A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines

Article abstract of DOI:10.1016/j.tet.2008.08.082

A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]p

Full text of DOI:10.1016/j.tet.2008.08.082

Tetrahedron 64 (2008) 10339–10343
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new strategy for the synthesis of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]-
pyrimidines and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines
*
Ahmad Sami Shawali , Hamdi M. Hassaneen, Nabil Kh. Shurrab
Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2008
Received in revised form 10 August 2008
Accepted 27 August 2008
Available online 2 September 2008
A series of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were prepared via oxidative cyclization of
aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-yl)hydrazones. Dimroth rearrangement of such
a series yielded pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Hydrazones
Nitrilimines
Dimroth rearrangement
1H-Pyrazolo[4,3-e]pyrimidine
Heterocycles
1. Introduction
[1,2,4]triazolo[1,5-c]pyrimidine exhibit interesting pharmacologi-
cal activities.14 For example, several 3- and/or 5-substituted 7H-
Reports from our laboratory1 and from others2 revealed that the
only possible route for the synthesis of pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]pyrimidine derivatives involves reaction of 5-amino-4-
imino-pyrazolo[3,4-d]pyrimidine with one-carbon cyclizing
agents. Furthermore, attempts to prepare the isomeric pyr-
azolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines via dehydrative cycli-
zation of the 4-acylhydrazino-pyrazolo[3,4-d]pyrimidines was
reported to give the corresponding pyrazolo[4,3-e][1,2,4]tri-
azolo[1,5-c]-pyrimidines.3 In view of these findings and in contin-
uation of our long standing interest for the utility of nitrilimines
derived from either hydrazonoyl halides or hydrazones in the
synthesis of heterocycles,4–13 we wish to report herein a simple and
convenient route for the synthesis of the title compounds. This
route involves 1,5-electrocyclization of nitrilimines generated in
situ from the hitherto unreported aldehyde N-(pyrazolo[3,4-d]
pyrimidin-4-yl)hydrazones to give the respective pyrazolo[4,3-e]
[1,2,4]triazolo[4,3-c]pyrimidines and Dimroth rearrangement of
the latter to give their isomeric pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]
pyrimidine derivatives.
pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines were reported to
be potent xanthine oxidase (XO) inhibitors.14 Also efforts made in
medicinal chemistry in the past 25 years have revealed that the
isomeric ring system pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimi-
dine is one of the structural requirements for compounds that be-
have as selective antagonists for human A2A and A3 adenosine
receptor subtypes.2 In addition, various derivatives have been used
as a new pharmacological tool for characterization of human A3
adenosine receptors.15
2. Results and discussion
The starting 5-amino-1,3-diphenyl-4-imino-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidine 1 was prepared as previously reported
from our laboratory.1 When compound 1 was stirred in ethanol in
the presence of excess hydrazine hydrate at room temperature, it
underwent Dimroth type rearrangement to give 1,3-diphenyl-4-
hydrazino-pyrazolo[3,4-d]-pyrimidine 2, which has not been
reported hitherto (Scheme 1). The isomerization of 1 into 2 seems
to occur through base-catalyzed tandem ring opening and ring
closure as shown in Scheme 2. This is consistent with a similar
rearrangement that was reported recently.16 The structure of 2 was
evidenced by its spectra and elemental analysis (see Section 3).
The required aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyr-
imidin-4-yl)hydrazones 4 were prepared by condensation of the
hydrazine derivative 2 with the appropriate aldehydes 3 (Scheme 1).
Our interest in developing a new synthesis of these two ring
systems results from the fact that some derivatives of both pyr-
azolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine and pyrazolo[4,3-e]
* Corresponding author.
E-mail address: as_shawali@yahoo.com (A.S. Shawali).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.082

10340
A.S. Shawali et al. / Tetrahedron 64 (2008) 10339–10343
NHNH2
N
NHN=CHR
R
N
N
N
Ph
Ph
N
N
N
RCHO
N
ii
..
Ph
Ph
Ph
R
:B
R
N
N:
N
N
N
3
N
Ph
N
N
Ph
N
4
B
B
H
N
N
N
N
N
N
N
Ph
N
Ph
N
N
Ph
N
2, 83%
Ph
H
R
81-92%
N
5
i
N
R
N
N
Ph
N
5
R
R
NH
N
Ph
N
N
..
Ph
NH2
75-85%
N
Ph
N
Ph
N
N
iv
iii
N
N
N
N
N
Ph
N
N
Ph
N
N
1
-
N
:B
B
N
Ph
N
N
Ph
N
6
H
6
78-86%
Scheme 1. Reagents: (i) H2NNH2$H2O/rt; (ii) FeCl3/EtOH/rt; (iii) MeCOONa/heat;
(iv) RCOCl, (RCO)2O or RCOOH. R¼ (a) C6H5; (b) 4-MeC6H4; (c) R ¼ 4-ClC6H4; (d)
4-MeOC6H4; (e) 4-O2NC6H4; (f) 4-Me2NC6H4; (g) PhCH]CH–; (h) 1-naphthyl; (i)
2-furyl; (j) 2-thienyl; (k) CH3; (l) H.
Scheme 3.
of 1 with 1 equiv quantity of each of benzoyl chloride, acetic anhy-
dride and formic acid gave products, 1 which proved identical in all
respects (mp, mixed mp, IR and 1H NMR spectra) with those
obtainedabove from base-catalyzed rearrangementof 5a, 5k, and 5l,
respectively (Scheme 1). This finding confirms the base-catalyzed
rearrangement of 5 into 6 (Scheme 1). A further evidence for the
rearrangement of 5 into 6 is provided by comparison of the 1H NMR
spectrum of 5l with that of 6l. For example, the 1H NMR spectrum of
All such hydrazones have not been reported hitherto. Their
structures were confirmed by their elemental analyses and spectral
(MS, IR and 1H NMR) data (see Section 3). For example, their 1H
NMR spectra in CDCl3 revealed, in each case, a characteristic signal
in the region
spectra showed the characteristic band for the N–H stretch of the
hydrazone group in the region 3393–3248 cmꢀ1
d 8.0–8.2 assignable to the –N]CH– proton. Their IR
.
5l reveals the triazole C3–H proton signal at
d 8.88, whereas thatof 6l
shows the C2–H proton signal at 8.47. This feature is consistent
d
..
with the literature reports, which indicate that the C3–H proton of
s-triazolo[4,3-c]pyrimidine is more deshielded than that of C2–H of
s-triazolo[1,5-c]pyrimidine.20 The driving force for the observed
rearrangement is the fact that [1,2,4]triazolo[1,5-c]pyrimidine ring
system is thermodynamically more stable than its isomer namely
[1,2,4]triazolo[4,3-c]pyrimidine.21
NH
NH
..
N-NH2
Ph
Ph
Ph
NH2
:B
NH2
B
Ph
N
N
NH
N
B
N
N
N
Ph
N
N
Ph
N
N
N
H
H
1
Ph
In conclusion, we have presented a facile strategy for the general
synthesis of the title compounds 5 and 6. Such new heterocycles
will be evaluated in pharmacological assays to determine their
activities as xanthine oxidase inhibitors and human adenosine
antagonists.
NHNH2
NHNH2
N
Ph
N
B
..
N
N
-
:B
N
Ph
N
N
N
Ph
H
2
Scheme 2.
3. Experimental
3.1. General
Treatment of each of the hydrazones 4 with 4 equiv of iron(III)
chloride in ethanol for 12 h gave, in each case, a single product as
evidenced by TLC analysis. Elemental analyses and mass spectra
revealed that each of such isolated products has two hydrogens less
than the respective hydrazone. This finding was confirmed by the 1H
NMR spectra, which indicated the absence of the –N]CH– and
hydrazone –NH-N]C protons. On thebasis of this finding, theisolated
products were assigned the structure of 3-substituted-7,9-diphe-
nylpyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines 5a–l (Scheme 1).
The conversion of 4 into 5 is reminiscent of other related oxidative
cyclization of aldehyde N-heteroarylhydrazones with iron(III) chlo-
ride, which have been reported to proceed via generation of the re-
spective nitrilimines, which undergo in situ 1,5-electrocyclization to
give the respective fused heterocycles.17,18
All melting points were determined on an electrothermal
Gallenkamp apparatus. The IR spectra were measured on a Pye-
Unicam SP300 instrument in potassium bromide discs. The 1H NMR
spectra were recorded on a Varian Mercury VXR-300 spectrometer
(300 MHz) in CDCl3. The mass spectra were recorded on a GCMS-
Q1000-EX Shimadzu and GCMS 5988-A HP spectrometers, the
ionizing voltage was 70 eV. Elemental analyses were carried out
by the Microanalytical Center of Cairo University, Giza, Egypt.
The starting 5-amino-1,3-diphenyl-4,5-dihydro-4-imino-1H-pyr-
azolo[3,4-d]pyrimidine 1 was prepared according to a literature
method.1 The 2-phenyl-, 2-methyl- and 2-unsubstituted derivatives
of 7,9-diphenylpyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines (6a,
6k, 6l) were also prepared as previously described from 1 and the
respective one-carbon atom cyclizing agents.1
When each of the pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimi-
dine derivatives 5 was heated in ethanol in the presence of sodium
acetate, they isomerized to the thermodynamically more stable
pyrazolo[4,3-e][1,2,4] [1,5-c]pyrimidine derivative 6 through tan-
dem ring opening and ring closure reactions (Scheme 3). This
3.2. 4-Hydrazino-1,3-diphenylpyrazolo[3,4-d]pyrimidine (2)
rearrangement is consistent with those reported in some earlier
3.2.1. Method A
19
reports.16,
The structures of 6 were determined by elemental
To 5-amino-1,3-diphenyl-4-imino-4,5-dihydro-1H-pyrazolo[3,4-d]
pyrimidine 1 (1.51 g, 5 mmol) in ethanol (30 mL) was added hydrazine
hydrate (80%, 8.5 mL). The mixture was stirred at room temperature
for 24 h. The solid that precipitated was filtered and crystallized from
dioxane to give 2 as white solid, yield 1.3 g (83%), mp 204 ꢁC.
analyses and spectral (MS, IR, 1H NMR) data (see Section 3).
To provide a decisive evidence for this rearrangement, the
products 6a, 6k and 6l were compared with authentic samples
prepared by an alternative synthesis.1 Thus, in our hands, treatment

A.S. Shawali et al. / Tetrahedron 64 (2008) 10339–10343
10341
3.2.2. Method B
15H, ArH and NH), 8.35 (s, 1H, –N]CH), 8.72 (s, 1H, pyrimidine-H);
MS m/z (%): 436 (Mþþ1, 16), 435 (Mþ, 100), 313 (58), 286 (95), 102
(14), 91 (9), 77 (48). Anal. Calcd for C24H17N7O2 (435.45): C, 66.20;
H, 3.94; N, 22.52. Found: C, 66.04; H, 3.82; N, 22.31%.
To 1,3-diphenyl-4-cyano-5-ethoxymethyleneaminopyrazole (1.58 g,
5 mmol) in ethanol was added hydrazine hydrate (10 mL, 80%). The
mixturewas stirred at room temperature for 24 h and then the solid that
precipitated was filtered and crystallized from dioxane to give 2 (1.3 g,
83%) as white solid, mp 204 ꢁC; IR
(CDCl3):
n
(KBr) 3420, 3307 cmꢀ1; 1H NMR
3.3.7. p-Dimethylaminobenzaldehyde N-(1,3-diphenylpyrazolo[3,4-
d
4.03 (s, 2H, NH2), 5.33 (s,1H, NH), 7.33–8.24 (m,10H, ArH), 8.58
d] pyrimidin-4-yl)hydrazone (4f)
(s, 1H, pyrimidine-H); MS m/z (%): 303 (Mþþ1, 26), 302 (Mþ, 100), 287
(36), 272 (41),194 (16),170 (16),143 (20),104 (21), 77 (84). Anal. Calcd for
C17H14N6 (302.34): C, 67.54; H, 4.67; N, 27.80. Found: C, 67.60; H, 4.34; N,
27.65%.
Yellow crystals (yield 1.84 g, 85%), mp 141–142 ꢁC (dioxane); IR
n
(KBr) 3305, 2893, 1637 cmꢀ1; 1H NMR (CDCl3),
d (ppm): 3.01 (s, 6H,
CH3), 6.65–7.56 (m, 15H, ArH and NH), 8.16 (s, 1H, –N]CH), 8.19 (s,
1H, pyrimidine-H); MS m/z (%): 434 (Mþþ1, 11), 433 (Mþ, 35), 286
(100), 146 (66), 118 (10), 77 (35). Anal. Calcd for C26H23N7 (433.52):
C, 72.04; H, 5.35; N, 22.62. Found: C, 72.17; H, 5.44; N, 22.38%.
3.3. Aldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-
yl)hydrazones 4a–l
3.3.8. Cinnamaldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-
3.3.1. General procedure
4-yl)hydrazone (4g)
To a mixture of 4-hydrazino-1,3-diphenylpyrazolo[3,4-d]py-
rimidine 2 (1.51 g, 5 mmol) and the appropriate aldehyde 3
(5 mmol) in ethanol (50 mL), few drops of acetic acid were added
and the reaction mixture was refluxed for 2 h and then cooled. The
precipitate, formed upon cooling, was filtered off, washed with
water and then with ethanol and finally crystallized from the ap-
propriate solvent to give the corresponding hydrazone derivative 4.
Yellow crystals (yield 1.83 g, 88%), mp 189–190 ꢁC (dioxane); IR
n
(KBr) 3322, 3053,1634 cmꢀ1; 1H NMR (CDCl3),
d (ppm): 6.85–7.05 (m,
2H, CH]CHPh), 7.29–8.22 (m,16H, ArH and NH), 8.06 (s,1H, –N]CH),
8.33 (s, 1H, pyrimidine-H); MS m/z (%): 417 (Mþþ1, 8), 416 (Mþ, 32),
413 (10), 339 (33), 286 (100),129 (18),115 (25),102 (15), 77 (90). Anal.
Calcd for C26H20N6 (416.49): C, 74.98; H, 4.84; N, 20.18. Found: C,
74.75; H, 4.75; N, 20.11%.
3.3.2. Benzaldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-
3.3.9. 1-Naphthaldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-
yl)hydrazone (4a)
4-yl)hydrazone (4h)
Yellow crystals (yield 1.6 g, 86%), mp 177–178 ꢁC (dioxane); IR
n
Yellow crystals (yield 1.87 g, 85%), mp 211–212 ꢁC (dioxane); IR
n
(KBr) 3332, 3057, 1637 cmꢀ1; 1H NMR (CDCl3):
d
7.34–8.18 (m, 16H,
(KBr) 3326, 3056, 1635 cmꢀ1 1H NMR (CDCl3),
; d (ppm): 7.39–8.55
ArH and NH), 8.08 (s, 1H, –N]CH), 8.36 (s, 1H, pyrimidine-H); MS
m/z (%): 391 (Mþþ1, 19), 390 (Mþ, 57), 388 (17), 313 (56), 286 (100),
259 (14),104 (17), 91 (16), 77 (92). Anal. Calcd for C24H18N6 (390.45):
C, 73.83; H, 4.65; N, 21.52. Found: C, 73.95; H, 4.76; N, 21.48%.
(m, 18H, ArH and NH), 8.04 (s, 1H, –N]CH), 8.31(s, 1H, pyrimidine-
H); MS m/z (%): 441 (Mþþ1, 9), 440 (Mþ, 30), 313 (20), 286 (100),
153 (14), 127 (17), 77 (38). Anal. Calcd for C28H20N6 (440.51): C,
76.35; H, 4.58; N, 19.08. Found: C, 76.15; H, 4.45; N, 18.93%.
3.3.3. p-Tolualdehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-4-
3.3.10. 2-Furanaldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-
yl)hydrazone (4b)
4-yl)hydrazone (4i)
Yellow crystals (yield 1.9 g, 88%), mp 213–215 ꢁC (dioxane); IR
n
Yellow crystals (yield 1.56 g, 82%), mp 191–192 ꢁC (dioxane); IR
n
(KBr) 3264, 3053, 1640 cmꢀ1
;
1H NMR (CDCl3):
d
2.38 (s, 3H, CH3),
(KBr) 3393, 3042, 1636 cmꢀ1 1H NMR (CDCl3),
; d (ppm): 6.49–8.14
7.17–8.19 (m, 15H, ArH and NH), 8.06 (s, 1H, –N]CH), 8.47 (s, 1H,
pyrimidine-H); MS m/z (%): 406 (Mþþ2, 1), 405 (Mþþ1, 17), 404
(Mþ, 38), 313 (26), 286 (100), 194 (20), 103 (11), 91 (14). Anal. Calcd
for C25H20N6 (404.48): C, 74.24; H, 4.98; N, 20.78. Found: C, 74.12; H,
4.90; N, 20.72%.
(m, 14H, ArH and NH), 8.01 (s, 1H, –N]CH), 8.24 (s, 1H, pyrimidine-
H); MS m/z (%): 380 (Mþ, 38), 287 (54), 286 (100), 195 (5), 194 (31),
77 (35). Anal. Calcd for C22H16N6O (380.41): C, 69.46; H, 4.24; N,
22.09. Found: C, 69.63; H, 4.13; N, 22.22%.
3.3.11. 2-Thiophenaldehyde N-(1,3-diphenylpyrazolo[3,4-
d]pyrimidin-4-yl)hydrazone (4j)
3.3.4. p-Chlorobenzaldehyde N-(1,3-diphenylpyrazolo[3,4-
d]pyrimidin-4-yl)hydrazone (4c)
Yellow crystals (yield 1.70 g, 86%), mp 192–193 ꢁC (dioxane); IR
Yellow crystals (yield 1.8 g, 87%), mp 231–232 ꢁC (dioxane); IR
n
n ; d (ppm): 7.06–
(KBr) 3326, 3053, 1634 cmꢀ1 1H NMR (CDCl3),
8.12 (m, 14H, ArH and NH), 7.99 (s, 1H, –N]CH), 8.31 (s, 1H,
pyrimidine-H); MS m/z (%): 398 (Mþþ2, 8), 397 (Mþþ1, 18), 396
(Mþ, 65), 286 (100), 259 (11), 96 (11), 77 (62). Anal. Calcd for
(KBr) 3262, 3058, 1640 cmꢀ1; 1H NMR (CDCl3):
d
7.33–8.18 (m, 15H,
ArH and NH), 8.09 (s, 1H, –N]CH), 8.31 (s, 1H, pyrimidine-H); MS
m/z (%): 426 (Mþþ2, 14), 425 (Mþþ1, 15), 424 (Mþ, 38), 286 (100),
259 (9), 104 (6), 77 (43). Anal. Calcd for C24H17ClN6 (424.90): C,
67.84; H, 4.03; N, 19.78. Found: C, 67.62; H, 4.28; N, 19.72%.
C22H16N6S (396.48): C, 66.65; H, 4.07; N, 21.20. Found: C, 66.59;
H, 4.14; N, 20.94%.
3.3.5. p-Methoxybenzaldehyde N-(1,3-diphenylpyrazolo[3,4-
3.3.12. 2-Acetaldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-
4-yl)hydrazone (4k)
d]pyrimidin-4-yl)hydrazone (4d)
Yellow crystals (yield 1.93 g, 92%), mp 187–188 ꢁC (dioxane); IR
n
Yellow crystals (yield 1.41 g, 86%), mp 209–210 ꢁC (dioxane); IR
n
(KBr) 3261, 3056, 2962, 1502 cmꢀ1; 1H NMR (CDCl3),
d
(ppm): 3.70
(KBr) 3248, 3066, 2930, 1640 cmꢀ1; 1H NMR (CDCl3),
d (ppm): 1.79
(s, 3H, CH3), 6.87–8.18 (m, 15H, ArH and NH), 8.02 (s, 1H, –N]CH),
8.31 (s, 1H, pyrimidine); MS m/z (%): 421 (Mþþ1, 14), 420 (Mþ, 33),
286 (100), 259 (12), 90 (11), 77 (38). Anal. Calcd for C25H20N6O
(420.48): C, 71.41; H, 4.79; N, 19.99. Found: C, 71.37; H, 4.51; N,
19.87%.
(d, J¼5.7, 3H, CH3), 6.38 (q, J¼5.7, 1H, –N]CH), 7.45–8.45 (m, 11H,
ArH and NH), 7.67 (s, 1H, pyrimidine-H); MS m/z (%): 330 (Mþþ2,1),
329 (Mþþ1, 3), 328 (Mþ, 15), 313 (85), 104 (11), 77 (100). Anal. Calcd
for C19H16N6 (328.38): C, 69.50; H, 4.91; N, 25.59. Found: C, 69.32;
H, 4.85; N, 25.67%.
3.3.6. p-Nitrobenzaldehyde N-(1,3-diphenylpyrazolo[3,4-
d]pyrimidin-4-yl)hydrazone (4e)
3.3.13. 2-Formaldehyde N-(1,3-diphenylpyrazolo[3,4-d]pyrimidin-
4-yl)hydrazone (4l)
Orange crystals (yield 1.95 g, 90%), mp 289–290 ꢁC (dioxane); IR
Yellow crystals (yield 1.27 g, 81%), mp 194–195 ꢁC (dioxane); IR
n
(KBr) 3319, 1633 cmꢀ1
;
1H NMR (CDCl3),
d
(ppm): 7.22–8.32 (m,
n ; d (ppm): 5.37 (s,
(KBr) 3330, 3058, 1655 cmꢀ1 1H NMR (CDCl3),

10342
A.S. Shawali et al. / Tetrahedron 64 (2008) 10339–10343
2H, –N]CH2), 7.25–8.49 (m, 11H, ArH and NH), 7.52 (s, 1H, py-
rimidine-H); MS m/z (%): 316 (Mþþ2, 5), 315 (Mþþ1, 5), 314 (Mþ,
15), 287 (49), 127 (9), 104 (10), 77 (100). Anal. Calcd for C18H14N6
(314.35): C, 68.78; H, 4.49; N, 26.74. Found: C, 68.83; H, 4.37; N,
26.63%.
(Mþþ2, 5), 432 (Mþþ1, 34), 431 (Mþ, 100), 145 (9), 77 (11). Anal.
Calcd for C26H21N7 (431.50): C, 72.37; H, 4.91; N, 22.72. Found: C,
72.14; H, 4.73; N, 22.78%.
3.4.8. 7,9-Diphenyl-3-(cinnamyl)pyrazolo[4,3-e][1,2,4]triazolo
[4,3-c]pyrimidine (5g)
3.4. 3-Substituted-7,9-diphenylpyrazolo[4,3-e][1,2,4]triazolo-
[4,3-c]pyrimidines 5a–l
White grey crystals (yield 0.33 g, 81%), mp277–278 ꢁC; IR
n
(KBr)
3054, 1625 cmꢀ1; 1H NMR (CDCl3):
d 6.83–6.96 (m, 2H, CH]CHPh),
7.42–8.26 (m, 15H, ArH), 8.89 (s, 1H, pyrimidine-H); MS m/z (%): 416
(Mþþ2, 22), 415 (Mþþ1, 48), 414 (Mþ, 90), 413 (100), 128 (14), 77
(41). Anal. Calcd for C26H18N6 (414.47): C, 75.35; H, 4.38; N, 20.28.
Found: C, 75.17; H, 4.48; N, 20.64%.
3.4.1. General procedure
To a solution of the appropriate hydrazone 4 (1 mmol) in eth-
anol (25 mL) was added a solution of ferric chloride (2 M, 2 mL) and
the mixture was stirred at room temperature for 12 h. The pre-
cipitated solid was filtered off, washed with water and then with
ethanol and finally crystallized from DMF–EtOH to give the re-
spective 3-substituted-7,9-diphenylpyrazolo[4,3-e][1,2,4]triazolo
[4,3-c]-pyrimidine.
3.4.9. 7,9-Diphenyl-3-(1-naphthyl)pyrazolo[4,3-e][1,2,4]
triazolo[4,3-c]pyrimidine (5h)
White-green crystals (yield 0.36 g, 83%), mp 256–257 ꢁC; IR
n
(KBr) 3053, 1624 cmꢀ1; 1H NMR (CDCl3):
d 7.51–8.96 (m, 17H, ArH),
8.52 (s, 1H, pyrimidine-H). MS m/z (%): 440 (Mþþ2, 14), 439 (Mþþ1,
50), 438 (Mþ, 59), 437 (100), 219 (19), 153 (23), 127 (18), 77 (99).
Anal. Calcd for C28H18N6 (438.50): C, 76.70; H, 4.14; N, 19.17. Found:
C, 76.79; H, 4.08; N, 19.51%.
3.4.2. 3,7,9-Triphenylpyrazolo[4,3-e][1,2,4]triazolo[4,3-
c]pyrimidine (5a)
White crystals (yield 0.3 g, 78%), mp 233–234 ꢁC; IR
n
(KBr)
3063, 1626 cmꢀ1; 1H NMR (CDCl3):
d 7.42–8.90 (m, 15H, ArH), 8.95
(s, 1H, pyrimidine-H); MS m/z (%): 390 (Mþþ2, 5), 389 (Mþþ1, 23),
388 (Mþ, 100), 103 (7), 77 (21). Anal. Calcd for C24H16N6 (388.44):
C, 74.21; H, 4.15; N, 21.64. Found: C, 73.97; H, 4.16; N, 21.34%.
3.4.10. 7,9-Diphenyl-3-(2-furyl)pyrazolo[4,3-e][1,2,4]triazolo
[4,3-c]pyrimidine (5i)
White grey crystals (yield 0.30 g, 80%), mp 265–266 ꢁC; IR
n
(KBr)
3059,1623 cmꢀ1; 1H NMR (CDCl3):
d 6.72–8.86 (m,13H, ArH), 9.48 (s,
3.4.3. 7,9-Diphenyl-3-(p-tolyl)pyrazolo[4,3-e][1,2,4]triazolo[4,3-
1H, pyrimidine-H); MS m/z (%): 380 (Mþþ2, 6), 379 (Mþþ1, 26), 378
(Mþ, 100), 103 (10), 77 (48). Anal. Calcd for C22H14N6O (378.40): C,
69.83; H, 3.73; N, 22.21. Found: C, 70.08; H, 3.72; N, 22.06%.
c]pyrimidine (5b)
White crystals (yield 0.31 g, 82%), mp 259–260 ꢁC; IR
n
(KBr)
3054, 2917, 1623 cmꢀ1 1H NMR (CDCl3):
; d 2.51 (s, 3H, CH3), 7.43–
8.91 (m, 14H, ArH), 8.95 (s, 1H, pyrimidine-H); MS m/z (%): 404
(Mþþ2, 5), 403 (Mþþ1, 37), 402 (Mþ, 100), 103 (17), 77 (48). Anal.
Calcd for C25H18N6 (402.46): C, 74.61; H, 4.51; N, 20.88. Found: C,
74.43; H, 4.55; N, 20.64%.
3.4.11. 7,9-Diphenyl-3-(2-theinyl)pyrazolo[4,3-e][1,2,4]
triazolo[4,3-c]pyrimidine (5j)
White-brown crystals (yield 0.33 g, 85%), mp 241–242 ꢁC; IR
n
(KBr)
3067,1621 cmꢀ1; 1H NMR (CDCl3):
d 7.31–8.89 (m,13H, ArH), 9.12 (s,1H,
pyrimidine-H); MS m/z (%): 396 (Mþþ2, 4), 395 (Mþþ1, 25), 394 (Mþ,
75), 197 (12), 129 (12), 103 (25), 77 (100). Anal. Calcd for C22H14N6S
(394.46): C, 66.99; H, 3.58; N, 21.31. Found: C, 67.25; H, 3.49; N, 21.47%.
3.4.4. 7,9-Diphenyl-3-(p-chlorophenyl) pyrazolo[4,3-e][1,2,4]
triazolo[4,3-c]pyrimidine (5c)
White crystals (yield0.34 g, 80%), mp254–255 ꢁC;IR
n
(KBr) 3058,
1624 cmꢀ1 1H NMR (CDCl3):
d
7.55–8.88 (m, 14H, ArH), 8.92 (s, 1H,
3.4.12. 7,9-Diphenyl-2-methylpyrazolo[4,3-e][1,2,4]triazolo[4,3-
pyrimidine-H); MS m/z (%): 424 (Mþþ2, 30), 423 (Mþþ1, 30), 422
(Mþ, 100), 153 (10), 103 (19), 77 (68). Anal. Calcd for C24H15ClN6
(422.88):C, 68.17;H, 3.58;N,19.87. Found:C, 68.10;H, 3.40;N,19.76%.
c]pyrimidine (5k)
White crystals (yield 0.25 g, 78%), mp 227–228 ꢁC; IR
n
(KBr)
3060, 2927, 1598 cmꢀ1 1H NMR (CDCl3):
; d 2.98 (s, 3H, CH3), 7.37–
8.23 (m, 10H, ArH), 8.87 (s, 1H, pyrimidine-H); MS m/z (%): 327
(Mþþ1, 9), 326 (Mþ, 6), 302 (47), 273 (13), 142 (15), 104 (11), 77
(100). Anal. Calcd for C19H14N6 (326.36): C, 69.93; H, 4.32; N, 25.75.
Found: C, 70.03; H, 4.11; N, 26.03%.
3.4.5. 7,9-Diphenyl-3-(p-methoxyphenyl)pyrazolo[4,3-
e][1,2,4]triazolo[4,3-c]pyrimidine (5d)
White grey crystals (yield 0.33 g, 81%), mp 199–200 ꢁC; IR
n
(KBr) 3064, 2934, 1626 cmꢀ1; 1H NMR (CDCl3):
d 3.93 (s, 3H, CH3),
7.31–8.91 (m,14H, ArH), 8.93 (s,1H, pyrimidine-H); MS m/z (%): 420
(Mþþ2, 4), 419 (Mþþ1, 26), 418 (Mþ, 100), 209 (9), 103 (20), 77 (50).
Anal. Calcd for C25H18N6O (418.46): C, 71.76; H, 4.34; N, 20.08.
Found: C, 71.43; H, 4.47; N, 19.94%.
3.4.13. 7,9-Diphenylpyrazolo[4,3-e][1,2,4]triazolo[4,3-c]
pyrimidine (5l)
White crystals (yield 0.25 g, 80%), 274–276 ꢁC; IR
n
(KBr) 3039,
1624 cmꢀ1; 1H NMR (CDCl3):
d 7.45–8.84 (m, 10H, ArH), 8.88 (s, 1H,
triazole-CH), 9.00 (s, 1H, pyrimidine-H). MS m/z (%): 313 (Mþþ1, 11),
312 (Mþ, 81), 129 (10), 103 (17), 77 (100). Anal. Calcd for C18H12N6
(312.34):C,69.22;H,3.87;N,26.91. Found:C,68.96;H, 3.65;N,27.06%.
3.4.6. 7,9-Diphenyl-3-(p-nitrophenyl)pyrazolo[4,3-e][1,2,4]
triazolo[4,3-c]pyrimidine (5e)
Orange brown crystals (yield 0.32 g, 75%), mp 213–214 ꢁC; IR
n
(KBr) 3059, 1634 cmꢀ1; 1H NMR (CDCl3):
d
7.49–9.24 (m, 14H, ArH),
3.5. 2-Substituted-7,9-diphenylpyrazolo[4,3-e][1,2,4]triazolo-
[1,5-c]pyrimidines 6a–l
9.28 (s,1H, pyrimidine-H); MS m/z (%): 435 (Mþþ2, 69), 434 (Mþþ1,
45), 433 (Mþ, 75), 286 (100), 259 (16), 156 (15), 103 (21), 77 (60).
Anal. Calcd for C24H15N7O2 (433.43): C, 66.51; H, 3.49; N, 22.62.
Found: C, 66.38; H, 3.35; N, 22.48%.
3.5.1. General procedure
To a solution of the appropriate 5 (1 mmol) in ethanol (50 mL)
was added sodium acetate (0.164 g, 2 mmol) and the mixture
was refluxed for 6 h and then cooled. The precipitated solid was
filtered off, washed with water and then with ethanol and finally
crystallized from dimethylformamide to give the respective
2-substituted-7,9-diphenylpyrazolo[3,4-e][1,2,4]triazolo[1,5-c]pyr-
imidine.
3.4.7. 7,9-Diphenyl-3-(p-dimethylaminophenyl)pyrazolo[4,3-
e][1,2,4]triazolo[4,3-c]pyrimidine (5f)
Yellow crystals (yield 0.34 g, 80%), mp 257–258 ꢁC; IR
n
(KBr)
3.08 (s, 6H, CH3),
7.55–8.93 (m,14H, ArH), 8.98 (s,1H, pyrimidine-H); MS m/z (%): 433
3059, 2860, 1609 cmꢀ1 1H NMR (CDCl3):
; d

A.S. Shawali et al. / Tetrahedron 64 (2008) 10339–10343
10343
3.5.2. 2,7,9-Triphenylpyrazolo[4,3-e][1,2,4]triazolo[1,5-
c]pyrimidine (6a)
(s, 1H, pyrimidine-H); MS m/z (%): 440 (Mþþ2, 30), 439 (Mþþ1, 92),
438 (Mþ, 100), 437 (38), 219 (22), 153 (25), 127 (17), 77 (72). Anal.
Calcd for C28H18N6 (438.50): C, 76.70; H, 4.14; N, 19.17. Found: C,
76.79; H, 3.95; N, 19.03%.
White crystals (yield 0.33 g, 86%), mp 223–225 ꢁC (lit. mp
222 ꢁC);1 IR
n d 7.42–8.91
(KBr) 3061, 1634 cmꢀ1; 1H NMR (CDCl3):
(m, 15H, ArH), 9.22 (s, 1H, pyrimidine-H); MS m/z (%): 388 (Mþ,
100), 387 (39), 104 (5), 77 (50). Anal. Calcd for C24H16N6 (388.44): C,
74.21; H, 4.15; N, 21.64. Found: C, 74.16; H, 4.97; N, 21.35%.
3.5.10. 7,9-Diphenyl-2-(2-furyl)pyrazolo[4,3-e][1,2,4]triazolo[1,5-
c]pyrimidine (6i)
White crystals (yield 0.30 g, 78%), mp 254–255 ꢁC; IR
n
(KBr)
3.5.3. 7,9-Diphenyl-2-(p-tolyl)pyrazolo[4,3-e][1,2,4]triazolo[1,5-
3065, 1623 cmꢀ1 1H NMR (CDCl3):
; d 6.63–8.82 (m, 13H, ArH),
c]pyrimidine (6b)
9.21 (s, 1H, pyrimidine-H); MS m/z (%): 380 (Mþþ2, 4), 379 (Mþþ1,
28), 378 (Mþ, 100), 377 (29), 77 (46). Anal. Calcd for C22H14N6O
(378.40): C, 69.83; H, 3.73; N, 22.21. Found: C, 69.56; H, 3.46;
N, 22.14%.
White crystals (yield 0.31 g, 79%), mp 271–272 ꢁC; IR
n
(KBr)
3056, 2916, 1632 cmꢀ1 1H NMR (CDCl3):
; d 2.47 (s, 3H, CH3), 7.34–
8.91 (m, 14H, ArH), 9.19 (s, 1H, pyrimidine-H); MS m/z (%): 404
(Mþþ2, 5), 403 (Mþþ1, 28), 402 (Mþ, 100), 77 (12). Anal. Calcd for
C
25H18N6 (402.46): C, 74.61; H, 4.51; N, 20.88. Found: C, 74.48; H,
3.5.11. 7,9-Diphenyl-2-(2-thienyl)pyrazolo[4,3-e][1,2,4]triazolo[1,5-
4.43; N, 21.03%.
c]pyrimidine (6j)
White crystals (yield 0.32 g, 82%), mp 277–278 ꢁC; IR
n
(KBr)
3.5.4. 7,9-Diphenyl-2-(p-chlorophenyl)pyrazolo[4,3-
e][1,2,4]triazolo[1,5-c]pyrimidine (6c)
3068, 1632 cmꢀ1 1H NMR (CDCl3):
; d 7.20–8.85 (m, 13H, ArH),
9.45 (s, 1H, pyrimidine-H); MS m/z (%): 396 (Mþþ2, 8), 395 (Mþþ1,
33), 394 (Mþ, 100), 393 (38), 77 (22). Anal. Calcd for C22H14N6S
(394.46): C, 66.99; H, 3.58; N, 21.31. Found: C, 67.10; H, 3.49;
N, 21.09%.
White crystals (yield 0.35 g, 83%), mp 298–300 ꢁC; IR
n (KBr)
3058,1629 cmꢀ1; 1H NMR (CDCl3):
d 7.45–8.88 (m,14H, ArH), 9.22 (s,
1H, pyrimidine-H); MS m/z (%): 424(Mþþ2, 40), 423 (Mþþ1, 42), 422
(Mþ, 100), 421 (34), 77 (37). Anal. Calcd for C24H15ClN6 (422.88): C,
68.17; H, 3.58; N, 19.87. Found: C, 68.40; H, 3.46; N, 19.94%.
3.5.12. 7,9-Diphenyl-2-methylpyrazolo[4,3-e][1,2,4]triazolo[1,5-
c]pyrimidine (6k)
3.5.5. 7,9-Diphenyl-2-(p-methoxyphenyl)pyrazolo[4,3-
White crystals (yield 0.25 g, 78%), mp 182–183 ꢁC (lit. mp
e][1,2,4]triazolo[1,5-c]pyrimidine (6d)
185 ꢁC);1 IR (KBr) 3062, 1635 cmꢀ1; 1H NMR (CDCl3):
n d 2.71 (s, 3H,
White crystals (yield 0.33 g, 81%), mp 283–284 ꢁC; IR
n
(KBr)
CH3), 7.34–8.78 (m,10H, ArH), 9.11 (s,1H, pyrimidine-H); MS m/z (%):
3059, 2834, 1633 cmꢀ1; 1H NMR (CDCl3):
d 3.92 (s, 3H, CH3), 7.06–
327 (Mþþ1, 29), 326 (Mþ, 100), 325 (32), 77 (29). Anal. Calcd for
8.91 (m, 14H, ArH), 9.19 (s, 1H, pyrimidine-H); MS m/z (%): 420
(Mþþ2, 5), 419 (Mþþ1, 30), 418 (Mþ, 100), 417 (20), 77 (21). Anal.
Calcd for C25H18N6O (418.46): C, 71.76; H, 4.34; N, 20.08. Found: C,
71.60; H, 4.28; N, 20.20%.
C19H14N6 (326.36): C, 69.93; H, 4.32; N, 25.75. Found: C, 69.81; H,
4.17; N, 25.62%.
3.5.13. 7,9-Diphenylpyrazolo[4,3-e][1,2,4]triazolo[1,5-c]
pyrimidine (6l)
3.5.6. 7,9-Diphenyl-2-(p-nitrophenyl)pyrazolo[4,3-
White crystals (yield 0.25 g, 80%), mp 234–235 ꢁC (lit. mp
e][1,2,4]triazolo[1,5-c]pyrimidine (6e)
233 ꢁC);1 IR (KBr) 3068, 1632 cmꢀ1; 1H NMR (CDCl3):
n d 7.44–8.76
Yellow crystals (yield 0.36 g, 85%), mp 346–348 ꢁC; IR
n
(KBr)
(m, 10H, ArH), 8.47 (s, 1H, triazole-CH), 9.23 (s, 1H, pyrimidine-H);
MS m/z (%): 313 (Mþþ1, 18), 312 (Mþ, 79), 311 (38), 156 (14), 127
(22), 77 (100). Anal. Calcd for C18H12N6 (312.34): C, 69.22; H, 3.87;
N, 26.91. Found: C, 69.08; H, 3.96; N, 26.67%.
3083, 1631 cmꢀ1; 1H NMR (CDCl3):
d 7.43–8.86 (m, 14H, ArH), 9.37
(s, 1H, pyrimidine-H). MS m/z (%): 435 (Mþþ2, 32), 434 (Mþþ1, 88),
433 (Mþ, 100), 432 (16), 386 (14), 77 (60). Anal. Calcd for
C
24H15N7O2 (433.43): C, 66.51; H, 3.49; N, 22.62. Found: C, 66.74; H,
3.59; N, 22.46%.
References and notes
3.5.7. 7,9-Diphenyl-2-(p-dimethylaminophenyl)pyrazolo[4,3-
e][1,2,4]triazolo[1,5-c]pyrimidine (6f)
1. Fahmi, A. A.; Mekki, S. T.; Albar, H. A.; Shawali, A. S.; Hassaneen, H. M.; Ab-
delhamid, H. J. Chem. Res., Synop. 1994, 6; J. Chem. Res., Miniprint 1994, 140.
2. Baraldi, P. G.; Elkashef, H.; Farghaly, A.; Vanelle, P.; Fruttarolo, F. Tetrahedron
2004, 60, 5093.
3. Mezheritsky, V. V.; Minkin, V. I.; Minyaeva, L. G.; Tyurin, R. G.; Krasnikov, V. V.;
Vorobyev, E. V.; Starikova, Z. A. Arkivoc 2005, x, 9.
4. Shawali, A. S.; Parkanyi, C. J. Heterocycl. Chem. 1980, 17, 833.
5. Shawali, A. S. Heterocycles 1983, 20, 2239.
6. Shawali, A. S. Chem. Rev. 1993, 93, 2731.
7. Shawali, A. S.; Abdallah, M. A. Adv. Heterocycl. Chem. 1995, 63, 277.
8. Shawali, A. S.; Elsheikh, S. M. J. Heterocycl. Chem. 2001, 38, 541.
9. Shawali, A. S.; Mosselhi, M. A. N. J. Heterocycl. Chem. 2003, 40, 1725.
10. Shawali, A. S.; Mosselhi, M. A. N. J. Sulfur Chem. 2005, 26, 267.
11. Shawali, A. S.; Edrees, M. M. Arkivoc 2007, ix, 293.
12. Shawali, A. S.; Sherif, S. M. Curr. Org. Chem. 2007, 11, 773.
13. Shawali, A. S.; Farghaly, T. M. Arkivoc 2008, i, 18.
14. Nagamatsu, T.; Fujita, T. Chem. Commun. 1999, 1461.
15. Seifi, N.; Niaki, M. H. Z.; Barzegari, M. R.; Davoodnia, A.; Zhiani, R.; Kaju, A. A.
J. Mol. Catal. A: Chem. 2006, 260, 77.
16. Rashad, A. E.; Heikel, O. A.; El-Nezhawy, A. O. H.; Abdel-Megeid, F. M. E. Het-
eroat. Chem. 2005, 16, 226.
17. Shaban, M. A.; Nasr, A. Z. Adv. Heterocycl. Chem. 1999, 49, 277.
18. Shawali, A. S.; Hassaneen, H. M.; Shurrab, N. K. Heterocycles 2008, 75, 1479.
19. Abdelfattah, B.; Kandeel, M. M.; Abdel-Hakeem, M.; Fahmy, Z. M. J. Chin. Chem.
Soc. 2006, 53, 403.
White crystals (yield 0.36 g, 84%), mp 308–310 ꢁC; IR
n (KBr)
3056, 2897, 1609 cmꢀ1; 1H NMR (CDCl3):
d 3.09 (s, 6H, CH3), 6.37–
8.92 (m, 14H, ArH), 9.17 (s, 1H, pyrimidine-H); MS m/z (%): 432
(Mþþ1, 89), 431 (Mþ, 80), 424 (25), 422 (100), 403 (34), 216 (18), 77
(31). Anal. Calcd for C26H21N7 (431.50): C, 72.37; H, 4.91; N, 22.72.
Found: C, 72.20; H, 4.86; N, 22.59%.
3.5.8. 7,9-Diphenyl-2-(cinnamyl)pyrazolo[3,4-e][1,2,4]triazolo
[1,5-c]pyrimidine (6g)
White crystals (yield 0.33 g, 80%), mp 251–252 ꢁC; IR
n
(KBr)
3062, 1625 cmꢀ1; 1H NMR (CDCl3):
d 7.25–7.30 (m, 2H, CH]CHPh),
7.33–8.85 (m, 15H, ArH), 9.15 (s, 1H, pyrimidine-H); MS m/z (%): 415
(Mþþ1, 21), 414 (Mþ, 92), 413 (100), 337 (11),128 (12), 77 (27). Anal.
Calcd for C26H18N6 (414.47): C, 75.35; H, 4.38; N, 20.28. Found: C,
75.39; H, 4.62; N, 20.34%.
3.5.9. 7,9-Diphenyl-2-(1-naphthyl)pyrazolo[4,3-e]1,2,4-
triazolo[1,5-c]pyrimidine (6h)
20. Shisho, C. J.; Devani, M. B.; Ullas, G. V.; Ananthan, S.; Bhadi, V. S. J. Heterocycl.
Chem. 1981, 18, 43.
21. Fischer, G. Adv. Heterocycl. Chem. 1993, 57, 81.
White crystals (yield 0.35 g, 80%), mp 249–250 ꢁC; IR
n
(KBr)
3055, 1635 cmꢀ1; 1H NMR (CDCl3):
d
7.45–9.43 (m, 17H, ArH), 9.23