A new approach to the synthesis of fused pyrazoles: The synthesis of new pyrazolo [4,3-e][1,2,4]triazolo-[4,3-a]pyrimidine-4(5H)-imines

Article abstract of DOI:10.1080/10426500601160462

A new route for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-a] pyrimidine-4(5H)-imines has been delineated through heterocyclization of suitably functionalized pyrazoles with phenylisothiocyanate followed by methylation, nucleophilic displacement

Full text of DOI:10.1080/10426500601160462

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A New Approach to the
Synthesis of Fused Pyrazoles:
The Synthesis of New Pyrazolo
[4,3-e][1,2,4]triazolo-[4,3-
a]pyrimidine-4(5H)-imines
A. Davoodnia a , R. Zhiani a , M. Roshani a , M.
Bakavoli a & M. Bashash a
a Department of Chemistry , Islamic Azad
University , Mashhad, Iran
Published online: 29 Aug 2007.
To cite this article: A. Davoodnia , R. Zhiani , M. Roshani , M. Bakavoli &
M. Bashash (2007) A New Approach to the Synthesis of Fused Pyrazoles: The
Synthesis of New Pyrazolo [4,3-e][1,2,4]triazolo-[4,3-a]pyrimidine-4(5H)-imines,
Phosphorus, Sulfur, and Silicon and the Related Elements, 182:6, 1219-1224, DOI:
10.1080/10426500601160462
To link to this article: http://dx.doi.org/10.1080/10426500601160462
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Phosphorus, Sulfur, and Silicon, 182:1219–1224, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601160462
A New Approach to the Synthesis of Fused Pyrazoles:
The Synthesis of New Pyrazolo
[4,3-e][1,2,4]triazolo-[4,3-a]pyrimidine-4(5H)-imines
A. Davoodnia
R. Zhiani
M. Roshani
M. Bakavoli
M. Bashash
Department of Chemistry, Islamic Azad University, Mashhad, Iran
A new route for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidine-
4(5H)-imines has been delineated through heterocyclization of suitably function-
alized pyrazoles with phenylisothiocyanate followed by methylation, nucleophilic
displacement with hydrazine, and finally cyclocondensation with orthoesters.
Keywords Fused pyrazoles; orthoesters; phenyl isothiocyanates; pyrazolotriazolo-
pyrimidines
INTRODUCTION
In recent years pyrazolotriazolopyrimidines have been the subject
of intense research due to the interesting pharmacological activities
found for several of their derivatives.1−3 Among the various pyra-
zolotriazolopyrimidine ring systems, pyrazolo[4,3-e][1,2,4]triazolo[4,3-
a]pyrimidines have been little explored, and there are very few reports
on the synthesis and chemical properties of these compounds.4,5 Deriva-
tives of pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines have solely
been prepared from suitably functionalized pyrimidines. Other routes
to these compounds still remain to be explored. Inspired by these facts
and due to our interest in the synthesis of heterocyclic compounds
with potential biological activities,6−10 we were interested to look for
specific routes to new derivatives of pyrazolo[4,3-e][1,2,4]triazolo[4,3-
a]pyrimidines.
Received October 22, 2005; accepted October 22, 2006.
Address correspondence to M. Bakavoli, Department of Chemistry, School of Sciences,
Ferdowsi University, Mashhad, 91775-1436, Iran. E-mail: mbakavoli@yahoo.com
1219

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A. Davoodnia et al.
RESULTS AND DISCUSSION
Our synthesis started from suitably functionalized pyrazoles 1a,b,11
which were converted directly to 6H-pyrazolo[3,4-d]pyrimidine-6-
thiones 2a,b when heated at reflux temperature with phenylisoth-
iocyanate in the presence of potassium tert-butoxide in tert-butanol.
Pyrazolopyrimidothiones 2a,b were transformed smoothly to their
thiomethyl derivatives 3a,b using methyl iodide in the presence of
potassium hydroxide at r.t. Displacement of the thiomethyl group
with hydrazine hydrate furnished hydrazino derivatives 4a,b. The
latter compounds subsequently underwent cyclocondensation with
triethylorthoesters in ethanol on heating to reflux to give the de-
sired tricyclic products, pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines
5a–e (Scheme 1).
SCHEME 1
The structural assignment of compounds 5a–e was based upon spec-
tral data and elemental analysis. For example, the 1H NMR spectrum
of 5c showed the disappearance of two broad signals belonging to NH2
and NH moieties of compound 4b. The mass spectral analysis showed
the expected molecular ion peak at m/e 341 for compound 5c.

New Pyrazolo [4,3-e][1,2,4]triazolo-[4,3-a]pyrimidine-4(5H)-imines
1221
In conclusion, the reaction of 1a,b with phenylisothiocyanate in the
presence of potassium tert-butoxide in tert-butanol proceeded smoothly
to give the corresponding pyrazolopyrimidothiones 2a,b. Methylation
of these compounds was followed by treatment with hydrazine gave
4a,b, which were converted to tricyclic products 5a–e.
EXPERIMENTAL
Melting points were recorded on an Electrothermal type 9100 melting
point apparatus. 1H NMR (100 MHz) spectra were recorded on a Bruker
AC 100 spectrometer. Mass spectra were obtained with a Varian CH-7
instrument at 70 eV. Elemental analyses were performed by Ferdowsi
University, Mashhad, Iran.
General Procedure for 2a,b
To a solution of the 5-amino-1-phenyl-1 H-pyrazole-4-carbonitrile 1a,b
(10 mmol) and potassium tert-butoxide (20 mmol) in tert-butanol (50
mL), phenylisothiocyanate (12 mmol) was added. The reaction mixture
was heated under reflux for 7 h. After completion of the reaction, the
mixture was cooled to r.t. The precipitate was collected and washed with
ethanol and chloroform to give compounds 2a and 2b as yellow powder
in 72% and 76% yields, respectively.
4-Imino-1,5-diphenyl-1,4,5,7-tetrahydro-6 H-pyrazolo[3,4-
d]pyrimidine-6-thione (2a)
M.p. 242–244◦C; 1H NMR (d6-DMSO): δ 7.2–8.1 (m, 11H, arom-
H), 10.3 (br, 2H, NH); MS, m/z: 319 (M+); anal. calcd. for C17H13N5S
(319.38): C, 63.93; H, 4.10; N, 21.93; S, 10.04%. Found: C, 63.89; H, 4.07;
N, 21.89; S, 10.08%.
4-Imino-3-methyl-1,5-diphenyl-1,4,5,7-tetra-hydro-6 H-
pyrazolo[3,4- d] pyrimidine-6-thione (2b)
1
M.p. 235–237◦C; H NMR (d6-DMSO): δ 2.4 (s, 3H, CH3), 7.1–8.2
(m, 10H, arom-H), 9.3 (br, 2H, NH); MS, m/z: 333 (M+); anal. calcd. for
C18H15N5S (333.41): C, 64.84; H, 4.53; N, 21.01; S, 9.62%. Found: C,
64.79; H, 4.58; N, 20.98; S, 9.63%.
General Procedure for 3a,b
4-Imino-1,5-diphenyl-1,4,5,7-tetrahydro-6 H-pyrazolo[3,4-d]pyrimidine-
6-thiones 2a,b (5 mmol) and methyl iodide (5 mmol) were dissolved
in EtOH (40 mL) and H2O (15 mL) containing KOH (10 mmol).
The reaction mixture was stirred at r.t. for 5 h. After this time, the

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A. Davoodnia et al.
crude product was collected and recrystallized from ethanol to give
compounds 3a and 3b as a white and a yellow powder in 80% and 86%
yields, respectively.
6-(Methylthio)-1,5-diphenyl-1,5-dihydro-4 H-pyrazolo[3,4-
d]pyrimidin-4-imine (3a)
M.p. 162–164◦C; 1H NMR (d6-DMSO): δ 2.7 (s, 3H, CH3), 7.0–8.2 (m,
11H, arom-H), 9.9 (s br, 1H, NH); MS, m/z: 333 (M+); anal. calcd. for
C18H15N5S (333.41): C, 64.84; H, 4.53; N, 21.01; S, 9.62%. Found: C,
64.87; H, 4.48; N, 20.97; S, 9.65%.
3-Methyl-6-(methylthio)-1,5-diphenyl-1,5-dihydro-4 H-
pyrazolo[3,4- d]pyrimidin-4-imine (3b)
M.p. 147–149◦C; 1H NMR (CDCl3): δ 2.4 (s, 3H, CH3), 2.7 (s, 3H, CH3),
7.2–8.3 (m, 10H, arom-H), 10.0 (s br, 1H, NH); MS, m/z: 347 (M+); anal.
calcd. for C19H17N5S (347.12): C, 65.68; H, 4.93; N, 20.16; S, 9.23%.
Found: C, 65.64; H, 4.98; N, 20.12; S, 9.21%.
General Procedure for 4a,b
6-(methylthio)-1,5-diphenyl-1,5-dihydro-4 H-pyrazolo[3,4- d]pyrimidin-
e-4-imines 3a,b (1 mmol) and hydrazine hydrate (2 mL) were heated
at 45◦C in ethanol (15 mL) for 10 h. Then the precipitate was collected
and recrystallized from ethanol, to give compounds 4a and 4b as a
white powder in 62% and 87% yields, respectively.
6-Hydrazino-1,5-diphenyl-1,5-dihydro-4 H-pyrazolo[3,4-
d]pyrimidin-4-imine (4a)
M.p. 221–223◦C; 1H NMR (d6-DMSO): δ 4.7 (s br, 2H, NH2), 6.8–8.3
(m, 11H, arom-H), 9.0 (s br, 1H, NH), 9.2 (s br, 1H, NH); MS, m/z: 317
(M+); anal. calcd. for C17H15N7 (317.14): C, 64.34; H, 4.76; N, 30.90%.
Found: C, 64.37; H, 4.73; N, 30.85%.
6-Hydrazino-3-methyl-1,5-diphenyl-1,5-dihydro-
4 H-pyrazolo[3,4- d]pyrimidin-4-imine (4b)
1
M.p. 239–241◦C; H NMR (d6-DMSO): δ 2.6 (s, 3H, CH3), 5.9 (s br,
2H, NH2), 7.4–8.0 (m, 10H, arom-H), 9.3 (br, 1H, NH), 10.1 (br, 1H, NH);
MS, m/z: 331 (M+); anal. calcd. for C18H17N7(331.37): C, 65.24; H, 5.17;
N, 29.59%. Found: C, 65.21; H, 5.22; N, 29.53%.
General Procedure for 5a–e
To
a
solution of the 6-hydrazino-1,5-diphenyl-1,5-dihydro-4 H-
pyrazolo[3,4- d]pyrimidin-4-imine 4a,b (5 mmol) in ethanol (40 mL),

New Pyrazolo [4,3-e][1,2,4]triazolo-[4,3-a]pyrimidine-4(5H)-imines
1223
the respective triethylorthoester (7 mmol) was added. The reaction
mixture was heated under reflux for 10 h. After completion of the
reaction, the mixture was cooled to r.t. The crude product was collected
and recrystallized from ethanol to give compounds 5a–e as white
powders.
1,5-Diphenyl-1 H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]-
pyrimidin-4(5 H)-imine (5a)
Yield 75%; m.p. 334–336◦C; 1H NMR (d6-DMSO): δ 7.4–8.5 (m, 11H,
arom-H), 9.7 (s, 1H, CH of triazole ring), 10.3 (s br, 1H, NH); MS, m/z:
327 (M+); anal. calcd. for C18H13N7(327.34): C, 66.04; H, 4.00; N, 29.95%.
Found: C, 66.09; H, 3.96; N, 29.90%.
8-Ethyl-1,5-diphenyl-1 H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-
a]pyrimidin-4(5 H)-imine (5b)
1
3
Yield 74%; m.p. 319–321◦C; H NMR (d6-DMSO): δ 1.2 (t, JHH
=
3
7.0 Hz, 3H, CH3), 3.8 (q, JHH = 7.0 Hz, 2H, CH2), 7.0–8.4 (m, 11H,
arom-H), 9.9 (s br, 1H, NH); MS, m/z: 355 (M+); anal. calcd. for
C20H17N7(355.40): C, 67.59; H, 4.82; N, 27.59%. Found: C, 67.65; H,
4.80; N, 27.52%.
3-Methyl-1,5-diphenyl-1 H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-
a]pyrimidin-4(5 H)-imine (5c)
Yield 77%; m.p. 329-331◦C; 1H NMR (d6-DMSO): δ 2.6 (s, 3H, CH3),
7.4-8.1 (m, 10H, arom-H), 9.5 (s, 1H, CH of triazole ring), 10.2 (s br, 1H,
NH); MS, m/z: 341 (M+); anal. calcd. for C19H15N7 (341.37): C, 66.85;
H, 4.43; N, 28.72%. Found: C, 66.88; H, 4.41; N, 28.67%.
3,8-Dimethyl-1,5-diphenyl-1 H-pyrazolo[4,3-
e][1,2,4]triazolo[4,3-a]pyrimidin-4(5H)-imine (5d)
Yield 85%; m.p. 312–314◦C; 1H NMR (d6-DMSO): δ 2.55 (s, 3H, CH3),
2.26 (s, 3H, CH3), 7.2–8.1 (m, 10H, arom-H), 9.9 (s br, 1H, NH); MS,
m/z: 355 (M+); anal. calcd. for C20H17N7 (355.40): C, 67.59; H, 4.82; N,
27.59%. Found: C, 67.63; H, 4.78; N, 27.54%.
8-Ethyl-3-methyl-1,5-diphenyl-1-pyrazolo[4,3-
e][1,2,4]triazolo[4,3-a] pyrimidin-4(5 H)-imine (5e)
Yield 78%; m.p. 307–309◦C; 1H NMR (d6-DMSO): δ 1.2 (t, 3 JHH = 8.0
Hz, 3H, CH3), 2.7 (s, 3H, CH3), 3.7 (q, 3 JHH = 8.0 Hz, 2H, CH2), 7.0–8.2
(m, 10H, arom-H), 9.9 (s br, 1H, NH); MS, m/z: 369 (M+); anal. calcd.
for C21H19N7 (369.42): C, 68.28; H, 5.18; N, 26.54%. Found: C, 68.32; H,
5.15; N, 26.49%.

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A. Davoodnia et al.
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