar
+
Ar
Ar
N
Ru
Ru
using piperidine (0.44 mL, 4.5 mmol). Yield: 1.01 g (94%) colorless
Ru
N
H2N
Ru
Ru
Cl
1
O
O
O
solid. M.p. 167 °C;
d = 1.32–1.41 (m, 2H, Hpip), 1.44–1.53 (m, 4H, Hpip), 2.36–2.44 (m,
H, Hpip), 3.47 (s, 2H, CH –N), 4.30 (s, 2H, CH ), 5.67 (br s, 1H,
OH), 6.31 (s, 1H, H5) ppm; C NMR (DMSO-d , 125.75 MHz,
25 °C): d = 24.1 (Cpip), 25.9 (Cpip), 54.2 (Cpip), 55.0 (CH –N), 60.1
(CH ), 109.4 (C5), 144.1 (C6), 147.3 (C2), 168.0 (C3), 174.0 (C4)
ppm. Elemental Anal. Calc. for C12
6
H NMR (DMSO-d , 500.10 MHz, 25 °C):
NH2
O
O
O
4
2
2
[Ru(arene)(en)Cl]+
13
O
6
O
2
N
N
2
Ar
H17NO
4
: C, 60.24; H, 7.16; N,
Ar
Ru
Cl
ꢀ1
5.85. Found: C, 60.23; H, 7.23; N, 5.90%. IR (ATR, cm , selected
bands): 3262, 2944, 2816, 1645, 1607, 1578, 1459, 1207. ESI-MS
Cl
P
N
N N
ꢀ
+
Ru(arene) metallarectangle
RAPTA-C
(
neg): m/z 238.0 [M–H] . ESI-MS (pos): m/z 501.3 [2M+Na] ,
+
2
40.1 [M+H] .
Fig. 1. Structures of ruthenium anticancer drug candidates.
2.2.2. 3-Hydroxy-6-hydroxymethyl-2-[(4-methylpiperidin-1-yl)-
methyl]pyran-4(1H)-one 1b
The reaction was performed according to the general procedure,
using 4-methylpiperidine (0.53 mL, 4.5 mmol). Yield: 0.98 g (86%)
vanadyl coordination compounds with maltol and ethylmaltol
recently entered clinical trials [32–36]. Kojic acid has antibacterial
and antifungal properties. Furthermore, kojic acid was shown to
inhibit different enzymes relevant to the undesirable melanosis
of agricultural products, which is related to its coordination ability
to, e.g., copper, in the active site of tyrosinase [37–39].
In this study, the kojic acid scaffold was modified by a Mannich
reaction with piperidine derivatives with the aim to link it to
Ru(II)–arene fragments and to obtain compounds with anticancer
activity. The synthesized complexes were characterized by stan-
dard methods and their behavior in aqueous solution and their
reactivity towards imidazole was studied.
1
colorless solid. M.p. 168 °C; H NMR (DMSO-d
6
, 500.10 MHz,
), 1.05–1.18 (m, 2H, Hpip),
.24–1.36 (m, 1H, Hpip), 1.51–1.60 (m, 2H, Hpip), 1.98–2.09 (m, 2H,
pip), 2.75– 2.83 (m, 2H, Hpip), 3.48 (s, 2H, CH –N), 4.29 (s, 2H, CH
3
2
1
H
5 °C): d = 0.87 (d, 3H, JH,H = 7 Hz, –CH
3
2
2
)
6
,
1
3
5
1
.69 (br s, 1H, OH), 6.31 (s, 1H, H5) ppm; C NMR (DMSO-d
25.75 MHz, 25 °C): d = 22.2 (Cpip), 30.4 (Cpip), 34.3 (Cpip), 53.6
pip), 54.6 (CH –N), 60.1 (CH ), 109.4 (C5), 144.1 (C6), 147.3
C2), 168.0 (C3), 174.0 (C4) ppm. IR (ATR, cm , selected bands):
269, 2926, 2817, 1645, 1607, 1576, 1459, 1203. Elemental Anal.
Calc. for C13 : C, 61.64 H, 7.56; N, 5.53. Found: C, 61.55; H,
.65; N, 5.60%. ESI-MS (neg): m/z 252.1 [M–H] , 505.2 [2M–H] .
(
C
2
2
ꢀ
1
(
3
H
19NO
4
ꢀ
+
ꢀ
7
+
2
. Experimental section
ESI-MS (pos): m/z 254.2 [M+H] , 529.3 [2M+Na] .
2.1. General
2.2.3. 3-Hydroxy-6-hydroxymethyl-2-[(morpholin-4-yl)-
methyl]pyran-4(1H)-one 1c
Analytical grade materials were obtained from commercial sup-
The reaction was performed according to the general procedure,
using morpholine (0.39 mL, 4.5 mmol). Yield: 0.93 g (85%) colorless
6
pliers and used without further purification. Bis[dichlorido(
g
-p-
1
cymene)ruthenium(II)] was synthesized as described elsewhere
40]. Melting points were determined with a Büchi B-540 appara-
tus and are uncorrected. NMR spectra were recorded at 25 °C in
DMSO-d on Bruker FT-NMR spectrometer Avance III™
00 MHz at 500.10 ( H) and 125.75 MHz ( C{ H}). Electrospray
solid. M.p. 172 °C; H NMR (DMSO-d
6
, 500.10 MHz, 25 °C): d = 2.43
3
3
[
2
(t, JH,H = 4 Hz, 4H, Hmorph), 3.50 (s, 2H, CH –N), 3.56 (t, JH,H = 4 Hz,
3
3
4H, Hmorph), 4.31 (d, JH,H = 4 Hz, 2H, CH
OH), 6.32 (s, 1H, H5), 9.01 (br s, 1H, OHpyrone) ppm; 13C NMR
(DMSO-d , 125.75 MHz, 25 °C): d = 53.40 (Cmorph), 54.4 (C8), 60.1
(C7), 66.6 (Cmorph), 109.4 (C5), 144.2 (C6), 146.7 (C2), 168.1 (C3),
174.1 (C4) ppm. IR (ATR, cm , selected bands): 3254, 2946,
2826, 1648, 1608, 1575, 1451, 1198. Elemental Anal. Calc. for
2
), 5.68 (t, JH,H = 6 Hz, 1H,
6
a
1
13
1
5
6
ionization mass spectra were recorded on a Bruker esquire3000 in
negative and positive ion modes. Elemental analyses were per-
formed by the Laboratory for Elemental Analysis of the Faculty of
Chemistry, University of Vienna, with a Perkin Elmer 2400 CHN
Elemental Analyzer. Thermogravimetric analysis (TGA) and differ-
ential thermal analysis (DTA) measurements were carried out
simultaneously with a Mettler-Toledo TGA/SDTA851e. The ther-
mograms were recorded in the temperature range 25–900 °C with
a heating rate of 5 °C per minute and nitrogen as purge gas with a
flow rate of 50 mL/min. The IR spectra were recorded on a Bruker
Vertex 70 FT-IR-spectrometer equipped with an ATR unit in the
ꢀ1
11 5
C H15NO : C, 54.77; H, 6.27; N, 5.81. Found: C, 54.84; H, 6.33;
ꢀ
ꢀ
N, 5.81%. ESI-MS (neg): m/z 240.2 [M–H] , 480.9 [2M–H] . ESI-
+
+
MS (pos): m/z 505.0 [2M+Na] , 264.0 [M+Na] .
2.2.4. 3-Hydroxy-6-hydroxymethyl-2-[(3-methylpiperidin-1-yl)-
methyl]pyran-4(1H)-one 1d
The reaction was performed according to the general procedure,
using 3-methylpiperidine (0.53 mL, 4.5 mmol). Yield: 0.65 g (57%)
ꢀ1
1
range of 4000–500 cm
.
colorless solid. M.p. 162 °C; H NMR (DMSO-d
6
, 500.10 MHz,

J.H. Kasser et al. / Journal of Organometallic Chemistry 695 (2010) 875–881
877
2
1
3
1
1
5 °C): d = 0.79–0.84 (m, 4H, Hpip), 1.38–1.49 (m, 1H, Hpip), 1.51–
.71 (m, 4H, Hpip), 1.92–2.00 (m, 1H, Hpip), 2.69–2.80 (m, 2H, Hpip),
bands): 3380, 3058, 2958, 2868, 1601, 1567, 1513, 1475, 1209. Ele-
mental Anal. Calc. for C22 30ClNO O: C, 50.13; H, 6.12; N,
RuꢂH
2.66. Found: C, 50.33; H, 5.99; N, 2.66%. ESI-MS (pos): m/z 474.5
H
4
2
.48 (s, 2H, CH
H, H5) 8.98 (br s, 1H, OHpyrone) ppm;
25.75 MHz, 25 °C): d = 20.0 (Cpip), 25.5 (Cpip), 31.1 (Cpip), 32.7
pip), 53.7 (Cpip), 54.7 (CH –N), 60.1 (CH ), 61.5 (Cpip), 109.4 (C5),
44.1 (C6), 147.3 (C2), 168.0. (C3), 174.0 (C4) ppm. IR (ATR,
2 2
–N), 4.29 (s, 2H, CH ), 5.68 (br s, 1H, OH), 6.31 (s,
13
+
+
C NMR (DMSO-d
6
,
[M–Cl] , 390.4 [M–Cl–piperidine] .
(
C
2
2
2
.3.2. Chlorido{3-(hydroxy- O)-6-hydroxymethyl-2-[(4-methyl
j
1
6
piperidin-1-yl)methyl]pyran-4(1H)-onato-jO}(g -p-cymene)
ꢀ1
cm , selected bands): 3266, 2928, 2803, 1649, 1609, 1578, 1460,
ruthenium(II) 2b
1
202. Elemental Anal. Calc. for C13
4
H19NO : C, 61.64; H, 7.56; N,
The reaction was performed according to the general procedure
for the synthesis of the Ru(II) complexes, using 3-hydroxy-6-
hydroxymethyl-2-[(4-methylpiperidin-1-yl)methyl]pyran-4-one
5
.53. Found: C, 61.59; H, 7.64; N, 5.57%. ESI-MS (neg): m/z 252.5
ꢀ
ꢀ
+
[
M–H] , 504.9 [2M–H] . ESI-MS (pos): m/z 254.5 [M+H] .
(
167 mg, 0.66 mmol). Yield: 288 mg (81%) red solid. IR (ATR, cmꢀ1,
2.2.5. 2-[(3,5-Dimethylpiperidin-1-yl)methyl]-3-hydroxy-6-hydroxy-
selected bands): 3268, 2920, 2870, 1603, 1563, 1505, 1474, 1201,
methylpyran-4(1H)-one 1e
1
6
051. Elemental Anal. Calc. for C23
H
32ClNO
4
RuꢂH
2
O: C, 51.05; H,
The reaction was performed according to the general procedure,
.33; N, 2.59. Found: C, 51.20; H, 6.29; N, 2.53%. ESI-MS (pos): m/
using 3,5-dimethylpiperidine (0.60 mL, 4.5 mmol). Yield: 0.30 g
+
+
z 488.4 [M–Cl] , 390.4 [M–Cl–4-methylpiperidine] .
1
(
25%) colorless solid. M.p. 163 °C;
H
6
NMR (DMSO-d ,
5
00.10 MHz, 25 °C): d = 0.41–0.53 (m, 1H, Hpip), 0.76–0.83 (d,
H,H = 6 Hz, 6H, Hpip), 1.54–1.65 (m, 5H, Hpip 2.73–2.81 (d,
3
2.3.3. Chlorido{3-(hydroxy- O)-6-hydroxymethyl-2-[(morpholin-
4-yl)methyl]pyran-4(1H)-onato-jO}(g -p-cymene)
ruthenium(II) 2c
j
J
J
6
3
H,H = 6 Hz, 2H, Hpip), 3.49 (s, 2H, CH
br s, 1H, OH), 6.31 (s, 1H, H5), 8.98 (br s, 1H, OHpyrone) ppm;
NMR (DMSO-d , 125.75 MHz, 25 °C): d = 19.9 (CH ), 31.1 (Cpip),
2.0 (Cpip), 54.4 (CH –N), 60.1 (CH ), 61.2 (Cpip), 109.4 (C5), 144.1
C6), 147.3 (C2), 168.0 (C3), 174.0 (C4) ppm. IR (ATR, cm , selected
bands): 3269, 2951, 2837, 1653, 1607, 1578, 1462, 1200. Elemental
2 2
–N), 4.29 (s, 2H, CH ), 5.68
1
3
(
C
The reaction was performed according to the general procedure
for the synthesis of the Ru(II) complexes, using 3-hydroxy-6-
hydroxymethyl-2-[(morpholin-4-yl)methyl]pyran-4-one (159 mg,
6
3
4
(
2
2
ꢀ1
ꢀ1
0
.66 mmol). Yield: 339 mg (98%) red solid. IR (ATR, cm , selected
bands): 3380, 3061, 2962, 2868, 1602, 1565, 1503, 1478, 1199,
Anal. Calc. for C14
H21NO
4
: C, 62.90; H, 7.92; N, 5.24. Found: C,
ꢀ
1088. Elemental Anal. Calc. for C21H28ClNO Ruꢂ0.5H O: C, 48.51;
6
2.78; H, 8.03; N, 5.37%. ESI-MS (neg): m/z 266.6 [M–H] . ESI-MS
5
2
+
H, 5.62; N, 2.69. Found: C, 48.43; H, 5.57; N, 2.77%. ESI-MS (pos):
(
pos): m/z 268.5 [M+H] .
+
m/z 476.4 [M–Cl] .
2.2.6. 2-[(2,6-Dimethylmorpholin-4-yl)methyl]-3-hydroxy-6-hydroxy-
methylpyran-4(1H)-one 1f
The reaction was performed according to the general procedure,
using 2,6-dimethylmorpholine (0.55 mL, 4.5 mmol). Yield: 0.69 g
2
.3.4. Chlorido{3-(hydroxy-jO)-6-hydroxymethyl-2-[(3-methylpi
6
peridin-1-yl)methyl]pyran-4(1H)-onato-jO}(g -p-cymene)
ruthenium(II) 2d
The reaction was performed according to the general procedure
for the synthesis of the Ru(II) complexes, using 3-hydroxy-6-
hydroxymethyl-2-[(3-methylpiperidin-1-yl)methyl]pyran-4-one
1
(
57%) colorless solid. M.p. 168 °C;
00.10 MHz, 25 °C): d = 1.03 (d, 6H, JH,H = 6 Hz, CH
3
J
H
NMR (DMSO-d
), 1.76 (t, 2H,
H,H = 10 Hz, Hmorph), 2.70 (d, 2H, JH,H 10 Hz, Hmorph), 3.49 (s, 2H,
6
,
3
5
3
3
3
CH
2
–N), 3.50–3.58 (m, 2H, Hmorph), 4.30 (d,
J
H,H = 6 Hz, 2H, CH
2
),
ꢀ1
(
167 mg, 0.66 mmol). Yield: 308 mg (88%) red solid. IR (ATR, cm
,
3
5
.68 (t, JH,H = 6 Hz, 1H, OH), 6.32 (s, 1H, H5), 8.98 (br s, 1H, OHpyr-
selected bands): 3334, 2927, 2871, 1602, 1564, 1476, 1276, 1201
1
3
one) ppm; C NMR (DMSO-d
6 3
, 125.75 MHz, 25 °C): d = 19.4 (CH
),
Elemental Anal. Calc. for C23H32ClNO Ruꢂ0.5H O: C, 51.92; H,
4
2
5
4.0 (C8), 59.12 (Cmorph), 60.1 (7), 71.4 (Cmorph), 109.4 (5), 144.2
6
.25; N, 2.63. Found: C, 51.86; H, 6.22; N, 2.62%. ESI-MS (pos): m/
ꢀ1
(
C6), 146.7 (C2), 168.1 (C3), 174.1 (C4) ppm. IR (ATR, cm , selected
+
+
z 488.5 [M–Cl] , 390.5 [M–Cl–3-methylpiperidine] .
bands): 3264, 2975, 2860, 1648, 1609, 1577, 1459, 1200. Elemental
Anal. Calc. for C13
H
19NO
5
: C, 57.98; H, 7.11; N, 5.20. Found: C,
ꢀ
2.3.5. Chlorido{2-[(3,5-dimethylpiperidin-1-yl)methyl]-3-(hydroxy-
jO)-
5
7.91; H, 7.18; N, 5.22%. ESI-MS (neg): m/z 268.5 [M–H] , 536.8
6
ꢀ
+
+
6-hydroxymethyl-pyran-4(1H)-onato-
jO}(g
-p-cymene)
[
2M–H] . ESI-MS (pos): m/z 560.9 [2M+Na] , 270.1 [M+H] .
ruthenium(II) 2e
The reaction was performed according to the general procedure
for the synthesis of the Ru(II) complexes, using 2-[(3,5-dimethylpi-
peridin-1-yl)methyl]-3-hydroxy-6-hydroxymethyl-pyran-4-one
2
.3. General procedure for synthesis of the Ru(II) complexes 2a–2f
The ligand (0.66 mmol) and sodium methoxide (42 mg,
(
176 mg, 0.66 mmol). Yield: 324 mg (89%) red solid. IR (ATR, cmꢀ1,
0
.77 mmol) were suspended in MeOH (30 mL) under an argon
6
selected bands): 3318, 3043, 2950, 2871, 1597, 1564, 1491, 1276,
035. Elemental Anal. Calc. for C24 34ClNO O: C, 52.36;
Ruꢂ0.75H
H, 6.50; N, 2.54. Found: C, 52.35; H, 6.33; N, 2.53%. ESI-MS (pos):
atmosphere. Bis[dichlorido(
.33 mmol) in CH Cl
g
-p-cymene)ruthenium(II)] (200 mg,
1
H
4
2
0
2
2
(20 mL) was added dropwise and the solu-
tion was stirred for 18 h at room temperature, filtered and concen-
trated under reduced pressure. The obtained residue was extracted
+
+
m/z 502.5 [M–Cl] , 390.4 [M–Cl–3,5-dimethylpiperidine] .
with CH
2
Cl
2
(3 ꢁ 15 mL), the organic phase was filtered and the
volume was reduced to 5 mL, and the product precipitated with
hexane (if necessary). The mixture was stored at 4 °C overnight
and the resulting solid was removed by filtration and dried in
vacuo.
2.3.6. Chlorido{2-[(2,6-dimethylmorpholin-4-yl)methyl]-3-(hydroxy-
6
j
O)-6-hydroxymethyl-pyran-4(1H)-onato-
jO}(
g
-p-cymene)
ruthenium(II) 2f
The reaction was performed according to the general procedure
for the synthesis of the Ru(II) complexes, using 2-[(2,6-dim-
ethylmorpholin-4-yl)methyl]-3-hydroxy-6-hydroxymethyl-pyran-
4-one (178 mg, 0.66 mmol). Yield: 297 mg (82%) red solid. IR (ATR,
2
.3.1. Chlorido{3-(hydroxy-
jO)-6-hydroxymethyl-2-[(piperidin-1-yl)
6
methyl]pyran-4(1H)-onato-
j
O}(g -p-cymene)ruthenium(II) 2a
ꢀ1
The reaction was performed according to the general procedure
for the synthesis of the Ru(II) complexes, using 3-hydroxy-6-
hydroxymethyl-2-[(piperidin-1-yl)methyl]pyran-4-one (158 mg,
cm , selected bands): 3349, 2970, 2871, 1603, 1563, 1501, 1477,
1199, 1082. Elemental Anal. Calc. for C23 32ClNO O: C,
H
5
Ruꢂ0.5H
2
50.40; H, 6.07; N, 2.55. Found: C, 50.13; H, 5.93; N, 2.38%. ESI-MS
ꢀ
1
+
0
.66 mmol). Yield: 291 mg (84%) red solid. IR (ATR, cm , selected
(pos): m/z 504.3 [M–Cl] .

8
78
J.H. Kasser et al. / Journal of Organometallic Chemistry 695 (2010) 875–881
ꢀ1
Table 1
Crystallographic data of 1f.
was set to a heat rate of 5 °C min from 25 to 900 °C followed
by 120 min at 900 °C.
Chemical formula
13 5
C H19NO
269.29
100(2)
0.20 ꢁ 0.15 ꢁ 0.10
Colorless, block
Monoclinic
ꢀ
1
M
r
(g mol
)
3
. Results and discussion
T (K)
Crystal size (mm )
3
Crystal color, shape
Mannich reactions between kojic acid, a close analogue to allo-
Crystal system
Space group
a (Å)
b (Å)
c (Å)
maltol, and cyclic secondary amines resulted in the ligands 1a–f
Scheme 1) with the yield (25–94%) strongly depending on the ste-
1
P2 /c
(
17.9436(12)
7.4072(5)
10.3390(6)
100.018(3)
1353.22(15)
4
ric bulk of the N-containing heterocycle. Alkyl substitution in the
para-position was favorable to meta substitution whereas ortho
derivatization did not show any conversion to the desired product.
Reactivity at the 2-position in the pyrone ring appears to be signif-
icantly lower for kojic acid compared to allomaltol, for which a ser-
ies of Mannich products were reported [46]. Accordingly, the
procedure used to derivatize allomaltol, i.e., an aldol reaction with
aldehydes at room temperature [47], was not suitable. However,
the coordination of the Ru to the ligand was performed using a
ß (°)3
V (Å )
Z
D
l
calc (g cmꢀ3)
1.322
0.102
ꢀ
1
(mm
)
F(0 0 0)
h range for data collection (°)
h range
k range
l range
576
2.98–30.11
ꢀ25/25
ꢀ10/10
ꢀ14/1
standard procedure, i.e., following deprotonation of the ligand with
6
Reflections collected
No. parameters
3983
174
0.0554
0.0405
0.1130
1.009
sodium methoxide in methanol. In the next step bis[dichlorido(
g
-
p-cymene)ruthenium(II)] was added and the complexes 2a–f were
obtained in high yield (82–98%).
Independent reflections (Rint
)
a
R
1
b
The compounds were characterized by 1D and 2D NMR spec-
troscopy (1a–f), IR spectroscopy, thermogravimetry/differential
thermal analysis (TG/DTA), electrospray ionization mass spectrom-
etry (ESI-MS) and elemental analysis. Single crystals of 1f suitable
for X-ray diffraction analysis were obtained from methanol.
The chemical shifts of the H5 proton of the pyrone ring and of
the aliphatic hydroxymethyl protons are very similar for all ligands
wR
Goodness-of-fit (GOF) on F
2
2
c
P
P
a
b
c
R
wR
1
¼
kF
P
o
j ꢀ jF
c
k= jF
o
j:
P
P
2
2
2
2
o
2
1=2
2
¼ f ½wðF ꢀ F Þ ꢃ=w ðF Þ ꢃg
o
c
:
2
o
2
2
1=2
GOF ¼ f ½wðF ꢀ F Þ ꢃ=ðn ꢀ pÞg , where n is the number of reflections and p
c
is the total number of parameters refined.
2
.4. X-ray diffraction analysis
in DMSO-d
as CDCl , DMSO-d
evidenced by NMR spectroscopy. In order to reduce the rate of
the hydrolysis reaction in D O, NaCl was added to the reaction
6
. The complexes 2a–f react rapidly with solvents such
3
6
, MeOH-d and D O forming several species, as
4
2
X-ray diffraction measurements were performed with a single
crystal of 1f on a Bruker X8 APEXII CCD diffractometer at 100 K.
The single crystal was positioned at 35 mm from the detector
and 3472 frames were measured each for 30 s over 1° scan width.
The data were processed using the SAINT software package [41].
Crystal data, data collection parameters, and structure refinement
details are given in Table 1.
The structure was solved by direct methods and refined by full-
matrix least-squares techniques. Non-hydrogen atoms were re-
fined with anisotropic displacement parameters. H atoms were in-
serted at calculated positions and refined with a riding model. The
following computer, software and tables were used: structure solu-
tion, SHELXS-97 [42]; refinement, SHELXL-97 [43]; molecular diagrams,
ORTEP-3 [44]; computer, Pentium IV; scattering factors [45].
2
mixture. However, in contrast to recent studies with other
Ru(II)–arene compounds [13], addition of NaCl did not shift the
equilibrium to the chlorido complexes. A similar behavior was ob-
served for structurally related (thio)pyrone complexes [22,25,47].
The IR spectra of the ligands show sharp bands at around
ꢀ1
3
260 cm , assignable to the hydroxy functionality of the pyrone
ꢀ1
(m
O–H), and bands at ca. 1645, 1605 and 1575 cm corresponding
to the dO–H and mC@C, mC@O as well as mC@C vibrations [48]. After
complex formation the band assigned to the OH group is signifi-
cantly weakened and becomes much broader. The signals between
ꢀ1
1
645 and 1570 cm are shifted to lower energies and appear at
ꢀ1
approximately 1600 (
m
C@C), 1560 (
m
C@O) and 1500 cm
(mC@C),
as reported for other pyrone complexes [48].
2
.5. Thermogravimetry/differential thermal analysis
The X-ray structure of 1f shows similar features to other pyr-
ones (Fig. 2) [49,50]. The pyrone ring in 1f is not perfectly planar
with an O1–C2–C3–C4 torsion angle of 5.95(16)°, compared to
2.0(4) in allomaltol and 3.00/ꢀ2.11° in two polymorphic forms of
The compounds were characterized by TG/DTA under nitrogen
ꢀ1
atmosphere (flow rate 50 mL min ). The temperature diagram
Ru
O
O
O
O
O
Cl
OH
OH
O
HCHO
i) NaOMe
HO
H
N
HO
HO
ii) [RuCl (cym)]
2
2
O
N
N
R2
X
R1
R3
R2
X
R1
R2
X
R1
R3
R3
1
a-f
2a-f
a
b
c
R1 = R2 = R3 = H, X = C
R1 = R2 = H, R3 = CH3, X = C
R1 = R2 = H, X = O
d
e
f
R1 = R3 = H, R2 = CH , X = C
R1 = R2 = CH3, R3 = H, X = C
R1 = R2 = CH3, X = O
3
Scheme 1. Synthesis of the ligands and of the corresponding Ru(II)– 6
g -p-cymene complexes.

J.H. Kasser et al. / Journal of Organometallic Chemistry 695 (2010) 875–881
879
+
Ru
X
X
X
3a
Ru
Ru
O
O
Cl
H O
2
X = OH, MeOH
O
HO
very slow
N
NH
N
+
Fig. 2. The molecular structure of 1f. The displacement ellipsoids are drawn at 50%
probability level. Selected bond lengths (Å) and angles (°): O2ꢀC3 1.3435(13),
O3ꢀC4 1.2502(14), O4ꢀC7 1.4062(14), O1ꢀC2 1.3702(13), O1ꢀC6 1.3420(13),
C2ꢀC3 1.3585(16), C5ꢀC6 1.3485(16); C3ꢀC4ꢀO3 121.06(10), C4ꢀC3ꢀO2
Ru
2
a
O
N
O
NH
1
20.81(10), C5ꢀC4ꢀO3 124.25(11).
HO
O
N
4
a
maltol. The bond lengths and angles are similar to those observed
for maltol [49] and allomaltol [50]. It appears that the pyrone
C2(X)@C3 bonds are generally slightly longer when X is an ali-
phatic substituent (1.36 vs. 1.32 for X = H), probably due to the
electron donating effect. The morpholine ring adopts a chair con-
formation and the two methyl groups are in equatorial positions
and cis to each other, although the starting material for the synthe-
sis contains a mixture of isomers. 1f is involved in a network of
intermolecular hydrogen bonding interactions in the solid state
2
Scheme 2. Reaction of 2a with H O and imidazole to yield 3a and 4a.
order reactions under release of the p-cymene and chlorido ligands
(e.g., for 2b 31.3% [theor. 32.4%]). However, no characteristic calo-
ric effects were observed which are necessary to exactly determine
the decomposition steps. The final residue for all complexes is as-
sumed to be elemental Ru after heating up to 900 °C (e.g., for 2b
18.5% [or 19.0% considering the drying effect in step 1; theor.
19.5%]), which is at slightly lower temperature than reported in lit-
erature (above 1000 °C) [51].
(
Fig. S1). The O2 partakes in a bifurcated hydrogen bond to O3
i
and N1 (see (Fig. S1). Another short hydrogen bonding interaction
is evident between the O4 as proton donor and O3ii as proton
acceptor.
The synthesized compounds were characterized by TG/DTA un-
der a nitrogen atmosphere. The TG curves of the ligands were very
similar and melting points between 160 and 180 °C were observed
in all cases (see Section 2). As soon as 1a–f are heated to temper-
atures greater than the melting point, decomposition occurs with
ESI-MS studies of the ligands were performed in positive and
negative ion modes and peaks assignable to protonated, sodiated
and deprotonated species were observed. For the complexes ana-
lyzed in positive ion mode immediately after dissolution the most
+
abundant peaks may be assigned to [M–Cl] ions. However, as
2
an initial loss of the CH OH group. For compounds 2a–f several
mentioned above, these compounds are unstable and their MS
change after prolonged incubation. For example, 2a was dissolved
in water and analyzed by ESI-MS after 60 h (sample was mixed
with MeOH in order to facilitate the spraying process) and the
degradation steps were observed (Fig. 3 for 2b), but no clear-cut
melting points were determined by DTA. The first step in the TG
curve is assignable to the release of water (ca. 0.50–0.92 eq.), fol-
lowed by the pyrone ligand in a first order reaction (e.g., for 2b
most abundant peaks at m/z 519.4, 551.2 and 565.1 were assigned
+
4
7.7% [theor. 48.2%]) and by decomposition of the residue in higher
to [(cym)Ru(
l
-CH OH)(
l
-OH)Ru(cym)–2H] , [(cym)Ru(
l
-CH OH) -
3
3
2
Fig. 3. Thermogravimetric and differential thermo analysis curves of 2b, determined in a temperature range between 25 and 900 °C. The measurement parameters are given
in Section 2.

8
80
J.H. Kasser et al. / Journal of Organometallic Chemistry 695 (2010) 875–881
(
l
-OH)Ru(cym)–2H]+ and [(cym)Ru(
l
-CH
3
OH)
3
Ru(cym)–3H]+,
tion of nucleophiles to the Ru center to replace the chlorido ligands
might be an option to obtain compounds with sufficient stability
for further studies.
respectively. In addition, a signal of low abundance at m/z 474.6
corresponding to [2a–Cl] was observed. Mass spectra of the com-
+
plexes revealed in aqueous solution the presence of dimeric spe-
cies, such as 3a (Scheme 2), which are formed by cleavage of the
chelating pyrone ligand. All the identified signals contained the
characteristic isotope pattern of either mono- or dinuclear ruthe-
nium compounds (mass spectrum of a freshly prepared solution
of 2f, Fig. 4). Similar observations were reported recently for struc-
turally related compounds [20,22,25].
4
. Conclusions
Organometallic Ru(II)–arene compounds with chelating ligands
have demonstrated potential as anticancer agents. However, one
major requirement is stability in aqueous solution in order to
administer such drugs formulated for intravenous infusion. Com-
plexes bearing pyrone ligands have been shown to form often sta-
ble species suitable for biological applications. In the present study,
a series of new pyrone-derived ligands was synthesized from kojic
acid in a Mannich reaction with aliphatic N-heterocycles and the
respective organometallic Ru(II)–arene compounds were obtained.
In contrast to related compounds, the complexes were not suffi-
ciently stable to characterize them in solution by NMR spectros-
copy (formation of dimeric Ru species) and therefore further
biological development appears to be limited. However, the com-
pounds were characterized by IR, TG/DTA, ESI-MS and elemental
analysis confirming the proposed structures. In an attempt to sta-
bilize the compounds they were reacted with imidazole to replace
the labile chlorido ligand. This approach yields stable species
which do not undergo hydrolysis and subsequent reaction to form
dimeric Ru(II) compounds. This reaction opens the route to obtain
cationic compounds with different properties in comparison to the
well established chlorido complexes.
In an attempt to stabilize the Ru complex and prevent dimer
formation, the chlorido complex 2a was reacted with an equimolar
amount of imidazole in D
a (Fig. 5, Scheme 2). In keeping with other Ru(II)–arene imidazole
compounds [52], 4a showed a much lower rate of hydrolysis to the
dimeric compound 3a in D O than the parent complex 2a. After
8 h incubation both the imidazole complex and decomposition
products were present in the reaction mixture, and the ratio of
a:3a was much higher than the ratio of 2a:3a observed under
2
O to the respective cationic compound
4
2
1
4
similar conditions.
The low stability of complexes 2 in aqueous solution limits the
compounds for further development as anticancer agents, and
makes them unsuitable for biological testing. However, coordina-
Acknowledgments
We thank the Hochschuljubiläumsstiftung Vienna, the FFG –
Austrian Research Promotion Agency (811591), the Austrian Coun-
cil for Research and Technology Development (IS526001), the The-
odor-Körner-Fonds, COST D39 and CM0902 and the Austrian
Science Fund for financial support. This research was supported
by a Marie Curie Intra European Fellowship within the 7th Euro-
pean Community Framework Programme project 220890-SuRuCo
(
A.A.N.). We gratefully acknowledge Alexander Roller for collecting
the X-ray diffraction data and Prof. Markus Galanski for recording
the 2D NMR spectra.
Appendix A. Supplementary material
2
Fig. 4. Mass spectrum recorded for 2f in H O/MeOH.
Crystallographic data for the structural analysis has been depos-
ited with the Cambridge Crystallographic Data Centre, CCDC No.
7
43776. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/da-
ta_request/cif. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.jorganchem.2010.01.007.
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