A facile one-pot synthesis of sulfur-Linked thieno[1,2,4]- Triazolo[4,3-c]pyrimidine derivatives containing phenylpyrazole or thienopyrimidinylpyrazole moiety

Article abstract of DOI:10.3987/COM-11-12371

A facile synthesis of sulfur-linked thieno[1,2,4]triazolo[4,3-c]pyrimidine derivatives containing phenylpyrazole or thienopyrimidinylpyrazole moiety via a one-pot reaction of thieno[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones, 3-chloropentane-2,4-dione

Full text of DOI:10.3987/COM-11-12371

HETEROCYCLES, Vol. 85, No. 1, 2012
155
HETEROCYCLES, Vol. 85, No. 1, 2012, pp. 155 - 164. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 8th October, 2011, Accepted, 4th November, 2011, Published online, 11th November, 2011
DOI: 10.3987/COM-11-12371
A FACILE ONE-POT SYNTHESIS OF SULFUR-LINKED THIENO[1,2,4]-
TRIAZOLO[4,3-c]PYRIMIDINE
DERIVATIVES
CONTAINING
PHENYLPYRAZOLE OR THIENOPYRIMIDINYLPYRAZOLE MOIETY
Jina Whang and Yang-Heon Song*
Department of Chemistry, Mokwon University, Daejeon 302-729, Republic of
Korea, e-mail address: yhsong@mokwon.ac.kr
Abstract
thieno[1,2,4]triazolo[4,3-c]pyrimidine derivatives containing phenylpyrazole or
thienopyrimidinylpyrazole moiety via one-pot reaction of
–
A
facile
synthesis
of
sulfur-linked
a
thieno[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thiones, 3-chloropentane-2,4-dione
and various hydrazines in the presence of potassium hydroxide in ethanol has
been achieved.
Thienotriazolopyrimidine derivatives have attracted much attention and are of great interest as potential
therapeutic agents. For instance, thienotriazolopyrimidine 1 as shown in Figure 1 and its analog have been
recently explored for inhibitor of Shiga toxin trafficking and A1/A2A or A2A/A3 adenosine receptor
antagonists, respectively.1,2 We have previously designed and synthesized thienotriazolopyrimidine
derivatives 2 with promising biological activity using iodobenzene diacetate.3 Moreover,
sulfur-containing 1,2,4-triazoles (3-thio-1,2,4-triazoles) were also reported to possess an impressive array
of biological activities such as antibacterial, antifungal, analgesic, somatostatin sst2/sst5 agonist and
carbonic anhydrase inhibitior.4-7 Particularly, sulfur-linked heterocyclic compounds containing
triazolopyrimidine or pyrazole such as 3 and 4 were investigated for antifungal agent and dopamine D3
receptor antagonist, respectively.8,9 We also have recently reported the synthesis of diheterocyclic
compound 5 and its analogs.10 In the other hand, many pyrazole derivatives are reported to possess a
broad spectrum of biological activities, such as antifungal, anti-inflammatory, A3 adenosine receptor
antagonist, etc.11-13
Therefore, we devised the introduction of 1H-pyrazole moiety to the thieno[1,2,4]triazolo[4,3-c]-
pyrimidine ring by sulfur to produce novel di- and triheterocyclic systems using the concept of molecular

156
HETEROCYCLES, Vol. 85, No. 1, 2012
hybridization.14 As a continuation of our synthetic works on heterocyclic compounds related to
thienopyrimidines and thienopyridines with biological interest,15 we wish to report herein the facile
one-pot synthesis of new sulfur-linked heterocyclic compounds 7a-i and 9a-i having
thieno[1,2,4]triazolo[4,3-c]pyrimidine and pyrazole ring, which are structurally related to 4 and 5 in the
hope of obtaining compounds of diverse biological activities.
N
O
N
N
R
N
N
N
N
R
N
N
S
S
S
N
N
N
N
S
N
3
2
1
4
N
N
S
N
N
N
N
N
S
S
N
N
N
S
N
N
5
N
Figure 1. Compounds 1-5
The initial one-pot reactions were performed by adding 3-chloropentane-2,4-dione and a phenylhydrazine
to thieno[1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione 6 or 810 in the presence of sodium acetate in
refluxing methanol for 24 h. After evaporation of the solvent, the residue was extracted with ethyl acetate,
and the solution was concentrated to afford crude product with side products. The pure solid products
were obtained in moderate yield after recrystallization in ethanol.
N
NH
N
N
N R
N
O
O
S
KOH
N
S
+
RNHNH2
+
N
EtOH
8 h
S
S
N
Cl
S
S
N
7a-g
6
N
NH
N
N
N R
N
O
O
S
N
KOH
S
N
+
+
RNHNH2
EtOH
8 h
N
Cl
N
8
9a-g
Scheme 1. Synthesis of diheterocyclic compounds in one-pot reaction

HETEROCYCLES, Vol. 85, No. 1, 2012
157
To explore the optimal condition of this one-pot reaction, various reaction conditions were investigated,
including solvent (THF, DMF, EtOH, CH3CN), base (CH3CO2Na, KOH, K2CO3, Et3N) and temperature
variations (rt and reflux). It was observed that the reaction using potassium hydroxide (2 eq) as base in
refluxing ethanol for 8 h gave the best result (Scheme 1).
Table 1. Diheterocyclic compounds 7a-g and 9a-g
Entry
7a
R
Yield (%)a
Entry
9a
R
Yield (%)a
Ph
56
61
55
70
62
44
56
Ph
65
62
55
67
51
48
60
7b
2-Cl-C6H4-
3-Cl-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-F-C6H4-
4-MeO-C6H4-
9b
2-Cl-C6H4-
3-Cl-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-F-C6H4-
4-MeO-C6H4-
7c
9c
7d
9d
7e
9e
7f
9f
7g
9g
a isolated yields
O
O
O
O
8
+
6
+
Cl
Cl
S
KOH EtOH
KOH EtOH
NHNH2
NHNH2
NHNH2
NHNH2
S
N
N
N
N
N
N
S
N
S
N
48%
55%
50%
54%
N
N
N
N
N
N
N
N
S
S
S
S
S
S
N
N
N
N
S
S
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
S
S
S
S
7h
7i
9h
9i
Scheme 2. Synthesis of triheterocyclic compounds in one-pot reaction

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HETEROCYCLES, Vol. 85, No. 1, 2012
The structure of all new synthesized compounds was evident from their elemental analysis, mass spectra
and 1H NMR spectra. The results of diheterocyclic compounds 7a-g and 9a-g were summarized in Table
1. For the synthesis of triheterocyclic compounds 7h-i and 9h-i containing thienopyrimidinylpyrazole
moiety, two thienopyrimidinylhydrazines were utilized in place of phenylhydrazine in one-pot reaction as
shown in Scheme 2. The structure of 7h-i and 9h-i was established by elemental analysis, mass spectra,
1
1H NMR and IR spectra. It is noteworthy that the H NMR signals of these compounds showed four
doublet signals (J = 5.9 Hz) because of two thiophene protons, and two singlet signals attributed to two
pyrimidine protons in low field.
NH
N
O
O
S
S
N
+
+
NH2NH
Cl
N
Cl
8
56%
O
68%
N
N
N
N
Cl
O
S
S
Cl
NH
56%
Cl
N
11
10
N
N
S
S
N
NH2NH
N
55%
52%
N
N
N
N
N
Cl
S
S
N
9d
Scheme 3. Proposed mechanism for the formation of 9d in one-pot reaction
The suggested mechanism for the conversion of reaction mixture to product 9d in one-pot reaction, for
instance, involves the initial formation of 10 and 11 from two different reactants through a simple
substitution or imine formation-condensation reaction (Scheme 3). Progress of the subsequent reaction
via fulfillment of condensation or substitution in the intermediates 10 and 11 gave the final product 9d in
56% yield. In order to elucidate the proposed mechanism, we have first prepared 10 and 11 from different

HETEROCYCLES, Vol. 85, No. 1, 2012
159
two reactants, separately, and these compounds were subjected to react with 4-chlorophenylhydrazine and
8 under the same reaction conditions, respectively. The overall yield did not exceed 40% in step-by-step
reaction by optimization of reaction condition. All of the spectral data and physical properties of the
products obtained from these two-step strategies by two routes and the products of the one-pot strategy
were identical. The intermediates 10 and 11 were also identified in reaction mixture of one-pot synthesis.
Compared to step-by-step reaction, the present one-pot method has advantages of good yields, short
reaction times and experimental simplicity. The compounds 7a-i and 9a-i were examined preliminarily
for the antibacterial activity in vitro against Escherichia coli and Staphylococcus aureus. Some of them
exhibited moderate activities. They are under evaluation for other biological activities and the results will
be published elsewhere.
In conclusion, we have reported a simple and efficient method for the synthesis of new sulfur-linked
heterocyclic compounds 7a-i and 9a-i with potential biological activities.
EXPERIMENTAL
Melting points were determined in capillary tubes on Büchi apparatus and are uncorrected. Each
compound of the reactions was checked on thin-layer chromatography of Merck Kieselgel 60F254 and
purified by column chromatography Merck silica gel (70-230 mesh). The 1H NMR spectra were recorded
on Bruker DRX-300 FT NMR spectrometer (300 MHz) with Me4Si as internal standard and chemical
shifts are given in ppm (). IR spectra were recorded using an EXCALIBUR FTS-3000 FT IR
spectrophotometer. Electron ionization mass spectra were recorded on a HP 59580 B spectrometer.
Elemental analyses were performed on a Carlo Erba 1106 elemental analyzer.
General procedure for the preparation of 7a-i and 9a-i. A suspension of thieno[1,2,4]triazolo[4,3-c]-
pyrimidine-3(2H)-thione 6 or 8 (0.50 g, 2.40 mmol) and potassium hydroxide (0.27 g, 4.80 mmol) in
EtOH (10 mL) was stirred at rt for 0.5 h. To this mixture 3-chloropentane-2,4-dione (0.32 g, 2.40 mmol),
appropriate hydrazine (2.40 mmol) were added and it was allowed to stir at reflux for 8 h. The solution
was cooled to rt and evaporated under reduced pressure. The residue was extracted with EtOAc and the
extract was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced
pressure. The solid product was purified by recrystallization from EtOH.
3-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (7a)
1
Mp 167-169 °C; IR (KBr) 1625 cm-1; H NMR (DMSO-d6):  9.62 (s, 1H, pyrimidine), 8.15 (d, J = 5.9
Hz, 1H, thiophene), 7.85 (d, J = 5.9 Hz, 1H, thiophene), 7.12-6.88 (m, 5H, Ar), 2.14 (s, 6H); MS: (m/z)
378 (M+), 354, 208, 147, 135, 106, 77. Anal. Calcd for C18H14N6S2: C, 57.12; H, 3.73; N, 22.20. Found: C,
57.30; H, 3.60; N, 22.42.

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3-[1-(2-Chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(7b)
1
Mp 171-173 °C; IR (KBr) 1631 cm-1; H NMR (DMSO-d6):  9.61 (s, 1H, pyrimidine), 8.08 (d, J = 5.9
Hz, 1H, thiophene), 7.81 (d, J = 5.9 Hz, 1H, thiophene), 7.39 (d, 1H, Ar), 7.37 (d, 1H, Ar), 7.17 (t, 1H,
Ar), 6.78 (t, 1H, Ar), 2.08 (s, 6H); MS: (m/z) 412 (M+), 388, 208, 140, 135, 111, 99. Anal. Calcd for
C18H13ClN6S2: C, 52.36; H, 3.17; N, 20.35. Found: C, 52.22; H, 3.29; N, 20.21.
3-[1-(3-Chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(7c)
1
Mp 176-178 °C; IR (KBr) 1630 cm-1; H NMR (DMSO-d6):  9.63 (s, 1H, pyrimidine), 8.08 (d, J = 5.9
Hz, 1H, thiophene), 7.81 (d, J = 5.9 Hz, 1H, thiophene), 7.17 (t, 1H, Ar), 7.08 (s, 1H, Ar), 7.00 (d, 1H,
Ar), 6.72 (d, 1H, Ar), 2.05 (s, 6H); MS: (m/z) 412 (M+), 388, 208, 140, 135, 111, 99. Anal. Calcd for
C18H13ClN6S2: C, 52.36; H, 3.17; N, 20.35. Found: C, 52.29; H, 3.25; N, 20.44.
3-[1-(4-Chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(7d)
1
Mp 168-169 °C; IR (KBr) 1633 cm-1; H NMR (DMSO-d6):  9.64 (s, 1H, pyrimidine), 8.09 (d, J = 5.9
Hz, 1H, thiophene), 7.82 (d, J = 5.9 Hz, 1H, thiophene), 7.19 (d, 2H, Ar), 7.06 (d, 2H, Ar), 2.03 (s, 6H);
MS: (m/z) 412 (M+), 388, 208, 140, 135, 111, 99. Anal. Calcd for C18H13ClN6S2: C, 52.36; H, 3.17; N,
20.35. Found: C, 52.19; H, 3.29; N, 20.24.
3-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(7e)
1
Mp 173-175 °C; IR (KBr) 1626 cm-1; H NMR (DMSO-d6):  9.63 (s, 1H, pyrimidine), 8.10 (d, J = 5.9
Hz, 1H, thiophene), 7.82 (d, J = 5.9 Hz, 1H, thiophene), 7.30 (d, 2H, Ar), 7.02 (d, 2H, Ar), 2.02 (s, 6H);
MS: (m/z) 456 (M+), 434, 220, 208, 186, 184, 157, 155, 145, 135. Anal. Calcd for C18H13BrN6S2: C,
47.27; H, 2.86; N, 18.37. Found: C, 47.40; H, 2.84; N, 18.20.
3-[1-(4-Fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(7f)
1
Mp 208-210 °C; IR (KBr) 1630 cm-1; H NMR (DMSO-d6):  9.67 (s, 1H, pyrimidine), 8.15 (d, J = 5.9
Hz, 1H, thiophene), 7.85 (d, J = 5.9 Hz, 1H, thiophene), 7.01 (d, 2H, Ar), 6.93 (d, 2H, Ar), 2.03 (s, 6H);
MS: (m/z) 396 (M+), 375, 277, 216, 208, 136, 97, 66. Anal. Calcd for C18H13FN6S2: C, 54.53; H, 3.30; N,
21.20. Found: C, 54.42; H, 3.21; N, 21.32.
3-[1-(4-Methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(7g)
1
Mp 158-160 °C; IR (KBr) 1633 cm-1; H NMR (DMSO-d6):  9.63 (s, 1H, pyrimidine), 8.10 (d, J = 5.9

HETEROCYCLES, Vol. 85, No. 1, 2012
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Hz, 1H, thiophene), 7. 80(d, J = 5.9 Hz, 1H, thiophene), 7.09 (d, 2H, Ar), 6.90 (d, 2H, Ar), 3.75 (s, 3H),
2.06 (s, 6H); MS: (m/z) 408 (M+), 384, 208, 135, 111. Anal. Calcd for C19H16N6OS2: C, 55.86; H, 3.95; N,
20.57. Found: C, 56.11; H, 3.99; N, 20.79.
3-[3,5-Dimethyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo-
[4,3-c]pyrimidine (7h)
1
Mp 151-154 °C; IR (KBr) 1625 cm-1; H NMR (DMSO-d6):  9.60 (s, 1H, pyrimidine), 8.45 (s, 1H,
pyrimidine), 8.16 (d, J = 5.9 Hz, 1H, thiophene), 8.08 (d, J = 5.9 Hz, 1H, thiophene), 7.81 (d, J = 5.9 Hz,
1H, thiophene), 7.62 (d, J = 5.9 Hz, 1H, thiophene), 2.22 (s, 6H); MS: (m/z) 436 (M+), 412, 208, 205, 191,
164, 135, 123, 109, 79, 64. Anal. Calcd for C18H12N8S3: C, 49.52; H, 2.77; N, 25.67. Found: C, 49.31; H,
2.62; N, 25.79.
3-[3,5-Dimethyl-1-(thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo-
[4,3-c]pyrimidine (7i)
1
Mp 193-194 °C; IR (KBr) 1620 cm-1; H NMR (DMSO-d6):  9.59 (s, 1H, pyrimidine), 8.48 (s, 1H,
pyrimidine), 8.30 (d, J = 5.9 Hz, 1H, thiophene), 8.13 (d, J = 5.9 Hz, 1H, thiophene), 7.80 (d, J = 5.9 Hz,
1H, thiophene), 7.73 (d, J = 5.9 Hz, 1H, thiophene), 2.19 (s, 6H); MS: (m/z) 436 (M+), 208, 191, 135, 109,
79. Anal. Calcd for C18H12N8S3: C, 49.52; H, 2.77; N, 25.67. Found: C, 49.44; H, 2.60; N, 25.55.
3-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (9a)
1
Mp 177-179 °C; IR (KBr) 1630 cm-1; H NMR (DMSO-d6):  9.58 (s, 1H, pyrimidine), 8.30 (d, J = 5.9
Hz, 1H, thiophene), 7.71 (d, J = 5.9 Hz, 1H, thiophene), 7.15-6.90 (m, 5H, Ar), 1.98 (s, 6H); MS: (m/z)
378 (M+), 354, 208, 135, 106, 77, 65. Anal. Calcd for C18H14N6S2: C, 57.12; H, 3.73; N, 22.20. Found: C,
57.01; H, 3.66; N, 22.30.
3-[1-(2-Chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(9b)
1
Mp 176-178 °C; IR (KBr) 1633 cm-1; H NMR (DMSO-d6):  9.57 (s, 1H, pyrimidine), 8.26 (d, J = 5.9
Hz, 1H, thiophene), 7.66 (d, J = 5.9 Hz, 1H, thiophene), 7.35 (d, 1H, Ar), 7.26 (d, 1H, Ar), 7.14 (t, 1H,
Ar), 6.73 (t, 1H, Ar), 2.04 (s, 6H); MS: (m/z) 412 (M+), 388, 262, 208, 181, 140, 135, 111, 99. Anal.
Calcd for C18H13ClN6S2: C, 52.36; H, 3.17; N, 20.35. Found: C, 52.30; H, 3.08; N, 20.28.
3-[1-(3-Chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(9c)
1
Mp 153-155 °C; IR (KBr) 1631 cm-1; H NMR (DMSO-d6):  9.58 (s, 1H, pyrimidine), 8.26 (d, J = 5.9
Hz, 1H, thiophene), 7.67 (d, J = 5.9 Hz, 1H, thiophene), 7.10 (t, 1H, Ar), 7.00 (s, 1H, Ar), 6.92 (d, 1H,
Ar), 6.66 (d, 1H, Ar), 1.97 (s, 6H); MS: (m/z) 412 (M+), 388, 208, 181, 162, 140, 135, 111, 99. Anal.
Calcd for C18H13ClN6S2: C, 52.36; H, 3.17; N, 20.35. Found: C, 52.28; H, 3.21; N, 20.47.

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3-[1-(4-Chlorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(9d)
Mp 93-95 °C; IR (KBr) 1635 cm-1; 1H NMR (DMSO-d6):  9.54 (s, 1H, pyrimidine), 8.24 (d, J = 5.9 Hz,
1H, thiophene), 7.65 (d, J = 5.9 Hz, 1H, thiophene), 7.19 (d, 2H, Ar), 7.06 (d, 2H, Ar), 2.03 (s, 6H); MS:
(m/z) 412 (M+), 388, 264, 222, 208, 177, 135, 111, 99. Anal. Calcd for C18H13ClN6S2: C, 52.36; H, 3.17;
N, 20.35. Found: C, 52.28; H, 3.05; N, 20.41.
3-[1-(4-Bromophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(9e)
1
Mp 106-108 °C; IR (KBr) 1626 cm-1; H NMR (DMSO-d6):  9.61 (s, 1H, pyrimidine), 8.32 (d, J = 5.9
Hz, 1H, thiophene), 7.73 (d, J = 5.9 Hz, 1H, thiophene), 7.33 (d, 2H, Ar), 7.04 (d, 2H, Ar), 2.03 (s, 6H);
MS: (m/z) 456 (M+), 222, 208, 185, 171, 155, 135, 91. Anal. Calcd for C18H13BrN6S2: C, 47.27; H, 2.86;
N, 18.37. Found: C, 47.17; H, 2.77; N, 18.44.
3-[1-(4-Fluorophenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(9f)
1
Mp 124-126 °C; IR (KBr) 1630 cm-1; H NMR (DMSO-d6):  9.55 (s, 1H, pyrimidine), 8.25 (d, J = 5.7
Hz, 1H, thiophene), 7.65 (d, J = 5.7 Hz, 1H, thiophene), 7.02 (d, 2H, Ar), 6.94 (d, 2H, Ar), 1.96 (s, 6H);
MS: (m/z) 396 (M+), 375, 277, 216, 208, 136, 97. Anal. Calcd for C18H13FN6S2: C, 54.53; H, 3.30; N,
21.20. Found: C, 54.59; H, 3.23; N, 21.29.
3-[1-(4-Methoxyphenyl)-3,5-dimethyl-1H-pyrazol-4-ylthio)thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine
(9g)
1
Mp 113-115 °C; IR (KBr) 1633 cm-1; H NMR (DMSO-d6):  9.58 (s, 1H, pyrimidine), 8.31 (d, J = 5.9
Hz, 1H, thiophene), 7.73 (d, J = 5.9 Hz, 1H, thiophene), 7.11 (d, 2H, Ar), 6.94 (d, 2H, Ar), 3.72 (s, 3H),
2.06 (s, 6H); MS: (m/z) 408 (M+), 384, 208, 164, 135, 111. Anal. Calcd for C19H16N6OS2: C, 55.86; H,
3.95; N, 20.57. Found: C, 55.74; H, 3.82; N, 20.69.
3-[3,5-Dimethyl-1-(thieno[2,3-d]pyrimidin-4-yl)-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo-
[4,3-c]pyrimidine (9h)
1
Mp 165-167 °C; IR (KBr) 1630 cm-1; H NMR (DMSO-d6):  9.53 (s, 1H, pyrimidine), 8.40 (s, 1H,
pyrimidine), 8.24 (d, J = 5.9 Hz, 1H, thiophene), 8.08 (d, J = 5.9 Hz, 1H, thiophene), 7.66 (d, J = 5.9 Hz,
1H, thiophene), 7.51 (d, J = 5.9 Hz, 1H, thiophene), 2.13 (s, 6H); MS: (m/z) 436 (M+), 208, 191, 164, 135,
109. Anal. Calcd for C18H12N8S3: C, 49.52; H, 2.77; N, 25.67. Found: C, 49.42; H, 2.66; N, 25.60.
3-[3,5-Dimethyl-1-(thieno[3,2-d]pyrimidin-4-yl)-1H-pyrazol-4-ylthio)thieno[2,3-e][1,2,4]triazolo-
[4,3-c]pyrimidine (9i)
1
Mp 203-204 °C; IR (KBr) 1625 cm-1; H NMR (DMSO-d6):  9.59 (s, 1H, pyrimidine), 8.50 (s, 1H,

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pyrimidine), 8.30 (d, J = 5.9 Hz, 1H, thiophene), 8.19 (d, J = 5.9 Hz, 1H, thiophene), 7.77 (d, J = 5.9 Hz,
1H, thiophene), 7.70 (d, J = 5.9 Hz, 1H, thiophene), 2.18 (s, 6H); MS: (m/z) 436 (M+), 208, 191, 135, 109.
Anal. Calcd for C18H12N8S3: C, 49.52; H, 2.77; N, 25.67. Found: C, 49.66; H, 2.60; N, 25.77.
3-(Thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidin-3-ylthio)pentane-2,4-dione (10)
1
Mp 149-151 °C; IR (KBr) 1726 cm-1; H NMR (DMSO-d6):  9.57 (s, 1H, pyrimidine), 8.26 (d, J = 5.9
Hz, 1H, thiophene), 7.64 (d, J = 5.9 Hz, 1H, thiophene), 2.44 (s, 6H); MS: (m/z) 306 (M+), 208, 162, 135,
123, 94. Anal. Calcd for C12H10N4O2S2: C, 47.04; H, 3.29; N, 18.29. Found: C, 47.10; H, 3.15; N, 18.40.
4-Chloro-1-(4-chlorophenyl)-3,5-dimethyl-1H-pyrazole (11)16
1
Mp 74-75 °C; IR (KBr) 1640 cm-1; H NMR (DMSO-d6):  7.58-7.56 (m, 4H, Ar), 2.29 (s, 3H), 2.19 (s,
3H).
ACKNOWLEDGEMENTS
The work was supported by the Korea Research Foundation (project number 2010-0021038).
REFERENCES
1. L. J. Guetzoyan, R. A. Spooner, J. M. Lord, L. M. Roberts, and G. J. Clarkson, Eur. J. Med. Chem.,
2010, 45, 275.
2. (a) M. R. Prasad, A. R. Rao, P. S. Rao, K. S. Rajan, S. Meena, and K. Madhavi, Eur. J. Med. Chem.,
2008, 43, 614; (b) T. Nagamatsu, S. Ahmed, A. M. L. Hossion, and S. Ohno, Heterocycles, 2007, 73,
777.
3. B. S. Jo, H. Y. Son, and Y.-H. Song, Heterocycles, 2008, 75, 3091.
4. K. Colanceska-Ragenovic, V. Dimova, V. Kakurinov, D. G. Molnar, and A. Buzarrovska, Molecules,
2001, 6, 815.
5. A. Siwek, M. Wujec, M. Dobosz, E. Jagiełło-Wójtowicz, A. Chodkowska, A. Kleinrok, and P.
Paneth, Cent. Eur. J. Chem., 2008, 6, 47.
6. M.-O. Contour-Galcéra, A. Sidhu, P. Plas, and P. Roubert, Bioorg. Med. Chem. Lett., 2005, 15, 3555.
7. G. L. Almajan, A. Innocenti, L. Puccetti, G. Manole, S. Barbuceanu, I. Saramet, A. Scozzafava, and
C. T. Supuran, Bioorg. Med. Chem. Lett., 2005, 15, 2347.
8. Q. Chen, X.-L. Zhu, L.-L. Jiang, Z.-M. Liu, and G.-F. Yang, Eur. J. Med. Chem., 2008, 43, 595.
9. F. Micheli, G. Bonanomi, F. E. Blaney, S. Braggio, A. M. Capelli, A. Checchia, O. Curcuruto, F.
Damiani, R. D. Fabio, D. Donati, G. Gentile, A. Gribble, D. Hamprecht, G. Tedesco, S. Terreni, L.
Tarsi, A. Lightfoot, G. Stemp, G. MacDonald, A. Smith, M. Pecoraro, M. Petrone, O. Perini, J. Piner,
T. Rossi, A. Worby, M. Pilla, E. Valerio, C. Griffante, M. Mugnaini, M. Wood, C. Scott, M. Andreoli,
L. Lacroix, A. Schwarz, A. Gozzi, A. Bifone, C. R. Ashby, Jr., J. J. Hagan, and C. Heidbreder, J.

164
HETEROCYCLES, Vol. 85, No. 1, 2012
Med. Chem., 2007, 50, 5076.
10. Y.-H. Song and H. Y. Son, J. Heterocycl. Chem., 2010, 47, 1183.
11. O. Prakash, R. Kumar, and V. Parkash, Eur. J. Med. Chem., 2008, 43, 435.
12. A. A. Bekhit, H. M. A. Ashour, Y. S. Ghany, A. E. A. Bekhit, and A. Baraka, Eur. J. Med. Chem.,
2008, 43, 456.
13. P. G. Baraldi, A. Bovero, F. Fruttarolo, R. Romagnoli, M. A. Tarbrizi, D. Pretti, K. Varani, P. A.
Borea, and A. R. Moorman, Bioorg. Med. Chem., 2003, 11, 4161
14. C. Viegas-Junior, A. Danuello, V. S. Bolzani, E. J. Barreiro, and C. A. M. Fraga, Curr. Med. Chem.,
2007, 14, 1829.
15. (a) Y.-H. Song and H. Y. Son, J. Heterocycl. Chem., 2011, 48, 597; (b) H. M. Lee and Y.-H. Song,
Bull. Korean Chem. Soc., 2010, 31, 2242; (c) B. S. Jo and Y.-H. Song, Synth. Commun., 2009, 39,
4407; (d) Y.-H. Song and B. S. Jo, J. Heterocycl. Chem., 2009, 46, 1132; (e) Y.-H. Song, B. S. Jo,
and H. M. Lee, Heterocycl. Commun., 2009, 15, 203; (f) Y.-H. Song and J. Seo, J. Heterocycl. Chem.,
2007, 44, 1439; (g) Y.-H. Song, Heterocycl. Commun., 2007, 13, 33.
16. (a) V. Polshettiwar and R. S. Varma, Tetrahedron, 2010, 66, 1091; (b) V. Polshettiwar and R. S.
Varma, Tetrahedron Lett., 2008, 49, 397.