Synthesis of new sulfur-linked 1,2,4-triazolothienopyrimidine and 1,2,4-triazolopyrazolopyrimidine derivatives containing fused heterocyclic pyrimidines

Article abstract of DOI:10.1002/jhet.461

(Chemical Equation Presented) A series of novel bis-heterocyclic compounds 12-20 were synthesized by integrating fused heterocyclic pyrimidines, such as thienopyrimidine and pyrazolopyrimidine into the scaffold of thienotriazolopyrimidines, and pyrazolotriazolopyrimidines through a sulfur-linkage.

Full text of DOI:10.1002/jhet.461

September 2010
Synthesis of New Sulfur-Linked 1,2,4-Triazolothienopyrimidine
and 1,2,4-Triazolopyrazolopyrimidine Derivatives Containing
Fused Heterocyclic Pyrimidines
1183
Yang-Heon Song* and Hoon Young Son
Department of Chemistry, Mokwon University, Daejeon 302-729, South Korea
*E-mail: yhsong@mokwon.ac.kr
Received August 29, 2009
DOI 10.1002/jhet.461
Published online 26 July 2010 in Wiley Online Library (wileyonlinelibrary.com).
A series of novel bis-heterocyclic compounds 12–20 were synthesized by integrating fused heterocy-
clic pyrimidines, such as thienopyrimidine and pyrazolopyrimidine into the scaffold of thienotriazolo-
pyrimidines, and pyrazolotriazolopyrimidines through a sulfur-linkage.
J. Heterocyclic Chem., 47, 1183 (2010).
INTRODUCTION
from our laboratories [15] and in continuation to our
works for biologically active heterocyclic compounds
[16] we now report the synthesis of new bis-heterocyclic
compounds 12–20 prepared by integrating fused hetero-
cyclic pyrimidines, such as thienopyrimidines and
pyrazolopyrimidines into the scaffold of thienotriazolo-
pyrimidines and pyrazolotriazolopyrimidines through a
sulfur-linkage in the hope of obtaining compounds of
diverse pharmaceutical activities.
The chemistry of heterocycles containing pyrimidine
moiety have attracted considerable interest for many
years because of their diverse biological activities, such
as anti-inflammatory, anti-HIV-1, antimicrobial, and
antitumor activities [1–4]. Some fused heterocyclic pyri-
midines have acquired much importance because of their
wide range of biological applications.
For instance, pyrazolopyrimidine 1 was as shown in
Figure 1 investigated as antifungal and antibacterial agents
[5], and other similar pyrazolopyrimidines were also
reported to possess inhibitory activities of the insulin-like
growth factor receptor (IGF-IR) and human cyclin-depend-
ent kinase 2 [6,7]. Various triazolopyrimidine derivatives
were known as dual thrombin/factor Xa inhibitors, human
adenosine A2A receptor ligands, and herbicides [8–10].
Also, new thienopyrimidine derivatives have been identi-
fied as potent inhibitors of VEGF receptor-2 kinase and
selective and potent ligands for the 5-HT3 receptor [11,12].
Furthermore, it has been noticed that introduction of an
additional ring to the fused heterocyclic pyrimidines tends
to exert profound influence in conferring new biological
activities in these molecules. Recently, thienotriazolopyri-
midine 2 and pyrazolotriazolopyrimidine 3 derivatives as
tricyclic heterocyclic compounds (five-six-five ring sys-
tems) have been explored for adenosine A1/A2A or A2A/A3
receptor antagonists [13,14].
RESULTS AND DISCUSSION
For the synthesis of key intermediates 9, 10, and 11,
2-aminothiophene-3-carbonitrile and 3-aminothiophene-
2-carboxamide as starting materials were obtained,
respectively, according to the modified Gewald method
[17]. 5-Amino-1-phenyl-1H-pyrazole-4-carbonitrile was
also prepared by the reaction of phenylhydrazine with
ethoxymethylenemalonitrile in refluxing ethanol [18].
Compounds 6 and 8 were obtained from the reaction of
starting materials with triethyl orthoformate and subse-
quent cyclization with hydrazine. Condensation of 3-
aminothiophene-2-carboxamide with aqueous formic
acid and subsequent treatment with POCl3 and hydra-
zine gave 7, as shown Scheme 1 [15]. Electrophilic
attack of CS2 in the presence of ethanolic KOH on the
hydrazines 6, 7, and 8 gave via further intramolecular
cyclization and elimination of H2S fused 1,2,4-triazolo-
pyrimidine-3-thiones 9–11, respectively, which exhibit a
Starting from using the thienotriazolopyrimidine
derivatives 4 and 5 which have been recently reported
C
V
2010 HeteroCorporation

1184
Y.-H. Song and H. Y. Son
Vol 47
and pyrimidine proton (H-20) of thieno[2,3-d]pyrimidine
ring, respectively. The mass spectrum of 12 revealed m/
z
¼
342 corresponding the molecular formula,
C13H6N6S3. The ions at 208, 135 were fragments
obtained from cleavage of sulfide bond of 12. The more
deshielded a proton (H-60) of thiophene of thieno
[3,2-d]pyrimidine ring in 3-(thieno[3,2-d]pyrimidin-4-
ylthio)thieno[3,2-e][1,2,4]tri-azolo[4,3-c]pyrimidine (13)
appeared as a doublet at d 8.43, whereas the b proton
(H-70) was found to appear at d 7.68 in little higher field
as a doublet when compared with 12. The mass frag-
mentation pattern of 13 was in agreement with
the pattern of 12, giving a molecular ion peak at 341.
1
The H-NMR of 3-(1-phenyl-1H-pyrazolo [3,4-d]pyrimi-
din-4-ylthio)thieno[3,2-e][1,2,4]triazolo
[4,3-c]pyrimi-
dine (14) displayed two singlets at d 8.75 and 8.65,
respectively for pyrimidine (H-60) and pyrazole protons
(H-30) of phenylpyrazolopyrimidine ring. Multiplets re-
sponsible for phenyl ring appeared at d 8.15, 7.54, and
7.71 as a doublet and two triplets, and the proton reso-
nance of the thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimi-
dine ring was observed as two doublets at d 8.19 and
8.00 for thiophene (H-8 and H-9) and as a singlet at d
9.34 for pyrimidine (H-5), respectively. The mass spec-
trum of 14 revealed m/z ¼ 402 corresponding the mo-
lecular formula, C18H10N8S2. The ions at 228, 208, and
195 were fragments due to cleavage of sulfide bond of
14.
Figure 1. Compounds 1–5.
thione-thiol equilibrium. The structure of these com-
1
pounds was confirmed by elemental analysis, H-NMR
and IR spectra. The IR spectra showed characteristic
peaks at 1200 (weak) and 3190 cmꢀ1 for the C¼¼S and
NH groups, respectively. The disappearance of the pri-
mary amino protons and the appearance of the second-
1
ary amino signal near at d 14.0 in H-NMR spectrum
indicated the thione tautomer of cyclization products.
The mass spectral data of 9 and 10, for instance, showed
a molecular ion peak at m/z 208, and also showed ion
at m/z 135 which could be attributed to the loss of
NANHAC¼¼S from the molecular ion.
1
The H-NMR spectra of 15–16 and 17 showed pat-
terns similar to those of corresponding 12–13 and 14. It
is noteworthy that the chemical shifts of thiophene and
pyrimidine protons for thieno[2,3-e][1,2,4]triazolo[4,3-
c]pyrimidine ring were changed at d 9.78–7.69 in higher
field or in more downfield because of sulfur-linked fused
heterocycles, such as thienopyrimidines or pyrazolo-
The compounds 12–20 were prepared as shown
Scheme 2 in moderate yield by treatment of fused 1,2,4-
triazolopyrimidine-3-thiones 9–11 with chlorothienopyri-
midines (A-Cl and B-Cl) or chlorophenylpyrazolopyri-
midine (C-Cl) in refluxing ethanol containing sodium
acetate. The structures of 12–20 were established on the
basis of their spectral data and elemental analysis. The
IR spectra of these compounds exhibited absorption
bands in the region of 1630–1490 cmꢀ1 for aromatic
C¼¼C, C¼¼N stretching vibrations, and disappearance of
NH and C¼¼S stretching signals of cyclic thiourea. The
1H-NMR spectra of 3-(thieno[2,3-d]pyrimidin-4-ylthio)-
thieno[3,2-e][1,2,4]triazolo[4,3-c] pyrimidine (12), for
example, showed four doublet signals because of pro-
tons of two thiophenes, and two singlet signals attrib-
uted to protons of two pyrimidine rings. Thus, one pair
of doublet signals at d 8.11 and 7.85 corresponded to
thiophene protons (H-8 and H-9) of thieno[3,2-e][1,2,4]
triazolo[4,3-c]pyrimidine ring, and the other one at d
8.03 and 7.50 attributed to thiophene protons (H-50 and
H-60) of thieno[2,3-d]pyrimidine ring. Two singlets at d
9.77 and 8.81 were observed for pyrimidine proton (H-
5) of thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine ring,
Scheme 1. Reagent and conditions: A: HC(OEt)3, reflux; B: NH2NH2-
H2O, reflux; C: HCOOH, reflux; D: (i) POCl3, reflux, (ii) NH2NH2-
H2O, reflux; E: HC(OEt)3, reflux; F: NH2NH2-H2O, reflux.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Synthesis of New Sulfur-Linked 1,2,4-Triazolothienopyrimidine and
1,2,4-Triazolopyrazolopyrimidine Derivatives Containing Fused Heterocyclic Pyrimidines
1185
Scheme 2. Reagents and conditions: A: CS2/KOH, ethanol, reflux; B: A-Cl, CH3CO2Na, ethanol, reflux; C: B-Cl, CH3CO2Na, ethanol, reflux;
D:C-Cl, CH3CO2Na, ethanol, reflux.
pyrimidine. The mass spectra of 15–16 and 17 revealed
the very similar fragmentations compared with corre-
sponding 12–13 and 14 having the same molecular for-
mulas, respectively.
(H-5) and pyrazole protons (H-9) of phenylpyrazolo tria-
zolopyrimidine ring were observed at d 8.84 and 8.32,
whereas the similar signals attributed to pyrimidine
(H-60) and pyrazole protons (H-30) of phenylpyrazolo-
pyrimidine ring were observed d 8.68 and 8.58, respec-
tively. Data from the elemental analysis and molecular
ion recorded in the mass spectrum further confirmed the
assign structure.
The compounds 18–19 were also characterized by
1H-NMR spectra, which exhibited three singlets at d
9.79–8.56 and two doublets at d 8.45–7.45 for fused het-
erocycles and multiplet signals at d 8.15–7.47 for phenyl
1
ring, like patterns of 14 and 17. The H-NMR spectrum
The compounds 12–20 were examined preliminarily
for the antibacterial activity in vitro against Escherichia
coli and were found to be slightly less active than that
of compound 1. They are under evaluation for other
of 20 containing two phenylpyrazolopyrimidine moieties
showed four singlets for pyrimidine and pyrazole pro-
tons of two rings. The signals attributed to pyrimidine
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1186
Y.-H. Song and H. Y. Son
Vol 47
6–8 h. After cooling, the solid products formed were filtered,
washed with water and recrystallized from ethanol.
biological activities and the results will be published
elsewhere.
3-(Thieno[2,3-d]pyrimidin-4-ylthio)thieno[3,2-e][1,2,4] tria-
zolo[4,3-c]pyrimidine (12). Yield 44%, mp 253–255ꢁC (from
ethanol); 1H-NMR (dimethyl sulfoxide-d6): d 9.77 (s, 1H,
H-5), 8.81 (s, 1H, H-20), 8.11 and 7.85 (d and d, J ¼ 5.8 Hz,
2H, H-8 and H-9), 8.03 and 7.50 (dþand d, J ¼ 5.8 Hz, 2H,
H-50 and H-60), ms: m/z (%) 342 (M , 99), 284 (9), 208 (12),
162 (5), 135 (22). Anal. Calcd. for C13H6N6S3: C, 45.60; H,
1.77, N, 24.54. Found: C, 45.51; H, 1.89; N, 24.37.
In conclusion, we have reported the synthesis of new
sulfur-linked bis-heterocyclic compounds 12–20 with
potential biological activities.
EXPERIMENTAL
3-(Thieno[3,2-d]pyrimidin-4-ylthio)thieno[3,2-e][1,2,4] tria-
zolo[4,3-c]pyrimidine (13). Yield 40%, mp 213–215ꢁC (from
ethanol); 1H-NMR (dimethyl sulfoxide-d6): d 9.77 (s, 1H,
H-5), 8.99 (s, 1H, H-20), 8.43 and 7.68 (d and d, J ¼ 5.8 Hz,
2H, H-60 and H-70), 8.12 and 7.84 (d and d, J ¼ 5.8 Hz, 2H,
H-8 and H-9), ms: m/z (%) 342 (Mþ, 100), 284 (5), 208 (42),
162 (15), 135 (31). Anal. Calcd. for C13H6N6S3: C, 45.60; H,
1.77, N, 24.54. Found: C, 45.48; H, 1.85; N, 24.43.
3-(1-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylthio)thieno
[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (14). Yield 50%, mp
244–246ꢁC (from ethanol); 1H-NMR (dimethyl sulfoxide-d6):
d 9.34 (s, 1H, H-5), 8.75 (s, 1H, H-60), 8.65 (s, 1H, H-30), 8.19
and 8.00 (d and d, J ¼ 5.8 Hz, 2H, H-8 and H-9), 8.15
(d, J ¼ 7.8 Hz, 2H, phenyl), 7.54 (t, 2H, phenyl), 7.41 (t, 1H,
phenyl), ms: m/z (%) 402 (Mþ, 100), 374 (10), 344 (11), 228
(8), 208 (5). Anal. Calcd. for C18H10N8S2: C, 53.72; H, 2.50,
N, 27.84. Found: C, 53.88; H, 2.59; N, 27.63.
3-(Thieno[2,3-d]pyrimidin-4-ylthio)thieno[2,3-e][1,2,4] tria-
zolo[4,3-c]pyrimidine (15). Yield 41%, mp 234–236ꢁC (from
ethanol); 1H-NMR (dimethyl sulfoxide-d6): d 9.32 (s, 1H,
H-5), 8.78 (s, 1H, H-20), 7.94 and 7.69 (d and d, J ¼ 5.8 Hz,
2H, H-8 and H-7), 7.62 and 7.44 (d and d, J ¼ 5.8 Hz, 2H,
H-60 and H-50), ms: m/z (%) 342 (Mþ, 95), 284 (10), 208 (12),
162 (10), 135 (15). Anal. Calcd. for C13H6N6S3: C, 45.60; H,
1.77, N, 24.54. Found: C, 45.49; H, 1.85; N, 24.66.
3-(Thieno[3,2-d]pyrimidin-4-ylthio)thieno[2,3-e][1,2,4] tria-
zolo[4,3-c]pyrimidine (16). Yield 43%, mp 228–230ꢁC (from
ethanol); 1H-NMR (dimethyl sulfoxide-d6): d 9.78 (s, 1H,
H-5), 9.00 (s, 1H, H-20), 8.46 and 7.69 (d and d, J ¼ 5.8 Hz,
2H, H-60 and H-70), 8.37 and 7.78 (d and d, J ¼ 5.8 Hz, 2H,
H-8 and H-7), ms: m/z (%) 342 (Mþ, 100), 298 (26), 284 (8),
208 (7), 168 (2), 135 (3). Anal. Calcd. for C13H6N6S3: C,
45.60; H, 1.77, N, 24.54. Found: C, 45.44; H, 1.90; N, 24.70.
3-(1-Phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylthio)thieno
[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (17). Yield 52%, mp
183–185ꢁC; 1H-NMR (dimethyl sulfoxide-d6): d 8.91 (s, 1H,
H-5), 8.58 (s, 1H, H-60), 8.28 (s, 1H, H-30), 7.91 and 7.69
(d and d, J ¼ 5.8 Hz, 2H, H-8 and H-7), 8.17 (d, J ¼ 7.8 Hz,
2H, phenyl), 7.56 (t, 2H, phenyl), 7.40 (t, 1H, phenyl), ms:
m/z (%) 402 (Mþ, 100), 358 (32), 228 (12), 208 (25), 195
(18), 135 (45), 77 (24). Anal. Calcd. for C18H10N8S2: C,
53.72; H, 2.50, N, 27.84. Found: C, 53.60; H, 2.61; N, 27.90.
4-(7-Phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c] pyrimi-
din-3-ylthio)thieno[2,3-d]pyrimidine (18). Yield 48%, mp
285–287ꢁC (from ethanol); 1H-NMR (dimethyl sulfoxide-d6):
d 9.23 (s, 1H, H-5), 8.79 (s, 1H, H-20), 8.56 (s, 1H, H-9), 7.70
and 7.45 (d and d, J ¼ 5.8 Hz, 2H, H-60 and H-50), 8.15 (d,
J ¼ 7.8 Hz, 2H, phenyl), 7.60 (t, 2H, phenyl), 7.47 (t, 1H,
phenyl), ms: m/z (%) 402 (Mþ, 100), 374 (19), 268 (30), 222
(14), 195 (12), 135 (31), 77 (18). Anal. Calcd. for
C18H10N8S2: C, 53.72; H, 2.50, N, 27.84. Found: C, 53.80; H,
2.64; N, 27.62.
Melting points were determined in capillary tubes on
Bu¨chi apparatus and are uncorrected. Each compound of the
reactions were checked on thin-layer chromatograpohy of
Merck Kieselgel 60F254 and purified by column chromatogra-
phy 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 (d). IR spectra were recorded using a
JASCO FT/IR-200 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 fused 1,2,4- tri-
azolopyrimidine-3-thione derivatives (9–11). A solution of
potassium hydroxide (10 mmol) and CS2 (2 mL) in ethanol
(30 mL) was added dropwise to a solution of appropriate thie-
nopyrimidinyl hydrazine or pyrazolopyrimidinyl hydrazine 6-8
(20 mmole) in ethanol (20 mL). The reaction mixture was then
refluxed for 8 hours. After cooling and evaporation of the sol-
vent, the residue was dissolved in water and acidified by add-
ing 10% HCl. The solid product was purified by recrystalliza-
tion from ethanol.
Thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thione(ꢀ91).
Yield 82%, mp 220–222ꢁC; IR (KBr) 3190, 1200 cm
,
1H-NMR (dimethyl sulfoxide-d6): d 14.0 (s, 1H, NH), 9.44
(s, 1H, H-5), 8.12 (d, J ¼ 5.8 Hz, 1H, H-8), 7.58 (d, J ¼ 5.8
Hz, 1H, H-9), ms: m/z (%) 208 (Mþ , 95) 181 (29), 162 (42),
135 (100), 84 (23). Anal. Calcd. for C7H4N4S2: C, 40.37; H,
1.94, N, 26.90. Found: C, 40.50; H, 1.82; N, 27.01.
Thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine-3(2H)-thioꢀn1e
(10). Yield 78%, mp 212–213ꢁC; IR (KBr) 3150, 1210 cm
,
1H-NMR (dimethyl sulfoxide-d6): d 13.8 (s, 1H, NH), 8.84 (s,
1H, pyrimidine), 7.90 (d, J ¼ 5.8 Hz, 1H, thiophene proton),
7.49 (d, J ¼ 5.8 Hz, 1H, thiophene proton), ms: m/z (%) 208
(Mþ, 60), 176 (61), 162 (15), 135 (34), 84 (99). Anal. Calcd.
for C7H4N4S2: C, 40.37; H, 1.94, N, 26.90. Found: C, 40.44;
H, 1.99; N, 26.76.
7-Phenyl-2H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimi-dine-
3(7H)-thione (11). Yield 84%, mp 259–261ꢁC; IR (KBr) 3190,
1210 cmꢀ1 1H-NMR (dimethyl sulfoxide-d6): d 14.2 (s, 1H,
,
NH), 9.47 (s, 1H, pyrimidine), 8.52 (s, 1H, pyrazole), 8.07
(d, J ¼ 7.8 Hz, 2H, phenyl), 7.64 (t, 2H, phenyl), 7.46 (t, 1H,
phenyl), ms: m/z (%) 268 (Mþ, 100), 222 (15), 195 (12), 84
(15). Anal. Calcd. for C12H8N6S: C, 53.72; H, 3.01, N, 31.32.
Found: C, 53.84; H, 2.88; N, 31.44.
General procedure for the preparation of sulfur-linked
bis-heterocyclic compounds (12–20). A suspension of anhy-
drous sodium acetate (15 mmol), chlorothienopyrimidine
(A-Cl or B-Cl) or chlorophenylpyrazolopyrimidine (C-Cl)
(10 mmol) and the appropriate fused 1,2,4-triazolopyrimidine-
3-thione 9-11 (10 mmol) in ethanol (30 mL) was refluxed for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2010 Synthesis of New Sulfur-Linked 1,2,4-Triazolothienopyrimidine and
1,2,4-Triazolopyrazolopyrimidine Derivatives Containing Fused Heterocyclic Pyrimidines
1187
[7] Williamson, D. S.; Parratt, M. J.; Bower, J. F.; Moore, J.
D.; Richardson, C. M.; Dokurno, P.; Cansfield, A. D.; Francis, G. L.;
Hebdon, R. J.; Howes, R.; Jackson, Philip S.; Lockie, A. M.; Murray,
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din-3-ylthio)thieno[3,2-d]pyrimidine (19). Yield 40%, mp
230–232ꢁC (from ethanol); 1H-NMR (dimethyl sulfoxide-d6):
d 9.79 (s, 1H, H-5), 9.02 (s, 1H, H-20), 8.79 (s, 1H, H-9), 8.45
and 7.69 (d and d, J ¼ 5.8 Hz, 2H, H-60 and H-70), 8.10 (d,
J ¼ 7.8 Hz, 2H, phenyl), 7.65 (t, 2H, phenyl), 7.50 (t, 1H,
phenyl), ms: m/z (%) 402 (Mþ, 100), 374 (18), 268 (26), 222
(28), 195 (18), 168 (12), 135 (84), 77 (43). Anal. Calcd. for
C18H10N8S2: C, 53.72; H, 2.50, N, 27.84. Found: C, 53.88; H,
2.40; N, 27.69.
[8] Deng, J. Z.; McMasters, D. R.; Rabbat, P. M. A.; Williams,
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7H-pyrazolo[4,3-e][1,2,4]triaqzolo[4,3-c]pyrimidine (20). Yield
1
52%, mp 297–299ꢁC (from ethanol); H-NMR (dimethyl sulf-
oxide-d6): d 8.84 (s, 1H, H-5), 8.68 (s, 1H, H-60), 8.58 (s, 1H,
H-30), 8.32 (s, 1H, H-9), 8.17 (d, J ¼ 7.8 Hz, 2H, phenyl),
8.14 (d, J ¼ 7.8 Hz, 2H, phenyl) 7.60–7.53 (m, 4H, phenyl),
7.47–7.37 (m, 2H, phenyl), ms: m/z (%) 462 (Mþ, 100), 434
(18), 404 (13), 268 (17), 228 (24), 195 (18), 168 (19), 141
(13), 77 (3). Anal. Calcd. for C23H14N10S: C, 59.73; H, 3.05,
N, 30.29 Found: C, 59.85; H, 2.91; N, 30.40.
[11] Munchhof, M. J.; Beebe, J. S.; Casavant, J. M.; Cooper, B.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet