Synthesis and antibacterial activities of novel biphenyltetrazole derivatives bearing 1,3,4-oxadiazole

Article abstract of DOI:10.1002/jccs.200500079

Several new 5-[4 -(5-phenyl-1,3,4-oxadiazol-2-ylsulfanylmethyl)-biphenyl-2- yl]-tetrazolesderivatives have been syn the sized. The structures of these new compounds were confirmed by elementary analyses and spectral data. The antibacterial activities of the compounds were also evaluated.

Full text of DOI:10.1002/jccs.200500079

Journal of the Chinese Chemical Society, 2005, 52, 539-544
539
Synthesis and Antibacterial Activities of Novel Biphenyltetrazole
Derivatives Bearing 1,3,4-Oxadiazole
Shu-Jun Chaoa (
Zao-Zao Qiua (
), Xin-Ping Huia (
), Peng-Fei Xua* (
), Shuo Lia (
),
), Zi-Yi Zhanga (
),
Qin Wangb (
) and Zuo-Wu Guanc (
)
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
bCollege of Life Science, Lanzhou University, Lanzhou 730000, P. R. China
cSchool of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. China
Several new 5-[4¢-(5-phenyl-1,3,4-oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-yl]-tetrazoles derivatives
have been synthesized. The structures of these new compounds were confirmed by elementary analyses and
spectral data. The antibacterial activities of the compounds were also evaluated.
Keywords: Biphenyltetrazole; 1,3,4-Oxazodiazole; Antibacterial activity.
INTRODUCTION
The discovery of the first potent and orally active non-
are the biphenyltetrazoles. The classic method of synthesiz-
ing tetrazoles from nitriles uses ammonium chloride/sodium
azide in acceptable yield and purity, but this fails to react on
sterically hindered nitriles.10 Hindered 5-substituted-tet-
razoles cannot be synthesized in acceptable yield or purity
using ammonium chloride/sodium azide. The method of
Duncia11 uses trimethyltin or tributyltin azide to produce
tetrazoles in good yield. Trimethyltin azide must be prepared
in advance and tributyltinazide is prepared in situ. When
working with large scale preparations, the tin by-products are
difficult to remove. This method of converting 2 to 3 requires
the use of highly toxic trialkyltin azide reagents. In this pa-
per, 5-(4¢-methylbiphenyl-2-yl)tetrazole (3) was synthesized
from 4¢-methylbiphenyl-2-carbonitrile (2) using sodium
azide/zinc chloride by a modified method described by
Galante.12 Treatment of 3 with triphenylmethyl chloride af-
forded triphenylmethyl protected tetrazole 4. The yield of the
two steps was sensibly improved by optimizing the experi-
mental conditions (previous yield 68%, optimal yield 87%).
Bromination of 4 with N-bromosuccinimide provided 5.
Alkylation of 1 with 5 in the presence of potassium carbon-
ate at the refluxing temperature of acetone afforded S-al-
kylated products 6a-6i in good yields. The trityl group was
cleaved by treatment with 10% aqueous hydrochloric acid in
THF/CH3OH to yield the desired compounds 7a-7i.
peptide AII antagonist, DuP 753 (losartan, Cozaar Ò), has
stimulated extensive research interest in this area, and numer-
ous derivatives have been reported as potent and selective an-
tagonists.1 The great majority of them contain a biphenyl-
tetrazole moiety.
Substituted 1,3,4-oxadiazole derivatives are becoming
an important member in the heterocyclic family not only be-
cause of their wide usage as photosensitive and electrical ma-
terials,2-3 but also because of their broad spectrum in biologi-
cal activities such as antibacterial,4 antifungal,5 anti-inflam-
matory,6 anticonvulsant,7 HIV-activity,8 and antihyperten-
sive9 activities. Combining biphenyltetrazole with substi-
tuted 1,3,4-oxadiazole by -SCH2- moiety is expected to give
novel heterocyclic compounds with better biological activi-
ties. Up till now, the antibacterial activities of these com-
pounds have not been reported. In this paper, we describ the
synthesis of the compounds which possess both biphenyl-
tetrazole and 1,3,4-oxadiazole moieties. The antibacterial ac-
tivities were also evaluated.
RESULTS AND DISCUSSION
The structures of 7a-7i were confirmed by elemental
analyses and spectral data. The 1H NMR spectra of 7a-7i ex-
hibited a singlet for SCH2 at d 4.43-4.51 ppm. The IR spectra
displayed an absorption band in the region 1402-1477 cm-1
due to C-S-C, whereas the characteristic absorption bands for
C=N and N-N=C functions appeared in the range 1595-1610
A general procedure employed in the preparation of the
compounds is demonstrated in Scheme I. 5-Aryl-2-mercap-
to-1,3,4-oxadiazole (1) was prepared by the reaction of hy-
drazide with CS2 in the presence of potassium hydrate in eth-
anol solution.6 An important class of compounds in this paper

540 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Chao et al.
Scheme I
Ar = C6H5 (7a), 4-pyridyl (7b), o-BrC6H4 (7c), p-BrC6H4 (7d), o-MeOC6H4 (7e), p-MeOC6H4 (7f),
m-ClC6H4 (7g), m-MeC6H4 (7h), p-MeC6H4 (7i)
Table 1. Physical properties and elemental analyses of compounds 6a-6i and 7a-7i
Elemental anal. Found (Calcd.) (%)
Yield
(%)
mp
(°C)
No.
Formula
N
C
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
7a
7b
7c
7d
7e
7f
7g
7h
7i
68
87
92
29
89
83
88
86
74
52
43
45
57
57
45
58
66
52
102-104
177-179
foam
190-192
foam
C41H30N6OS
C40H29N7OS
C41H29BrN6OS
C41H29BrN6OS
C42H32N6O2S
C42H32N6O2S
C41H29ClN6OS
C42H32N6OS
C42H32N6OS
C22H16N6OS
C21H15N7OS
C22H15BrN6OS
C22H15BrN6OS
C23H18N6O2S
C23H18N6O2S
C22H15ClN6OS
C23H18N6OS
C23H18N6OS
13.01 (12.83)
15.21 (14.95)
11.15 (11.45)
11.21 (11.45)
11.96 (12.27)
12.00 (12.27)
11.93 (12.19)
12.80 (12.57)
12.30 (12.57)
20.11 (20.38)
23.74 (23.71)
16.94 (17.10)
16.84 (17.10)
18.74 (18.99)
18.76 (18.99)
18.99 (18.80)
19.58 (19.70)
19.45 (19.70)
75.04 (75.21)
72.56 (73.26)
66.85 (67.12)
66.83 (67.12)
73.44 (73.66)
73.37 (73.66)
71.22 (71.45)
75.71 (75.43)
75.27 (75.43)
64.03 (64.06)
61.11 (61.00)
53.97 (53.78)
53.88 (53.78)
62.42 (62.43)
62.58 (62.43)
59.39 (59.12)
64.60 (64.77)
64.51 (64.77)
4.38 (4.62)
4.34 (4.46)
3.86 (3.98)
3.81 (3.98)
4.91 (4.71)
5.00 (4.71)
4.16 (4.24)
4.84 (4.82)
4.99 (4.82)
4.01 (3.91)
3.80 (3.66)
3.33 (3.08)
3.23 (3.08)
4.08 (4.10)
4.38 (4.10)
3.61 (3.38)
4.18 (4.25)
4.12 (4.25)
157-158
171-172
155-157
169-171
163-165
170-172
146-147
180-182
219-221
173-176
166-168
174-176
188-189

Biphenyltetrazole Derivatives with 1,3,4-Oxadiazole
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 541
Table 2. 1H NMR data of compounds 6a-6i
No.
1H NMR (d, ppm)
6a
6b
6c
6d
6e
6f
8.01-7.98 (m, 3H, ArH), 7.48 (dd, J = 6.9, 2.7 Hz, 5H, ArH), 7.36-7.08 (m, 14H, ArH), 6.88
(d, J = 9.0 Hz, 6H, ArH), 4.44 (s, 2H, SCH2).
8.80 (d, J = 4.5 Hz, 2H, ArH), 7.97 (dd, J = 6.6, 2.4 Hz, 1H, ArH), 7.84 (d, J = 4.8 Hz, 2H,
ArH), 7.50-7.10 (m, 16H, ArH), 6.90 (d, J = 7.2 Hz, 6H, ArH), 4.46 (s, 2H, SCH2).
7.98 (d, J = 8.1 Hz, 1H, ArH), 7.86 (dd, J = 7.5, 1.8 Hz, 1H, ArH), 7.75 (d, J = 8.4 Hz, 1H,
ArH), 7.50-7.09 (m, 18H, ArH), 6.90 (d, J = 7.2 Hz, 6H, ArH), 4.44 (s, 2H, SCH2).
7.99-7.96 (m, 1H, ArH), 7.86 (dd, J = 8.7, 2.4 Hz, 2H, ArH), 7.64 (dd, J = 8.1, 1.8 Hz, 2H,
ArH), 7.50-7.08 (m, 16H, ArH), 6.89 (dd, J = 7.8, 1.2 Hz, 6H, ArH), 4.43 (s, 2H, SCH2).
7.98 (dd, J = 4.5, 1.8 Hz, 1H, ArH), 7.86 (dd, J = 8.1, 1.8 Hz, 1H, ArH), 7.51-7.03 (m, 19H,
ArH), 6.90 (dd, J = 7.2, 1.2 Hz, 6H, ArH), 4.43 (s, 2H), 3.93(s, 3H, SCH2).
7.98 (d, J = 7.5 Hz, 1H, ArH), 7.58-7.04 (m, 20H, ArH), 6.90 (d, J = 7.8 Hz, 6H, ArH), 4.43 (s,
2H, SCH2), 3.87 (s, 3H, CH3O).
6g
6h
6i
7.98-7.96 (m, 2H, ArH), 7.89 (d, J = 7.5 Hz, 1H, ArH), 7.52-7.08 (m, 18H, ArH), 6.89 (d, J =
7.8 Hz, 6H, ArH), 4.43 (s, 2H, SCH2).
7.98 (dd, J = 5.1, 1.8 Hz, 1H, ArH), 7.83-7.78 (t, J = 7.9 Hz, 2H, ArH), 7.50-7.09 (m, 18H,
ArH), 6.91-6.88 (dd, J = 7.2, 1.2 Hz, 6H, ArH), 4.43 (s, 2H, SCH2), 2.43 (s, 3H, CH3).
7.99-7.87 (m, 2H, ArH), 7.49-7.11 (m, 19H, ArH), 7.10-6.98 (d, J = 7.8 Hz, 6H, ArH), 4.42 (s,
2H, SCH2), 2.42 (s, 3H, CH3).
Table 3. 1H NMR data of compounds 7a-7i
No.
1H NMR (d, ppm)
7a
7.89 (dd, J = 7.5, 1.2 Hz, 2H, ArH), 7.60-7.33 (m, 9H, ArH), 7.04 (d, J = 8.1 Hz, 2H,
ArH), 4.44 (s, 2H, CH2S).
7b
7c
7d
7e
7f
8.73 (s, 2H, ArH), 7.78-7.18 (m, 8H, ArH), 7.04 (d, J = 6.3 Hz, 2H, ArH), 4.51 (s, 2H,
CH2S).
7.77 (dd, J = 7.5, 1.8 Hz, 1H, ArH), 7.67 (d, J = 7.5 Hz, 1H, ArH), 7.61-7.32 (m, 8H,
ArH), 7.04 (d, J = 8.1 Hz, 2H, ArH), 4.46 (s, 2H, CH2S).
7.78 (d, J = 8.4 Hz, 2H, ArH), 7.71-7.29 (m, 8H, ArH), 7.03 (d, J = 7.5 Hz, 2H, ArH),
4.45 (s, 2H, CH2S).
7.74 (dd, J = 7.5, 1.2 Hz, 1H, ArH), 7.60-7.31 (m, 7H, ArH), 7.04-6.96 (m, 4H, ArH),
4.43 (s, 2H, CH2S), 3.84 (s, 3H, OCH3).
7.81 (dd, J = 8.7, 1.8 Hz, 1H, ArH), 7.59-7.33 (m, 7H, ArH), 7.04-6.96 (m, 4H, ArH),
4.45 (s, 2H, CH2S), 3.80 (s, 3H, OCH3).
7g
7h
7i
7.87-7.80 (m, 2H, ArH), 7.60-7.33 (m, 8H, ArH), 7.04 (d, J = 8.1 Hz, 2H, ArH), 4.50
(s, 2H, CH2S).
7.71-7.30 (m, 10H, ArH), 7.05 (d, J = 8.7 Hz, 2H, ArH), 4.51 (s, 2H, CH2S), 2.36 (s,
3H, CH3).
7.76 (d, J = 8.1 Hz, 2H, ArH), 7.61-7.23 (m, 8H, ArH), 7.04 (d, J = 7.8 Hz, 2H, ArH),
4.43 (s, 2H, CH2S), 2.34 (s, 3H, CH3).
cm-1 and 1216-1258 cm-1, respectively. The molecular ions of
7a-7i could be detected by FAB-MS.
fect to these bacteria. The investigation on the structure-
activity relationship shows that chlorine enhances the anti-
bacterial action of the title compounds. Further investigation
on the biological activity of these compounds is in progress.
Compounds 7a-7i were screened for their antibacterial
activity against Escherichia coli, Bacillus subtilis, Staphylo-
coccus aureu and Streptococcus employing the cup-plate
method at the concentration of 100 mg/mL in nutrient agar
media.13 The results are listed in Table 6. The antibacterial ac-
tivity showed that most of the compounds were active against
microorganisms. Compound 7 g showed a good inhibitory ef-
EXPERIMENTAL
The melting points were taken on an X-4 microscopic

542 J. Chin. Chem. Soc., Vol. 52, No. 3, 2005
Chao et al.
Table 4. 13C NMR data of compounds 7a-7i
No.
13C NMR (d, ppm)
7a
164.83, 162.85, 154.70, 140.37, 138.49, 134.52, 131.09, 130.16, 129.97, 128.60,
128.46, 128.26, 127.03, 125.71, 123.01, 122.57, 35.28
7b
7c
7d
7e
7f
164.48, 163.15, 154.58, 150.13, 140.43, 138.53, 134.52, 130.31, 129.96, 129.64,
128.64, 128.37, 127.13, 122.92, 119.33, 35.26
163.57, 154.67, 140.38, 138.50, 134.49, 133.73, 132.17, 130.69, 130.2, 130.02,
129.93, 128.61, 128.32, 127.24, 127.07, 123.88, 123.03, 120.36, 35.29
164.18, 163.17, 140.34, 138.44, 138.00, 134.28, 131.62, 130.69, 129.94, 129.82,
129.25, 128.60, 128.22, 127.27, 127.01, 125.38, 121.58, 35.34
163.73, 162.53, 156.79, 154.71, 140.38, 138.47, 134.63, 132.61, 130.20, 130.00,
129.93, 129.32, 128.64, 128.29, 127.04, 122.90, 120.00, 111.55, 111.36, 55.21, 35.31
164.77, 161.96, 161.49, 140.40, 138.38, 134.72, 130.20, 129.99, 129.88, 128.55,
128.26, 127.53, 127.03, 122.92, 114.95, 113.93, 54.74, 35.26
7g
7h
7i
163.64, 163.46, 140.43, 138.50, 134.63, 133.94, 131.02, 130.31, 130.03, 128.61,
128.35, 127.10, 125.45, 124.37, 124.16, 123.01, 35.25
164.91, 162.74, 140.47, 138.21, 134.87, 131.96, 130.34, 130.08, 128.60, 128.40,
127.15, 126.20, 122.98, 122.52, 35.22, 20.50
165.02, 162.47, 141.51, 140.41, 134.63, 130.03, 129.93, 129.13, 128.63, 128.32,
127.09, 125.71, 119.84, 35.32, 20.85
Table 5. FAB-MS and IR data of compounds 7a-7i
IR nmax/cm-1
No.
MS (m/z)
nC=N
nN-N=C
nC-O
nC-S-C
7a
7b
7c
7d
7e
7f
7g
7h
7i
413.2 (M+1)
414.2 (M+1)
491.1 (M+1), 493.1 (M+3)
491.1 (M+1), 493.1 (M+3)
443.4 (M+1)
443.4 (M+1)
447.2 (M+1), 449.2 (M+3)
427.2 (M+1)
1604
1610
1595
1600
1597
1610
1605
1605
1609
1248
1219
1247
1250
1258
1257
1244
1216
1248
1186
1189
1187
1183
1181
1170
1184
1174
1185
1470
1454
1469
1468
1489
1471
1473
1477
1472
1411
1413
1424
1402
1419
1413
1409
1413
1411
427.2 (M+1)
1
melting point apparatus and are uncorrected. IR spectra were
recorded on a Nicloet NEXUS 670 FT-IR spectrometer in
KBr disc. All the H NMR and 13C NMR spectra were re-
corded at room temperature on a Varian Mercury-300 MHz
spectrometer with TMS as internal standard. Mass spectra
were performed on a VG ZAB-HS (FAB) instrument. Ele-
mental analysis was performed on an Elementar Vario EL ap-
paratus.
Table 6. Inhibition effect of compounds 7a-7i
No.
E. coli
B. subtilis
S. aureus Streptococcus
7a
7b
7c
7d
7e
7f
7g
7h
7i
-
++
-
-
-
+
++
-
+
+
-
+
++
+
++
++
-
+
-
-
-
-
-
+
-
++
+
-
++
+
+
4¢-Methylbiphenyl-2-carbonitrile (2) is a commercial
reagent. 2-Aryl-5-mercapto-1,3,4-oxadiazole (1a-1i) were
synthesized according to the literature.6
Preparation of 5-(4¢-methylbiphenyl-2-yl)-tetrazole (3)
A mixture of 2 (0.1 mol), zinc chloride (0.3 mmol), so-
dium azide (0.9 mmol), and 150 mL of dry DMF was refluxed
for 36 h. The reaction mixture was allowed to cool to room
temperature and acidified with 10% aqueous hydrochloric
acid (pH = 1). The resulting solution was added with stirring
-
+++
-
++
++
Zone diameter of growth inhibition: < 15 mm (-), 16-19 mm (+),
20-23 mm (++), 24-27 mm (+++).

Biphenyltetrazole Derivatives with 1,3,4-Oxadiazole
J. Chin. Chem. Soc., Vol. 52, No. 3, 2005 543
to ice-water (1320 mL), and the mixture was stirred for one
hour. The precipitate was collected, washed with water, dried
and recrystallized from ethyl acetate to provide 3 as a white
solid in 96% yield. mp 158-160 °C (lit.[12] 144-148 °C); IR
(KBr): 3442 (NH), 1600 (C=N) cm-1; 1H NMR (CDCl3, 200
MHz) d: 11.52 (s, 1H, NH), 8.12 (d, J = 7.0 Hz, 1H, ArH),
7.55-7.03 (m, 7H, ArH), 2.33 (s, 3H, CH3); EI-MS m/z (%):
236 (28.8), 235 (100), 207 (58.6).
residue was chromatographed on silica gel with petroleum
ether/ethyl acetate as eluent. An analytical sample was re-
crystallized from petroleum ether/ethyl acetate.
General procedure for preparation of 5-[4¢-(5-phenyl-
1,3,4-oxadiazol-2-ylsulfanylmethyl)-biphenyl-2-yl]-tetra-
zoles (7a-7i)
A solution of compounds 6a-6i (1 mmol), 8.77 mL 10%
hydrochloric acid, 50 mL tetrahydrofuran, and 50 mL metha-
nol was stirred at room temperature for 8 h. To the solution
was added excess 2 N aqueous sodium hydroxide (13 mL),
and the solvents were removed under vacuum. The resulting
residue was dissolved in water, and the mixture was filtered
to remove the triphenylmethanol. The filtrate was adjusted to
pH = 3 employing 10% aqueous hydrochloric acid. The re-
sulting precipitate was collected by filtration and further pu-
rified by crystallization.
Preparation of 5-(4¢-methylbiphenyl-2-yl)-2-trityl-
tetrazole (4)
To a suspension of 3 (5 mmol) in toluene (20 mL) at
room temperature was added 10 M sodium hydroxide solu-
tion (0.50 mL) and triphenylmethyl chloride (5 mmol), and
the resulting mixture was stirred at room temperature for 3 h.
To the reaction mixture was added distilled water (3 mL) and
petroleum ether (7 mL), and the resulting slurry was stirred at
0 °C for 3 h. The slurry was filtered and the solids were
washed with water. The solution was extracted with methy-
lene dichloride. The combined organic phases were dried
over anhydrous magnesium sulfate, filtered, and concen-
trated under vacuum to afford 4 as a white solid. The com-
bined solids were dried and recrystallizd from ethyl ace-
tate/methylene dichloride to furnish 2.17 g of 4 (91%). mp
166-169 °C (lit.[14] 163-165 °C); 1H NMR (CDCl3, 400 MHz)
d: 7.92 (d, J = 7.0 Hz, 1H, ArH), 7.50-6.92 (m, 22H, ArH),
2.29 (s, 3H, CH3).
ACKNOWLEDGEMENT
We wish to thank the National Natural Science Founda-
tion of P. R. China (No. 20021001) and Natural Science
Foundation of Gansu Province (No. YS-011-A25-001) for
their financial support.
Received October 1, 2004.
Preparation of 5-(4¢-bromomethylbiphenyl-2-yl)-2-trityl-
tetrazole (5)
A solution of 4 (10 mmol), N-bromosuccinimide (10
mmol) and dibenzoyl peroxide (1 mmol) in 60 mL of dry car-
bon tetrachloride was refluxed for 8 h, cooled to room tem-
perature, and then filtered. The filtrate was concentrated un-
der reduced pressure to afford the product. Trituration of the
product with diethyl ether furnished 5 as a white solid in 92%
yield. mp 135-137 °C (lit.[14] 135-138 °C); 1H NMR (CDCl3,
200 MHz) d: 7.98-7.94 (m, 1H, ArH), 7.51-6.87 (m, 22H,
ArH), 4.38 (s, 2H, CH2).
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