II
Anticancer Activity of Ru Complexes
FULL PAPER
6
6
[
Ru
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(h cymene)Cl
2
(3-methyl-2-benzothiazolinthion)] (H3): [(h cymene)-
was washed several times with dichloromethane and diethyl ether to get
a free flowing powder. Crystals suitable for X-ray diffraction were grown
RuCl
2
]
2
(100 mg, 0.16 mmol) was dissolved in dry methanol (20 mL). 3-
Methyl-2-benzothiazolinthion (59.8 mg, 0.33 mmol) was added to this
methanolic solution, The mixture was stirred for 30 h at room tempera-
ture. The solvent was removed and the obtained solid was dissolved in di-
chloromethane (3 mL). A brownish red precipitate was obtained on addi-
by slow evaporation from a methanol solution of the complex. Yield:
1
74%; H NMR (400 MHz, [D
6
]DMSO): d=1.23 (d, J=6.8 Hz, 6H), 2.12
(s, 3H), 2.86 (sept, 1H), 5.82 (d, J=6.4 Hz, 2H), 5.86 (d, J=6.4 Hz, 2H),
1
3
7.13–7.18 (m, 4H), 12.57 ppm (sbr, 2H; NH); C NMR (100 MHz,
tion of petroleum ether. The solid was filtered, washed with diethyl
[D
6
]DMSO): d=18.8, 22.4, 30.9, 86.4, 87.3, 101.0, 107.2, 110.4, 123.2,
1
ꢀ1
ether, and dried. Yield: 76%; H NMR (400 MHz, CDCl
3
, 208C): d=1.28
133.1, 169.0 ppm; IR: n˜ =1142, 3037 cm ; elemental analysis calcd (%)
(
d, J=7.2 Hz, 6H), 1.34 (d, J=6.8 Hz, 6H), 2.16 (s. 3H), 2.35 (s, 3H),
.91 (sept, 1H), 3.03 (sept, 1H), 3.92 (sbr, 6H), 5.35 (d, J=6.0 Hz, 2H),
2 2
for C17H20Cl N RuS: C 44.7, H 4.3, N 6.1, S 7.0; found: C 44.8, H 4.7, N
ꢀ
+ +
2
5
7
7.1, S 6.6; ESI-MS: m/z calcd for C17
found: 385.67.
H
19
N
2
RuS: 385.03 [Mꢀ2Cl ꢀH ] ;
.45 (d, J=6.0 Hz, 2H), 5.48 (d, J=6.0 Hz, 2H), 5.62 (d, J=6.0 Hz, 2H),
1
3
.35 (sbr, 2H), 7.45 (sbr, 2H), 7.52 ppm (sbr, 2H); C NMR (100 MHz,
, 208C): d=19.2, 19.4, 22.6, 22.8, 31.0, 31.3, 81.7, 83.0, 84.4, 97.2,
01.3, 101.6, 104.4, 112.9, 122.3, 125.8, 127.8, 142.5, 189.9 ppm; IR: n˜ =
[
2-Mercaptobenzoimidazole-5-carboxylicacid] (L8): 3,4-Diaminobenzoic
CDCl
3
acid (5 g, 33.9 mmol) was dissolved in ethanol/water (1:2, 60 mL) in the
presence of excess KOH (3.8 g, 66 mmol). To the dark red brown solu-
tion, CS (5 g, 66 mmol) was added and the mixture was stirred for 7 h to
2
1
1
4
ꢀ
1
2 2
177, 2959 cm ; elemental analysis calcd (%) for C18H21Cl NRuS : C
4.4, H 4.3, N 2.9, S 13.2; found: C 44.1, H 4.4, N 3.8, S 13.2.
get a precipitate. The precipitate was filtered and dissolved in water
(60 mL) to get a dark-brown-colored clear solution. On addition of gla-
cial acetic acid (two drops), a grey-colored precipitate formed, which was
6
[
Ru(h -cymene)Cl
2
(thiouracil)] (H4): Thiouracil (21.4 mg, 0.163 mmol)
6
2 2
was added to a solution of [(h -cymene)RuCl ] (50 mg, 0.08 mmol) in
1
acetonitrile (20 mL). Within 10 min of stirring, an orange precipitate ap-
peared. The reaction mixture was stirred for 5 h at room temperature to
complete the precipitation. The orange solid was filtered, washed with di-
washed with cold water and dried in vacuum. Yield: 80%; H NMR
(400 MHz, [D
J=8 Hz, 1H), 12.65 ppm (sbr, 2H; NH);
6
]DMSO): d=7.07 (d, J=8 Hz, 1H), 7.54 (s, 1H), 7.63 (d,
1
3
C NMR (100 MHz,
1
ethyl ether, and dried in vacuum. Yield: 86%; H NMR (400 MHz,
[D
6
]DMSO): d=109.9, 111.2, 125.1, 125.8, 133.0, 136.4, 168.1, 170.6 ppm.
[
1
1
D
6
]DMSO, 208C): d=1.20 (d, J=6.8 Hz6H), 2.09 (s, 3H), 2.83 (sept,
6
[
[
(
0
Ru(h -cymene)Cl
2
(2-mercaptobenzoimidazole-5-carboxylicacid)] (H8):
(100 mg, 0.16 mmol) was dissolved in dry methanol
2-Mercaptobenzoimidazole-5-carboxylic acid (64 mg,
.33 mmol) was added to this methanolic solution. The insoluble ligand
H), 5.78–5.83 (m, 5H; Ph, thiouracil), 7.42 (dd, J=12.8, J=5.2 Hz, 1H),
2.29 (sbr, 1H; NH), 12.45 ppm (sbr, 1H; NH); C NMR (100 MHz,
]DMSO, 208C): d=18.8, 22.4, 30.9, 86.4, 87.3, 101.0, 106.2, 107.3,
6
2 2
(h cymene)RuCl ]
10 mL).
1
3
[
D
6
ꢀ
1
1
43.0, 161.9, 177.0 ppm; IR: n˜ =1235, 1702, 3063 cm ; elemental analysis
slowly dissolved and the color changed from light red to dark brown. The
mixture was stirred for 24 h at room temperature. The solvent was re-
moved and the solid obtained was washed with dichloromethane and di-
ethyl ether several times to get a free flowing powder. Yield: 52%;
6
H NMR (400 MHz, [D ]DMSO): d=1.17 (d, J=6.8 Hz, 6H), 2.07 (s,
3H), 2.81 (sept, 1H), 5.77 (d, J=6.0 Hz, 2H), 5.81 (d, J=6.0 Hz, 2H),
7.19 (d, J=8.4 Hz, 1H), 7.64 (s, 1H), 7.75 (d, J=8.4 Hz, 1H), 12.79 ppm
(sbr, 2H; NH), 12.84 ppm (sbr, 1H; NH); C NMR (100 MHz,
[D ]DMSO): d=18.8, 22.4, 30.9, 86.4, 87.3, 101.0, 107.2, 110.0, 111.2,
125.2, 125.6 133.1, 136.6 168.1, 170.8 ppm; IR: n˜ =1094, 1668 cm
calcd (%) for C14
3
H
18Cl
2
ON
2
RuS: C 38.7, H 4.1, N 6.45, S 7.4; found: C
8.56, H 4.27, N 6.2, S 6.94.
6
6
Ru(h -cymene)Cl
mene)RuCl
solution of mercaptonicotinic acid (50.6 mg, 0.326 mmol) in methanol
10 mL). The mixture was stirred for 24 h at room temperature. Removal
2
(mercaptonicotinic acid)] (H5): A solution of [(h -cy-
1
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
]
2
(100 mg, 0.16 mmol) in methanol (20 mL) was added to a
(
1
3
of the solvent from the red reaction mixture under vacuum resulted in a
sticky oily product. The oily product was thoroughly triturated with cold
diethyl ether for 30 min. A brownish red precipitate was obtained. The
6
ꢀ
1
,
ꢀ
1
solid was filtered, washed with diethyl ether, and dried. Yield: 87%;
3045 cm ; elemental analysis calcd for RuC18
H 4.3, N 5.4; found: C 41.4, H 3.91, N 5.4; ESI-MS: m/z calcd for
2 2 2 2
H20SN O Cl ·H O: C 41.7,
1
H NMR (400 MHz, [D
6
]DMSO, 208C): d=1.03 (d, J=6.8 Hz, 3H), 1.19
ꢀ
+ +
(
d, J=6.8 Hz, 3H), 2.33 (s, 3H), 2.85 (sept, 1H), 5.93 (d, J=6 Hz, 1H),
.01 (t, J=5.6 Hz, 2H), 6.62 (d, J=6.4 Hz, 1H), 7.47–7.50 (m, 1H), 7.88–
.91 (m, 1H), 8.59–8.61 ppm (m, 1H); C NMR (100 MHz, [D ]DMSO,
6
08C): d=19.2, 22.2, 24.0, 31.8, 83.4, 85.2, 85.6, 86.9, 107.3, 107.7, 125.0,
C
18
H
19
N
2
O
2
RuS: 429.02 [Mꢀ2Cl ꢀH ] ; found: 429.35.
Methoxy-2-mercaptobenzoimidazole-5-carboxylate] (L9): 3,4-Diamino-
benzoic acid (2.1 g, 15 mmol) was dispersed in methanol (80 mL) and the
mixture was cooled to 08C. To this ice cold suspension, SOCl (4.3 mL,
0 mmol) was added in a dropwise manner, through a dropping funnel.
6
7
2
1
C
N
[
1
3
2
30.2, 140.3, 156.3, 163.9, 168.0 ppm; elemental analysis calcd (%) for
6
16
H
2.98,
19Cl
2
NO
S
2
RuS: C 41.65, H 4.15, N 3.04, S 6.95; found: C 41.53, H 4.3,
2
After complete addition of SOCl , the heterogeneous mixture was heated
+
6.86; ESI-MS: m/z calcd for
C
16
H
18NO
2
RuS : 390.01
to reflux for 5 h to get a clear solution. The solvent was evaporated in
order to get the desired ester (94%). The ester was obtained as the HCl
salt of the amine and was used for the next step. 3,4-Diaminomethyl ben-
zoate·2HCl (0.5 g, 2.1 mmol) was dissolved in an ethanolic solution of
KOH (0.57 g, 40 mL). The precipitated KCl was dissolved by addition of
ꢀ
+ +
[
Mꢀ2Cl ꢀH ] ; found: 390.16.
Ru
100 mg, 0.16 mmol) was dissolved in dry methanol (30 mL). 2-Mercapto-
6
6
[
(
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(h cymene)Cl
2
(2-mercaptobenzoxazole)] (H6): [(h cymene)RuCl
2
]
2
benzoxazole (49.9 mg, 0.33 mmol) was added to this methanolic solution,
The mixture was stirred for 48 h at room temperature. The solvent was
removed and the solid obtained was dissolved in dichloromethane
2
water. Addition of CS (5 g, 66 mmol) resulted in a red-colored solution,
which was stirred for 24 h. The insoluble residue was filtered from the re-
action mixture and ethanol was removed from the filtrate to get an
orange–yellow-colored free flowing powder, which was washed with
water and dried in vacuum to get the desired product. Yield: 90%;
6
H NMR (400MHz, [D ]DMSO): d=3.83 (s, 3H), 7.21 (d, J=8.4 Hz,
(
3 mL). A brownish red precipitate was obtained on addition of petrole-
um ether. The solid was filtered, washed with diethyl ether, and dried.
Crystals suitable for X-ray diffraction were grown by diffusing a metha-
nol solution of the complex with petroleum ether. Yield: 84%; H NMR
1
1
(
(
(
400 MHz, CDCl
3
, 208C): d=1.37 (d, J=6.8 Hz, 6H), 2.32 (s, 3H), 3.08
1H), 7.65 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 12.81 ppm (sbr, 1H; NH),
12.83 ppm (sbr, 1H; NH); C NMR (100 MHz, [D ]DMSO): d=53.0,
6
110.2, 111.0, 124.4, 125.1, 133.2, 136.9, 167.0, 171.1 ppm.
1
3
sept, 1H), 5.33 (d, J=6.0 Hz, 2H), 5.53 (d, J=6.0 Hz, 2H), 7.25–7.38
m, 4H), 12.62 ppm (sbr, 1H; NH); C NMR (100 MHz, CDCl
1
3
3
, 208C):
d=18.9, 22.7, 31.1, 82.8, 84.3, 99.7, 104.6, 110.9, 112.8, 125.4, 126.4, 129.8,
6
[
(
Ru
A
H
U
G
R
N
N
(h cymene)Cl
2
(Methoxy-2-mercaptobenzoimidazole-5-carboxylate)]
(100 mg, 0.16 mmol) was dissolved in dry
ꢀ
1
1
49.3 181.5 ppm; IR: n˜ =1182, 2929 cm ; elemental analysis calcd (%)
6
2 2
H9): [(h cymene)RuCl ]
for C17 NORuS: C 44.6, H 4.2, N 3.0; found: C 44.2, H 4.1, N 2.98;
H
19Cl
2
methanol (10 mL). Compound L9 (66.6 mg, 0.33 mmol) was added to this
methanolic solution, The insoluble ligand slowly dissolved and the color
changed from light red to dark brown. The mixture was stirred for 24 h
at room temperature. The solvent was removed and the solid obtained
was washed with dichloromethane and diethyl ether several times to get
a free flowing powder. Crystals suitable for X-ray diffraction were grown
ꢀ
+ +
ESI-MS: m/z for C17
H
18NORuS: 386.02 [Mꢀ2Cl ꢀH ] ; found: 386.36.
6
6
[
Ru(h -cymene)Cl
2
(2-mercaptobenzoimidazole)] (H7): [(h -cymene)-
2 2
RuCl ] ( 100 mg, 0.16 mmol) was dissolved in dry methanol (10 mL). 2-
Mercaptobenzoimidazole (49.9 mg, 0.33 mmol) was added to this metha-
nolic solution. The insoluble ligand slowly dissolved and the color
changed from light red to dark brown. The mixture was stirred for 24 h
at room temperature. The solvent was removed and the obtained solid
by slow evaporation from a methanol solution of the complex. Yield:
1
77%; H NMR (400 MHz, [D
6
]DMSO): d=1.19 (d, J=6.8 Hz, 6H), 2.08
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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