Synthesis and isomerization of some novel pyrazolopyrimidine and pyrazolotriazolopyrimidine derivatives

Article abstract of DOI:10.3390/molecules19055459

4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2) and (1-ptolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3) were prepared starting from ethyl 4-cyano-1-p-tolyl-1H-pyrazol-5-ylimidoformate (1). The structure of compound 3 was confirme

Full text of DOI:10.3390/molecules19055459

Molecules 2014, 19, 5459-5469; doi:10.3390/molecules19055459
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Isomerization of Some Novel Pyrazolopyrimidine
and Pyrazolotriazolopyrimidine Derivatives
Aymn E. Rashad 1,2,*, Ahmed H. Shamroukh 1,3, Randa E. Abdel-Megeid 1,4 and Hatem S. Ali 5
1
Photochemistry Department, National Research Center, Dokki, Cairo 1258943, Egypt;
E-Mails: ahshamroukh@yahoo.com (A.H.S.); randaabdelmegeid@yahoo.com (R.E.A.-M.)
2
Chemistry Department, Faculty of Science and Human Studies, Shaqra University,
Huraiymla 11961, Kingdom of Saudi Arabia
3
Chemistry Department, Faculty of Science, Hail University, Hail 81411, Kingdom of Saudi Arabia
4
Chemistry Department, Faculty of Education, Shaqra University, Afif 11921, Kingdom of Saudi Arabia
5
Food Science and Nutrition Department, College of Food Science and Agriculture,
King Saud University, Riyadh 11564, Kingdom of Saudi Arabia; E-Mail: hali@ksu.edu.com
* Author to whom correspondence should be addressed; E-Mail: aymnelzeny@yahoo.com or
aelzeny@su.edu.sa; Tel.: +9-665-549-79492; Fax: +2-020-337-0931.
Received: 30 March 2014; in revised form: 16 April 2014 / Accepted: 17 April 2014 /
Published: 25 April 2014
Abstract: 4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2) and (1-p-
tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3) were prepared starting from ethyl
4-cyano-1-p-tolyl-1H-pyrazol-5-ylimidoformate (1). The structure of compound 3 was
confirmed through preparation of the pyrazole derivatives 4 and 5. Also, the synthesis and
structural characterization of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 7
and 9 and their isomerization to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives
6 and 8, respectively, under different suitable reaction conditions were reported. Moreover,
the syntheses of 2-substituted-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives
10 and 11 was described.
Keywords: pyrazoles; pyrazolopyrimidines; pyrazolotriazolopyrimidines; isomerization

Molecules 2014, 19
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1. Introduction
As part of our ongoing research program on heterocyclic compounds which may serve as leads for
designing novel chemotherapeutic agents, we were particularly interested in pyrazoles and fused
pyrazolopyrimidines [1,2]. Pyrazolo[3,4-d]pyrimidines and their related fused heterocycles are of
considerable significance chemical and pharmaceutical utility as purine analogs [3] and many of their
derivatives were reported to possess antiviral [1,4] antimicrobial [2,5] anti-inflammatory [6,7]
anticancer [8] and xanthine oxidase inhibitor [9] activities.
Moreover, the synthesis of fused triazolopyrimidine moieties has been described by many
investigators and these compounds have been proved to have pronounced biological activities [2,10–13].
Previous observations revealed that the [1,2,4]triazolo[4,3-c]pyrimidine derivatives can isomerize under
different suitable reaction conditions to the thermodynamically more stable [1,2,4]triazolo[1,5-
c]pyrimidines [14–16]. This isomerization was first reported by Miller and Rose [17,18] when they
treated [1,2,4] triazolo[4,3-c]pyrimidine derivatives with an acid, base, or thermally. Based on the above
mentioned research results, the goal of this study is to synthesize some novel pyrazolopyrimidine,
pyrazolotriazolo[4,3-c]pyrimidines and pyrazolotriazolo[1,5-c]pyrimidines not only to study their
isomerization, but also to obtain new compounds which are expected to possess notable
pharmacological applications.
2. Results and Discussion
Stirring of compound 1 [19], in anhydrous benzene with hydrazine hydrate, afforded 4-imino-1-p-
tolyl-1,4-dihydro-pyrazolo[3,4-d]pyrimidin-5-ylamine (2) (Scheme 1). The IR spectrum of the latter
compound revealed the absence of the cyano group and the 1H-NMR spectrum revealed the absence of
the ethoxy group protons and showed signals at 5.90, 11.60 ppm for NH2 and imine NH protons,
13
respectively. Moreover, the C-NMR spectrum of compound 2 revealed a signal at 164.42 ppm for
C=NH (C-4). Compound 2 was isomerized to its corresponding more thermodynamically stable
4-hydrazino derivative 3 upon refluxing in dioxane in the presence of a few drops of piperdine.
Actually, piperdine acts as a base in this Dimroth-type rearrangement which involves a sequence of
ring opening and ring closure reactions (Scheme 2) [15,20,21].
1
The H-NMR spectrum of compound 3 revealed signals at 4.80, 7.20 ppm for the NH2 and NH,
13
protons, respectively and the C-NMR spectrum revealed a signal at 168.20 ppm for =C-NHNH2
(C-4) (cf. Experimental Section). Moreover, the structure of compound 3 was confirmed chemically
by refluxing it with ethoxymethylenemalononitrile or bis-(methylthio)methylenemalononitrile to
afford the corresponding substituted pyrazole derivatives 4 and 5, respectively. The IR spectra of the
1
latter compounds showed absorption bands characteristic for NH2 and CN groups and the H-NMR
spectra showed signals at δ = 6.79 and 6.85 ppm due to NH2 (exchangeable with D2O). Also, the MS
gave the molecular ion peaks at m/z (%) = 316 (23.49) and 362 (33.25) for compounds 4 and 5,
respectively [22,23].

Molecules 2014, 19
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Scheme 1. Synthesis of compounds 2–5.
NH
11.60
CN
N
5.90
NH2
N2H4. H2O
N
N
N
C2H5
dry benzene
O
7.60
N
N
N
Ar
1
Ar
2
pipridine, dioxane
reflux
7.20
4.80
HN NH2
N
N
8.39
N
N
Ar
3
EtOH, heat
H3CS
H3CS
CN
CN
EtO
CN
CN
CN
CN
H3CS
N
N
NH2
NH2
N
N
N
N
N
N
N
N
N
N
Ar
Ar
4
5
Ar= - C6H4-CH3 (p)
Scheme 2. Isomerization of compound 2 to 3.
..
..
NH
:
NNH2
NH
N
..
..
NH
..
NNH
2
3
NNH2
N
B
N
B
N
N
N
B
:
N
N
N
Ar
Ar
Ar
2
Heating of compounds 2 or 3 with triethyl orthoacetate at its boiling temperature, gave 2-methyl-7-
p-tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (6) or 3-methyl-7-p-tolyl-7H-pyrazolo[4,3-
e][1,2,4]triazolo[4,3-c]pyrimidine (7), respectively (Scheme 3). It was noticed that the two
triazolopyrimidine derivatives 6 and 7 showed no appreciable difference in fragmentation pattern
1
under electron impact (cf. Experimental Section). However, the H-NMR spectra of triazolo[4,3-
c]pyrimidine derivative 7 revealed that the C3-CH3 and C5-H protons appeared at a more downfield
location when compared with the C2-CH3 and C5-H protons of the [1,2,4]triazolo[1,5-c]pyrimidine

Molecules 2014, 19
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derivative 6 (Table 1). These data are in agreement with reported results of related
compounds [15–18,21,22,24] and confirmed that the product obtained from the reaction with
hydrazino derivative 3 differ than those obtained from the reaction with imino derivative 2.
Scheme 3. Synthesis of compounds 6–11.
NH
NH2
N
N
N
N
Ar
2
H3C-C(OEt)3
heat
HC(OEt)3
heat
CH3
N
N
N
N
N
N
N
N
N
N
N
Ar
N
6
Ar
8
CH3COOH
heat
HCOOH
heat
HN NH2
N
ethanol
ethanol
N
CH3COOH
N
N
HCOOH
heat
heat
Ar
3
HC(OEt)3
heat
H3C-C(OEt)3
heat
COOH
COOH
POCl3, heat
N
N
N
N
N
N
N
CH3
N
N
POCl3, heat
N
N
N
N
Ar
Ar
Ar`
N
7
9
Ar`
N
N
N
N
N
Ar` =
N
Ar` =
N
N
N
N
N
N
Ar
Ar
11
10
Ar = -C6H4-CH3 (p)

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Table 1. M.p., 1H- and 13C-NMR values of triazole and pyrimidine protons of compounds 6–9.
δ 1H-NMR
C5-H C3-H C2-H C3-H3 C2-CH3
δ 13C-NMR
Compd. No.
m.p.
C-5
C-3
C-2
C3-CH3 C2-CH3
6
7
8
9
264–265 9.15
275–277 9.35
257–259 9.20
–
–
–
–
–
–
2.80
–
2.55
159.30
160.50
11.60
–
–
–
162.00 164.27
157.99
13.60
9.00
–
158.66
290–292 9.40 9.25
–
160.05 161.90
However, when compound 3 was heated under reflux in acetic acid, it afforded compound 6,
probably via the intermediacy of its [1,2,4]triazolo[4,3-c]pyrimidine isomer 7 which was not isolated
in this reaction, but rather underwent a Dimroth-type rearrangement [15,20] under the reaction
conditions. To prove this assumption, compound 7 was converted into its corresponding [1,2,4]
triazolo[1,5-c]pyrimidine derivative 6 by heating in ethanol in the presence of few drops of glacial
acetic acid (Scheme 3).
Likewise, when compounds 2 or 3 were refluxed with triethyl orthoformate, it gave 7-p-tolyl-7H-
pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (8) and 7-p-tolyl-7H-pyrazolo[4,3-e] [1,2,4] triazolo[4,3-
c]pyrimidine (9), respectively (Scheme 3). The 1H-NMR spectra of the latter compounds revealed that the
C3-H and C5-H protons of compound 9 appeared more downfield when compared with the C2-H and C5-H
protons of [1,2,4]triazolo[1,5-c]pyrimidine derivative 8 (Table 1). Also, when compound 3 was refluxed
with formic acid, it afforded compound 8, probably via the intermediacy of its isomer [1,2,4]triazolo[4,3-
c]pyrimidine 9. To prove this assumption, compound 9 was converted into the corresponding [1,2,4]
triazolo[1,5-c]pyrimidine derivative 8 by heating in ethanol in the presence of few drops of formic acid
(Scheme 3). It was noticed that, the NMR spectra and m.p. values for [1,2,4]triazolo[4,3-c]pyrimidines 7, 9
are greater than those of [1,2,4] triazolo[1,5-c]pyrimidines 6, 8 (Table 1).
Moreover, when the hydrazino derivative 3 was refluxed with 1-naphthylacetic acid or nicotinic
acid in the presence of phosphorus oxychloride, it afforded the polycyclic 2-naphthyl-3-yl-7-p-tolyl-
7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (10) 2-pyridin-3-yl-7-p-tolyl-7H-pyrazolo[4,3-
e][1,2,4]triazolo[1,5-c]pyrimidine (11), respectively via a Dimroth-type rearrangement of the
[1,2,4]triazolo[4,3-c]pyrimidine under the acidic reaction conditions.
3. Experimental
General Information
All melting points are uncorrected and were measured using an Electro-Thermal IA 9100
apparatus (Shimadzu, Tokyo, Japan). Infrared spectra were recorded as potassium bromide pellets
1
on a Perkin-Elmer 1650 spectrophotometer (Perkin-Elmer, Norwalk, CT, USA). H-NMR and
13C-NMR spectra were determined on a Jeol-Ex-400-NMR spectrometer (Jeol, Tokyo, Japan) and
chemical shifts are expressed as δ values in parts per million using TMS as internal reference.
Mass spectra were recorded on a VG 2AM-3F mass spectrometer (Thermo Electron Corporation,
Waltham, MA, USA). Microanalyses were obtained using a Mario El Mentar apparatus, and the
results were within the accepted range (±0.20) of the calculated values. The reactions were
followed and the purity of the compounds was checked by TLC on silica gel-precoated aluminum

Molecules 2014, 19
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sheets (Type 60 F254; Merck, Darmstadt, Germany). Compound 1 was prepared according to a
reported method (m.p. 82–84 °C; lit. [19] m.p. 82–84 °C).
4-Imino-1-p-tolyl-1,4-dihydropyrazolo[3,4-d]pyrimidin-5-ylamine (2): To a solution of compound 1
(2.54 g, 0.01 mol) in anhydrous benzene (30 mL), hydrazine hydrate (99%, 3 mL) was added with
stirring for 1 h at room temperature. The obtained product was filtered, dried, and recrystallized from
dry dioxane to give compound 2. Yield 92%; m.p. 163–164 °C. IR (KBr, ν, cm−1): 3288, 3262 (NH2),
1
and 3199 (NH); H-NMR (DMSO-d6, δ ppm): 2.40 (s, 3H, CH3), 5.90 (bs, 2H, NH2, D2O
exchangeable), 7.30–7.45 (d, 2H, Ar-H, J = 8.5 Hz), 7.50–7.60 (m, 3H, 2Ar-H + C6-H), 8.30 (s, 1H,
13
C3-H), 11.60 (s, 1H, NH, D2O exchangeable). C-NMR (DMSO-d6, δ ppm): 20.88 (CH3), 103.57
(C-3a), 113.70, 127.82, 130.21, 133.40 (Ar-C), 133.72 (C-3), 154.50 (C-7a), 163.27 (C-6), 164.42
(C-4). MS, m/z (%): 240 (M+, 100). Anal. Calcd. for C12H12N6: C, 59.99; H, 5.03; N, 34.98; found: C,
60.06; H, 4.99; N, 34.94.
(1-p-Tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-hydrazine (3): Compound 2 (1.20 g, 0.005 mol) in
anhydrous dioxane (20 mL) containing a few drops of piperidine was refluxed for 6 h. Then the
reaction mixture was evaporated under reduced pressure and recrystallized from dioxane to give
compound 3. Yield 83%, m.p. 180–182 °C. IR (KBr, ν, cm−1): 3295, 3271 (NH2), and 3150 (NH);
1H-NMR (DMSO-d6, δ ppm): 2.45 (s, 3H, CH3), 4.80 (s, 2H, NH2, D2O exchangeable), 7.20 (s, 1H,
NH, D2O exchangeable), 7.32 (d, 2H, Ar-H, J = 8.5 Hz), 7.80 (d, 2H, Ar-H, J = 8.5 Hz), 8.31 (s, 1H,
C3-H), 8.39 (s, 1H, C6-H). 13C-NMR (DMSO-d6, δ ppm): 20.90 (CH3), 102.75 (C-3a), 113.51, 127.90,
130.35, 133.41 (Ar-C), 133.72 (C-3), 154.50 (C-7a), 158.47 (C-6), 168.20 (C-4). MS, m/z (%): 240
(M+, 56). Anal. Calcd. for C12H12N6: C, 59.99; H, 5.03; N, 34.98; found: C, 59.93; H, 5.05; N, 35.00.
General procedure for the synthesis of 5-amino-3-substituted-1-(1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-
4-yl)-1H-pyrazole-4-carbonitriles 4 and 5: To a solution of compound 3 (1.20 g, 0.005 mol) in ethanol
(30 mL), ethoxymethylenemalononitrile, or bis(methylthio)methylenemalononitrile (0.005 mol), was
added, respectively. The reaction mixture was heated for 2–3 h. The formed precipitate was filtered off
and recrystallized from an appropriate solvent to give compounds 4 and 5, respectively.
5-Amino-1-(1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile (4): 2 h, yield:
(96%, dioxane); m.p. 222–225 °C. IR (KBr, ν, cm−1): 3430, 3300 (NH2), 3220 (NH), 2222 (CN).
1H-NMR (DMSO-d6, δ ppm): 2.41 (s, 3H, CH3), 6.79 (s, 2H, NH2, D2O exchangeable), 7.33 (d, 2H,
Ar-H, J = 8.5 Hz), 8.12 (d, 2H, Ar-H, J = 8.5 Hz), 8.33 (s, 1H, C3-H), 8.34 (s, 1H, C3'-H), 8.50 (s, 1H,
C6'-H). 13C-NMR (DMSO-d6, δ ppm): 20.64 (CH3), 103.06 (C-3'a), 111.04 (C-4), 116.23 (CN), 113.61,
128.01, 130.41, 133.33 (Ar-C), 132.50 (C-3), 134.00 (C-3'), 153.92 (C-5), 154.72 (C-4`), 157.57
(C-6'), 159.33 (C-7'a). MS, m/z (%): 316 (M+, 23.49). Anal. calcd for C16H12N8: C, 60.75; H, 3.82; N,
35.42. Found: C, 60.80; H, 3.79; N, 35.40.
5-Amino-3-methylsulfanyl-1-(1-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazole-4-carbonitrile (5):
3 h, yield: (84%, dioxane); m.p. 209–211 °C. IR (KBr, ν, cm−1): 3313, 3299 (NH2), 3200 (NH), and
1
2222 (CN). H-NMR (DMSO-d6, δ ppm): 2.40 (s, 3H, CH3), 3.76 (s, 3H, SCH3), 6.85 (s, 2H, NH2,
D2O exchangeable), 7.32 (d, 2H, Ar-H, J = 8.5 Hz), 8.15 (d, 2H, Ar-H, J = 8.5 Hz), 8.35 (s, 1H,

Molecules 2014, 19
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'
'
13
C3 -H), 8.55 (s, 1H, C6 -H). C-NMR (DMSO-d6, δ ppm): 20.64 (CH3), 25.15 (CH3), 102.57 (C-3'a),
113.04 (C-4), 115.59 (CN), 113.50, 127.90, 130.30, 133.40 (Ar-C), 133.50 (C-3), 133.70 (C-3'),
153.83 (C-5), 154.43 (C-4'), 157.27 (C-6'), 159.42 (C-7'a). MS, m/z (%): 362 (M+, 33.25). Anal. calcd
for C17H14N8S: C, 56.34; H, 3.89; N, 30.92; S, 8.85. Found: C, 56.26; H, 3.94; N, 30.95; S, 8.80.
2-Methyl-7-p-tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (6)
Method A: A mixture of compound 2 (1.20 g, 0.005 mol) and triethyl orthoacetate (30 mL) was
refluxed for 10 h. The reaction mixture was evaporated till dryness and the remaining solid was
1
recrystallized from dioxane to give compound 6. Yield 70%, m.p. 264–265 °C. H-NMR (DMSO-d6,
δ ppm): 2.40 (s, 3H, CH3), 2.55 (s, 3H, C2-CH3), 7.35 (d, 2H, Ar-H, J = 8.5 Hz), 8.10 (d, 2H, Ar-H,
13
J = 8.5 Hz), 8.50 (s, 1H, C9-H), 9.15 (s, 1H, C5-H). C-NMR (DMSO-d6, δ ppm): 11.6 (C2-CH3),
20.78 (CH3), 107.30 (C-9a), 113.46, 127.16, 130.37, 134.15 (Ar-C), 144.50 (C-9), 147.45 (C-6a),
157.27(C-9b), 159.30 (C-5), 160.50 (C-2). MS m/z (%): 264 (M+, 18.01). Anal. calcd for C14H12N6: C
63.62, H 4.58, N 31.80. Found: C 63.70, H 4.54, N 31.75.
Method B: Compound 3 (1.20 g, 0.005 mol) was heated under reflux temperature in glacial acetic
acid (30 mL) for 8 h. The reaction mixture was cooled and poured into water. The formed solid was
filtered off, dried and recrystallized from dioxane to give product identical in all aspects with
compound 6 obtained before. Yield 77%, m.p. 264–265 °C.
Method C: A solution of compound 7 (1.32 g, 0.005 mol) in ethanol (20 mL) containing 3–5 drops
of glacial acetic acid was heated under reflux temperature for 30 min. The solvent was removed under
reduced pressure leaving a solid product which was recrystallized from dioxane to give compound
identical in all aspects with compound 6 obtained before. Yield 62%, m.p. 264–265 °C.
3-Methyl-7-p-tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine (7): Compound 3 (1.20 g,
0.005 mol) was heated under reflux temperature in triethyl orthoacetate (40 mL) for 5 h. The product
which separated on cooling was filtered off, dried and recrystallized from dioxane to give compound 7.
1
Yield 80%, m.p. 275–277 °C. H-NMR (DMSO-d6, δ ppm): 2.40 (s, 3H, CH3), 2.80 (s, 3H, C3-CH3),
7.34 (d, 2H, Ar-H, J = 8.5 Hz), 8.20 (d, 2H, Ar-H, J = 8.5 Hz), 8.50 (s, 1H, C9-H), 9.35 (s, 1H, C5-H).
13C-NMR (DMSO-d6, δ ppm): 13.6 (C3-CH3), 20.90 (CH3), 107.35 (C-9a), 113.50, 127.17, 130.39,
134.16 (Ar-C), 144.70 (C-9), 147.80 (C-6a), 156.37 (C-9b), 162.00 (C-5), 164.27 (C-3). MS m/z (%):
264 (M+, 29.98). Anal. calcd for C14H12N6: C 63.62, H 4.58, N 31.80. Found: C 63.55, H 4.60, N 31.82.
7-p-Tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (8)
Method A: A mixture of compound 2 (1.20 g, 0.005 mol) and triethyl orthoformate (30 mL) was
refluxed for 10 h. After cooling, the formed precipitate was filtered off, dried, and recrystallized from
dioxane to give compound 8. Yield 80%, m.p. 257–259 °C. 1H-NMR (DMSO-d6, δ ppm): 2.40 (s, 3H,
CH3), 7.34 (d, 2H, Ar-H, J = 8.5 Hz), 8.20 (d, 2H, Ar-H, J = 8.5 Hz), 8.50 (s, 1H, C9-H), 9.00 (s, 1H,
C2-H), 9.20 (s, 1H, C5-H). 13C-NMR (DMSO-d6, δ ppm): 20.28 (CH3), 106.88 (C-9a), 113.47, 127.14,
130.35, 134.15 (Ar-C), 144.10 (C-9), 147.50 (C-6a), 150.57 (C-9b), 157.99 (C-5), 158.66 (C-2). MS

Molecules 2014, 19
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m/z (%): 250 (M+, 18.01). Anal. calcd for C13H10N6: C, 62.39; H, 4.03; N, 33.58. Found: C, 62.49; H,
4.00; N, 33.55.
Method B: Compound 3 (1.20 g, 0.005 mol) was heated under reflux temperature in formic acid
(40 mL, 85%) for 10 h. The reaction mixture was cooled and poured into water. The formed solid was
filtered off, dried and recrystallized from dioxane to give product identical in all aspects with
compound 8 obtained before. Yield 77%, m.p. 257–259 °C.
Method C: A solution of compound 9 (1.25 g, 0.005 mol), ethanol (20 mL) containing 3–5 drops of
formic acid was heated under reflux temperature for 1 h. The reaction mixture was evaporated to
dryness and the remaining solid was recrystallized from dioxane to give compound identical in all
aspects with compound 8 obtained before. Yield 50%, m.p. 257–259 °C.
7-p-Tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine (9): Compound 3 (1.20 g, 0.005 mol) was
heated under reflux temperature in triethyl orthoformate (40 mL) for 5 h. The reaction mixture was kept
at room temperature overnight, then the solvent was evaporated to dryness and the remaining solid was
purified on TLC plate using chloroform: methanol (9:1) as an eluent to separate compound 9 as the
1
major product. Yield 79%, m.p. 290–292 °C. H-NMR (DMSO-d6, δ ppm): 2.42 (s, 3H, CH3), 7.30 (d,
2H, Ar-H, J = 8.5 Hz), 8.15 (d, 2H, Ar-H, J = 8.5 Hz), 8.50 (s, 1H, C9-H), 9.25 (s, 1H, C3-H), 9.40 (s,
13
1H, C5-H). C-NMR (DMSO-d6, δ ppm): 20.30 (CH3), 106.75 (C-9a), 113.51, 127.16, 130.38, 134.17
(Ar-C), 144.50 (C-9), 147.22 (C-6a), 150.87 (C-9b), 160.05 (C-5), 161.90 (C-3). MS m/z (%): 250
(M+, 50.74). Anal. calcd for C13H10N6: C, 62.39; H, 4.03; N, 33.58. Found: C, 62.30; H, 4.05; N, 33.60.
General procedure for the synthesis of 2-substituted-7-p-tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-
c]pyrimidines 10 and 11: A mixture of compound 3 (2.40 g, 0.01 mol) in phosphorus oxychloride
(40 mL) and 1-naphthylacetic acid (1.86 g, 1 mmol) or nicotinic acid (1.23 g, 1 mmol) was heated under
reflux temperature for 5–6 h. The reaction mixture was poured onto crushed ice and the obtained
solid was filtered off, dried, and recrystallized from an appropriate solvent to give compounds 10
and 11 respectively.
2-Naphthalen-1-ylmethyl-7-p-tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (10): 5 h, yield:
1
(65%, DMF/H2O); m.p. 296–297 °C. H-NMR (DMSO-d6, δ ppm): 2.40 (s, 3H, CH3), 4.0 (s, 2H,
13
CH2), 7.30–8.15 (m, 11H, Ar-H), 8.55 (s, 1H, C9-H), 9.20 (s, 1H, C5-H). C-NMR (DMSO-d6, δ
ppm): 20.66 (CH3), 35.68 (C2-CH2), 107.41 (C-9a), 113.46, 123.90, 125.20, 125.40 126.20, 126.40,
126.50, 127.16, 128.30, 130.37, 132.50, 133.40, 134.10, 134.15 (Ar-C), 144.62 (C-9), 147.61 (C-6a),
157.00(C-9b), 158.98 (C-5), 160.40 (C-2). MS m/z (%): 390 (M+, 33.02). Anal. calcd for C24H18N6: C,
73.83; H, 4.65; N, 21.52. Found: C, 73.76; H, 4.61; N, 21.57.
2-Pyridin-3-yl-7-p-tolyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (11): 6 h, yield: (77%,
dioxane); m.p. 288–289 °C. 1H-NMR (DMSO-d6, δ ppm): 2.39 (s, 3H, CH3), 7.10–8.15 (m, 8H, Ar-H),
13
8.50 (s, 1H, C9-H), 9.25 (s, 1H, C5-H). C-NMR (DMSO-d6, δ ppm): 20.54 (CH3), 107.42 (C-9a),
113.44, 123.80, 127.20, 130.40, 133.40, 134.16, 134.20, 148.11, 149.45 (Ar-C), 143.92 (C-9), 147.52

Molecules 2014, 19
5467
(C-6a), 157.22 (C-9b), 157.92 (C-5), 159.80 (C-2). MS m/z (%): 327 (M+, 33.02). Anal. calcd for
C18H13N7: C, 66.04; H, 4.00; N, 29.95. Found: C, 65.96; H, 4.05; N, 29.90.
4. Conclusions
The synthesis and structure characterization of new pyrazoles and pyrazolopyrimidines was
discussed. Also, structure characterization of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives
7 and 9 and their isomerization to pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives 6 and 8,
respectively, under different suitable reaction conditions were reported.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud
University for supporting this work through the research group project No. RGP-VPP-032.
Author Contributions
The listed authors contributed to this work as described in the following. Aymn E. Rashad gave the
concepts of work, interpreted the results and prepared the manuscript. Ahmed H. Shamroukh
interpreted the results and cooperated in the preparation of the manuscript, Randa E. Abdelmegeid
carried out of the synthetic work, interpreted the results and cooperated in the preparation of the
manuscript. Hatem S. Ali contributed with valuable discussions and scientific input and funding of
Spectra for Substances. All authors read and approved the final manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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