Synthesis of triazoles, oxadiazoles and condensed heterocyclic compounds containing cinchopheny and studies on biological activity of representative compounds

Article abstract of DOI:10.1002/jccs.200400049

Compounds 2-arylamino-5-cinchophenyl-1,3,4-oxadiazoline (7) and 3-thio-4-amino-5-cinchophenyl-1,2,4-triazole (3) have been synthesized utilizing cinchophen as the starting material. The compound 3-cinchopheny-s-triazolo[3,4- b]-1,2,3,4-thiatriazole (4) was prepared from compound 3. Condensation of 3 with aromatic acid in the presence of POCl₃ gave 10 new 6-aryl-3-cinchopheny-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (5). Some of the representative compounds were screened for antibacterial activity. The structures of these new compounds have been confirmed by means of elemental analysis, IR, ¹H NMR and MS.

Full text of DOI:10.1002/jccs.200400049

Journal of the Chinese Chemical Society, 2004, 51, 315-319
315
Synthesis of Triazoles, Oxadiazoles and Condensed Heterocyclic
Compounds Containing Cinchopheny and Studies on Biological Activity
of Representative Compounds
Peng-Fei Xua* (
), Zhi-Hui Zhanga (
), Xin-Ping Huia (
),
Zi-Yi Zhanga (
) and Rong-Liang Zhengb (
)
aState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou, 730000, P. R. China
bLife School, Lanzhou University, Lanzhou, 730000, P. R. China
Compounds 2-arylamino-5-cinchophenyl-1,3,4-oxadiazoline (7) and 3-thio-4-amino-5-cinchophenyl-
1,2,4-triazole (3) have been synthesized utilizing cinchophen as the starting material. The compound 3-
cinchopheny-s-triazolo[3,4-b]-1,2,3,4-thiatriazole (4) was prepared from compound 3. Condensation of 3
with aromatic acid in the presence of POCl3 gave 10 new 6-aryl-3-cinchopheny-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazoles (5). Some of the representative compounds were screened for antibacterial activity. The struc-
tures of these new compounds have been confirmed by means of elemental analysis, IR, 1H NMR and MS.
Keywords: Cinchophen; Synthesis; Triazoles; Oxadiazoles; Condensed heterocyclic compounds;
Biological activity.
INTRODUCTION
tivity.
The derivatives of 1,2,4-s-triazole and 1,3,4-thiadi-
azole possess broad-spectrum biological activities and many
other uses.1-5 There have been more and more reports on these
fused heterocyclic compounds; the studies on them have been
very active since M. Kanaoka6 first condensed these two cy-
clic compounds into one molecule to yield s-triazolo[3,4-b]-
1,3,4-thiadiazole derivatives. These papers indicate that the
triazolothiadiazole 3,6-substituted by aryl, alkyl or hetero-
cyclic radical possesses broad-spectrum biological activities
such as antibacterial,7 anti-inflammatory,8 herbicidal,9 plant
growth regulative activity10 and anti-HIV-1 activities.11
Though a lot of reports on s-triazolo[3,4-b]-1,3,4-thiadiazole
derivatives are available, their derivatives 3,6-substituted by
alkyl, aryl, alkoxyl or 3-substituted by heterocyclic radical
are rarely reported.
RESULTS AND DISCUSSION
The synthesis of compounds: the synthesis of all com-
pounds was accomplished as shown in Scheme I.
After esterification and hydrazinolysis, cinchophen
was converted to 2-phenylquinolyl-4-formylhydratide (1)
which was refluxed with isocyanate in absolute ethanol to
give compound 6 which was changed to compound 7 in
POCl3. Compound 1 reacted with CS2 in KOH absolute etha-
nol solution to give 2-phenylquinolyl-4-potassium formyl-
hydrazino dithioformate (2) which was refluxed in excess
hydrazine hydrate to obtain 3-(2-phenylquinolyl-4-yl)-4-
amino-5-thio-1,2,4-triazole (3). Compound 3 was refluxed
with substituted benzoic acid in POCl3 to yield desired com-
pounds 5a-j.
As is well known, 2-phenlquinolyl-4-carboxylic acid
(cinchophin) displays antifebrile anodyne, antirheumatic and
glucosuria metabolic activities, etc.,12 but it has become ob-
solete in recent years due to its side-effects in clinical use.
With a view to explore other uses of cinchophin, we decided
to use cinchophin as parent material to synthesize some new
derivatives. So, we decided to combine 2-phenyquinolyl to
oxadiazole or condensed heterocycle in order to obtain new
heterocyclic compounds exhibiting promising biological ac-
In order to explore biological properties of cinchophen
we designed such methods that involved diazotization reac-
tion of parent compound 3-(2-phenylquinolyl-4-yl)-4-ami-
no-5-thio-1,2,4-triazole (3). As compound 3 has 5-thio and
4-amino simultaneously, the formed diazonium could cyclize
with thiohydroxy to give triazolothiatriazole. We referred to
the papers on compound 4 and found that A. K. El-Shafei, in
1982, utilized 3-thio-4-amino-5-phenyl-1,2,4-triazole as

316 J. Chin. Chem. Soc., Vol. 51, No. 2, 2004
Xu et al.
Scheme I
C2H5OH
H2SO4
N
COOH
N
COOC2H5
N2H4.H2O
PhNCO
N
CONHNH2
(1)
N
CONHNHCONHPh
(6)
POCL3
CS2 , KOH
O
S
Abs.C2H5OH
N
CNHNHCSK
N
N
N
NHPh
(2)
O
(7)
N
N
N
SH
N
NH2
N
N
Ar-COOH
N
(3)
N
S
N
R
N
N
N
(5a-j)
N
S
N
N
(4)
5a R = p-Cl, 5b R = p-F, 5c R = p-I, 5d R = p-CH3, 5e R = p-Br
5f R = m-F, 5g R = m-Cl, 5h R = m-CH3, 5i R = m-Br, 5j R= o-Cl
starting material to realize diazotization reaction in NaNO2/
HCl at 0 °C. The diazonium spontaneously coupled to give
5-phenyl-1,2,4-triazolo[3,4-b]-1,2,3,4-thiatrizole. The IR
data of compound 4 accorded with those of the compounds
synthesized by A. K. El-Shafei.
Their molecule ion peaks were strong resulting from aryl.
All compounds exhibited m/z 229, m/z 230 and m/z 302
piece peaks. We chose compound 5a to investigate its scission
mechanism, as shown in Scheme II.
Because of no proton on the condensed ring of com-
pounds 5a-j, their 1H NMR spectra consisted only of the ben-
zene ring proton absorption peaks. The single peaks at d 2.41
and d 2.42 appeared owing to the methyl on 6-aryl of com-
pounds 5d and 5h. The detailed 1H NMR data are listed in Ta-
ble 2.
EXPERIMENTAL SECTION
Melting points were determined on a National X4 mi-
croscropic melting point apparatus and are uncorrected. The
IR spectra (KBr) were obtained on a Nicolet FT-IR170SX
1
As Table 3 shows, five representative compounds of
compound 5 had strong isotope peaks to the halogen on them.
spectrophotometer; H NMR spectrum was recorded on a
FT-80A instrument in DMSO-d6 with TMS as internal stan-

Heterocyclic Compounds from Cinchopheny
J. Chin. Chem. Soc., Vol. 51, No. 2, 2004 317
Scheme II
CN
1.2
+
.
_
N
N
N
_
Ph
+
N
Cl
Cl
CS
N
S
_
CN , N2
pathway 1
3.4
N
m/z 155 (A)
_
CS
Cl
+
CN
m/z 111 (B)
_
_
+
N
Ph
.
Cl
CN
_
N2 ,
CS
m/z 137 (C)
pathway 2
CN
N
CN
+
+
.
Cl
CN
_
.
H
_
_
N2 ,
CS
pathway 3
Ph
N
Ph
m/z 229 (D)
m/z 230
+
.
Cl
CN
N
N
N
pathway 4
N
S
m/z 302 (E)
dard. Mass spectrum was on a VG-7070 spectrometer and el-
emental analysis was on an Elementar Vario EL analyzer.
64.05; H, 3.95; N, 21.65.
5-Cinchophenyl-1,2,4-triazolo[3,4-b]-1,2,3,4-thiatriazole
(4)
Ethyl cinchophenate (mp 51 °C) and cinchopen hydra-
zide (mp 223-225 °C)
The compound 3 (1.0 mmol) was stirred in sulphuric
acid at 0-5 °C, then NaNO2 (1.0 mmol) was added to it. Salt
diazoate solution was added to the mixture of NaOAc ethanol
solution (15 mg NaOAc dissolved in 10 mL ethanol) and
acetyl methylene acetone. The resulting mixture was stirred
for 10 min, filtered, washed and recrystallised from aqueous
These were prepared by the reported methods and their
melting points were measured with those therein.
3-Cinchophenyl-4-amino-5-thio-1,2,4-triazole (3)
To 250 mL KOH (0.015 mol) abs. ethanol solution
cinchophen hydrazide (0.01 mol) and CS2 (0.015 mol) were
added. The solution was stirred at room temperature for 24 h,
then abs. ether (50 mL) was added to it and left as such for 2 h.
The residue was filtered, washed (with ether and ethanol) and
dried to give white solid potassium hydrazino dithioformate.
This solid was dissolved in excess hydrazine hydrate (85%).
The mixture was heated and refluxed for 6 h, cooled and
poured into ice water (pH = 2 modulated by HCl) to give ca-
nary deposit which was filtered, dried and recrystallised from
abs. ethanol. Yield 75%. MS: M+ 319 (100), 229 (26); Anal.
Calcd for C17H13N5S: C, 63.95; H, 4.07; N, 21.94. Found: C,
ethanol. IR (cm-1) 3046 (m, uArH); 1598 (s, uC=N); 1239 (s,
1
u
N-N=C); 693 (s, LN-C-N); H NMR d (ppm): 7.51-9.10 (m,
10H); Anal. Calcd for C17H10N6S: C, 61.82; H, 3.03; N,
25.45. Found: C, 61.64; H, 3.17; N, 24.98.
6-Aryl-3-cinchopheny-1,2,4-triazolo[3,4-b]-1,3,4-thiadizole
(5a-j)
The compound 3 (1.0 mmole) was refluxed with aro-
matic acid (1.0 mmol) in POCl3 (6.0 mL) for 4 h. The reaction
mixture was cooled and poured into NaOH ice water solution,
filtered, washed and dried. The crude product was recrys-

318 J. Chin. Chem. Soc., Vol. 51, No. 2, 2004
Xu et al.
tallised from DMF. The elemental analysis, 1H NMR, IR and
MS data of compound 5a-j are respectively listed in Table 1,
Table 2 and Table 3.
ethanol. When hydrazide was dissolved, an equal molar
phenyl isocyanate was added into the solution that was re-
fluxed for 3-4 h, cooled, filtered, washed and dried to give
compound 6. Yield 90%. mp 208-210 °C. Anal. Calcd for
C23H18N4O: C, 72.25; H, 4.71; N, 14.66. Found: C, 72.34; H,
4.84; N, 14.85.
1-Cinchophenyamino-5-phenylcarbamide (6)
Cinchopheny hydrazide (10 mmol) was refluxed in abs.
Table 1. Physical Data and Elemental Analyses of Compounds 5a-j
No.
Formula
Color
Yield
(%)
mp
Elemental anal. Found (Calcd.) (%)
(°C)
C
H
N
5a
5b
5c
5d
5e
5f
5g
5h
5i
C24H14N5SCl
C24H14N5SF
C24H14N5SI
C25H17N5S
C24H14N5SBr
C24H14N5SF
C24H14N5SCl
C25H17N5S
canary
canary
canary
yellow
canary
yellow
canary
canary
canary
yellow
73
81
84
82
67
79
79
80
70
80
303-305
278-280
313-315
299-301
308-310
218-220
241-242
223-224
231-233
214-216
65.66 (65.53)
68.16 (68.09)
54.07 (54.24)
70.89 (71.50)
59.33 (59.50)
67.80 (68.09)
65.21 (65.53)
71.34 (71.50)
59.98 (59.50)
65.49 (65.53)
3.09 (3.19)
3.22 (3.31)
2.56 (2.64)
3.94 (4.06)
3.07 (2.89)
3.40 (3.31)
3.28 (3.19)
4.04 (4.06)
3.06 (2.89)
3.22 (3.19)
15.95 (15.93)
16.87 (16.55)
13.41 (13.18)
16.86 (16.71)
14.11 (14.46)
16.71 (16.55)
16.43 (16.71)
17.04 (16.71)
14.48 (14.46)
15.58 (15.93)
C24H14N5SBr
C24H14N5SCl
5j
Table 2. 1H NMR and IR Data of Compounds 5a-j
IR (cm-1)
Compd.
1H NMR (ppm)
nArH (m)
nC=N (s)
nN-N=C (s)
nC-S-C (s)
5a
5b
5c
5d
7.50-8.93 (m, 14H)
7.36-8.96 (m, 14H)
7.56-8.66 (m, 14H)
2.41 (s, 3H, CH3)
7.49-8.89 (m, 14H)
7.73-8.86 (m, 14H)
7.40-8.87 (m, 14H)
7.43-8.93 (m, 14H)
2.42 (s, 3H, CH3)
7.47-8.99 (m, 14H)
7.43-9.00 (m, 14H)
7.27-8.97 (m, 14H)
3037
3034
3033
3061
1593
1595
1589
1591
1237
1236
1237
1235
687
687
688
687
5e
5f
5g
5h
3050
3057
3037
3040
1589
1591
1597
1593
1238
1236
1233
1285
683
676
679
689
5i
5j
3055
3033
1592
1591
1239
1237
686
683
Table 3. MS Data of Compounds 5a-i
Compd.
m/z (relative abundance)
5a
5b
439 (M+, 100), 440 (M+1, 56), 402 (12), 229 (22).
423 (M+, 66), 424 (M+1, 19), 302 (24), 244 (12), 229 (62), 230 (25), 139 (100),
95 (10), 44 (26).
5c
5h
5i
531 (M+, 55), 532 (M+1, 16), 404 (30), 302 (23), 247 (62), 230 (42), 229 (100),
203 (16), 202 (14), 120 (50), 26 (17), 44 (37).
419 (M+, 94), 418 (M-1, 79), 386 (15), 346 (11), 302 (24), 230 (28), 229 (68),
135 (100), 91 (18), 44 (34).
483 (M+, 35), 484 (M+1, 34), 404 (24), 302 (31), 230 (40), 229 (100), 201(20),
200 (51), 199 (43), 76 (16), 44 (18).

Heterocyclic Compounds from Cinchopheny
J. Chin. Chem. Soc., Vol. 51, No. 2, 2004 319
2-Arylamino-5-cinchopheny-1,3,4-oxadiazoline (7)
ACKNOWLEDGEMENT
1-cinchophenoylamino-5-phenylcarbamide (6) (1.0
mmol) in POCl3 (6.0 mL) was refluxed for 5 h, then the re-
sulting mixture was poured into NaOH ice water solution re-
sulting in much deposition that was filtered, washed, dried
and recrystallised from aqueous ethanol to give compound 7.
mp 244-246 °C. Anal. Calcd for C23H16N4O: C, 75.82; H,
4.40; N, 15.38. Found: C, 75.35; H, 4.68; N, 15.30.
This work is supported by the National Natural Science
Foundation of China and the Found of Ministry of Education
of P. R. China.
Received March 31, 2003.
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