Catalyst-free grinding method: a new avenue for synthesis of 6-amino-3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile and DFT studies on the mechanistic pathway of this category of compounds

Article abstract of DOI:10.1007/s11164-018-3701-9

A novel, efficient, one-pot, catalyst-free grinding procedure for synthesis of 6-amino-3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile is reported. The condensation of substituted?benzaldehydes, 3-amino-5-methylpyrazole, and malononitrile accord

Full text of DOI:10.1007/s11164-018-3701-9

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-018-3701-9
Catalyst‑free grinding method: a new avenue for synthesis
of 6‑amino‑3‑methyl‑4‑aryl‑1H‑pyrazolo[3,4‑b]
pyridine‑5‑carbonitrile and DFT studies on the mechanistic
pathway of this category of compounds
Mohammad Nikpassand1 · Leila Zare Fekri2 · Parissa Naddaf Rahro1
Received: 7 August 2018 / Accepted: 5 December 2018
© Springer Nature B.V. 2019
Abstract
A novel, efcient, one-pot, catalyst-free grinding procedure for synthesis of
6-amino-3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile is reported.
The condensation of substituted benzaldehydes, 3-amino-5-methylpyrazole, and
malononitrile according to a three-component reaction was investigated using den-
sity functional theory (DFT) at B3LYP/6-311G level to explore the reaction mecha-
nism. All the routes were studied, the structure of the intermediates was optimized,
and all the respective transition states were found. The results of the calculations
show that the proposed mechanism relies on four intermediates.
Keywords Grinding reaction · DFT · Mechanism · Intermediate · Transition state
Introduction
In recent years, pyrazolopyridines have attracted considerable attention owing to
their high bioactivity [1–3]; For example, they are used as antagonists of angioten-
sin II and dopamine D3 receptor [4], inhibitors of cyclin-dependent kinase (CDK)
[5], antileishmanial drugs [6], adenosine receptors [7], anxiolytic, antiherpetic and
antitumor agents [8, 9], and antimicrobial and potent antitumor agents [10, 11]. The
original procedure for preparation of this type of compounds involves one-pot con-
densation of benzaldehyde (R1), malononitrile (R2), and 3-amino-5-methylpyrazole
(R3) [12] (Scheme 1).
Computational chemistry is an important feld that studies the properties of
compounds, their reactions, and the optimization of existing chemical methods
*
Mohammad Nikpassand
Nikpassand@iaurasht.ac.ir
1
2
Department of Chemistry, Rasht Branch, Islamic Azad University, Rasht, Iran
Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
Vol.:(0123456789)
1 3

M. Nikpassand et al.
X
X
CHO
H3C
N
H3C
N
H3C
+
CN
CN
Grinding
NH2
CN
CN
NOT
+
N
N
N
N
H
NH2
N
NH2
X
N
P
H
H
H
R1
R2
BP
R3
Scheme 1 Synthesis of some pyrazolo[3,4-b]pyridines
using advanced and specialized software. One important area of such study is to
analyze proposed mechanisms, which can be done using theoretical methods.
Multicomponent reactions (MCRs) represent one of the most efcient routes in
synthetic organic chemistry, ofering advantages such as simplicity, high speed,
easy implementation, and high atom efciency. They ofer a model for diversity-
oriented synthesis [13–17].
Experimental
Chemicals were purchased from Merck and Fluka. All solvents used were dried
and distilled according to standard procedures. Thin-layer chromatography (TLC)
was carried out on TLC silica gel 60 aluminum sheet from Merck. Melting points
were measured on an Electrothermal 9100 apparatus. Infrared (IR) spectra were
1
determined on a Shimadzu FT-IR 8600 spectrophotometer. H and 13C nuclear
magnetic resonance (NMR) spectra were determined on a Bruker 400 DRX
Avance instrument at 500 and 125 MHz. Elemental analyses were carried out on
a Carlo-Erba EA1110CNNO-S analyzer and agreed with the calculated values.
For the ultrasound reactions, Astra 3D ultrasound apparatus (9.5 dm3, 45 kHz
frequency, input power with heating, 305 W, number of transducers, 2) from
TECNO-GAZ was used.
General procedure for synthesis of pyrazolo[3,4‑b]pyridines 4a–o
A mixture containing benzaldehyde (1 mmol), malononitrile (1 mmol), and 5-amino-
3-methylpyrazole (1 mmol) was ground at room temperature for the required reac-
tion times. Reaction progress was monitored by TLC (EtOAc:petroleum ether 1:2).
After reaction completion, EtOH (20 mL) was added, and the mixture was fltered.
The solvent was removed under reduced pressure to aford the pure products. The
solvent was recovered by rotary evaporator. All synthesized compounds were char-
1
acterized by their physical constants, comparison with authentic samples, IR, H
NMR, and 13C NMR spectroscopy, and elemental analysis.
1 3

Catalyst-free grinding method: a new avenue for synthesis…
6‑Amino‑3‑methyl‑4‑(4‑nitrophenyl)‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4a)
Of-white solid, m.p. 309–311 °C, FT-IR (KBr, cm−1) νmax 3414, 3312, 2206, 1639,
1603, 1565, 1343, 1261 cm−1. 1H NMR (500 MHz, DMSO): δH; 2.47 (s, 3H), 7.56
(d, J=7.8 Hz, 2H), 7.81 (d, J=7.8 Hz, 2H), 8.52 (s, 1H) ppm. 13C NMR (125 MHz,
DMSO): δC; 31.6, 108.4, 119.3, 121.4, 129.5, 133.0, 141.3, 145.0, 149.3, 152.2,
154.8, 159.3 ppm. Anal. Calc. for C14H10N6O2: C, 57.14; H, 3.43; N, 28.56. Found:
C, 57.16; H, 3.41; N, 28.59.
6‑Amino‑3‑methyl‑4‑(3‑nitrophenyl)‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4b)
Of-white solid, m.p. 287–289 °C, FT-IR (KBr, cm−1) νmax 3372, 3305, 3232, 3094,
2917, 2180, 1603, 1505, 1354 cm−1. 1H NMR (500 MHz, DMSO): δH; 2.45 (s, 3H),
7.44 (t, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 8.02 (dd, J=8.2 Hz, 2.4 Hz, 1H),
8.10 (t, J=2.6 Hz, 1H), 8.54 (s, 1H) ppm. 13C NMR (125 MHz, DMSO): δC; 31.8,
109.5, 118.5, 120.4, 127.4, 129.6, 131.9, 133.4, 140.7, 143.6, 148.0, 151.3, 154.5,
159.7 ppm. Anal. Calc. for C14H10N6O2: C, 57.14; H, 3.43; N, 28.56. Found: C,
57.15; H, 3.45; N, 28.53.
6‑Amino‑3‑methyl‑4‑(2‑nitrophenyl)‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4c)
Brown solid, m.p. 288–290 °C, FT-IR (KBr, cm−1) νmax 3406, 3125, 2931, 2183,
1
1626, 1580, 1482, 1437 cm−1. H NMR (500 MHz, DMSO): δH; 2.49 (s, 3H),
7.41 (t, J=7.8 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.82 (t, J=8.2 Hz, 1H), 7.87 (d,
J=8.2 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO): δC; 31.5, 108.3, 117.7, 119.8,
126.7, 128.9, 131.3, 133.2, 140.4, 142.0, 147.2, 150.6, 153.3, 157.9 ppm. Anal.
Calc. for C14H10N6O2: C, 57.14; H, 3.43; N, 28.56. Found: C, 57.17; H, 3.45; N,
28.53.
6‑Amino‑4‑(4‑chlorophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4d)
Of-white solid, m.p. 266–268 °C, FT-IR (KBr, cm−1) νmax 3441, 3309, 3211, 3172,
2947, 1587, 1554, 1092 cm−1. 1H NMR (500 MHz, DMSO): δH; 2.46 (s, 3H), 7.58
(d, J=8.2 Hz, 2H), 7.83 (d, J=8.6 Hz, 2H), 8.84 (s, 2H) ppm. 13C NMR (125 MHz,
DMSO): δC; 33.1, 109.3, 118.5, 120.7, 127.8, 133.5, 141.4, 145.6, 148.6, 151.5,
154.5, 159.4 ppm. Anal. Calc. for C14H10ClN5: C, 59.27; H, 3.55; N, 24.68. Found:
C, 59.25; H, 3.53; N, 24.70.
6‑Amino‑4‑(3‑chlorophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4e)
White solid, m.p. 261–263 °C, FT-IR (KBr, cm−1) νmax 3405, 3294, 3223, 3150,
1
2951, 1589, 1548, 1085 cm−1. H NMR (500 MHz, DMSO): δH; 2.39 (s, 3H),
7.46 (t, J=7.6 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H), 8.04 (dd, J=8.2 Hz, 2.4 Hz, 1H),
8.13 (t, J=2.4 Hz, 1H), 8.51 (s, 1H) ppm. 13C NMR (125 MHz, DMSO): δC; 31.2,
1 3

M. Nikpassand et al.
109.8, 118.3, 120.8, 126.5, 129.0, 131.2, 133.4, 139.3, 143.2, 147.3, 151.6, 153.8,
158.2 ppm.. Anal. Calc. for C14H10ClN5: C, 59.27; H, 3.55; N, 24.68. Found: C,
59.30; H, 3.57; N, 24.65.
6‑Amino‑4‑(2‑chlorophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4f)
White solid, m.p. 256–258 °C, FT-IR (KBr, cm−1) νmax 3306, 32824, 3209, 3138,
1
2957, 1586, 1538, 1082 cm−1. H NMR (500 MHz, DMSO): δH; 2.53 (s, 3H),
7.45 (t, J=7.6 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.84 (t, J=8.4 Hz, 1H), 7.89 (d,
J=8.4 Hz, 1H) ppm. 13C NMR (125 MHz, DMSO): δC; 33.4, 108.7, 117.2, 119.5,
126.9, 129.5, 131.6, 133.5, 140.7, 142.4, 147.3, 150.8, 153.5, 158.3 ppm. Anal.
Calc. for C14H10ClN5: C, 59.27; H, 3.55; N, 24.68. Found: C, 59.26; H, 3.53; N,
24.66.
6‑Amino‑4‑(4‑bromophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4g)
Of-white solid, m.p. 274–276 °C, FT-IR (KBr, cm−1) νmax 3614, 3108, 2904, 1605,
1
1574, 1466, 1114 cm−1. H NMR (500 MHz, DMSO): δH; 2.48 (s, 3H), 8.07 (d,
J=7.8 Hz, 2H), 8.39 (d, J=7.8 Hz, 2H), 8.74 (s, 2H) ppm. 13C NMR (125 MHz,
DMSO): δC; 33.6, 110.7, 118.9, 121.0, 126.9, 133.8, 141.6, 145.3, 147.8, 150.2,
154.2, 157.3 ppm. Anal. Calc. for C14H10BrN5: C, 51.24; H, 3.07; N, 21.34. Found:
C, 51.22; H, 3.09; N, 21.31.
6‑Amino‑4‑(3‑bromophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4h)
Of-white solid, m.p. 268–270 °C, FT-IR (KBr, cm−1) νmax 3532, 3246, 2932, 1611,
1
1571, 1462, 1109 cm−1. H NMR (500 MHz, DMSO): δH; 2.49 (s, 3H), 7.43–7.62
(m, 2H), 7.92 (dd, J=7.8 Hz, 2.2 Hz, 1H), 8.12 (t, J=2.2 Hz, 1H), 8.39 (s, 1H) ppm.
13C NMR (125 MHz, DMSO): δC; 32.6, 110.1, 118.2, 120.5, 127.6, 129.7, 131.3,
133.0, 139.4, 142.4, 148.4, 150.5, 154.1, 158.2 ppm. Anal. Calc. for C14H10BrN5: C,
51.24; H, 3.07; N, 21.34. Found: C, 51.23; H, 3.10; N, 21.36.
6‑Amino‑4‑(4‑iodophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4i)
Yellow solid, m.p. 283–285 °C, FT-IR (KBr, cm−1) νmax 3418, 3120, 2918, 1631,
1
1583, 1472, 786 cm−1. H NMR (500 MHz, DMSO): δH; 2.38 (s, 3H), 8.11 (d,
J=7.6 Hz, 2H), 8.41 (d, J=7.6 Hz, 2H), 8.69 (s, 1H) ppm. 13C NMR (125 MHz,
DMSO): δC; 33.8, 111.4, 119.4, 120.5, 127.0, 133.5, 140.7, 145.9, 145.8, 150.9,
154.4, 158.9 ppm. Anal. Calc. for C18H18IN5: C, 50.13; H, 4.21; N, 16.24. Found: C,
50.10; H, 4.18; N, 16.26.
1 3

Catalyst-free grinding method: a new avenue for synthesis…
6‑Amino‑4‑(4‑fuorophenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4j)
White solid, m.p. 261–263 °C, FT-IR (KBr, cm−1) νmax 3371, 3126, 2971, 1617,
1
1564, 1432, 848 cm−1. H NMR (500 MHz, DMSO): δH; 2.47 (s, 3H), 7.96 (d,
J=7.8, 5.3 Hz, 2H), 8.23 (dd, J=19.2, 7.8 Hz, 2H), 8.76 (s, 2H) ppm. 13C NMR
(125 MHz, DMSO): δC; 33.0, 109.3, 118.5, 120.4, 125.3, 133.1, 142.4, 144.7, 148.9,
150.0, 154.5, 158.4 ppm. Anal. Calc. for C18H18FN5: C, 66.86; H, 5.61; N, 21.66.
Found: C, 66.84; H, 5.58; N, 21.69.
6‑Amino‑3‑methyl‑4‑phenyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4k)
White solid, m.p. 275–277 °C, FT-IR (KBr, cm−1) νmax 3463, 3161, 2983, 1627,
1
1559, 1446 cm−1. H NMR (500 MHz, DMSO): δH; 2.48 (s, 3H), 8.01–8.09 (m,
2H), 8.39 (m, 2H), 8.46–8.72 (s, 3H) ppm. 13C NMR (125 MHz, DMSO): δC; 33.8,
109.7, 119.6, 121.6, 125.5, 133.3, 142.0, 144.9, 148.0, 149.7, 154.3, 158.5 ppm.
Anal. Calc. for C14H11N5: C, 67.46; H, 4.45; N, 28.10. Found: C, C, 67.48; H, 4.43;
N, 28.07.
6‑Amino‑3‑methyl‑4‑p‑tolyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile (4l)
White solid, m.p. 272–274 °C, FT-IR (KBr, cm−1) νmax 3543, 3194, 2940, 1638,
1
1549, 1460, 1182 cm−1. H NMR (500 MHz, DMSO): δH; 2.43 (s, 3H), 2.58 (s,
3H), 7.63 (d, J=7.8 Hz, 2H), 8.04 (d, J=7.8 Hz, 2H), 8.77 (s, 2H) ppm. 13C NMR
(125 MHz, DMSO): δC; 33.8, 42.6, 109.5, 119.4, 120.6, 125.4, 133.9, 142.7, 145.4,
148.4, 149.0, 154.5, 157.4 ppm. Anal. Calc. for C15H13N5: C, 68.42; H, 4.98; N,
26.60. Found: C, 68.40; H, 4.96; N, 26.63.
6‑Amino‑4‑(4‑ethylphenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4m)
White solid, m.p. 271–273 °C, FT-IR (KBr, cm−1) νmax 3482, 3164, 2971, 1640,
1562, 1467, 1148 cm−1. 1H NMR (500 MHz, DMSO): δH; 1.04 (s, br, 3H), 2.48 (s,
3H), 2.64 (s, br, 2H), 7.83 (d, J=7.6 Hz, 2H), 8.19 (d, J=7.6 Hz, 2H), 8.48 (s, 2H)
ppm. 13C NMR (125 MHz, DMSO): δC; 19.8, 33.8, 46.5, 109.5, 118.5, 121.7, 125.9,
132.6, 141.6, 145.0, 147.6, 148.6 154.6, 159.3 ppm. Anal. Calc. for C16H15N5: C,
69.29; H, 5.45; N, 25.25. Found: C, 69.31; H, 5.43; N, 25.22.
6‑Amino‑4‑(4‑methoxyphenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4n)
White solid, m.p. 279–281 °C, FT-IR (KBr, cm−1) νmax 3548, 3121, 2904, 1624,
1
1548, 1460, 1238 cm−1. H NMR (500 MHz, DMSO): δH; 2.43 (s, 3H), 3.57 (s,
3H), 7.85 (d, J=7.8 Hz, 2H), 8.05 (d, J=7.8 Hz, 2H), 8.82 (s, 2H) ppm. 13C NMR
(125 MHz, DMSO): δC; 33.8, 60.7, 109.4, 118.9, 121.8, 125.7, 131.9, 141.7, 143.6,
147.8, 149.9, 153.6, 159.2 ppm. Anal. Calc. for C15H13N5O: C, 64.51; H, 4.69; N,
25.07. Found: C, 64.48; H, 4.72; N, 25.09.
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M. Nikpassand et al.
6‑Amino‑4‑(3‑methoxyphenyl)‑3‑methyl‑1H‑pyrazolo[3,4‑b]pyridine‑5‑carbonitrile
(4o)
White solid, m.p. 271–273 °C, FT-IR (KBr, cm−1) νmax 3424, 3184, 2962, 1617,
1573, 1464, 1262 cm−1. 1H NMR (500 MHz, DMSO): δH; 2.48 (s, 3H), 3.61 (s, 3H),
7.41–7.60 (m, 2H), 7.83 (dd, J=7.6 Hz, 2.4 Hz, 1H), 8.09 (t, J=2.4 Hz, 1H), 8.41 (s,
2H) ppm. 13C NMR (125 MHz, DMSO): δC; 34.3, 63.4, 110.4, 118.5, 121.5, 125.6,
129.6, 131.7, 133.8, 138.7, 142.6, 150.6, 151.6, 154.7, 158.8 ppm. Anal. Calc. for
C15H13N5O: C, 64.51; H, 4.69; N, 25.07. Found: C, 64.53; H, 4.66; N, 25.05.
Results and discussion
In continuation of our studies on synthesis of heterocyclic and pharmaceutical com-
pounds using mild and practical protocols and theoretical study of heterocyclic
compounds [18–24], we report herein experimental results on synthesis of 6-amino-
3-methyl-4-aryl-1H-pyrazolo[3,4-b]pyridine-5-carbonitriles, using various benzal-
dehydes, 3-amino-5-methylpyrazole, and malononitrile under grinding at room tem-
perature (Scheme 1).
Table 1 compares the efciency of the grinding method with some available
methods previously reported for synthesis of pyrazolo[3,4-b]pyridines. It is clear
from Table 1 that our method is more efcient, less time consuming, and simpler for
synthesis of pyrazolo[3,4-b]pyridine derivatives (Table 1; entry 11).
On the other hand, solvent-free grinding is more efcient than use of classical
Lewis acids such as ZnCl2, K10, and nano-Fe3O4 or ionic liquids.
To expand the scope of the efcient grinding reaction, we synthesized alde-
hydes with various substituents in this reaction condition (Table 2). According to
Table 1 Efciency of grinding compared with other methods for synthesis of 4a
Entry Catalysta
Catalyst amountb Condition
Time (min) Yield (%)c
1
2
3
4
5
6
7
8
–
–
–
–
Refux [11]
Ultrasound irradiation, 60 °C [11]
Refux
Refux
Refux
Refux
Refux
Refux
Heat, 80 °C
Heat, 80 °C
Grinding, r.t.
Grinding, ice chamber
360
10
50
85
80
72
70
73
68
80
80
70
95
0
l-Proline
I2
ZnCl2
Nano-Fe3O4 0.2 g
K10 0.2 g
RuCl3·5H2O 0.2 g
[bmim]Br 2 mL
[bmim]BF4 0.2 g
1 mmol
1 mmol
1 mmol
120
300
240
240
300
360
240
240
5
9
10
11d
12e
–
–
–
–
60
b
a10 mL EtOH was used as solvent in all reactions expect entries 1–8; Catalyst amount per 1 mmol of
c
d
e
aldehyde; Isolated yield based on starting aldehyde; solvent-free condition; grinding with a cold ice-
chamber condition
1 3

Catalyst-free grinding method: a new avenue for synthesis…
Table 2, the rate of reaction and reaction time were improved for aldehydes with
electron-withdrawing rather than electron-donating groups, although considerable
yield improvement was not observed. It was found that the grinding procedure in
this case can increase the reaction rate and thereby reduce energy consumption.
All the synthesized compounds in Table 2 were characterized by spectroscopic
methods (IR, 1H NMR, and 13C NMR) and elemental analysis.
Calculation method
The main purpose of this research is to carry out density functional theory (DFT) cal-
culations at B3LYP level of the reactants, intermediates, transition states, and products
in this reaction. First, all reactants, intermediates, and products were optimized using
Gaussian 2009 software, and the total energy (Hartrees/particles) of the target com-
pounds was evaluated. Calculations to characterize the obtained structures as minima
or transition states on the TS (QST2) were carried out (Table 3).
Method of analysis
All theoretical calculations were performed using Gaussian 09 W program pack-
age [25] without any constraint on the geometry. All possible structures of reac-
tants, intermediates, and products were fully optimized at B3LYP level using the
6-311G** basis set.
Table 2 Grinding synthesis of
Entry
Product
X
Time (min)
pyrazolo[3,4-b]pyridines 4a–o
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4-NO2
3-NO2
2-NO2
4-Cl
3-Cl
2-Cl
4-Br
3-Br
4-I
4-F
5
5
7
5
8
8
5
5
5
5
8
8
10
8
95
90
90
94
92
88
95
90
94
93
90
88
89
88
92
9
10
11
12
13
14
15
H
4-CH3
4-C2H5
4-OCH3
3-OCH3
5
aAll products were characterized by their physical constant, IR,
NMR, and elemental analyses; bIsolated yield based on starting alde-
hyde
1 3

M. Nikpassand et al.
Table 3 Relative energy
(kJ/mol) of various species
involved in synthesis of some
pyrazolo[3,4-b]pyridines
Entry
Species
ΔE
1
2
R1+R2+R3
TS1+R3
0.00
380.615027794
3
4
IM1+R3
TS2+R3
− 57.901724174
15.235899899
5
6
7
8
IM2+R3+H2O
TS3+H2O
IM3+H2O
TS4+H2O
IM4+H2O
TS5+H2O
PP+H2O
P+H2+H2O
TS6+R2
IM5+R2
TS7
TS8+R2
IM6+R2
TS9+R2
IM7+R2+H2O
TS10+H2O
BP+H2O
9.863167016
1912.734241624
1897.017279237
12,010.572955308
1894.60092315405
11,592.1513261277
− 38.49192331065
− 6385.2770442652
25,694.134401928
− 2,329,718.30634687
19,785.6522994665
16,681.860167678
413.6457291585
17,257.731561578
− 182,811.809840122
− 885.5510318
9
10
11
12
13
14
15
16
17
18
19
20
21
− 885.5570318
Quantum-chemistry methods are widely used for elucidating the mechanisms
[26–29] of chemical reactions. The mechanism of the one-pot reaction for synthesis
of some pyrazolo[3,4-b]pyridines was investigated using the DFT method here.
The progress of the reaction can be divided into three routes. The frst route for
synthesis of these pyrazolo[3,4-b]pyridines consists of fve steps. Structures of four
intermediates were optimized, and fve transition states were found. The imaginary
total energy (Hartrees/particles) of the fve transition states are − 570.38, − 570.52,
− 814.77, − 814.78, and − 815.52, respectively. The frst step in this condensation is
the reaction of R1 with R2 to produce IM1 via transition state TS1. A four-member
ring is formed in TS1. Next, IM1 is expected to undergo rapid dehydration to α,β-
unsaturated compound IM2. This step can be regarded as Michael addition of R3
to IM3. Then, IM3 converts to IM4 by intramolecular nucleophilic attack of amino
group to nitryl group. This step is followed by tautomerization in intermediate IM4,
producing compound PP. Finally, PP is changed to the fnal product P via a dehydra-
tion reaction (Scheme 2).
In the second pathway, there are three intermediates and four transition states
for synthesis of these pyrazolo[3,4-b]pyridines. The imaginary total energy (Har-
trees/particles) values of the four transition states are − 658.5 (TS6), − 844.4
(TS7), − 814.78 (TS4), and − 815.52 (TS5), respectively. The frst step in this
condensation is reaction of R1 with R3 to produce IM5 via TS6 as a four-member
ring transition state. Next, IM5 and R2 undergo a dehydration reaction via TS7.
1 3

Catalyst-free grinding method: a new avenue for synthesis…
H
O
OH
H
O
CN
CN
H
CN
Ph
Ph
R1
+ R2
- H2O
Ph
IM1
TS2
TS1
CN
CN
CN
Ph
CN
Ph
H3C
CN
CN
H3C
Ph
H
CN
R3
N
CN
CN
NH2
IM3
NH2
N
IM2
N
TS3
H
N
H
Ph
Ph
H3C
H3C
Ph
H3C
N
CN
CN
NH
CN
H
N
N
N
H
N
N
NH
HN
TS4
N
H
N
H
N
H
H
H
IM4
TS5
Ph
H3C
N
CN
- H2
P
NH2
N
N
H
H
PP
Scheme 2 First route for synthesis of pyrazolo[3,4-b]pyridine 4k
The other steps are in accordance with the mechanism in the frst route as shown
in Scheme 3.
The third route consists of three steps (Scheme 4). The structures of the two inter-
mediates were optimized, and three transition states were found. The total energy
(Hartrees/particles) values of the transition states are − 662.02, − 661.81, and
− 809.56, respectively. The frst step in this condensation is reaction of R1 with
R3 to produce IM7 via transition state TS8. Next, IM7 is expected to undergo rapid
dehydration to compound IM8. This step can be regarded as nucleophilic addition of
R2 to IM8. Finally, BP is produced as a byproduct in this proposed route.
The frst route is the best proposed mechanistic pathway because the transition
states in this mechanism have the lowest energy level. The rate-determining step is
the third step of this route, including TS3 (Fig. 1).
Some studies have related the highest occupied molecular orbital (HOMO)–low-
est unoccupied molecular orbital (LUMO) gap to the stability of a structure. How-
ever, the HOMO and LUMO values are completely dependent on the chemical
1 3

M. Nikpassand et al.
Ph
Ph
H
3C
H
3C
H
O
O
+
R1
R
3
H
N
N
NH2
NH2
N
H
N
H
IM5
T
S6
H
Ph
O
H
CN
H
3C
-
H
2O
R2
T 4
S
IM
3
CN
N
NH2
N
H
T 7
S
-
H2
P
PP
IM4
T 5
S
Scheme 3 Second route for synthesis of pyrazolo[3,4-b]pyridine 4k
H
3C
H
3C
N
N
NH
+
R1
R
3
N
H
NH
N
H
H
Ph
T
IM7
S8
Ph
O
H
O
H
3C
H
3C
R2
N
N
N
-
H
2O
N
N
N
H
H
H
IM
8
T
S9
Ph
Ph
O
H
3C
H
3C
H
N
N
NH
N
N
N
H
H
H
Ph
Ph
NC
T 1
S 0
BP
NC
CN
CN
Scheme 4 A route for synthesis of byproduct
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Catalyst-free grinding method: a new avenue for synthesis…
structure of the compound. The HOMO and LUMO values were thus determined by
DFT calculations, then the HOMO–LUMO gaps of all the intermediates were also
considered. The results indicated that the HOMO–LUMO gap of IM1 was maxi-
mum, revealing that IM1 is the most stable form among the intermediates. These
results confrm that the frst route for synthesis of pyrazolo[3,4-b]pyridine 4k in
Scheme 2 is correct (Fig. 2).
Conclusions
This is the frst report of synthesis of pyrazolo[3,4-b]pyridines by multicomponent
reaction between benzaldehydes, 3-amino-5-methylpyrazole, and malononitrile
under grinding at room temperature as a green and low-cost method with high yield
in very short time.
According to the calculated mechanisms, the reaction starts with Knoevenagel
condensation between the benzaldehyde and malononitrile, followed by rapid C–C
bond formation. Next, a synthesized α,β-unsaturated compound is produced by
rapid dehydration. Then, Michael addition of 3-amino-5-methylpyrazole with inter-
mediate, as the rate-limiting step, occurs. The fnal product is then produced by
25694.1
12010.57
19785.6
TS7
TS6+R2
TS4+H2O
11592.15
TS5+H2O
TS9+R2
17257.7
1912.73
TS3+H2O
1897.02
16681.9
TS8+R2
1894.60
IM4+H2O
IM3+H2O
380.62
TS1+R3
15.24
TS2+R3
-38.49
PP+H2O
0.00
R1+R2+R4
9.86
IM2+R3+H2O
-57.90
IM1+R3
-885.55
TS10+H2O
-885.56
BP+H2O
-182735.4
IM7+R2
-6385.28
-203754.2
P+H2+H2O
IM8+R2+H2O
-2321718.3
IM5+R2
Fig. 1 Relative energy diagram for various routes for synthesis of pyrazolo[3,4-b]pyridine 4k and related
byproduct
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M. Nikpassand et al.
Fig. 2 HOMO–LUMO gap of intermediates
intramolecular nucleophilic attack of amino group to nitryl group, tautomerization
in the related intermediate, and a dehydration reaction.
Acknowledgements Financial support from the Research Council of Islamic Azad University, Rasht
Branch is sincerely acknowledged.
References
1. A.M. Li, Y. Ouyang, Z.Y. Wang, Y.Y. Cao, X.Y. Liu, L. Ran, C. Li, L. Li, L. Zhang, K. Qiao, J.
Med. Chem. 56, 3593 (2013)
2. A.H. Shamroukh, A.E. Rashad, H.H. Sayed, J. Phosphorus Sulfur Silicon Rel. Elem. 180, 2347
(2005)
3. L. Commeiras, S.C. Woodcock, J.E. Baldwin, R.M. Adlington, A.R. Cowley, P. Wilkinson, Tetrahe-
dron 60, 933 (2004)
4. A. Cappelli, C. Nannicini, A. Gallelli, G. Giuliani, S. Valenti, G.P. Mohr, M. Anzini, L. Mennuni,
F. Ferrari, G. Caselli, A. Giordani, W. Pereis, F. Makovec, G. Giorgi, S. Vomero, J. Med. Chem. 51,
2137 (2008)
5. R. Lin, P.J. Connolly, Y. Lu, G. Chin, S. Li, Y. Yu, S. Huang, X. Li, S.L. Emanuel, S.A. Middleton,
R.H. Gruninger, M. Adams, A.R. Fuentes-Pesquera, L.M. Greenberger, J. Bioorg. Med. Chem. Lett.
17, 4557 (2007)
6. H. de Mello, A. Echevarria, A.M. Bernardino, M. CantoCavalheiro, L.L. Leon, J. Med. Chem. 47,
5427 (2004)
7. F. Manetti, S. Schenone, F. Bondavalli, C. Brullo, O. Bruno, A. Ranise, L. Mosti, G. Menozzi, P.
Fossa, M.L. Trincavelli, C. Martini, A. Martinelli, C. Tintori, M. Botta, J. Med. Chem. 48, 7172
(2005)
8. B.A. Johns, K.S. Gudmundsson, E.M. Turner, S.H. Allen, V.A. Samano, J.A. Ray, G.A. Freeman,
F.L. Boyd, C.J. Sexton, D.W. Selleseth, K.L. Creech, K.R. Moniri, J. Bioorg. Med. Chem. 13, 2397
(2005)
9. K.S. Gudmundsson, B.A. Johns, Z. Wang, E.M. Turner, S.H. Allen, G.A. Freeman, F.L.B. Jr, C.J.
Sexton, D.W. Selleseth, K.R. Monirib, K.L. Creech, J. Bioorg. Med. Chem. 13, 5346 (2005)
10. F.E. Goda, A.A.M. Abdel-Aziz, O.A. Attef, J. Bioorg. Med. Chem. Lett. 12, 1845 (2004)
11. N.M. Parekh, K.C. Maheria, J. Res. Chem. Intermed. 38, 885 (2012)
12. L. Zare, N.O. Mahmoodi, A. Yahyazadeh, M. Mamaghani, Syn. Commun. 41, 2323 (2011)
13. P.A. Wender, J. Nat. Prod. Rep. 31, 433 (2014)
1 3

Catalyst-free grinding method: a new avenue for synthesis…
14. A.Z. Halimehjani, I.N. Namboothiri, S.E. Hooshmand, RSC Adv. 4, 48022 (2014)
15. A.Z. Halimehjani, I.N. Namboothiri, S.E. Hooshmand, RSC Adv. 4, 51794 (2014)
16. V. Estévez, M. Villacampa, J.C. Menéndez, J. Chem. Soc. Rev. 43, 4633 (2014)
17. A. Domling, W. Wang, K. Wang, J. Chem. Rev. 112, 3083 (2012)
18. M. Nikpassand, L. Zare Fekri, M. Nabatzadeh, Comb. Chem. High Throughput Screen. 20, 533
(2017)
19. L. Zare Fekri, M. Nikpassand, J. Chil. Chem. Soc. 57, 1415 (2012)
20. M. Nikpassand, L. ZareFekri, S. Sanagou, Dyes Pigm. 136, 140 (2017)
21. H. Taherkhorsand, M. Nikpassand, Comb. Chem. High Throughput Screen. 21, 65 (2018)
22. L. Zare Fekri, M. Nikpassand, M. Goldoost, Russ. J. Gen. Chem. 83, 2352 (2013)
23. L. Zare Fekri, M. Nikpassand, Russ. J. Gen. Chem. 83, 2395 (2013)
24. M. Nikpassand, L. Zare Fekri, K. Hematinezhad, J. Polycycl. Arom. Comp. in press (2018)
25. M.J. Frisch, et al., GAUSSIAN09, Gaussian, Inc., Revision B. 05, Pittsburgh PA (2009)
26. J.G. Ma, J.M. Zhang, H.H. Jiang, W.Y. Ma, J.H. Zhou, Chin. Chem. Lett. 19, 375 (2008)
27. S. Karmakar, A. Datta, J. Org. Chem. 82, 1558 (2017)
28. S. Karmakar, A. Datta, J. Phys. Chem. B 121, 7621 (2017)
29. K. Bhattacharyya, S. Karmakar, A. Datta, Phys. Chem. Chem. Phys. 19, 22482 (2017)
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