Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines

Article abstract of DOI:10.1007/s00706-008-0939-8

Starting from 1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones, a synthesis pathway to the tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines is described. Reaction of 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl chloride afforded

Full text of DOI:10.1007/s00706-008-0939-8

Monatsh Chem 139, 1405–1407 (2008)
DOI 10.1007/s00706-008-0939-8
Printed in The Netherlands
Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines
Abolghasem Davoodnia, Rahele Zhiani, Niloofar Tavakoli-Hoseini
Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad, Iran
Received 29 March 2008; Accepted 3 April 2008; Published online 2 June 2008
# Springer-Verlag 2008
Abstract Starting from 1,5-dihydro-4H-pyrazolo[3,4-
d]pyrimidin-4-ones, a synthesis pathway to the
tricyclic pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimi-
dines is described. Reaction of 1,5-dihydro-4H-
pyrazolo[3,4-d] pyrimidin-4-ones with phosphoryl
chloride afforded the corresponding 4-chloro-1H-
pyrazolo[3,4-d]pyrimidines. Treatment of these
compounds with hydrazine hydrate at reflux tempera-
ture gave the hydrazino derivatives, which were sub-
sequently cyclized to the titled compounds on heating
with orthoesters in ethanol.
of new heterocyclic compounds with potential bio-
logical activities [12–21], and in continuation of
our work on the synthesis of new pyrazolotriazo-
lopyrimidines [22], we report herein a convenient
synthesis of some new pyrazolo[4,3-e][1,2,4]tria-
zolo[4,3-c]pyrimidines 4a–4f that might be of phar-
macological importance.
Results and discussion
Our approach is based on the use of 1,5-dihydro-4H-
pyrazolo[3,4-d]pyrimidin-4-ones 1a and 1b as the
starting materials [23]. Reaction of these compounds
with phosphoryl chloride gave the corresponding 4-
chloro-1H-pyrazolo[3,4-d]pyrimidines 2a and 2b.
The chloro derivatives 2a and 2b were then stirred
with hydrazine hydrate at room temperature to
give the hydrazino derivatives 3a and 3b. The lat-
ter compounds subsequently underwent cyclo-
condensation with triethylorthoesters in ethanol on
heating under reflux to give the desired tricyclic
pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines 4a–
4f (Scheme 1).
Keywords Pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines;
Phosphoryl chloride; Hydrazine hydrate; Triethylorthoesters;
Cyclocondensation.
Introduction
Pyrazolotriazolopyrimidines are a class of fused het-
erocycles interesting from the view point of phar-
macological activities [1–4]. There are few reports
on the synthesis and chemistry of these compounds
in literature [1, 2, 5–11]. The pyrazolo[4,3-e]-
[1,2,4]triazolo[4,3-c]pyrimidine ring system is one
of them that has not received much attention and
very little is known about the synthesis and proper-
ties of these compounds [1, 10, 11]. Prompted by
these findings and due to our interest in the synthesis
The structural assignment of the new compounds
2–4 is based upon spectroscopic and microanalyt-
1
ical data. For example, the H NMR spectrum of
4d did not show the NH2 and NH signals of the
precursor 3b at ꢀ ¼ 4.75 and 8.68 ppm, but instead
1
showed a sharp H signal at ꢀ ¼ 9.53 ppm belong-
Correspondence: Abolghasem Davoodnia, Department of
Chemistry, School of Sciences, Islamic Azad University,
Mashhad Branch, Mashhad 91735-413, Iran. E-mail:
adavoodnia@yahoo.com
ing to the triazole ring indicating the formation
of the tricyclic 4d. The IR spectrum was devoid
of the NH2 and NH absorption bands at ꢁꢀ¼ 3375,

1406
A. Davoodnia et al.
for 5.0 h. After the completion of the reaction (monitored
by TLC, CHCl3:MeOH, 95:5), the solvent was evaporated
in vacuo, ice–water was added, and the mixture extracted
with chloroform. The chloroform layer was separated and
evaporated to dryness to give 2a and 2b in 73 and 70%
yields.
4-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
(2a, C12H9ClN4)
1
Mp 91–93ꢁC; H NMR (100 MHz, DMSO-d6): ꢀ ¼ 2.70 (s,
CH3), 7.30–8.20 (m, 5H-phenyl), 8.92 (s, 1H, CH-6) ppm;
MS: m=z (%) ¼ 246 [Mþ þ 2] (12), 244 [Mþ] (35), 210 (28),
182 (22), 153 (31), 102 (37), 91 (25), 77 (100).
4-Chloro-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]-
pyrimidine (2b, C13H11ClN4)
1
Mp 85–87ꢁC; H NMR (100 MHz, DMSO-d6): ꢀ ¼ 2.65 (s,
CH3), 2.83 (s, CH3), 7.25–8.20 (m, 5H-phenyl) ppm; MS:
m=z (%) ¼ 260 [Mþ þ 2] (18), 259 (33), 258 [Mþ] (53),
257 (100), 222 (23), 196 (34), 152 (12), 102 (20), 91 (17),
77 (81).
General procedure for the synthesis of 4-hydrazino-1H-
pyrazolo[3,4-d]pyrimidines 3a and 3b
A mixture of 3 mmol 2a or 2b and 10cm3 hydrazine hydrate
was stirred at room temperature for 10.0 h. After the comple-
tion of the reaction (monitored by TLC, CHCl3:MeOH, 95:5),
the precipitate was filtered off and recrystallized from ethanol
to give 3a and 3b in 95% and 89% yields.
Scheme 1
4-Hydrazino-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]-
pyrimidine (3a, C12H12N6)
3330, and 3265 cmꢀ1 of the precursor. The MS of 4d
showed a molecular ion peak at m=z ¼ 264 (Mþ)
corresponding to the molecular formula C14H12N6.
In conclusion, we describe the synthesis of new
pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines 4a–
4f through cyclocondensation of hydrazino deriva-
tives 3a–3b with triethylorthoesters in boiling ethanol.
Mp 218–220ꢁC; 1H NMR (100MHz, DMSO-d6): ꢀ ¼ 2.62 (s,
CH3), 4.63 (broad, NH2), 7.20–8.25 (m, 5H-phenyl), 8.32 (s,
1H, CH-6), 8.80 (broad, NH) ppm; IR (KBr): ꢁꢀ¼ 3380, 3315,
and 3250 (NH2, NH) cmꢀ1; MS: m=z (%) ¼ 240 [Mþ] (17),
239 (51), 238 (92), 224 (32), 183 (28), 154 (12), 103 (36), 91
(29), 77 (100).
4-Hydrazino-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]-
pyrimidine (3b, C13H14N6)
Mp 225–227ꢁC; 1H NMR (100MHz, DMSO-d6): ꢀ ¼ 2.49 (s,
CH3), 2.60 (s, CH3), 4.75 (broad, NH2), 7.15–8.20 (m, 5H-
phenyl), 8.68 (broad, NH) ppm; IR (KBr): ꢁꢀ¼ 3375, 3330,
and 3265 (NH2, NH) cmꢀ1; MS: m=z (%) ¼ 254 [Mþ] (11),
253 (35), 252 (100), 238 (21), 197 (19), 153 (16), 102 (23), 91
(15), 77 (73).
Experimental
Melting points were recorded on an Electrothermal type
9100 melting point apparatus. The IR spectra were obtained
on a 4300 Shimadzu spectrophotometer as KBr disks. The
1H NMR (100 MHz) spectra were recorded on a Bruker AC
100 spectrometer. The mass spectra were scanned on a
Varian Mat CH-7 instrument at 70 ev. Elemental analysis
was performed on a Thermo Finnigan Flash EA microana-
lyzer and the results were found to agree satisfactorily with
the calculated values.
General procedure for the synthesis of pyrazolo[4,3-e]-
[1,2,4]triazolo[4,3-c]pyrimidines 4a–4e
To a solution of 2 mmol 3a or 3b in 10cm3 ethanol 3 mmol of
the respective triethylorthoester was added. The reaction mix-
ture was heated under reflux for 6.0 h. After the completion of
the reaction (monitored by TLC, CHCl3:MeOH, 95:5), the
mixture was cooled to room temperature. The crude product
was collected and recrystallized from ethanol to give 4a–4e in
high yields.
General procedure for the synthesis of 4-chloro-1H-pyrazolo-
[3,4-d]pyrimidines 2a and 2b
1,5-Dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-ones 1a and 1b
(5mmol) and 20cm3 POCl3 were heated under reflux

Synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines
1407
9-Methyl-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]-
References
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1
Yield 80%; mp 260–263ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 2.74 (s, CH3), 7.35–8.15 (m, 5H-phenyl), 9.32 (s, 1H, CH-
5), 9.43 (s, 1H, CH-3) ppm; MS: m=z (%) ¼ 250 [Mþ] (9), 249
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1
Yield 74%; mp 255–257ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 2.71 (s, CH3), 2.82 (s, CH3), 7.30–8.20 (m, 5H-phenyl),
9.23 (s, 1H, CH-5) ppm; MS: m=z (%) ¼ 264 [Mþ] (2), 263
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3-Ethyl-9-methyl-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo-
[4,3-c]pyrimidine (4c, C15H14N6)
1
Yield 72%; mp 228–230ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 1.41 (t, J ¼ 7.0 Hz, CH3), 2.72 (s, CH3), 3.19 (q, J ¼
7.0 Hz, CH2), 7.35–8.30 (m, 5H-phenyl), 9.26 (s, 1H, CH-5)
ppm; MS: m=z (%) ¼ 278 [Mþ] (3), 277 (28), 276 (98), 252
(12), 224 (12), 152 (10), 103 (22), 91 (17), 77 (100).
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5,9-Dimethyl-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo-
[4,3-c]pyrimidine (4d, C14H12N6)
1
Yield 75%; mp 238–240ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 2.72 (s, CH3), 2.92 (s, CH3), 7.30–8.20 (m, 5H-phenyl),
9.53 (s, 1H, CH-3) ppm; MS: m=z (%) ¼ 264 [Mþ] (14), 263
(81), 262 (100), 238 (10), 221 (20), 154 (19), 103 (26), 91
(11), 77 (94).
3,5,9-Trimethyl-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo-
[4,3-c]pyrimidine (4e, C15H14N6)
1
Yield 70%; mp 198–199ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 2.66 (s, CH3), 2.94 (s, CH3), 3.02 (s, CH3), 7.35–8.20 (m,
5H-phenyl) ppm; MS: m=z (%) ¼ 278 [Mþ] (3), 277 (13), 276
(62), 275 (75), 266 (34), 251 (18), 238 (34), 222 (11), 154
(10), 103 (19), 91 (18), 77 (100).
3-Ethyl-5,9-dimethyl-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]-
triazolo[4,3-c]pyrimidine (4f, C16H16N6)
1
Yield 68%; mp 180–182ꢁC; H NMR (100 MHz, DMSO-d6):
ꢀ ¼ 1.45 (t, J ¼ 7.0 Hz, CH3), 2.68 (s, CH3), 3.03 (s, CH3),
3.25 (q, J ¼ 7.0 Hz, CH2), 7.25–8.20 (m, 5H-phenyl) ppm;
MS: m=z (%) ¼ 292 [Mþ] (2), 291 (7), 290 (56), 289 (100),
274 (16), 154 (5), 103 (22), 91 (7), 77 (80).
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Roshani M (2006) Indian J Heterocycl Chem 16:151