Synthesis of thienotriazolopyrimidine derivatives containing triazolothiadiazole moiety

Article abstract of DOI:10.1002/jhet.1574

A series of diheterocyclic compounds 15 and 16 was synthesized by the introduction of 6-aryl or 6-benzyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moiety to thieno[1,2,4]triazolo[4,3-c]pyrimidine ring through a sulfur linkage.

Full text of DOI:10.1002/jhet.1574

May 2013
Synthesis of Thienotriazolopyrimidine Derivatives Containing
Triazolothiadiazole Moiety
603
*
Jina Whang and Yang-Heon Song
Department of Chemistry, Mokwon University, Daejeon 302-729, South Korea
*
E-mail: yhsong@mokwon.ac.kr
Received April 16, 2011
DOI 10.1002/jhet.1574
Published online in Wiley Online Library (wileyonlinelibrary.com).
N
N
N
HN
N
N
N
N
S
S
N
S
CH3CO2Na
S
N
Cl
N
N
N
N
ethanol, reflux
+
S
n
N
n
S
N
n = 0 or 1
R
R
A series of diheterocyclic compounds 15 and 16 was synthesized by the introduction of 6-aryl or 6-
benzyl-1,2,4-triazolo[3,4-b][1,3,4]thiadiazole moiety to thieno[1,2,4]triazolo[4,3-c]pyrimidine ring through
a sulfur linkage.
J. Heterocyclic Chem., 50, 603 (2013).
INTRODUCTION
wish to report herein the synthesis of sulfur-linked dihetro-
cyclic compounds 15a–h and 16a–h, which are structurally
related to 5 and 6 in the hope of obtaining compounds of
diverse biological activities.
Thienopyrimidines and their condensed derivatives have
attracted the constantly increasing attention of researchers
because of wide-ranging biological activities. For instance,
thienotriazolopyrimidine 1 as shown in Figure 1 and its an-
alog have been explored for adenosine A1/A2A or A2A/A3
receptor antagonists [1,2]. We have previously designed
and synthesized thienotriazolopyrimidine derivatives 2
with promising biological activity [3]. Moreover, sulfur-
containing 1,2,4-triazoles (3-thio-1,2,4-triazoles) were also
reported to possess an impressive array of biological activ-
ities such as antibacterial, antifungal, analgesic, somato-
statin sst2/sst5 agonist, and carbonic anhydrase inhibitor
[4–7]. Particularly, sulfur-linked dihetrocyclic compounds
containing triazolopyrimidine or triazole such as 3 and 4
were investigated for antifungal agent and plant growth
regulator, respectively [8,9]. We also have recently
reported the synthesis of diheterocyclic compound 5 and
its analogs [10].
In the other hand, 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole
derivatives obtained by fusing 1,2,4-triazole and 1,3,4-
thiadiazole ring together have been reported to possess
antibacterial, antifungal, anti-inflammatory, analgesic effects,
and anticancer activity [11–13]. For example, compound 6
and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole derivatives con-
taining sugar moiety were reported to have anti-inflammatory
and antimicrobial activities, respectively [14–16].
RESULTS AND DISCUSSION
As reported in a previous communication [10], key
intermediates, fused triazolopyrimidine-3-thiones 11 and
12 can be, respectively, prepared in a few step sequence
using 2-aminothiophene-3-carbonitrile (7) and ethyl 3-
aminothiophene-2-carboxylate (8) as starting materials
(Scheme 1). The compounds 3-chlorothieno[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine (13) and 3-chlorothieno[2,3-e]
[1,2,4]triazolo[4,3-c]pyrimidine (14) were obtained,
respectively, in moderate yield by treatment of thieno
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione (11)
or thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione
(12) with thionyl chloride containing two drops of DMF
[19]. They were used for the next reaction without further
purification. The structure of these compounds was evident
from their elemental analysis, 1H NMR and IR spectra. The
disappearance of characteristic peaks at 1200 (weak) and
3190cmÀ1 for the C═S and NH groups in IR spectrum
1
and the secondary amino signal near at d 14.0 in H NMR
spectrum indicated that the thiones 11 and 12 were converted
into the corresponding chlorinated cyclization products. The
mass spectral data of 13 and 14 showed a molecular ion peak
at m/z 210 and also showed ions at m/z 175 (21%) that could
be attributed to the loss of chlorine atom from the molecular
ion. The 6-aryl and 6-benzyl-2H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazole-3-ones (19a–e and 20a–c) were prepared
from the reaction of 4-amino-4H-[1,2,4]triazole-3,5-dithiol
(18) with the appropriate benzoic acid or phenylacetic
Therefore, we devised the introduction of a 1,2,4-
triazolo[3,4-b][1,3,4]thiadiazole moiety to the thieno
[1,2,4]triazolo[4,3-c]pyrimidine ring by sulfur to produce
diheterocyclic systems using the concept of molecular
hybridization [17]. As a continuation of our synthetic
works on heterocyclic compounds related to thienopyrimi-
dines and thienopyridine with biological interest [18], we
© 2013 HeteroCorporation

604
J. Whang and Y.-H. Song
Vol 50
acid using phosphorus oxychloride as the cyclizing
agent (Scheme 2) [15].
The synthesis of sulfur-linked dihetrocyclic compounds
15a–h and 16a–h was achieved in moderate yield by treat-
ment of 13 and 14 with 19 and 20 in refluxing ethanol
containing sodium acetate, respectively. The structures of
15a–h and 16a–h were established by elemental analysis,
mass spectra, 1H NMR, and IR spectra. IR spectra of these
compound revealed characteristic absorption bands at
1625–1470 cmÀ1 for aromatic C═C, C═N stretching
1
vibrations. The H NMR signals of 3-(6-(4-fluorophenyl)
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-ylthio)thieno[3,2-
e][1,2,4]triazolo[4,3-c]pyrimidine (15e), for example,
showed two doublets at 8.06 and 7.78 for thiophene pro-
tons, two doublet signals at d 7.99 and 7.43 for aromatic
protons, and singlet at d 9.63 for pyrimidine proton,
respectively. The more deshielded a proton (H-8) of thio-
phene of thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimi-dine
ring in (3-(6-(4-fluorophenyl)[1,2,4]triazolo[3,4-b] [1,3,4]
thiadiazol-3-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3- c]pyri-
midine (16e) appeared as a doublet at d 8.32, whereas the
b proton (H-7) was found to appear at d 7.69 in little higher
field as a doublet when compared with 15e. The mass spec-
tral data of these two compounds showed same molecular
ion peak at m/z = 426 with very similar fragmentation
pattern and showed m/z = 252 (99%) and 208 (22%) as
the most intense ion, corresponding to the fragment
obtained from the cleavage of sulfide bond of the molecu-
lar ion. Fragments of m/z = 84 and 66 (15%) for triazole
and thiadiazole ion were also identified.
R
N
N
R
N
N
O
N
N
S
S
N
N
H
2
1
N
N
N
R
N
N
N
S
N
N
N
N
S
N
N
O
S
N
3
4
O
N
N
N
N
S
N
N
S
N
S
S
N
N
N
1
The H NMR spectra of 15f and 16f having benzyl
groups instead of phenyl groups showed patterns similar
5
6
R
Figure 1. Compounds 1–6.
to those of 15a and 16a except singlet signals at d 4.35
Scheme 1. Reagent and conditions. (A): HC(OEt)3, reflux; (B): NH2NH2-H2O, reflux; (C): CS2/KOH, ethanol, reflux; (D): SOCl2, DMF(two drops),
reflux; (E): 19 or 20, CH3CO2Na, ethanol, reflux; (F): HCONH2, reflux; (G): (i) POCl3, reflux; (ii) NH2NH2-H2O, reflux; H: CS2/KOH, ethanol, reflux; I:
SOCl2, DMF(two drops), reflux; and (J): 19 or 20, CH3CO2Na, ethanol, reflux.
O
CN
S
OEt
O
N
A
F
S
CN
NH2
NH2
S
8
7
NH
S
CHOEt
N
G
B
N
N
N
N
N
N
NHNH2
N
N
N
NHNH2
N
S
S
N
S
S
S
S
N
N
N
N
N
n
N
N
S
n
S
N
N
10
16
15
9
H
R
C
R
NH
N
NH
N
S
S
n = 0 or 1
J
E
N
S
N
N
N
I
N
N
D
N
S
N
12
Cl
Cl
S
N
11
N
S
N
13
N
14
R: a, H (n=0); b, 4-Cl (n=0); c, 4-NH2 (n=0); d, 4-NO2 (n=0); e, 4-F (n=0);
f, H (n=1); g, 4-Cl (n=1); h, 4-Br (n=1)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2013
Synthesis of Thienotriazolopyrimidine Derivatives Containing Triazolothiadiazole Moiety
605
Scheme 2
Elemental analyses were performed on a Carlo Erba 1106 ele-
mental analyzer.
N
N
General procedure for the preparation of 13 and 14. The
HS
SH
N
thieno[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione 11 or 12
(17 mmol) and thionyl chloride (20 mL) were mixed under
nitrogen. Two drops of DMF were added, and the mixture was
heated to 70ꢀC for 5 h. The dark brown solution was cooled to
room temperature and diluted with dichloromethane (70 mL).
After evaporation of the solvent and excess thionyl chloride, the
solid product was purified by recrystallization from ethanol.
3-Chlorothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (13).
The compound was obtained from 11 in 59% yield, mp 191ꢀC
NH2
18
PhCH2COOH/
POCl3
PhCOOH/POCl3
N
HN
S
S
N
N
HN
N
S
S
N
1
(decompose); H NMR (dimethyl sulfoxide-d6): d 8.98 (s, 1H,
N
H-5, pyrimidine), 8.32 (s, 1H, J = 5.8 Hz, H-8), 7.73 (1 H,
J = 5.8 Hz, H-9), MS: (m/z) 210 (M+), 175, 157, 78, 63. Anal.
Calcd for C7H3ClN4S: C, 39.91; H, 1.44, N, 26.60. Found: C,
40.13; H, 1.51; N, 26.44.
R
R
19
20
R: a, H; b, 4-Cl; c, 4-NH2;
d, 4-NO2, e, 4-F
R: a, H; b, 4-Cl; c, 4-Br
3-Chlorothieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (14).
The compound was obtained from 11 in 66% yield, mp 189ꢀC
1
(decompose); H NMR (dimethyl sulfoxide-d6): d 8.84 (s, 1H,
H-5, pyrimidine), 8.02 (d, 1H, J = 5.8 Hz, H-8), 7.70 (d, 1H,
J = 5.8 Hz, H-7), MS: (m/z) 210 (M+), 175, 78, 63. Anal. Calcd
for C7H3ClN4S: C, 39.91; H, 1.44, N, 26.60. Found: C, 39.75;
H, 1.60; N, 26.49.
General procedure for the preparation of 19a–e and 20a–c. A
mixture of 4-amino-4H-1,2,4-triazole-3,5-dithiol (18) (6.7 mmol) and
the appropriate carboxylic acid (6.7 mmol) in phosphorus oxychloride
(10 mL) was heated at reflux for 6 h. The excess phosphorus
oxychloride was removed under reduced pressure, and the residue
was diluted with ice–water mixture. The precipitated solid was
collected by filtration and purified by recrystallization from DMF.
6-Phenyl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
(19a). Mp 235–237ꢀC (Lit. [15] 238–240ꢀC).
for benzyl protons, respectively. The mass spectra of these
compounds revealed m/z = 422 corresponding the molecu-
lar formula, C17H10N8S3. The ions at 248 (61%) and 175
(55%) were fragments because of the cleavage of sulfide
bond of the molecular ion. Just as the results of previous
study have shown [10], it is noteworthy that the chemical
shifts of thiophene and pyrimidine protons for thienotriazo-
lopyrimidine ring of 15a–h and 16a–h were changed a bit
in higher field or more downfield because of sulfur-linked
1,2,4-triazolo[3,4-b][1,3,4]thiadiazole ring.
The compounds 15a–h and 16a–h were examined for
the antibacterial activity in vitro against Escherichia coli
and Staphylococcus aureus. They exhibited no to very
low activities. However, some of them were identified as
strong inhibitors of interleukin-6 (IL-6) action, which
inhibit IL-6 induced STAT3-dependent luciferase activities.
They are under evaluation for systematic biological activi-
ties, and the results will be published elsewhere.
6-(4-Chlorophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thia- diazole-
3-thione (19b). Mp 277–279ꢀC (Lit. [15] 260–262ꢀC).
6-(4-Aminophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole-
3-thione (19c). Mp >300ꢀC (Lit. [15] >324ꢀC).
6-(4-Nitrophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4]thia- diazole-
3-thione (19d). Mp 286–288ꢀC (Lit. [15] 244–246ꢀC).
6-(4-Fluorophenyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole-
3-thione (19e). Yield 80%, mp 265–267ꢀC; IR(KBr) 3195,
1
1600 cmÀ1, H NMR (dimethyl sulfoxide-d6): d 8.49 (s, 1H, NH),
7.98 (d, 2H, ArH), 7.43 (d, 2H, ArH), MS: (m/z) 252 (M+), 139,
121, 102, 95. Anal. Calcd for C9H5FN4S2: C, 42.85; H, 2.00, N,
22.21. Found: C, 42.60; H, 2.21; N, 22.02.
CONCLUSION
6-Benzyl-2H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
1
(20a). Yield 86%, mp 86–88ꢀC; IR(KBr) 3190, 1605 cmÀ1, H
In conclusion, we have reported the synthesis of sulfur-
linked diheterocyclic compounds 15a–h and 16a–h.
NMR (dimethyl sulfoxide-d6): d 11.9 (s, 1H, NH), 7.33–7.24 (m,
5H, ArH), 4.33 (s, 2H, benzyl), MS: (m/z) 248 (M+), 121, 102.
Anal. Calcd for C10H8N4S2: C, 48.37; H, 3.25, N, 22.56. Found:
C, 48.55; H, 3.40; N, 22.38.
EXPERIMENTAL
6-(4-Chlorobenzyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole-
3-thione (20b). Yield 88%, mp 106–108ꢀC; IR(KBr) 3195,
Melting points were determined in capillary tubes on Büchi
(Flawil, Switzerland) apparatus and are uncorrected. Each com-
pound of the reactions was checked on thin-layer chromatography
of Merck Kieselgel 60 F254 and purified by column chromatogra-
phy Merck (Darmstadt, Germany) silica gel (70–230 mesh). The
1H NMR spectra were recorded on Bruker (Rheinstetten, Ger-
many) DRX-300 FT NMR spectrometer (300 MHz) with Me4Si
as internal standard, and chemical shifts are given in ppm (d).
IR spectra were recorded using an EXCALIBUR (Hercules,
CA) FTS-3000 FTIR spectrophotometer. Electron ionization
mass spectra were recorded on a HP 59580 B spectrometer.
1602cmÀ1 1H NMR (dimethyl sulfoxide-d6): d 7.33 (d, 2H,
,
ArH), 7.22 (d, 2H, ArH), 4.33 (s, 2H, benzyl), MS: (m/z) 282
(M+), 121, 102. Anal. Calcd for C10H7ClN4S2: C, 42.47; H, 2.50,
N, 19.81. Found: C, 42.62; H, 2.32; N, 19.99.
6-(4-Bromobenzyl)-2H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazole-
3-thione (20c). Yield 76%, mp 99–101ꢀC; IR(KBr) 3195,
1600cmÀ1 1H NMR (dimethyl sulfoxide-d6): d 7.48 (d, 2H,
,
ArH), 7.22 (d, 2H, ArH), 4.34 (s, 2H, benzyl), MS: (m/z) 328
(M+). Anal. Calcd for C10H7BrN4S2: C, 36.70; H, 2.16, N,17.12.
Found: C, 36.81; H, 2.02; N, 17.40.
Journal of Heterocyclic Chemistry
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606
J. Whang and Y.-H. Song
Vol 50
General procedure for the preparation of sulfur-linked bis-
NMR (dimethyl sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine),
8.06 (d, J = 5.8 Hz, 1H, H-8, thiophene), 7.79 (d, J = 5.8 Hz,
1H, H-9, thiophene), 7.33 (d, 2H, J = 7.5 Hz, ArH), 7.25
(d, 2H, J = 7.5 Hz, ArH), 4.33 (s, 2H, benzyl), MS: (m/z) 456
(M+), 414, 324, 208, 193, 135, 116, 84, 66. Anal. Calcd for
C17H9ClN8S3: C, 44.68; H, 1.99; N, 24.52. Found: C, 44.77;
H, 1.90; N, 24.41.
heterocyclic compounds (15a–h and 16a–h). A suspension of
anhydrous sodium acetate (2 mmol), 13 or 14 (1.2 mmol), and
the appropriate [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole-3-thione
19 or 20 (1.2 mmol) in ethanol (20 mL) was refluxed for 6–8 h.
After cooling, the solid products formed were filtered, washed
with water, and recrystallized from ethanol.
3-(6-Phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-ylthio)
3-(6-(4-Bromobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (15h). The
thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (15a).The compound
1
was obtained in 65% yield, mp 259–261ꢀC; H NMR (dimethyl
1
compound was obtained in 65% yield, mp 152–154ꢀC; H NMR
sulfoxide-d6): d 9.65 (s, 1H, H-5, pyrimidine), 8.06 (d, J = 5.8Hz,
1H, H-8, thiophene), 7.88 (t, 2H, J = 7.5Hz, ArH), 7.78 (d,
J = 5.8Hz, 1H, H-9, thiophene), 7.65 (d, 1H, J = 7.5Hz, ArH),
7.52 (t, 2H, J = 7.5Hz, ArH), MS: (m/z) 408 (M+), 252, 208, 139,
84, 66. Anal. Calcd for C16H8N8S3: C, 47.04; H, 1.97, N, 27.43.
(dimethyl sulfoxide-d6): d 9.66 (s, 1H, H-5, pyrimidine), 8.05
(d, J= 5.8 Hz, 1H, H-8, thiophene), 7.78 (d, J= 5.8 Hz, 1H, H-9,
thiophene), 7.49 (d, 2H, J= 7.5 Hz, ArH), 7.21 (d, 2H, J=7.5Hz,
ArH), 4.35 (s, 2H, benzyl), MS: (m/z) 500 (M+), 167, 149, 116, 84,
66. Anal. Calcd for C17H9BrN8S3: C, 40.72; H, 1.81; N, 22.35.
Found: C, 44.82; H, 1.73; N, 24.40.
Found: C, 46.90; H, 2.05; N, 27.29.
3-(6-(4-Chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
3-(6-Phenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-ylthio) thieno
[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (16a). The compound
was obtained in 54% yield, mp 250–252ꢀC; 1H NMR (dimethyl
sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine), 8.30 (d,
J = 5.8 Hz, 1H, H-8, thiophene), 7.86 (t, 2H, J = 7.5 Hz, ArH),
7.69 (d, J = 5.8 Hz, 1H, H-7, thiophene), 7.63 (d, 1H,
J = 7.5 Hz, ArH), 7.53 (t, 2H, J = 7.5 Hz, ArH), MS: (m/z) 408
(M+), 252, 208, 139, 84, 66. Anal. Calcd for C16H8N8S3: C,
47.04; H, 1.97, N, 27.43. Found: C, 47.13; H, 1.90; N, 27.49.
3-(6-(4-Chlorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c] pyrimidine (16b). The
ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (15b). The
1
compound was obtained in 60% yield, mp 128–130ꢀC; H NMR
(dimethyl sulfoxide-d6): d 9.68 (s, 1H, H-5, pyrimidine), 8.05 (d,
J= 5.8 Hz, 1H, H-8, thiophene), 7.88 (d, 2H, J= 7.5 Hz, ArH), 7.79
(d, J= 5.8 Hz, 1H, H-9, thiophene), 7.60 (d, 2H, J= 7.5 Hz, ArH),
MS: (m/z) 442 (M+), 252, 234, 84, 66. Anal. Calcd for C16H7ClN8S3:
C, 43.39; H, 1.59, N, 25.30. Found: C, 43.47; H, 1.49; N, 25.48.
3-(6-(4-Aminophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (15c). The
compound was obtained in 71% yield, mp 285–287ꢀC; 1H
NMR (dimethyl sulfoxide-d6): d 9.65 (s, 1H, H-5, pyrimidine),
8.05 (d, J = 5.8 Hz, 1H, H-8, thiophene), 7.94 (d, 2H,
J = 7.5 Hz, ArH), 7.78 (d, J = 5.8 Hz, 1H, H-9, thiophene), 7.74
(d, 2H, J = 7.5 Hz, ArH), MS: (m/z) 423 (M+), 216, 208, 84, 66.
Anal. Calcd for C16H9N9S3: C, 45.38; H, 2.14, N, 29.77.
1
compound was obtained in 68% yield, mp 222–224ꢀC; H NMR
(dimethyl sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine), 8.31 (d,
J= 5.8 Hz, 1H, H-8, thiophene), 7.88 (d, 2H, J= 7.5 Hz, ArH), 7.70
(d, J = 5.8 Hz, 1H, H-7, thiophene), 7.60 (d, 2H, J = 7.5 Hz, ArH),
MS: (m/z) 442 (M+), 234, 84, 66. Anal. Calcd for C16H7ClN8S3:
C, 43.39; H, 1.59, N, 25.30. Found: C, 43.45; H, 1.50; N, 25.40.
3-(6-(4-Aminophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c] pyrimidine (16c). The
compound was obtained in 58% yield, mp 281–282ꢀC; 1H
Found: C, 45.45; H, 2.01; N, 29.60.
3-(6-(4-Nitrophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[3,2-e][1,2,4]triazolo[4,3c] pyrimidine (15d). The
1
compound was obtained in 69% yield, mp 253–255ꢀC; H NMR
(dimethyl sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine), 8.35 (d,
2H, J = 7.5 Hz, ArH), 8.17 (d, 2H, J = 7.5 Hz, ArH), 8.06 (d,
J = 5.8 Hz, 1H, H-8, thiophene), 7.78 (d, J = 5.8 Hz, 1H, H-9,
thiophene), MS: (m/z) 453 (M+), 278, 208, 139, 84, 66. Anal.
Calcd for C16H7N9O2S3: C, 42.38; H, 1.56, N, 27.80. Found: C,
NMR (dimethyl sulfoxide-d6):
d
9.65 (s, 1H, H-5,
pyrimidine), 8.30 (d, J = 5.8 Hz, 1H, H-8, thiophene), 7.95
(d, 2H, J = 7.5 Hz, ArH), 7.75 (d, 2H, J= 7.5 Hz, ArH), 7.69 (d,
J= 5.8 Hz, 1H, H-7, thiophene), MS: (m/z) 423 (M+), 216, 208, 84, 66.
Anal. Calcd for C16H9N9S3: C, 45.38; H, 2.14, N, 29.77. Found: C,
45.30; H, 2.09; N, 29.84.
42.30; H, 1.69; N, 27.60.
3-(6-(4-Fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
3-(6-(4-Nitrophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (16d)T. he compound
was obtained in 60% yield, mp 258–259ꢀC; 1H NMR (dimethyl
sulfoxide-d6): d 9.63 (s, 1H, H-5, pyrimidine), 8.34 (d, 2H, J=7.5Hz,
ArH), 8.30 (d, J= 5.8 Hz, 1H, H-8, thiophene), 8.18 (d, 2H, J=7.5Hz,
ArH), 7.70 (d, J= 5.8 Hz, 1H, H-7, thiophene), MS: (m/z) 453 (M+),
278, 208, 139, 121, 84, 66. Anal. Calcd for C16H7N9O2S3: C, 42.38;
H, 1.56, N, 27.80. Found: C, 42.44; H, 1.50; N, 27.69.
ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (15e). The
1
compound was obtained in 55% yield, mp 231–234ꢀC; H NMR
(dimethyl sulfoxide-d6): d 9.63 (s, 1H, H-5, pyrimidine), 8.06 (d,
J = 5.8 Hz, 1H, H-8, thiophene), 7.99 (d, 2H, J = 7.5 Hz, ArH),
7.78 (d, J = 5.8 Hz, 1H, H-9, thiophene), 7.43 (d, 2H, J = 7.5 Hz,
ArH), MS: (m/z) 426 (M+), 252, 208, 179, 139, 84, 66. Anal.
Calcd for C16H7FN8S3: C, 45.06; H, 1.65, N, 26.27. Found: C,
45.17; H, 1.71; N, 26.10.
3-(6-Benzyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-ylthio) thieno
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (15f). The compound
was obtained in 61% yield, mp 99–101ꢀC;1H NMR (dimethyl
sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine), 8.05 (d,
J = 5.8 Hz, 1H, H-8, thiophene), 7.78 (d, J = 5.8 Hz, 1H, H-9,
thiophene), 7.30–7.26 (m, 5H, ArH), 4.35 (s, 2H, benzyl), MS:
(m/z) 422 (M+), 248, 208, 175, 149, 135, 117, 102, 91. Anal.
Calcd for C17H10N8S3: C, 48.33; H, 2.39, N, 26.52. Found: C,
48.44; H, 2.26; N, 26.66.
3-(6-(4-Fluorophenyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c] pyrimidine (16e). The
1
compound was obtained in 66% yield, mp 243–245ꢀC; H NMR
(dimethyl sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine), 8.32 (d,
J= 5.8 Hz, 1H, H-8, thiophene), 8.00 (d, 2H, J= 7.5 Hz, ArH), 7.69
(d, J= 5.8 Hz, 1H, H-7, thiophene), 7.44 (d, 2H, J= 7.5 Hz, ArH),
MS: (m/z) 426 (M+), 252, 208, 179, 139, 84, 66. Anal. Calcd for
C16H7FN8S3: C, 45.06; H, 1.65, N, 26.27. Found: C, 45.13; H,
1.60; N, 26.33.
3-(6-(4-Chlorobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (15g). The
compound was obtained in 72% yield, mp 216–218ꢀC; 1H
3-(6-Benzyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-3-ylthio)
thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (16f). The compound
was obtained in 60% yield, mp 154–156ꢀC; 1H NMR (dimethyl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2013
Synthesis of Thienotriazolopyrimidine Derivatives Containing Triazolothiadiazole Moiety
607
[2] Prasad, M. R.; Rao, A. R.; Rao, P. S.; Rajan, K. S.; Meena, S.;
Madhavi, K. Eur J Med Chem 2008, 43, 614.
sulfoxide-d6): d 9.63 (s, 1H, H-5, pyrimidine), 8.31 (d,
J = 5.8 Hz, 1H, H-8, thiophene), 7.69 (d, J = 5.8 Hz, 1H, H-7,
thiophene), 7.30–7.25 (m, 5H, ArH), 4.36 (s, 2H, benzyl), MS:
(m/z) 422 (M+), 248, 208, 175, 149, 135, 91. Anal. Calcd for
C17H10N8S3: C, 48.33; H, 2.39, N, 26.52. Found: C, 48.42; H,
2.29; N, 26.60.
[3] Jo, B. S.; Son, H. Y.; Song, Y.-H. Heterocycles 2008, 75, 3091.
[4] Colanceska-Ragenovic, K.; Dimova, V.; Kakurinov, V.;
Molnar, D. G.; Buzarrovska, A. Molecules 2001, 6, 815.
[5] Siwek, A.; Wujec, M.; Dobosz, M.; Jagiełło-Wójtowicz,
E.; Chodkowska, A.; Kleinrok, A.; Paneth, P. Cent Eur J Chem
2008, 6, 47.
3-(6-(4-Chlorobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-
3-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c] pyrimidine (16g). The
[6] Contour-Galcéra, M.-O.; Sidhu, A.; Plas, P.; Roubert, P.
Bioorg Med Chem Lett 2005, 15, 3555.
1
compound was obtained in 59% yield, mp 101–103ꢀC; H NMR
[7] Almajan, G. L.; Innocenti, A.; Puccetti, L.; Manole, G.;
Barbuceanu, S.; Saramet, I.; Scozzafava, A.; Supuran, C. T. Bioorg Med
Chem Lett 2005, 15, 2347.
[8] Chen, Q., Zhu, X.-L.; Jiang, L.-L.; Liu, Z.-M.; Yang, G.-F. Eur
J Med Chem 2008, 43, 595.
[9] Eliazyan, K. A.; Shahbazyan, L. V.; Pivazyan, V. A.;
Yengoyan, A. P. J Heterocycl Chem 2011, 48, 188.
[10] Song, Y.-H.; Son, H. Y. J Heterocycl Chem 2010, 47, 1183.
[11] Omar, A.-M. M. E.; AboulWafa, O. M. J Heterocycl Chem 1986,
23, 1339.
(dimethyl sulfoxide-d6): d 9.64 (s, 1H, H-5, pyrimidine), 8.29
(d, J = 5.8 Hz, 1H, H-8, thiophene), 7.70 (d, J = 5.8 Hz, 1H, H-7,
thiophene), 7.34 (d, 2H, J = 7.5 Hz, ArH), 7.24 (d, 2H,
J = 7.5 Hz, ArH), 4.33 (s, 2H, benzyl), MS: (m/z) 456 (M+), 324,
208, 193, 135, 84, 66. Anal. Calcd for C17H9ClN8S3: C, 44.68;
H, 1.99; N, 24.52. Found: C, 44.60; H, 1.92; N, 24.60.
3-(6-(4-Bromobenzyl)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-3-
ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c] pyrimidine (16h). The
1
compound was obtained in 70% yield, mp 124–127ꢀC; H NMR
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Sulfur and Silicon 2004, 179, 1595.
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(dimethyl sulfoxide-d6): d 9.65 (s, 1H, H-5, pyrimidine), 8.31 (d,
J = 5.8 Hz, 1H, H-8, thiophene), 7.71 (d, J = 5.8 Hz, 1H, H-7,
thiophene), 7.48 (d, 2H, J = 7.5 Hz, ArH), 7.21 (d, 2H, J = 7.5 Hz,
ArH), 4.34 (s, 2H, benzyl), MS: (m/z) 500 (M+), 167, 149, 84, 66.
Anal. Calcd for C17H9BrN8S3: C, 40.72; H, 1.81; N, 22.35.
Found: C, 44.80; H, 1.86; N, 24.26.
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REFERENCES AND NOTES
[1] Nagamatsu, T.; Ahmed, S.; Hossion, A. M. L.; Ohno, S.
Heterocycles 2007, 73, 777.
Acknowledgment. This work was supported by the Korea Research
Foundation (project number 2010–0021038).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet