Synthesis, structure, and in vitro antiproliferative activity of cyclic hypervalent organobismuth(III) chlorides and their triphenylgermylpropionate derivatives

Article abstract of DOI:10.1016/j.jorganchem.2009.05.003

Six compounds of cyclic hypervalent organobismuth(III) chlorides and triphenylgermylpropionates bearing a nitrogen or sulfur atom as intramolecular coordination atom have been synthesized and characterized. The results of single-crystal X-ray analysis reveal that the eight-membered tetrahydroazabismocine rings are highly flexible. The Bi-S or Bi-N bond lengths in the thiabismocine or azabismocine derivatives are dependent on how the substituted groups are acting on the Bi, S or N atom. The replacement of the chlorine atom in azabismocine and thiabismocine with the triphenylgermylpropionic group (Ph₃GeCH₂CH₂COO{single bond}) leads to the lengthening of Bi-N and Bi-S bond. The substituents connected with the nitrogen atom also have an effect on the Bi-N bond length of azabismocine. For example, a cyclohexyl group has electron-donating ability higher than a phenyl group; the replacement of the former by the latter would lead to the decline of Bi-N bond length and increase of C_Ar-Bi-C_Ar angle in the eight-membered ring. The in vitro antiproliferative activities of the fabricated materials were compared on gastric carcinoma cells by means of the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT) method. It was found that the compounds show antiproliferative activity on gastric carcinoma cells (MGC-803) much higher than that of cisplatin. Moreover, there is enhancement of antiproliferative activity when the chlorine atom of the bismocine compounds is replaced by the triphenylgermylpropionic group, giving a low IC₅₀ value of 0.7 μM for thiabismocine triphenylgermylpropionate.

Full text of DOI:10.1016/j.jorganchem.2009.05.003

Journal of Organometallic Chemistry 694 (2009) 3019–3026
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Synthesis, structure, and in vitro antiproliferative activity of cyclic hypervalent
organobismuth(III) chlorides and their triphenylgermylpropionate derivatives
Xiao-Wen Zhang a,b, Jun Xia a, Hui-Wen Yan c, Sheng-Lian Luo a, Shuang-Feng Yin a,
,
*
e,
Chak-Tong Au a,d, , Wai-Yeung Wong
*
*
a College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, PR China
b Key Laboratory of Pollution Control and Resource Use of Hunan Province, University of South China, Hengyang 421001, PR China
c Cell Biology of Bioscience and Technology Academy, Central South University, Changsha 410013, PR China
d Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, PR China
e Department of Chemistry and Centre for Advanced Luminescence Materials, Hong Kong Baptist University, Kowloon Tong, Hong Kong, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Six compounds of cyclic hypervalent organobismuth(III) chlorides and triphenylgermylpropionates
bearing a nitrogen or sulfur atom as intramolecular coordination atom have been synthesized and char-
acterized. The results of single-crystal X-ray analysis reveal that the eight-membered tetrahydroazab-
ismocine rings are highly flexible. The Bi–S or Bi–N bond lengths in the thiabismocine or azabismocine
derivatives are dependent on how the substituted groups are acting on the Bi, S or N atom. The replace-
ment of the chlorine atom in azabismocine and thiabismocine with the triphenylgermylpropionic group
(Ph3GeCH2CH2COOA) leads to the lengthening of Bi–N and Bi–S bond. The substituents connected with
the nitrogen atom also have an effect on the Bi–N bond length of azabismocine. For example, a cyclohexyl
group has electron-donating ability higher than a phenyl group; the replacement of the former by the lat-
ter would lead to the decline of Bi–N bond length and increase of CAr–Bi–CAr angle in the eight-membered
ring. The in vitro antiproliferative activities of the fabricated materials were compared on gastric carci-
noma cells by means of the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide (MTT)
method. It was found that the compounds show antiproliferative activity on gastric carcinoma cells
(MGC-803) much higher than that of cisplatin. Moreover, there is enhancement of antiproliferative activ-
ity when the chlorine atom of the bismocine compounds is replaced by the triphenylgermylpropionic
Received 28 March 2009
Received in revised form 5 May 2009
Accepted 5 May 2009
Available online 10 May 2009
Keywords:
Bismuth
Germanium
Hypervalent
Antiproliferative activity
group, giving a low IC50 value of 0.7
lM for thiabismocine triphenylgermylpropionate.
Ó 2009 Elsevier B.V. All rights reserved.
1. Introduction
the report of Chiba that these salts are helpful in Helicobacter py-
lori eradication therapy [16], various bismuth compounds have
been studied for antibacterial [17,18] or antitumor [14,19] pur-
poses. For example, Murafuji et al. [17] systematically studied
the antifungal activity of triarylbismuth dichlorides and halob-
ismuthanes against Saccharomyces cerevisiae, and they reported
that {Bi(Cl)(C6H4-2-SO2C6H4-10-)} showed the best effect on
growth inhibition of the yeast. Also, Kotani et al. [18] investigated
the antibacterial properties of some cyclic organobismuth com-
pounds bearing a nitrogen or sulfur atom as an additional ring
member, and found that the eight-membered bismacycles have
potent antibacterial activity against gram-negative as well as
gram-positive bacteria, including methicillin-resistant S. aureus
(MRSA).
Bismuth is a nontoxic and noncarcinogenic element and many
of its compounds are low in toxicity and can be safely used in areas
such as medicine, catalysis, and organic synthesis [1–3]. In the past
decade, there has been a rapid development on bismuth chemistry,
and some novel bismuth compounds have been reported [4–11].
Over 200 years, inorganic bismuth salts have been used as medic-
inal drugs because of their low toxicity and high effectiveness in
the treatment of a variety of microbial infections [12–15]. Typical
examples are the widespread use of the commercially available
Pepto-Bismol (bismuth subsalicylate, BSS) and De-Nol (colloidal
bismuth subcitrate, CBS) drug for gastrointestinal disorders. Since
It is known that organogermanium is biologically active [20–22].
In view of the biological functions of organobismuth(V) and organ-
ogermanium compounds, Yu et al. [22] synthesized (4-BrC6H4)3-
Bi(O2CCH2CH2GePh3)2 and (4-BrC6H4)3Bi[O2CCH(CH3)CH2GePh3]2
and reported that the two showed good in vitro antiproliferative
activity towards HCT-8, Bel-7402 and KB cells, higher than
* Corresponding authors. Address: College of Chemistry and Chemical Engineer-
ing, Hunan University, Changsha 410082, PR China (C.-T. Au). Tel./fax: +86 731
5118161.
E-mail addresses: sf_yin@hnu.cn (S.-F. Yin), pctau@hkbu.edu.hk (C.-T. Au),
rwywong@hkbu.edu.hk (W.-Y. Wong).
0022-328X/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2009.05.003

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X.-W. Zhang et al. / Journal of Organometallic Chemistry 694 (2009) 3019–3026
cisplatin which is used clinically as an antitumor drug. Although
the mechanism of antifungal or antiproliferative action of the
organobismuth compounds remains unclear, many researchers be-
lieve that the biological action of organobismuth compounds is re-
lated to the coordination of bismuth center [12].
to 87% and 92%, respectively. The reactions of compounds 4a and
4b with triphenylgermylpropionic acid in the presence of NaOH
(as neutralizing agent) gave compounds 5a and 5b, respectively,
in good yields (above 90%). Moreover, recrystallization of these
cyclic hypervalent organobismuth compounds from CH2Cl2/hexane
gave crystals suitable for single-crystal X-ray diffraction analysis.
In view of the ‘‘green” property of bismuth, we have made a ser-
ies of studies on the chemistry of bismuth compounds [10,23,24].
We found that organobismuth compounds with cyclic framework
are potentially good antiproliferative drugs. As an extension of
our research, we introduced an organogermanium group to the
cyclic organobismuth compounds, and examined the antiprolifera-
tive properties of the as-synthesized compounds. Overall, we syn-
thesized six compounds of cyclic organobismuth (III) chlorides and
their triphenylgermylpropionate derivatives. In this paper, we re-
port the bonding nature and structure as well as the antiprolifera-
tive activities of these compounds. We attempted to establish a
relationship between structural properties and antiproliferative
activities. To the best of our knowledge, no work of this kind has
been reported in the literature.
2.2. Molecular structure and physiochemical property
Although many bismuth compounds were found to show good
biological activity, the structures of some of them are unclear or
have only been characterized recently. For example, bismuth
subsalicylate (BSS), colloidal bismuth citrate (CBS), and ranitidine
bismuth citrate (RBC) have been used as antiulcer drugs for
decades, but their structures have been discovered only recently.
Considerable efforts have been made to model the structure of
BSS through bismuth salicylate [Bi(Hsal)3] (H2sal = (2-HO)C6H4-
COOH) ‘‘trapped” by chelating amines, e.g., bismuth thiosalicylate
complexes [Bi(Hsal)3(bpy)]2ꢁ(C7H8)2, (bpy = 2,20-bipyridine) [26].
Recently, a new structural model of BSS with two bismuth oxosal-
icylate clusters, viz. [Bi38O44(Hsal)26(Me2CO)16(H2O)2]ꢁ(Me2CO)4
and [Bi9O7(Hsal)13(Me2CO)5]ꢁ(Me2CO)1.5 was reported, and the
mechanism of hydrolysis and core formation proposed [15,27].
Our interest was directed towards what the intramolecular coordi-
nation between the bismuth and nitrogen (or sulfur) atom is and
the effect of substitution group of the organogermanium segment.
The generation and quality of the crystals of compounds 1, 2,
4a,b, and 5a,b were verified by single-crystal X-ray diffraction.
Listed in Table 1 are the crystal data, data collection and structure
refinement details. The molecular structures of the six compounds
are shown in Figs. 1 and 2. The values of selected bond lengths and
bond angles are listed in Table 2. Despite compound 1 has been
known for many years, its crystal structure has not been deter-
mined by X-ray analysis. One can see that the central bismuth-con-
taining part of the six compounds exhibits a pseudo-trigonal
bipyramidal (TBP) structure, where both the C(1) and C(14) atoms
of 1 and 2, C(1) and C(20) atoms of 4a, 4b and 5a, 5b exist in the
equatorial position of the TBP structure along with a lone electron
pair of bismuth, and the S(1) of 1, 2 or N(1) of 4a, 4b and 5a, 5b
are at the apical position, with CAr–Bi–CAr bond angles in the
92.9–99.5° range. These results strongly support the existence of
transannular interaction between Bi and N or Bi and S atoms. For
example, in compound 2, the distance between S(1) and Bi(1) is
2.909 Å, smaller than the sum of the van der Waals radius of the
sulfur (1.8 Å) and bismuth (2.4 Å) atom but longer than the cova-
lent Bi–S bond distance (2.54 Å). In other words, there is a Bi S
coordination bond in the thiabismocine compounds.
2. Results and discussion
2.1. Synthesis
Scheme 1 shows the synthesis routes for organobismuth chlo-
ride 1 and organobismuth triphenylgermylpropionate 2. Previ-
t
ously, compound 1 was synthesized with the use of BuLi [18]. In
this study, we used nBuLi instead for the sake of safety. The lithia-
tion reaction was conducted at ꢀ30 °C and the resulting dianion
was treated with anhydrous bismuth chloride to produce com-
pound 1. The reaction of compound 1 with triphenylgermylprop-
ionic acid in the presence of NaOH (as neutralizing agent) and
THF-H2O (as solvent) under the protection of a N2 atmosphere
yielded compound 2. The yield of organobismuth triphenylgermyl-
propionate 2 (a new compound) was 90%.
Depicted in Scheme 2 are the synthesis routes of organobis-
muth chlorides 4a, 4b and organobismuth triphenylgermylpropio-
nates 5a, 5b. It is noted that the synthesis and structure of
6-methyl-5,6,7,12-tetrahydrodibenz[c,f][1,5]azabismocine deriva-
tives have been reported by Akiba and co-workers [25]. Shimada
t
et al. also introduced a Bu group in place of the methyl group on
the N atom to increase the electron-donating ability of the N atom
and to protect the N atom from being involved in undesirable side
reactions [7]. In order to manipulate the electron-donating ability
of the N atom, we adopted phenyl and cyclohexyl groups. Com-
pounds 3a and 3b are new compounds and can be synthesized
via the reaction of 1-bromo-2-(bromomethyl)benzene with RNH2
(R = phenyl, cyclohexyl) using K2CO3 as neutralizing agent and
DMF as solvent in refluxing conditions under N2 atmosphere. The
methodology for synthesis of compounds 4a and 4b was similar
to that for compound 1. The isolated yields of 4a and 4b are up
The Bi–S bond distance in compound 1 (2.845(4) Å) is slightly
shorter than that in compound 2 (2.909(3) Å), and the Bi–C bond
distance of compound 1 (ranging from 2.242(15) to 2.285(4) Å)
and that of compound 2 (ranging from 2.229(12) to 2.251(12) Å)
1) nBuLi
2) BiCl3
CH2Br
Na2S
THF
S
S
Br
Br Br
Bi
Cl
1
HOC(O)CH2CH2GePh3
NaOH
S
Bi
OC(O)CH2CH2GePh3
2
Scheme 1. Synthesis of thiabismocine derivatives 1, 2.

X.-W. Zhang et al. / Journal of Organometallic Chemistry 694 (2009) 3019–3026
3021
R
N
R
N
1) nBuLi
2) BiCl3
CH2Br
Br
RNH2,Et3N
DMF
Br Br
Bi
Cl
3a
:R=phenyl
3b
:R=cyclohexyl
4a:R=phenyl
4b:R=cyclohexyl
R
N
HOC(O)CH2CH2GePh3
NaOH
Bi
OC(O)CH2CH2GePh3
5a:R=phenyl
5b:R=cyclohexyl
Scheme 2. Synthesis of azabismocine derivatives 4a,b and 5a,b.
Table 1
Crystal data, data collection and structure refinement details for compounds 1, 2, 4, and 5.
1
2
4a
5a
4b
5b
Chemical formula
Crystal habit
Crystal size [mm]
Crystal system
Space group
a [Å]
C14H12BiClS
C35H31BiGeO2S
PALE yellow block
0.32 ꢂ 0.26 ꢂ 0.22
Monoclinic
P21
17.8094(18)
9.5078(9)
18.0861(18)
90
96.321(2)
90
3043.9(5)
4
1.74
797.23
1552
20
56.4
6.86
18293
11141
C20H17BiClN
C41H36BiGeNO2
Colorless block
0.32 ꢂ 0.25 ꢂ 0.22
Monoclinic
P21/c
8.9187(5)
35.6350(2)
10.7230(6)
90
94.512 (10)
90
3397.4(3)
4
1.674
856.28
1680
-100
56.6
6.09
20217
8204
C20H23BiClN
Colorless block
0.32 ꢂ 0.27 ꢂ 0.24
Monoclinic
P21/c
10.2934(14)
16.3880(2)
12.0708(17)
90
113.975(2)
90
1860.5(4)
4
1.863
521.82
1000
-100
50
9.62
8331
3214
C41H42BiGeNO2
Colorless block
0.33 ꢂ 0.23 ꢂ 0.16
Triclinic
P-1
8.9433(4)
19.9454(9)
20.0095(9)
78.948(10)
88.436(10)
88.354(10)
3500.7(3)
4
1.636
862.33
1704
-100
50
5.91
17084
11974
Colorless block
0.28 ꢂ 0.24 ꢂ 0.22
Triclinic
Colorless block
0.32 ꢂ 0.25 ꢂ 0.23
Triclinic
ꢀ
ꢀ
P
P
8.9590(6)
9.0096(6)
34.2740(3)
93.165(2)
93.306 (10)
90.187 (10)
2757.6(3)
8
2.2
456.73
1696
20
50
9.2370(11)
9.2770(11)
10.8761(12)
78.655(2)
78.668(2)
72.185(2)
860.6 (17)
2
1.99
515.78
488
20
50
b [Å]
c [Å]
a
[°]
b [°]
c
[°]
V [Å3]
Z
Dc [g cmꢀ3
M
]
F (0 0 0)
T [°C]
2hmax [°]
l(Mo K
a
) [mmꢀ1
]
13.106
13143
9349
10.397
3959
2856
No. of reflections measured
No. of unique reflections
No. of observed reflections (Rint
)
7386 (0.032)
0.057
0.164
613
1.01
9283 (0.043)
0.051
0.141
721
1.14
2761 (0.029)
0.034
0.093
208
1.06
7373 (0.032)
0.039
0.109
416
1.03
3025 (0.027)
0.029
0.08
209
1.07
10717 (0.021)
0.026
0.07
829
1.01
R (I > 2r(I))
wR2 (F2, all reflections)
No. of parameters
Goodness of fit on F2
Fig. 1. Molecular structures of 1, 4a, and 4b. Thermal ellipsoids are drawn at the 50% probability levels.

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X.-W. Zhang et al. / Journal of Organometallic Chemistry 694 (2009) 3019–3026
Fig. 2. Molecular structures of 2, 5a, and 5b. Thermal ellipsoids are drawn at the 50% probability levels.
Table 2
Selected bond distances (Å) and bond angles (°) of compounds 1, 2, 4a,b and 5a,b.
Xd
c
C2
f
b
C1
Bi
a
E
e
R g
Bond length/angle
1
2
4a
5a
4b
5b
a
b
c
d
ab
ac
ad
bc
bd
cd
ae
af
2.845(4)
2.285(14)
2.242(15)
2.632(4)
75.20(4)
73.30(4)
155.2(13)
98.90(5)
91.80(4)
88.40(4)
92.5(6)
2.909(3)
2.251(12)
2.229(12)
2.256(7)
74.70(3)
73.60(3)
151.0(2)
99.50(4)
91.40(4)
84.20(4)
91.9 (4)
92.9 (4)
2.607(5)
2.259(6)
2.238(6)
2.597(19)
72.30(2)
73.10(2)
158.9(13)
92.90(2)
92.38(19)
93.82(17)
99.4(4)
2.631(4)
2.256(4)
2.235(5)
2.251(3)
70.32(14)
71.99(15)
148.2(13)
97.75(16)
86.35(14)
90.88(15)
102.7(3)
104.4(3)
104.1(3)
110.8(4)
1.959(4)b
2.517(4)
2.228(6)
2.252(5)
2.654(13)
73.64(17)
75.23(16)
159.0(10)
96.72(19)
92.24(14)
91.49(13)
103.5 (3)
106.6(3)
109.2(3)
110.6(4)
2.563(3)
2.232(3)
2.250(3)
2.298(2)
73.03(11)
73.62(11)
149.3(9)
98.30(12)
83.75(11)
90.55(11)
102.7(19)
106.4(19)
111.1(2)
110.0(3)
1.964(3)c
91.9(6)
106.0(4)
107.1(4)
111.7(5)
ag
ef
Others
103.9(9)
104.4(7)
1.978(11)a
a
The bond length of C(17)–Ge(1).
The bond length of C(23)–Ge(1).
The bond length of C(23)–Ge(1).
b
c
are also different. The Bi–Cl single bond of compound 1 is
2.632(4) Å, while the Bi–O single bond of compound is
atom to deviate from the axial position of TBP geometry and is
rather flexible in nature. Also, the Bi–S bond distance reflects the
influence of the substituent that is acting on the bismuth center.
The results of X-ray diffraction analysis show that the Bi–N
bond distance in compounds 4a, 4b, 5a and 5b is 2.607(5),
2.517(4), 2.631(4), and 2.563(3) Å; the Bi–Cl single bond in com-
pounds 4a and 5a is 2.597(19) and 2.654(19) Å while the Bi–O
bond distance in compounds 4b and 5b is 2.251(3) and 2.298
(2) Å, respectively. Obviously, the replacement of the Cl atom by
–OC(O)CH2CH2GePh3 lengthens the Bi–N bond, and this phenome-
non can be attributed to the electron-donating effect of O(1). Com-
2
2.256(7) Å. In compound 2, the bonding interactions between
Bi(1) and the carbonyl oxygens of carboxylate is relatively strong.
This can be attributed to the electron-donating effect of O(1) of
the triphenylgermylpropionic group (Ph3GeCH2CH2COOA). Af-
fected by the adjacent O(1) atom, the O(1)–Bi(1)–S(1) angle of
compound 2 (151.0(2)°) is smaller than Cl(1)–Bi(1)–S(1) of com-
pound 1 (155.2(13)°). The CAr–Bi–CAr angle of compound 1 and 2
is 98.9o and 99.5°, respectively. These results suggest that the
eight-membered tetrahydrothiabismocine ring forces the sulfur

X.-W. Zhang et al. / Journal of Organometallic Chemistry 694 (2009) 3019–3026
3023
pared to the Cl(1)–Bi(1)–N(1) angle of compound 4a (158.9(13)°)
and compound 4b (159.0(10)°), there is a reduction in the O(1)–
Bi(1)–N(1) angle of compound 5a (148.2(13)°) and compound 5b
(149.3(9)°). The Ge–C bonds of compounds 2, 5a, and 5b are consis-
tent with those reported in the literature [28], ranging from
1.959(4) to 1.978(11) Å. The stereochemistry of germanium is
essentially tetrahedral in geometry in 5a and 5b.
more active against the MGC-803 cell in vitro. Compound 2 shows
a significant activity against the MGC-803 cell, showing inhibition
ratios higher than 60%. At concentration of 1.25, 2.5, 5, 10, and
20
65%, 77%, 82% and 86%, respectively. Moreover, the IC50 value for
compound 2 is 0.7 M, lower than those for other organobismuth
l
g mlꢀ1, the inhibition ratio against MGC-803 cells is 62%,
l
complexes, and much lower than that for the cisplatin.
It is known that the nature of hypervalent compounds having
intramolecular Bi–N or Bi–O coordination, e.g., [2-(Me2NCH2)C6-
H4]Bi-[C6H4{C(CF3)2O}-2], [2-(MeOCMe2)C6H4]Bi-[C6H4{C(CF3)2O}-
The results of Table 3 also illustrate how the electronic action of
the substituents on Bi or N atom affects the antiproliferative activ-
ity. Due to the fact that the cyclohexyl group has an electron-
donating ability stronger than the phenyl group, compounds 4a
and 5a show better activity than compounds 4b and 5b, respec-
tively. Thus, it is apparent that a proper coordination ability of Bi
center is very important for good antiproliferative activity. Mur-
afuji et al. [17] employed X-ray crystallographic method to disclose
the structure-activity relationship of triarylbismuth dichlorides
and halobismuthanes against the yeast S. cerevisiae. They found
that the bismuth center of the compounds adopts a seven-coordi-
nate geometry through intramolecular and intermolecular coordi-
nation between bismuth and oxygen atoms. The authors attributed
the antifungal activity to the highly coordinated geometry which
allows the bismuth center to bind tightly with biomolecules that
play important roles in the growth of S. cerevisiae. Kotani et al.
[18] deduced that the bismuth and chlorine atoms in the organo-
bismuth compounds can undergo transannular interaction with
the nitrogen or sulfur atom via a state of hypervalent transition,
and attributed the bismacycle action to both the physical proper-
ties of bismuth and the chemical properties of heterocyclic struc-
ture. Comparing our work with those of Murafuji et al. [17] and
Kotani et al. [18], there are apparent discrepancies. Nevertheless,
it is clear that it is difficult for bacteria to develop resistance to
the reported compounds. Further work is underway to disclose
the antiproliferative mechanism of these complexes.
t
2] [29,30], BuN(CH2C6H4)2BiX (X = Cl, Br, F, Ph, 3,5-(CF3)2C6H3–,
3,4-(CH2O2)2C6H3–,
2,4,6-(MeO)3C6H2–,
CH2@C(Me)–)
and
[tBuN(CH2C6H4)2Bi]+ [B(C6F5)4]ꢀ [7,9,31], is highly affected by the
electronic nature of the Bi atom. According to the works by
Shimada et al., the Bi–N distances of 5,6,7,12-tetrahydrodi-
benz[c,f][1,5]azabismocines have a good linear relationship versus
the Hammett’s rm-constants of the substituents on the Bi atom [9].
All these compounds exhibit similar coordination geometries with
two Bi–C bonds and the lone pair of electrons on bismuth occupy-
ing the equatorial position of TBP geometry. The equatorial
position of the other compounds is occupied by two carbon atoms
with the CAr–Bi–CAr angle considerably diminished (less than 120°)
and with the N (O, S)–Bi–X bond angle ranging from 148.5(1) to
160.6(2) Å. The Bi–N distance (2.357(2) Å) in the cationic complex
[tBuN(CH2C6H4)2Bi]+[B(C6F5)4]ꢀ is much shorter than those of pre-
viously reported neutral 5,6,7,12-tetrahydrodibenz[c,f][1,5]azab-
ismocines (2.559(4)–2.894(4) Å) [7,9], and those of the newly
synthesized compounds 4a,b and 5a,b (2.517(4)–2.631(4) Å).
We found that the as-synthesized cyclic bismuth compounds
are stable with high melting points. Generally speaking, ordinary
organobismuth(III) compounds bearing Bi–Cl bond are moisture
sensitive and readily decompose under atmospheric conditions.
However, the six compounds fabricated in the present study are
comparatively stable and can be stored for over one year in air
without appreciable degradation. The enhanced stability of these
3. Conclusion
cyclic compounds may be attributed to the efficient 6s2-
p conjuga-
tion between the benzene and bismuth center, and to the transan-
nular coordinative interaction between the nitrogen (or sulfur) and
the bismuth center; both factors make the bismuth less susceptible
to the attack of water and oxygen molecules.
We have synthesized six cyclic hypervalent organobismuth
compounds. The compounds show high degrees of stability. The re-
sults of structure determination by means of single-crystal X-ray
diffraction reveal that the eight-membered tetrahydroazabismo-
cine rings are highly flexible and the Bi–S or Bi–N bond lengths
in thiabismocine or azabismocine derivatives are dependent on
the influence of the substituted groups that is acting on the N
and Bi atom. The replacement of Cl atom by organogermanium
segment resulted in the lengthening of the Bi–S or Bi–N bonds.
The six compounds show antiproliferative activities on MGC-803
better than that of cisplatin. The IC50 value for compound 2 is
2.3. Antiproliferative activity assay
The antiproliferative activity of the compounds newly fabri-
cated by us was assessed by the MTT method as described previ-
ously by Skehan et al. [32]. We examined the viability of gastric
carcinoma cells in a span of 24 h with compounds 1, 2, 4a,b and
5a,b in different concentrations. The activities of the compounds
are listed in Table 3. Compared to cisplatin, the compounds are
0.7 l
M. It is apparent that a proper coordination ability of Bi3+
and the introduction of organogermanium group is beneficial for
achieving good antiproliferative activity of bismocine compound.
Table 3
4. Experimental
Inhibition ratio (%) of the organobismuth complexes on MGC-803 in vitro.a
g mlꢀ1
5
)
IC50
(lM)
b
Compounds
Concentration (
l
4.1. General procedures
20
10
2.5
1.25
All manipulations of air-sensitive materials were conducted in a
glovebox filled with argon or under the protection of N2 atmo-
sphere according to the standard Schlenk tube techniques. Tetra-
hydrofuran, toluene, and ether were dried and distilled from a
purple solution of sodium/benzophenone ketyl. N,N-Dimethyl
formamide (DMF) was dried by 4 Å molecular sieves, followed by
distillation under reduced pressure. Chloroform and dichlorometh-
ane were dried with CaH2 and distilled under nitrogen. The glass-
ware was dried in an oven at 120 °C prior to use. The commercially
available chemicals were purchased from Aldrich or Sinopharm
1
2
4a
5a
4b
5b
Cisplatin
84
86
76
80
78
81
63
81
82
74
77
72
75
53
73
77
71
75
67
69
40
60
65
58
68
60
63
30
55
62
50
61
25
30
10
2.1
0.7
2.0
0.9
5.3
2.6
30.5
a
Inhibition ratio (%) = (A1/A2)/A1 ꢂ 100%. A1: mean optical densities of untreated
cells; A2: mean optical densities of drug-treated cells.
b
The concentration of a compound needed to reduce population growth of
organisms by 50% in vitro.

3024
X.-W. Zhang et al. / Journal of Organometallic Chemistry 694 (2009) 3019–3026
Chemical Reagent Co. Ltd., and were used as received without fur-
ther purification unless denoted otherwise. BiCl3 was purified by
refluxing with SOCl2, followed by sublimation under vacuum.
NMR spectra were recorded on a Brucker 400M spectrometer (1H
NMR, 400 MHz; 13C NMR 100 MHz); chemical shifts of 1H (d
ppm) were reported with reference to internal tetramethylsilane
standard (d 0.0), while the chemical shifts of 13C NMR were re-
ported using CDCl3 as internal standard (d 77.0). Melting points
of compounds were determined over a XT-4 micro melting point
apparatus (Beijing Tech Instrument Co. LTD). The IR spectra of
the compounds were recorded in the range 650ꢃ4000 cmꢀ1 on
Nexus 670 FT-IR equipment (Thermo Nicolet) using powder-
pressed KBr pellets. Elemental analyses were performed over a
VARIO EL III instrument.
MgSO4. Removal of the solvent under vacuum resulted in
450.6 mg (94%) of a pale yellow solid compound 3. Melting point,
202–204 °C; 1H NMR (400 MHz, CDCl3): d 2.04 (2H, t, J = 8.4 Hz),
2.72 (2 H, t, J = 8.4 Hz), 4.16 (2H,d, J = 14.8 Hz), 4.40(2H,d,
J = 15.2 Hz), 7.25–7.56 (23 H, m), 8.18 (2H, d, J = 6.8 Hz). 13C NMR
(100 MHz, CDCl3): d 10.27, 31.89, 40.71, 127.69, 128.19, 128.88,
130.25, 130.98, 135.05, 136.78, 137.73, 147.48, 177.50, and
181.36. Anal. Calc. for C35H31BiGeO2S (797.30): C, 52.72; H, 3.92;
Bi, 26.21; Ge, 9.11; O, 4.01; S, 4.02. Found: C, 52.63; H, 3.99; Bi,
26.16; Ge, 9.16; O, 4.09; S, 3.96.
1619, 1429, 1349, 1259, 1090, 738, and 699.
c
max(KBr)/cmꢀ1: 3046, 1964,
4.4. Preparation of PhN (CH2C6H4)2BiCl (4a)
To a hexane solution of nBuLi (2.5 M, 81.6 ml, 204.0 mmol) was
added an Et2O (300 ml) solution of phenylamine 3a (43.1 g,
100.0 mmol) at ꢀ30 °C. The mixture was gradually warmed to
room temperature over 3 h. The mixture was then added to a
mixture of BiCl3 (31.4 g, 102.0 mmol) in Et2O (400 ml) at
ꢀ78 °C. The resulting mixture was stirred overnight, during which
the temperature was allowed to rise gradually to room tempera-
ture. The solvent was removed under vacuum and the residue
was subject to 3-times extraction with toluene/brine (2 M NH4Cl)
(250 ml ꢂ 3), and the insoluble material was removed by filtra-
tion. The organic layer was washed with de-ionized H2O
(450 ml ꢂ 3) and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure to leave an oil brownish yellow
in color. The obtained residue was recrystallized from CH2Cl2/
hexane to give compound 4a in the form of colorless crystals
(44.87 g, 87%). Melting point, 257–259 °C; 1H NMR (400 MHz,
CDCl3): 4.52 (2H, d, J = 14.8 Hz), 4.76 (2H, d, J = 14.8 Hz), 6.47
(2H, d, J = 7.6 Hz), 6.65 (2H, t, J = 7.2 Hz), 7.31 (1H, t, J = 7.2 Hz),
7.44 (2H, d, J = 7.2 Hz), 7.51 (4H, t, J = 8.0 Hz), 8.59 (2H, d,
4.2. Preparation of S (CH2C6H4)2BiCl (1)
Bis(2-bromobenzyl) sulfide (14.88 g, 40.0 mmol) was dissolved
in dried ethyl ether (150 ml), and 32.6 ml (81.6 mmol, 2.5 M in
hexane) of n-butyllithium was added dropwise at ꢀ30 °C. The as-
obtained mixture was stirred for 3 h, which was then added a solu-
tion of BiCl3 (12.87 g, 40.8 mmol) in dried ethyl ether (120 ml) at
ꢀ50 °C. The resulting mixture was stirred overnight with the tem-
perature of the mixture rose gradually to room temperature. After
removal of solvent under vacuum and 3-times toluene extraction
(100 ml ꢂ 3), the insoluble material was filtered out, and the
resulting organic layer washed with de-ionized H2O (300 ml ꢂ 3)
and dried over anhydrous MgSO4. The solvent was removed under
reduced pressure to leave oil that is yellow in color (13.86 g, 76%).
The yellow oil was dissolved in CH2Cl2 and recrystallized from
CH2Cl2/hexane to give compound 1 in the form of colorless crystals
(8.22 g, 45%). Melting point, 179–180 °C; 1H NMR (400 MHz,
CDCl3): d 4.26 (2H, d, J = 15.2 Hz), 4.52 (2H, d, J = 15.6 Hz), 7.37
(2H, t, J = 7.6 and 7.2 Hz), 7.49–7.56 (4H, m), and 8.80 (2H, d,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): d 41.05, 127.98, 130.81,
130.84 (2C), 139.12, 147.63, and 173.65. Anal. Calc. for C14H12BiClS
(456.74): C, 36.81; H, 2.65; Bi, 45.75; Cl, 7.76; S, 7.02. Found: C,
J = 3.2 Hz). 13C NMR (100 MHz, CDCl3):
d 62.27 (2C, NCH2),
118.06, 124.06, 127.13, 127.33, 128.79, 130.66, 137.43, 146.98,
147.47 and 172.66. Anal. Calc. for C20H17BiClN (515.79): C,
46.57; H, 3.32; Bi, 40.52; Cl, 6.87; N, 2.72. Found: C, 46.49; H,
36.55; H, 2.75; Bi, 45.79; Cl, 7.73; S, 7.17.
c
max(KBr)/cmꢀ1: 3,047,
3.36; Bi, 40.48; Cl, 6.95; N, 2.62. c
max(KBr)/cmꢀ1: 3,043, 2,915,
2,959, 1,574, 1,452, 1,433, 1,236, 908, 754, and 700.
1,594, 1,491, 1,430, 1,205, 931, 754, and 698.
4.3. Preparation of S (CH2C6H4)2BiO2CCH2CH2GePh3 (2)
4.5. Preparation of C6H11N (CH2C6H4)2BiCl (4b)
The b-(triphenylgermyl)propionic acids were synthesized as de-
scribed by Barton et al. [33,34] 2.0 g (19.0 mmol) GeO2, 4.4 g
(40.0 mmol) NaH2PO2ꢁH2O, 25 ml HCl and 4 ml distilled water
were mixed in a four-necked round bottomed flask, and the mix-
ture was refluxed at 99–102 °C for 4 h under vigorously agitation
to obtain a clear HGeCl3 solution. 1.38 g (19.0 mmol) acrylic acid
was added dropwise with temperature controlled in the
ꢀ10 ꢃ ꢀ5 °C range (using a bath of ice brine) for 2 h. The so-ob-
tained mixture was stirred for 10 h, during which the temperature
was allowed to rise gradually to room temperature. Then the mix-
ture was subject to 3-times extraction with ethyl ether (20 ml ꢂ 3).
The organic layer was separated and dried with anhydrous MgSO4
for 4 h. The solvent was removed in vacuo and the resulting resi-
due was recrystallized from CH2Cl2/oil ether to obtain 4.08 g
Compound 4b was prepared according to a procedure similar to
that of 4a. Amine 3b (20.2 g, 46.0 mmol) was allowed to react with
nBuLi (2.5 M, 37.7 ml, 94.0 mmol) at ꢀ30 °C, and the resulting solu-
tion was added to a mixture of BiCl3 (14.8 g, 47.0 mmol) in Et2O
(200 ml) at ꢀ78 °C. The obtained mixture was gradually warmed
to room temperature and stirred for 12 h. Then the solvent was re-
moved under vacuum and the residue subject to 3-times extraction
with toluene/brine (2 M NH4Cl) (150 ml ꢂ 3), and the insoluble
material was removed by filtration. The organic layer was washed
with de-ionized H2O (240 ml ꢂ 3) and dried over anhydrous
MgSO4. The solvent was removed under reduced pressure to leave
a yellowish solid. The resulting residue was recrystallized from
CH2Cl2/hexane to obtain compound 4b in the form of colorless
crystals (22.08 g, 92%). Melting point, 266–269 °C; 1H NMR
(400 MHz, CDCl3): 1.12 (1H, td, J = 12.8 Hz), 1.23–1.42 (4H, m),
1.63 (1H, d, J = 12.8 Hz), 1.84 (2H, d, J = 12.8 Hz,), 1.99 (2H, d,
J = 11.6 Hz), 2.92 (1H, td, J = 11.6 Hz), 4.15 (2H, d, J = 15.2 Hz),
4.36 (2H, d, J = 15.2 Hz), 7.31 (2H, t, J = 7.6 and 7.2 Hz), 7.39–7.48
(4H, m), and 8.62 (2H, d, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3): d
25.48, 25.65, 30.69, 60.67, 64.81, 127.63, 128.05, 130.80, 138.15,
149.69, and 170.85. Anal. Calc. for C20H23BiClN (521.84): C, 46.03;
H, 4.44; Bi, 40.05; Cl, 6.79; N, 2.68. Found: C, 45.99; H, 4.48; Bi,
(85%) of
a
white solid Cl3GeCH2CH2CO2H. The b-(trip-
henylgermyl)propanoic acid (Ph3GeCH2CH2CO2H) was prepared
by reacting 3.83 g (15.0 mmol) Cl3GeCH2CH2CO2H with 76.0 mmol
PhMgBr in THF (51.7% yield).
A mixture of compound 1 (274.2 mg, 0.6 mmol), 237.6 mg
(0.63 mmol) Ph3GeCH2CH2CO2H (dissolved in 12 ml THF), and
240 mg (6.0 mmol) NaOH (dissolved in 6 ml de-ionized water)
was refluxed for 10 h. Then THF was removed under reduced pres-
sure. The residue was dissolved in 10 ml CH2Cl2 and washed with
H2O (10 ml ꢂ 3). The organic layer was separated and dried over
40.18; Cl, 6.65; N, 2.67.
1,462, 1,448, 1,202, 931, 752, and 704.
c
max(KBr)/cmꢀ1: 3,055, 2,945, 1,579,

X.-W. Zhang et al. / Journal of Organometallic Chemistry 694 (2009) 3019–3026
3025
4.6. Preparation of PhN(CH2C6H4)2BiO2CCH2CH2GePh3 (5a)
(SUNRISE TECAN) with 570 nm filter and the survival rate of cells
calculated according to the provided formula.
A mixture of compound 4a (516 mg, 1.0 mmol), Ph3GeCH2CH2-
CO2H (396 mg, 1.05 mmol) dissolved in 20 ml THF, and NaOH
(400 mg, 10.0 mmol) dissolved in 5 ml de-ionized water was re-
fluxed for 10 h. THF was removed under reduced pressure. The res-
idue was dissolved in 10 ml CH2Cl2 and washed with H2O
(10 ml ꢂ 3). The organic layer was separated and dried over
MgSO4. Removal of the solvent under vacuum gave 790 mg (93%)
of 5a in the form of a white solid. Melting point, 216–217 °C; 1H
NMR (400 MHz, CDCl3): d 2.08 (2H, t, J = 8.8 Hz), 2.71 (2H, t,
J = 8.8 Hz), 4.53 (2H, d, J = 15.2 Hz), 4.80 (2H, d, J = 15.2 Hz), 7.12
(1H, t, J = 7.2 Hz), 7.18 (2H, d, J = 7.2 Hz), 7.28–7.37 (13H, m),
7.47–7.55 (10H, m), 8.13 (2H, d, J = 7.2 Hz). 13C NMR (100 MHz,
CDCl3): d 10.38, 31.56, 62.75, 118.75, 124.51, 127.94, 128.17,
128.24, 128.85, 129.61, 130.97, 135.03, 136.78, 137.50, 148.15,
148.44, 178.02, and 181.20. Anal. Calc. for C41H36BiGeNO2
(856.35): C, 57.50; H, 4.24; Bi, 24.40; Ge, 8.48; N, 1.64; O, 3.74.
Found: C, 57.43; H, 4.28; Bi, 24.28; Ge, 8.46; N, 1.68; O, 3.86.
Survival rate of cells = (mean optical densities of drug-treated
cells/mean optical densities of untreated cells) ꢂ 100%. IC50 value
was estimated according to the survival rate.
5. X-ray crystallography
Crystals suitable for X-ray diffraction studies were grown by
slow evaporation of each of the respective solutions in CH2Cl2/hex-
ane at room temperature. Geometric and intensity data were
collected at 293 or 173 K using graphite-monochromated Mo K
a
radiation (k = 0.71073 Å) on a Bruker Axs SMART 1000 CCD
diffractometer. The crystallinity, orientation matrix, and accurate
unit-cell parameters were determined according to standard
procedures. The collected frames were processed with the software
SAINT [35] and an absorption correction (SADABS) [36] was
applied to the collected reflections. The structure was solved by
the Direct or Patterson methods (SHELXTL) [37] in conjunction with
standard difference Fourier techniques and subsequently refined
by full-matrix least-squares analyses on F2. Hydrogen atoms were
generated in their idealized positions and all non-hydrogen atoms
were assigned with anisotropic displacement parameters.
c
max(KBr)/cmꢀ1: 3066, 1964, 1619, 1432, 1354, 1255, 1093, 764,
and 698.
4.7. Preparation of C6H11N(CH2C6H4)2BiO2CCH2CH2GePh3 (5b)
A mixture of compound 4b (1.04 g, 2.0 mmol), Ph3GeCH2CH2-
CO2H (789 mg, 2.1 mmol) dissolved in 40 ml THF, and NaOH
(800 mg, 20.0 mmol) dissolved in 10 ml de-ionized water was re-
fluxed for 10 h. THF was removed under reduced pressure. The res-
idue was dissolved in 20 ml CH2Cl2 and washed with H2O
(20 ml ꢂ 3). The organic layer was separated and dried over
MgSO4. Removal of the solvent under vacuum gave 1.62 g (94%)
of 5b in the form of white solid. Melting point, 219–223 °C; 1H
NMR (400 MHz, CDCl3): d 1.10 (1H, t, J = 12.8 Hz), 1.20ꢃ1.39 (4H,
m), 1.62 (1H, d, J = 12.8 Hz), 1.81 (2H, d, J = 12.8 Hz), 2.02 (4H, t,
J = 11.6 Hz), 2.71 (2H, t, J = 8.0 Hz), 2.82 (1H, t, J = 11.2 Hz), 4.07
(2H, d, J = 15.2 Hz), 4.28 (2H, d, J = 15.2 Hz), 7.24 (2H, t,
J = 14.8 Hz), 7.36 (11H, d, J = 8.0 Hz), 7.42 (2H, t, J = 7.2 Hz), 7.55
(6H, s), and 8.11 (2H, d, J = 7.6 Hz). 13C NMR (100 MHz, CDCl3): d
10.39, 25.57, 25.71, 30.46, 31.74, 60.24, 64.26, 127.69, 127.78,
128.14, 128.79, 130.29, 135.05, 136.89, 137.37, 149.72, 174.59,
and 181.39. Anal. Calc. for C41H42BiGeNO2 (862.40): C, 57.10; H,
4.91; Bi, 24.23; Ge, 8.42; N, 1.62; O, 3.71. Found: C, 57.01; H,
Acknowledgments
This project is financially supported by the National Natural
Science Foundation of China (20507005) and the National out-
standing Youth Foundation of China (E50725825). C.T. Au and
W.Y. Wong thank the Hong Kong Baptist University for financial
support (FRG/08-09/II-09). C.T. Au thanks the Hunan University
for an adjunct professorship. Prof. S.F. Yin thanks Dr. S. Shimada
of AIST in Japan for helpful advices.
Appendix A. Supplementary material
CCDC 724767, 724768, 724769, 724770, 724771 and 724772
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via http://www.ccdc.
cam.ac.uk/conts/retrieving.html, or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
(+44) 1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk. Supple-
mentary data associated with this article can be found, in the
online version, at doi:10.1016/j.jorganchem.2009.05.003.
4.86; Bi, 24.25; Ge, 8.39; N, 1.64; O, 3.75. c
max(KBr)/cmꢀ1: 3052,
2931, 2850, 1963, 1620, 1430, 1360, 1267, 1092, 743, and 700.
4.8. Antiproliferative activity assay
References
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line MGC-803 was purchased from Xiang Ya Central Experiment
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just before use. MGC-803 cells that grow exponentially were inoc-
ulated at cell concentration of 1 ꢂ 104 cells/well in a 96-well tissue
culture plate. The bismocine solution was immediately added into
a cell suspension after 12 h incubation and kept at different final
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