A facile synthesis of new pyrazolo[3,4-d]pyrimidine derivatives via a one-pot four-component reaction with sodium acetate supported on basic alumina as promoter

Article abstract of DOI:10.1002/hlca.201300060

An efficient one-pot procedure for the synthesis of 3-amino-6-aryl-2- phenylpyrazolo[3,4-d]pyrimidine derivatives, through the reaction of aldehydes, malononitrile, benzamidine hydrochloride, and hydrazine hydrate in the presence of basic alumina-supported sodium acetate (AcONa/Al₂O₃) under reflux conditions, is reported. This protocol has some advantages, including the use of a simple and one-pot synthetic approach to attain pyrazolo[3,4-d]pyrimidine directly from four readily available starting materials, simple workup, high overall yields of the products, and the simultaneous conversion of a NO₂ to an amino group, offering an opportunity to synthesize more complex structures. Copyright

Full text of DOI:10.1002/hlca.201300060

Helvetica Chimica Acta – Vol. 96 (2013)
2267
A Facile Synthesis of New Pyrazolo[3,4-d]pyrimidine Derivatives via a One-
Pot Four-Component Reaction with Sodium Acetate Supported on Basic
Alumina as Promoter
by Shahnaz Rostamizadeh*a), Masoomeh Nojavana), Reza Aryanb), and Elyass Isapoora)
a) Department of Chemistry, Faculty of Science, K. N. Toosi University of Technology, P.O. Box 15875-
4416, Tehran, Iran (fax: þ 98-21-22853650; e-mail: shrostamizadeh@yahoo.com)
b) Department of Chemistry, Faculty of Science, University of Zabol, Zabol, Iran
(fax: þ 98-54-22242503; e-mail: rezaaryan@yahoo.com)
An efficient one-pot procedure for the synthesis of 3-amino-6-aryl-2-phenylpyrazolo[3,4-d]pyrimi-
dine derivatives, through the reaction of aldehydes, malononitrile, benzamidine hydrochloride, and
hydrazine hydrate in the presence of basic alumina-supported sodium acetate (AcONa/Al2O3) under
reflux conditions, is reported. This protocol has some advantages, including the use of a simple and one-
pot synthetic approach to attain pyrazolo[3,4-d]pyrimidine directly from four readily available starting
materials, simple workup, high overall yields of the products, and the simultaneous conversion of a NO2
to an amino group, offering an opportunity to synthesize more complex structures.
Introduction. – Fused pyrimidine derivatives have been shown to possess diverse
biological activities, and among them, pyrazolo[3,4-d]pyrimidines as purine analogs
have attracted considerable interest due to their remarkable pharmacological proper-
ties. These compounds were designed and synthesized as potent and selective kinase
inhibitors [1], antileishmanial and antitrypanosomal [2], antibacterial [3], and antiviral
agents [4], and adenosine A2A receptor antagonists [5].
With these pharmacological profile of pyrazolo[3,4-d]pyrimidines, it seems
beneficial to develop a more efficient synthetic route toward the synthesis of novel
derivatives of this class of heterocycles. A literature survey provided information on
methods used so far for the synthesis of pyrazolo-pyrimidines [6]. However, all these
methods suffer from some drawbacks such as stepwise reaction conditions and tedious
workup procedures.
Thus, the development of a simpler and more direct method for the preparation of
pyrazolo-pyrimidines without one or more of these disadvantages appears to be crucial.
Herein, we report a novel one-pot and multicomponent procedure for the synthesis of
novel pyrazolo[3,4-d]pyrimidine derivatives directly through the reaction of aldehydes,
malononitrile, benzamidine hydrochloride, and NH2NH2 · H2O in the presence of basic
alumina-supported sodium acetate, AcONa/Al2O3, as base.
Results and Discussion. – Initially, equimolar amounts of 4-chlorobenzaldehyde
(1b), malononitrile (2), and benzamidine hydrochloride (3) were mixed and heated in
different solvents and in the presence of various bases (Scheme 1).
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. Model Reaction Used for the Synthesis of Pyrimidine-5-carbonitrile Derivatives (e.g. 4b)
t
NaOH, Cs2CO3, BuOK, CuO, Nano-MgO, AcONa, basic Al2O3, and AcONa/
Al2O3 were examined as base in different solvents (EtOH, H2O, BuOH, i-BuOH, i-
PrOH, and no solvent at all).
The best results were obtained by using basic alumina-supported AcONa, CuO, and
nano-MgO in EtOH as solvent under reflux condition.
To obtain the pyrazolo[3,4-d]pyrimidine derivatives, the process outlined in
Scheme 1 was repeated, however, this time in the presence of basic alumina-supported
AcONa, followed by addition of 0.5 ml of NH2NH2 · H2O to the reaction mixture after
consumption of all reactants without separation of the formed pyrimidine product
(Scheme 2). On the other hand, an unrecoverable dark-brown gum was formed in the
case of using CuO and nano-MgO as base, in which TLC analysis did not show the
formation of any new spot. In the case of basic alumina-supported AcONa as base, the
reaction proceeded well in refluxing EtOH to form a new spot along with the
disappearance of pyrimidine (Scheme 2). After aqueous workup, a pure pale-yellow
solid was obtained. Full characterization of this compound was accomplished by
spectroscopic methods (IR, 1H-, and 13C-NMR, and mass spectra).
The IR spectrum (KBr disc) of this compound revealed no CN absorption bond. In
1H-NMR spectrum, we observed two different NH peaks at d(H) 12.82 and 5.19 with
signal-intensity ratio of 1:2, which can be attributed to the NH of pyrazolo ring and its
amino group at C(3), respectively. Moreover, the mass spectrum showed a peak at m/z
321, which is compatible with 4-(4-chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyri-
midin-3-amine (5b). Elemental analysis and thorough interpretation of 13C-NMR
spectra also supported the formation of 5b (Scheme 2).
Scheme 2. Model Reaction for the Synthesis of 4-(4-Chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyr-
imidin-3-amines (e.g. 5b)

Helvetica Chimica Acta – Vol. 96 (2013)
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The reaction depicted in Scheme 2 was also investigated under different base
loadings, and the best results were obtained by using 0.1 g of basic alumina-supported
AcONa. Increasing the amount of base did not affect the reaction time and yield.
To explore the scope and generality of this reaction, we have extended this process
to various substituted benzaldehydes with malononitrile 2 and benzamidine hydro-
chloride 3, in the presence of NH2NH2 · H2O. The reaction proceeded efficiently with
various substituted benzaldehydes (Table).
Table. Synthesis of 5a – 5j, by a One-Step Reaction, under Reflux Conditions
Entry
R
Product
R’
Time [h]
Yield [%]a)
M.p. [8]
1
2
3
4
5
6
7
8
9
H
4-Cl
2,3-Cl2
2-Cl
4-CN
5a
5b
5c
5d
5a
5e
5f
5g
5h
5i
H
4-Cl
–
2-Cl
H
4-Me
–
3-NH2
4-NH2
–
4-NH2
4-MeO
6
8
–
2
6
2
–
5
5
1
5
8
97
95
–
98
85
97
–
90
88
–
90
95
261 – 264
267
–
212
261
215
–
311
223 – 229
–
228 – 231
211
4-Me
2,4-Cl2
3-NO2
4-NO2
1H-Indol-3-yl
4-Acetamido
4-MeO
10
11
12
5h
5j
a) Yield of isolated product.
When the pyrimidine derivatives with 4-(3-nitrophenyl), 4-(4-nitrophenyl), and 4-
(4-acetamido) groups were used, the reaction led to the corresponding amino products
(Table, Entries 8, 9, and 11) [7]. Similarly, when a pyrimidine derivative 4e with a 4-(4-
cyanophenyl) substituent (cf. Scheme 1) was used, we obtained again 5a, i.e., the H-
atom replaced the CN group (Table, Entry 5) [8]. When bulky aryl substituents such as
2,3- and 2,4-dichlorophenyl (Table, Entries 3, 7, and 10) were at C(4) of the pyrimidine
ring, the addition of NH2NH2 · H2O led to the decomposition of the pyrimidine to the
benzylidene malononitrile and benzamidine reactants rather than to the formation of
the expected pyrazolo[3,4-d]pyrimidine derivatives.
A plausible mechanism for the formation of pyrazolo[3,4-d]pyrimidine derivatives
is proposed in Scheme 3. First, NH2NH2 attacks C(6) of the pyrimidine ring as a
nucleophile (Scheme 3). Then, the resulting hydrazino derivative 6 (this intermediate

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Helvetica Chimica Acta – Vol. 96 (2013)
Scheme 3. Proposed Mechanism for the Formation of 4-Aryl-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-
amines 5 Directly from Aldehydes, Malononitrile, Benzamidine Hydrochloride, and NH2NH2 · H2O
was isolated and characterized) intramolecularly undergoes the nucleophilic attack at
the CN group leading to iminopyrazolo-pyrimidine 7, which is transformed to the
desired pyrazolo derivative 5 through aromatization.
Furthermore, considering that piperidine and piperazine are important structural
motifs in a number of bioactive compounds, the potential of this protocol for the
synthesis of pyrazolo[3,4-d]pyrimidine derivatives containing such motifs was studied
using two other pyrimidine derivatives with piperidine and piperazine substituents at
C(2), i.e., 4m and 4n, under the optimized reaction conditions (Scheme 4). For this
purpose, 4-amino-6-(4-chlorophenyl)-2-(piperazin-1-yl)pyrimidine-5-carbonitrile (4m)
and 4-amino-6-(4-chlorophenyl)-2-(piperidin-1-yl)pyrimidine-5-carbonitrile (4n) were
prepared through a different synthetic pathway from 4-amino-6-(4-chlorophenyl)-2-
(methylsulfanyl)pyrimidine-5-carbonitrile (8) [9]. To our surprise, no reaction was
observed between these two pyrimidine derivatives and NH2NH2 · H2O in the presence
of AcONa/Al2O3 in EtOH under reflux conditions (Scheme 4).
To find out why fused pyrimidine derivatives were not formed from the reaction
between these pyrimidine derivatives and NH2NH2 · H2O, we investigated the effect of
pyrimidine-ring substituents at C(2) by computational methods. In this context, DFT
calculations, using Gaussian03w software package [10], were performed at B3LYP/6-
31G* level of theory on the structures A, B, and C (Fig. 1).
The structures in Fig. 1 were first drawn and fully optimized using GaussView 3.0
software and Gaussian03w software, respectively, at the above mentioned level of
theory. The DFT calculations on the three pyrimidine derivatives supported the above
mentioned experimental results. The computed lowest unoccupied molecular orbital
(LUMO) of these three compounds elicited from the checkpoint files are depicted in
Fig. 2.

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Scheme 4. Investigation of the Reaction of NH2NH2 · H2O with 4-Amino-6-(4-chlorophenyl)-2-(methyl-
sulfanyl)pyrimidine-5-carbonitrile
a) 1 mmol of 4-amino-6-(4-chlorophenyl)-2-(methylsulfanyl)pyrimidine-5-carbonitrile, 3 mmol of
Oxone, acetone/H2O, r.t., overnight (quant.). b) Piperazine or piperidine (2 equiv.), dioxane, r.t.,
overnight. c) 1 mmol of 4m or 4n, AcONa/Al2O3 (0.1 g), NH2NH2 (0.5 ml), EtOH, reflux.
Fig. 1. Pyrimidine derivatives selected for DFT calculations in the present study
Fig. 2. The optimized structures and LUMO molecular orbitals of compounds A, B, and C
In the case of pyrimidine A, which possesses a Ph group at C(2), the LUMO is
placed on C(6)ꢀN(1), while for the other two, on C(2)ꢀN(3) bond. This could imply
that the most electrophilic C-atom would be C(6) in structure A, while C(2) would be

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the most electrophilic one for the other two, i.e., B and C. This means that hydrazine
can attack the pyrimidine derivative A at C(6) of the ring in a nucleophilic manner,
while the situation is different for compounds B and C, and these compounds would not
undergo such a reaction at C(6). So, these results are in agreement with the observation
that no pyrazolo-pyrimidine is formed from the reactions of pyrimidines B and C, and
NH2NH2 under the optimized reaction conditions.
Conclusions. – In summary, we have developed a novel efficient protocol for the
direct synthesis of fused pyrazolo[3,4-d]pyrimidine derivatives from the corresponding
pyrimidine-5-carbonitriles. This protocol offers several advantages over the previously
reported methods such as excellent yields of the products, simple workup, and
straightforward synthesis of pyrazolo[3,4-d]pyrimidine derivatives via available start-
ing materials. The simultaneous conversion of NO2 to NH2 group, which provides an
opportunity to synthesize more complex structures by additional reaction steps, is a
unique advantage of this protocol. We are attempting to expand this protocol to
synthesis other heterocyclic building blocks.
The authors gratefully acknowledge K. N. Toosi University Research Council for partial financial
support of this study, and Dr. Reza Aryan from University of Zabol, Zabol, Iran, for helpful consultation
of computational part of this work.
Experimental Part
General. M.p.: Bꢀchi B-540 apparatus. IR Spectra: ABB Bomem spectrometer Model FTLA200 –
1
100 instrument. H- and 13C-NMR spectra: Bruker DRX-300 spectrometer at 300 and 75 MHz, resp.,
with TMS as an internal standard; chemical shifts (d) in ppm, and coupling constants (J) in Hz. MS:
Shimadzu QP 1100 EX mass spectrometer with 70-eV ionization potential. Elemental analyses: Vario EL
III 0 Serial No. 11024054 instrument, results in agreement with calculated values.
Catalyst Preparation. AcONa (22 g, 0.27 mol) was poured into a flask containing H2O (200 ml) and
stirred for 4 min. Basic alumina (20 g, 0.19 mol) was then added gradually to this mixture while stirring,
and the mixture was kept stirring for another 4 min. The resulting suspension was then dried in vacuo, and
the solid residues were collected, dried at 1108 for 24 h, and kept in well-closed container.
General Procedure for the Synthesis of 4a – 4l. Malononitrile (1 mmol), aldehyde (1 mmol),
benzamidine hydrochloride (1 mmol), and AcONa/Al2O3 (0.1 g) in 5 ml of EtOH were mixed, heated
under reflux, and the reaction was monitored by TLC (AcOEt/petroleum ether (PE) 1:2). After
completion of the reaction, the mixture was cooled to r.t., filtered to separate the solid catalyst, and
evaporated in vacuo. Then, the solid residues were washed with brine, and the org. solid was separated by
filtration on a Bꢀchi funnel and further purified by crystallization from EtOH to furnish the desired
pyrimidine product.
4-Amino-2,6-diphenylpyrimidine-5-carbonitrile (4a). Yield: 266 mg (98%). White powder. M.p. 2148
([11]: 210 – 2128). IR: 3450, 3385, 2235.1H-NMR: 8.38 – 8.41 (m, 2 H); 7.95 – 7.98 (m, 2 H); 7.47 – 7.68 (m,
5 H); 7.47 – 7.68 (NH2). 13C-NMR: 168.1; 164.6; 164.0; 136.5; 131.5; 130.9; 128.6; 128.5; 128.4; 116.4; 84.4.
4-Amino-6-(4-chlorophenyl)-2-phenylpyrimidine-5-carbonitrile (4b). Yield: 293 mg (96%). Yellow
1
powder. M.p. 2228 ([11]: 2228). IR: 3450, 3390, 2237. H-NMR: 8.37 (d, J ¼ 6.2, 2 H); 7.99 (d, J ¼ 8.5,
2 H); 7.64 (d, J ¼ 8.5, 2 H); 7.48 – 7.57 (m, 3 H); 7.39 (NH2). 13C-NMR: 166.9; 164.5; 164.0; 136.4; 135.8;
135.3; 131.6; 130.5; 128.6; 128.5; 128.4; 116.2; 84.4.
4-Amino-6-(2,3-dichlorophenyl)-2-phenylpyrimidine-5-carbonitrile (4c). Yield: 326 mg (96%). Yel-
low powder. M.p. 231 – 2348. IR: 3473, 3388, 2235. 1H-NMR: 8.29 – 8.31 (m, 3 H); 8.04 (s, NH2); 7.82 – 7.85
(m, 1 H); 7.47 – 7.61 (m, 4 H). 13C-NMR: 167.8; 164.3; 163.4; 138.3; 136.1; 132.2; 131.8; 129.3; 129.1;
128.6; 128.5; 114.9; 87.1. EI-MS: 340 (75), 342 (49), 317 (25), 315 (34), 312 (14), 311 (76), 310 (50), 309

Helvetica Chimica Acta – Vol. 96 (2013)
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(100), 308 (22), 307 (30), 282 (13), 280 (38), 239 (8), 237 (12), 206 (21), 198 (11), 189 (23), 166 (9), 164
(27), 104 (91), 77(35), 43 (14). Anal. calc. for C17H10Cl2N4 (341.19): C 59.84, H 2.95, N 16.42; found: C
59.33, H 2.91, N 17.10.
4-Amino-6-(2-chlorophenyl)-2-phenylpyrimidine-5-carbonitrile (4d). Yield: 290 mg (96%). Yellow
powder. M.p. 200 – 2028 ([12]: 1968). IR: 3475, 3390, 2235. 1H-NMR: 8.31 – 8.34 (m, 2 H); 8.07 – 8.10 (s,
NH2); 7.58 – 7.65 (m, 3 H); 7.48 – 7.56 (m, 4 H). 13C-NMR: 168.3; 164.2; 163.5; 136.3; 136.1; 131.7; 131.4;
131.0; 130.4; 129.7; 128.5; 128.4; 127.4; 115.1; 87.4.
4-Amino-6-(4-cyanophenyl)-2-phenylpyrimidine-5-carbonitrile (4e). Yield: 290 mg (98%). White
powder. M.p. 299 – 3008. IR: 3475, 3390, 2220. 1H-NMR: 8.36 – 8.39 (m, 2 H); 8.11 – 8.14 (m, 2 H); 8.05 (d,
J ¼ 8.4, 2 H); 7.48 – 7.56 (m, 3 H), 8.04 – 8.14 (NH2). 13C-NMR: 166.6; 164.3; 164.1; 140.7; 136.2; 132.4;
131.7; 129.5; 128.5; 128.4; 118.3; 115.8; 113.2; 85.0. EI-MS: 297 (100), 296 (60), 194 (92), 167 (18), 152
(11), 104 (53), 103 (201), 102 (12), 77 (28), 76 (19), 51 (14), 41 (7). Anal. calc. for C18H11N5 (297.31): C
72.72, H 3.73, N 23.56; found: C 72.70, H 3.66, N 23.63.
4-Amino-6-(4-methylphenyl)-2-phenylpyrimidine-5-carbonitrile (4f). Yield: 326 mg (96%). White
powder. M.p. 2118 ([11]: 2108). IR: 3484, 3381, 2238. 1H-NMR: 8.72 – 8.69 (m, 2 H); 8.40 – 8.37 (m, 2 H);
7.88 (d, J ¼ 9.0, 2 H); 7.63 (s, NH2); 7.50 – 7.54 (m, 3 H); 3.33 (s, 3 H). 13C-NMR: 170.9; 167.9; 164.6;
143.3; 136.6; 135.4; 133.7; 132.6; 129.5; 128.5; 128.4; 116.5; 84.0; 21.2.
4-Amino-6-(2,4-dichlorophenyl)-2-phenylpyrimidine-5-carbonitrile (4g). Yield: 323 mg (96%). Yel-
low powder. M.p. 1748 ([13]: 170 – 1748). IR: 3475, 3388, 2235. 1H-NMR: 8.31 (dd, J ¼ 8.1, 2 H); 7.94 (s,
NH2); 7.82 (d, J ¼ 1.7, 1 H); 7.59 – 7.67 (m, 2 H); 7.39 – 7.53 (m, 3 H). 13C-NMR: 167.3; 164.3; 163.4; 136.2;
135.3; 135.0; 132.3; 131.8; 131.7; 129.3; 128.5; 128.4; 127.7; 115.0; 87.4.
4-Amino-6-(3-nitrophenyl)-2-phenylpyrimidine-5-carbonitrile (4h). Yield: 303 mg (96%). Yellow
powder. M.p. 201 – 2028. IR: 3455, 3385, 2230. 1H-NMR: 8.75 (s, 1 H); 8.68 – 8.71 (m, 1 H); 8.37 – 8.52 (m,
3 H); 8.13 (s, NH2); 7.86 – 7.91 (m, 1 H); 7.65 – 7.71 (m, 1 H); 7.52 – 7.54 (m, 2 H). 13C-NMR: 165.9; 164.4;
164.1; 147.7; 137.9; 136.2; 135.0; 131.7; 130.3; 128.5; 128.4; 125.4; 123.3; 116.0; 84.9. EI-MS: 317 (84), 271
(59), 214 (56), 168 (67), 156 (100), 141 (91), 104 (71), 103 (72), 76 (72), 57 (45), 43 (44). Anal. calc. for
C17H11N5O2 (317.30): C 64.35, H 3.49, N 22.07; found: C 64.35, H 3.33, N 22.28.
4-Amino-6-(4-nitrophenyl)-2-phenylpyrimidine-5-carbonitrile (4i). Yield: 304 mg (96%). Yellow
powder. M.p. 215 – 2178 ([12][14]: 2158). IR: 3455, 3388, 2228.,1H-NMR: 8.65 (d, J ¼ 6.1, 2 H); 8.52 (d,
J ¼ 6.1, 2 H); 8.00 (s, NH2); 8.40 – 8.42 (m, 2 H); 7.43 – 7.52 (m, 3 H). 13C-NMR: 170.2; 168.6; 160.8;
144.5; 140.4; 136.9; 130.2; 128.2; 127.1; 120.0; 116.0; 79.5.
4-Amino-6-(1H-indol-3-yl)-2-phenylpyrimidine-5-carbonitrile (4j). Yield: 280 mg (90%). Yellow
powder. M.p. 230 – 2328. IR: 3450, 3385, 3315, 2222. 1H-NMR: 12.68 (s, NH); 8.60 (s, 1 H); 8.49 (s, NH2);
8.43 (d, J ¼ 6.2, 2 H); 8.27 (d, J ¼ 9.0, 1 H); 7.61 – 7.64 (m, 2 H); 7.51 (d, J ¼ 9.1, 1 H); 7.39 – 7.42 (m,
3 H). 13C-NMR: 177.2; 168.1; 162.5; 136.1; 133.1; 126.6; 123.8; 122.4; 118.9; 115.9; 115.8; 112.9; 110.9;
69.2. EI-MS: 311 (6), 208 (16), 194 (28), 193 (100), 166 (61), 165 (39), 142 (29), 138 (24), 88 (18), 63
(15), 51 (12). Anal. calc. for C19H13N5 (311.34): C 73.30, H 4.21, N 22.49; found: C 72.55, H 4.93, N 22.52.
N-[4-(6-Amino-5-cyano-2-phenylpyrimidin-4-yl)phenyl]acetamide (4k). Yield: 326 mg (95%). Pale-
1
yellow powder. M.p. 2458 ([14]: 243 – 2448). IR: 3488, 3387, 3323, 2232, 1665. H-NMR: 10.25 (s, NH);
8.40 (d, J ¼ 6.1, 2 H); 7.99 (d, J ¼ 9.2, 2 H); 7.89 (s, NH2); 7.77 (d, J ¼ 9.2, 2 H); 7.50 – 7.52 (m, 3 H); 2.1 (s,
3 H). 13C-NMR: 168.7; 167.1; 164.7; 163.8; 141.8; 136.6; 131.4; 130.7; 129.4; 128.5; 128.4; 118.3; 116.7;
83.5; 24.1.
4-Amino-6-(4-methoxyphenyl)-2-phenylpyrimidine-5-carbonitrile (4l). Yield: 286 mg (95%). Pale-
yellow powder. M.p. 2138 ([11]: 2138). IR: 3490, 3388, 2238. 1H-NMR: 8.38 – 8.41 (m, 2 H); 8.01 (d, J ¼
9.1, 2 H); 7.87 (s, NH2); 7.50 – 7.52 (m, 3 H); 7.10 (d, J ¼ 9.1, 2 H); 3.84 (s, 3 H). 13C-NMR: 167.1; 164.7;
163.7; 161.5; 136.6; 131.4; 130.3; 128.6; 128.4; 128.3; 116.7; 113.8; 83.3; 55.3.
General Procedure for the Synthesis of 5a – 5j. Malononitrile (1 mmol), aldehyde (1 mmol),
benzamidine hydrochloride (1 mmol), and AcONa/Al2O3 (0.1 g) in 5 ml of EtOH were mixed, refluxed
for the specified time, and the reaction was monitored by TLC (AcOEt/PE 1:2). After completion of the
reaction, NH2NH2 · H2O (0.5 ml) was added to the mixture, and the mixture was again refluxed. After
completion of the reaction, the mixture was cooled, and the solid catalyst was separated by filtration.
Then, H2O was added (10 ml) to the filtrate, and the solid residues were filtered and further recrystallized
from EtOH.

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Helvetica Chimica Acta – Vol. 96 (2013)
4,6-Diphenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5a). Yield: 278 mg (97%). White powder. M.p.
261 – 2648. IR: 3432, 3329, 3301. 1H-NMR: 12.78 (s, NH); 8.48 – 8.51 (m, 2 H); 7.99 – 8.02 (m, 2 H); 7.61 –
7.63 (m, 3 H); 7.51 – 7.53 (m, 3 H); 5.08 (NH2). 13C-NMR: 161.1; 160.0; 156.0; 147.7; 137.7; 137.3; 130.5;
130.4; 129.1; 128.8; 128.5; 128.0; 100.7. EI-MS: 286 (100), 258 (4), 167 (7), 155 (6), 149 (19), 128 (13), 104
(12), 77 (16), 58 (10), 43 (4), 41 (3). Anal. calc. for C17H13N5 (287.32): C 71.06, H 4.56, N 24.37; found: C
70.92, H 4.61, N 24.45.
4-(4-Chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5b). Yield: 304 mg (95%).
Pale-yellow powder. M.p. 2678. IR: 3449, 3325, 3307. 1H-NMR: 12.82 (s, NH); 8.48 – 8.49 (m, 2 H);
8.05 (d, J ¼ 8.3, 2 H); 7.67 (d, J ¼ 8.3, 2 H); 7.51 – 7.53 (m, 3 H); 5.19 (NH2). 13C-NMR: 159.9; 159.8;
156.1; 147.8; 137.6; 136.0; 135.3; 131.2; 130.6; 128.8; 128.6; 128.1; 100.7. EI-MS: 321 (54), 258 (4), 167
(30), 149 (72), 145 (14), 136 (13), 135 (100), 117 (22), 113 (13), 111 (17), 105 (85), 97 (26), 77 (44), 71
(33), 69 (31), 57 (48), 55 (38), 43 (39), 41 (25). Anal. calc. for C17H12ClN5 (321.76): C 63.46, H 3.76, N
21.77; found: C 63.58, H 3.75, N 21.65.
4-(2-Chlorophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5d). Yield: 314 mg (98%).
Pale-yellow powder. M.p. 2128. IR: 3445, 3328, 3310. 1H-NMR: 12.79 (s, NH); 8.42 – 8.49 (m, 2 H);
7.50 – 7.67 (m, 7 H); 4.79 (NH2). 13C-NMR: 160.3; 159.2; 155.3; 147.6; 137.5; 135.5; 131.2; 130.7; 130.6;
130.0; 129.1; 128.7; 128.5; 128.1; 127.5; 102.2. EI-MS: 321 (100), 320 (39), 287 (37), 286 (61), 276 (12), 139
(29), 128 (14), 127 (19), 126 (16), 104 (30), 103 (13), 77 (37), 76 (17), 55 (14), 51 (16), 43 (15). Anal.
calc. for C17H12ClN5 (321.76): C 63.46, H 3.76, N 21.77; found: C 63.43, H 3.72, N 21.75.
4-(4-Methylphenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5e). Yield: 291 mg (97%).
1
White powder. M.p. 2158. IR: 3433, 3320, 3303. H-NMR: 12.75 (s, NH); 8.49 (d, J ¼ 7.6, 2 H ) ; 7.51 –
7.52 (m, 3 H); 7.42 (d, J ¼ 7.7, 2 H); 5.08 (s, NH2); 2.42 (s, 3 H). 13C-NMR: 161.1; 160.0; 156.1; 147.7;
140.2; 137.7; 134.5; 130.4; 129.3; 129.1; 128.5; 128.0; 100.6; 21.0. EI-MS: 301 (100), 287 (20), 221 (11), 199
(20), 139 (35), 104 (63), 97 (20), 83 (42), 77 (53), 76 (32), 71 (12), 69 (22), 55 (48), 43 (52), 41 (15).
Anal. calc. for C18H15N5 (301.35): C 71.74, H 5.02, N 23.24; found: C 71.98, H 5.13, N 22.90.
4-(3-Aminophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5g). Yield: 271 mg (90%).
1
Pale-yellow powder. M.p. 311.58. IR: 3430, 3416, 3341. H-NMR: 12.00 (s, NH); 8.47 – 8.50 (m, 2 H);
7.50 – 7.52 (m, 3 H); 7.23 – 7.28 (m, 1 H); 7.13 (s, 1 H); 7.01 (d, J ¼ 7.5, 1 H); 6.78 (d, J ¼ 7.4, 1 H); 5.42 (s,
NH2); 5.09 (NH2). 13C-NMR: 162.1; 160.0; 155.8; 149.2; 147.6; 138.0; 137.7; 130.4; 129.3; 128.5; 128.0;
116.1; 115.7; 113.7;100.4. EI-MS: 302 (100), 301 (64), 288 (15), 287 (69), 286 (17), 272 (25), 184 (15), 183
(17), 142 (18), 104 (24), 103 (14), 77 (25), 43 (18). Anal. calc. for C17H14N6 (302.33): C 67.54, H 4.67, N
27.80; found: C 67.47, H 4.56, N 28.18.
4-(4-Aminophenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5h). Yield: 265 mg (88%).
Yellow powder. M.p. 223 – 2298. IR: 3432, 3416, 3338. 1H-NMR: 12.58 (s, NH); 8.47 – 8.50 (m, 2 H);
7.83 (d, J ¼ 8.4, 2 H); 7.49 – 7.51 (m, 3 H); 6.74 (d, J ¼ 8.4, 2 H); 5.78 (s, NH2); 5.07 (NH2). 13C-NMR:
161.3; 159.6; 156.3; 151.5; 147.8; 138.1; 130.8; 130.2; 128.4; 127.9; 124.1; 113.4; 99.6. EI-MS: 302 (87), 301
(100), 210 (14), 143 (23), 142 (24), 104 (38), 103 (17), 77 (26), 76 (13), 65 (14), 51 (7), 43 (5). Anal. calc.
for C17H14N6 (302.33): C 67.54, H 4.67, N 27.80; found: C 67.61, H 4.66, N 27.72.
4-(4-Methoxyphenyl)-6-phenyl-1H-pyrazolo[3,4-d]pyrimidin-3-amine (5j). Yield: 301 mg (95%).
White powder. M.p. 2138. [14]: 2118. IR: 3432, 3414, 3300. 1H-NMR: 8.47 – 8.49 (m, 2 H); 8.36 – 8.39 (s,
NH); 8.01 (d, J ¼ 8.5, 2 H); 7.49 – 7.51 (m, 3 H); 7.15 (d, J ¼ 8.5, 2 H); 5.11 (s, NH2); 3.85 (s, 3 H).
13C-NMR: 161.2; 160.7; 159.9; 156.1; 147.8; 137.8; 137.8; 131.0; 130.4; 129.6; 128.5; 128.0; 114.2; 100.3;
55.3. EI-MS: 317 (79), 316 (60), 302 (38), 301 (20), 221 (17), 199 (26), 157 (14), 139 (22), 123 (14), 114
(33), 104 (83), 103 (30), 102 (20), 97 (25), 91 (20), 85 (20), 83 (33), 81 (20), 77 (70), 76 (36), 71 (28), 69
(51), 67 (27), 57 (51), 55 (68), 51 (27), 43 (100), 41 (49). Anal. calc. for C18H15N5O (317.34): C 68.13, H
4.76, N 22.07; found: C 68.41, H 4.66, N 22.11.
General Procedure for the Synthesis of 4m and 4n. To a soln. of 4-amino-6-(4-chlorophenyl)-2-
(methylsulfanyl)pyrimidine-5-carbonitrile (1 mmol) in 5 ml of acetone was added Oxone (3 mmol) in
15 ml of H2O at r.t., and the mixture was stirred overnight. After completion of the reaction, the solvent
was evaporated, and the precipitates were dissolved in 5 ml of 1,4-dioxane, and piperazine or piperidine
(2 mmol) was added to the mixture, which was stirred overnight. After completion (monitored by TLC
(AcOEt/MeOH 10 :1)), solvent was evaporated, and the solid residues were washed with H2O and
separated by filtration to obtain 4m and 4n as pale-yellow solids.

Helvetica Chimica Acta – Vol. 96 (2013)
2275
4-Amino-6-(4-chlorophenyl)-2-(piperazin-1-yl)pyrimidine-5-carbonitrile (4m). Yield: 292 mg
1
(93%). Pale-yellow powder. M.p. 2078. IR: 3491, 3358, 2202. H-NMR: 7.90 (d, J ¼ 8.5, 2 H); 7.84 (d,
J ¼ 8.5, 2 H); 7.08 (s, NH, NH2); 3.49 – 3.68 (m, 2 H); 2.88 – 3.01 (m, 2 H). 13C-NMR: 44.5; 45.2; 85.6;
116.3; 128.9; 136.8; 137.6; 140.0; 164.3; 165.7; 170.9. EI-MS: 314 (10), 272 (30), 258 (34), 246 (55), 229
(24), 187 (21), 111 (15), 85 (16), 75 (18), 68 (24), 56 (100). Anal. calc. for C15H15ClN6 (314.77): C 57.24, H
4.80, Cl 11.26, N 26.70; found: C 57.11, H 4.92, N 26.81.
4-Amino-6-(4-chlorophenyl)-2-(piperidin-1-yl)pyrimidine-5-carbonitrile (4n). Yield: 303 mg (97%).
Pale-yellow powder. M.p. 183 – 1858. IR: 3491, 3347, 2202. 1H-NMR: 8.88 (s, NH2); 7.88 (d, J ¼ 8.5, 2 H);
7.80 (d, J ¼ 8.5, 2 H); 3.49 – 3.61 (m, 4 H); 1.48 – 1.59 (m, 3 H). 13C-NMR: 24.5; 25.2; 46.6; 83.4; 116.4;
128.3; 136.9; 137.4; 140.8; 164.6; 165.1; 171.2. EI-MS: 313 (100), 284 (63), 258 (25), 229 (23), 195 (11), 84
(66), 55 (21). Anal. calc. for C16H16ClN5 (313.78): C 61.24, H 5.14, N 22.32; found: C 61.35, H 5.12, N
22.48.
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Received January 28, 2013