Synthesis, x-ray crystal structure, and computational study of novel pyrazolo[3,4-B]pyridin-3-Ol derivatives

Article abstract of DOI:10.1080/10426507.2013.844141

6-(Pyrazol-1-yl)pyrazolo[3 4-b]pyridin-3-ol (3a) was synthesized by cyclization reaction from 2,6-dichloro-4-methylnicotinonitrile. The related sulfonyl and acylated product (4-7) were obtained from the compound 3a and different sulfonyl and acyl chloride

Full text of DOI:10.1080/10426507.2013.844141

This article was downloaded by: [The Aga Khan University]
On: 10 October 2014, At: 10:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis, X-Ray Crystal Structure,
and Computational Study of Novel
Pyrazolo[3,4-B]pyridin-3-Ol Derivatives
Li-Qun Shenab, Yong Tanga, Ai-Qun Wua, Dan Pana & Kai-Sheng Diaoa
a College of Chemistry and Chemical Engineering, Guangxi University
for Nationalities, Guangxi Key Laboratory of Chemistry and
Engineering of Forest Products, Nanning 530006, China
b Department of Chemistry and Biology, Hechi University, Yizhou
546300, China
Accepted author version posted online: 25 Sep 2013.Published
online: 14 May 2014.
To cite this article: Li-Qun Shen, Yong Tang, Ai-Qun Wu, Dan Pan & Kai-Sheng Diao (2014)
Synthesis, X-Ray Crystal Structure, and Computational Study of Novel Pyrazolo[3,4-B]pyridin-3-
Ol Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 189:5, 674-686, DOI:
10.1080/10426507.2013.844141
To link to this article: http://dx.doi.org/10.1080/10426507.2013.844141
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 189:674–686, 2014
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2013.844141
SYNTHESIS, X-RAY CRYSTAL STRUCTURE,
AND COMPUTATIONAL STUDY OF NOVEL
PYRAZOLO[3,4-B]PYRIDIN-3-Ol DERIVATIVES
Li-Qun Shen,1,2 Yong Tang,1 Ai-Qun Wu,1 Dan Pan,1
and Kai-Sheng Diao1
1College of Chemistry and Chemical Engineering, Guangxi University for
Nationalities, Guangxi Key Laboratory of Chemistry and Engineering of Forest
Products, Nanning 530006, China
2Department of Chemistry and Biology, Hechi University, Yizhou 546300, China
GRAPHICAL ABSTRACT
Abstract 6-(Pyrazol-1-yl)pyrazolo[3,4-b]pyridin-3-ol (3a) was synthesized by cyclization re-
action from 2,6-dichloro-4-methylnicotinonitrile. The related sulfonyl and acylated product
(4–7) were obtained from the compound 3a and different sulfonyl and acyl chloride com-
pounds. The sulfonylation of the compound 3a afforded the O1-sulfonylation, only, to give
3-substituted products 4–6. The acylation of the compound 3a gives 1,3-diacylated products
7 via N2, O1-diacylation. All compounds were characterized by spectroscopic methods and
the molecular structures of 3a and 4–7 were determined by X-ray diffraction analysis. The
molecular structure of 5 and 7 were studied by density functional theory (DFT) calculations,
reproduced the experimental geometry. The energies of the three molecules of the tautomeric
forms of the compound 3a were calculated by DFT calculations. It was shown that the 3a
predominated in the gas phase. Besides, molecular electrostatic potential (MESP) and fron-
tier molecular orbital (FMO) analysis of the compound 3a were investigated by theoretical
calculations.
Received 7 June 2013; accepted 9 September 2013.
This work was supported by National Natural Science Foundation of China (No. 21062002), the Project
supported by the excellent talents of Education Department of Guangxi (No. 2009.26). The calculations in this
paper were done at the GHPCC of Jiangnan University, P. R. China.
Address correspondence to Kai-Sheng Diao, College of Chemistry and Chemical Engineering, Guangxi
University for Nationalities, Guangxi Key Laboratory of Chemistry and Engineering of Forest Products, Nanning
530006, China. E-mail: liqunshen@126.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/gpss.
674

SYNTHESIS, X-RAY CRYSTAL STRUCTURE, AND COMPUTATIONAL STUDY OF NOVEL 675
[Supplementary materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
files: Additional text, tables, and figures.]
Keywords Pyrazolo[3,4-b]pyridine-3-ol; synthesis; X-ray diffraction; DFT calculations
INTRODUCTION
Pyrazolo[3,4-b]pyridines are a, very important class of heterocyclic compounds
due to their biological and pharmacological properties, such as antitubercular and anx-
iolytic activities.1–3 Also, they are used as important intermediates for the synthesis of
agrochemicals and pharmaceutical compounds.4,5 Nowadays, the studies on pyrazolo[3,4-
b]pyridines heterocyclics are motivated by the search for easy and practical approaches to
a variety of pyrazolo[3,4-b]pyridine derivatives decorated with useful pharmacophores.
This prompted us to prepare and structurally characterize directly the 6-(pyrazol-1-
yl)pyrazolo[3,4-b]pyridin-3-ol (3a) and its sulfonyl and acylated derivations (4–7).
Among pyrazolo[3,4-b]pyridine compounds, 6-(pyrazol-1-yl)pyrazolo[3,4-
b]pyridines-3-ol exhibits three possible tautomeric forms 3a, 3b, and 3c (Scheme 1).6
Theoretically, the sulfonylation and acylation of 6-(pyrazol-1-yl)pyrazolo[3,4-b]pyridines-
3-ol (3a) could have occurred either toward O-versus or N-versus upon treatment with
different sulfonyl and acyl chloride reagents. However, in this study, we have found that
the O-sulfonylation is the sole product, while the acylation of the compound 3a yielded
1,3-diacylated products via N2, O1-diacylation (Scheme 2). Details of our investigations
are presented in this contribution.
Scheme 1 Three tautomers of compound 3a.
RESULT AND DISCUSSION
The synthesis of compounds 3a and 4–7 was shown in Scheme 2 (see Experimental).
The crystals of 3a and 4–7 were grown from slow evaporation of ethanol at ambient
conditions. The crystallographic and refinement data of 3a and 4–7 are shown in Table 1.
The structures of these compounds were assigned from their spectral data and X-
ray analysis. These data revealed that the compound 3a exhibits 3-hydroxy tautomer that
has only rarely been reported. In the solid state, the structure 3a was determined by
X-ray crystallography. The IR spectra of 4–6 exhibit bands at 1367−1364 cm−1 and
1195−1180 cm−1 (R SO2 OR). They showed no absorption in the C O or −OH regions.
The 1H NMR signal at 13.58, 13.45, and 13.43 ppm comes from the proton in the NH group
1
of compounds 4−6, respectively. The H NMR signal of compound 7 was absent from
the proton of the NH. The characteristic signal of the pyrazolyl proton compounds 3a and

676
L.-Q. SHEN ET AL.
Scheme 2 Synthesis of compounds 2, 3a, and 4–7.
4−7 appears at 6.11, 6.17, 6.15, 6.16, and 6.16, respectively. The protons of aromatic rings
appear at 8.55−7.32 ppm and the signal of methyl appears at 3.65−2.21 ppm.
The molecular structure of compound 3a with atomic numbering scheme is shown
in Figure 1. Selected geometric parameters derived from the structure refinement are listed
in Table 2. The atomic numbering scheme of all studied molecules was chosen to be
Figure 1 The molecular structure of 3a showing 30% probability displacement ellipsoids.

SYNTHESIS, X-RAY CRYSTAL STRUCTURE, AND COMPUTATIONAL STUDY OF NOVEL 677
Table 1 Crystal structure and data refinement parameters for 3a and 4–7
Compound
3a
4
5
6
7
Empirical
formula
Formula
weight
Crystal
system/space
group
a/Å
C12H13N5O
243.27
2C13H15N5
O3S·H2O
660.74
C18H17N5
O3S·H2O
401.44
C19H19.50N5
C26H21N5O3
451.48
O3.50
S
405.96
Monoclinic/
P2(1)/n
Triclinic/
P-1
Monoclinic
P2(1)/n
Monoclinic/
Monoclinic/
P2/n
C2/c
7.648(7)
7.992(7)
19.393(18)
90
92.482(11)
90
1184.3(18)
4
1.364
8.698(5)
14.393(8)
15.202(8)
64.19(2)
73.377(2)
72.640(2)
1607.9(17)
2
8.8538(6)
9.0980(6)
24.1702(16)
90
91.978(2)
90
1945.8(2)
4
1.370
13.6373(7)
8.4287(4)
16.8449(9)
90
92.470
90
26.154(3)
9.5303(10)
21.558(2)
90
122.445(5)
90
4534.7(9)
8
1.418
b/Å
c/Å
α/◦
β/◦
γ /◦
V/Å3
1934.43(17)
4
Z
Dcalc (g/cm3)
1.365
0.225
1.394
0.201
μ (mm−1
)
0.0935
0.201
0.127
Crystal size
(mm)
Color/shape
0.20 × 0.18
0.25 × 0.22 ×
0.35 × 0.26 ×
0.20 × 0.18 ×
0.25 × 0.22 ×
× 0.17
0.19
0.20
0.15
0.19
Colorless/
block
Colorless/
block
Colorless/
block
Colorless/
block
Colorless/
block
Temp (K)
296(2)
296(2)
296(2)
296(2)
296(2)
Theta range
for collection
Reflections
collected
Independent
reflections
2.10◦–25.00◦
1.51◦–25.00◦
1.69◦–25.00◦
1.88◦–25.00◦
1.85◦–25.00◦
5924
2078
18,834
3972
22,130
4773
22,011
3406
28,820
5623
Data/restraints/
parameters
Goodness of fit
on F2
2078/0/167
1.052
5628/0/414
1.043
3423/0/256
1.038
34/0/262
1.057
56/0/310
1.053
Final R indices
[I > 2σ(I)]
R1 = 0.0447,
wR2 =
R1 = 0.0417,
wR2 = 0.1107
R1 = 0.0393,
wR2 = 0.0986
R1 = 0.0483,
wR2 = 0.1151
R1 = 0.0545,
wR2 = 0.1589
0.1151
R indices (all
data)
R1 = 0.0597,
R1 = 0.0548,
wR2 = 0.1205
R1 = 0.0511,
wR2 = 0.1075
R1 = 0.0401,
wR2 = 0.1104
R1 = 0.0745,
wR2 = 0.1723
wR2 =
0.1301
Largest
difference
peak/hole
0.268 and
−0.200 e
Å−3
0.251 and
−0.292 e Å−3
0.168 and
−0.302 e Å−3
0.264 and
−0.292 e Å−3
0.285 and
−0.314 e Å−3
identical. The molecular geometry of 3a is similar to that reported for simple 1,2-dihydro-
3H- pyrazolo[3.4-b] pyridine-3-One.7 The fused core pyrazolo[3,4-b]pyridin fragment lies
approximately in one planar with a maximum mean plane deviation of −0.031 Å for atom
N1. The substituted pyrazolyl ring plane is rotated with respect to its parent pyridine ring
by 38.3◦, as seen for similar cases.8 Compound 3a exhibits three possible tautomeric form
as shown in Scheme 2. Crystals of 3a show a probable tautomerism of this compound.
The C1 O1 bond length of 1.332(3) Å is close to that of a nearly pure C O single bond
(average length of C O sp3 O single bond is 1.34 Å9), in accordance with recently reported

678
L.-Q. SHEN ET AL.
Table 2 Selected geometric parameters (Å and ◦) of compounds 3a, 4, and 6
Parameter
Parameter
Parameter
Bond lengths (Å)
3a
Bond lengths (Å)
4
Bond lengths (Å)
6
C1−N1
1.317(3)
1.387(2)
1.352(3)
1.347(3)
1.375(2)
1.329(3)
1.397(3)
1.498(3)
1.323(3)
1.420(3)
1.486(3)
1.332(3)
S1−O6
S1−O5
1.419(2)
1.619(2)
1.413(2)
1.613(2)
1.386(2)
1.331(3)
1.381(3)
1.421(3)
1.327(3)
1.343(3)
1.364(3)
1.371(3)
1.315(3)
1.316(3)
1.373(3)
1.360(3)
1.328(3)
1.341(3)
1.383(3)
1.386(2)
1.418(3)
1.397(3)
1.395(3)
C2−C7
C5−S1
1.383(3)
1.7489(19)
1.356(2)
1.365(2)
0.8600
1.335(2)
1.415(2)
1.415(2)
1.373(2)
1.364(2)
1.369(2)
1.3713(19)
1.4122(17)
1.6088(15)
N1−N2
N2−C2
S2−O3
N2−C10
C2−N3
S2−O2
N2−N1
N4−N5
N1−N2
N2−H2
N5−C12
C3−C2
N1−C2
C10−N3
N2−C4
C12−N4
C4−C5
N2−C6
C12−C11
C13−C11
C16−C17
C16−N4
C7−N3
N3−N6
C7−N4
N3−C10
C8−C9
N4−C10
O1−C1
N4−C5
N4−N5
Bond angles
C1−N1−N2
C2−N2−N1
C7−N3−C2
C9−N4−N5
C12−N5−N4
N5−C12
O1−S1
105.87(17)
110.53(17)
113.16(18)
111.60(17)
105.15(17)
N6−C25
O3−S1
N6−N7
Bond angles
C7−C2−C3
C6−C5−S1
C10−N2−N1
C10−N2−H2
C10−C9−C8
N3−C10−N2
C16−C17−C18
N5−C18−C17
N5−N4−C12
N7−C23
118.12(19)
119.55(15)
111.37(15)
124.3
102.51(16)
125.13(16)
106.83(16)
110.86(16)
119.42(13)
N8−C19
N8−C23
N9−C17
N9−N10
N9−C19
O2−C12
O5−C25
Bond angles
O7−S1−C26
O3−S2−C13
C4−N2−C6
C6−N3−C10
C10−N4−N5
C25−N6−N7
C19−N8−C23
C17−N9−N10
C17−N9−C19
C12−O2−S2
C25−O5−S1
110.99(14)
110.47(14)
130.16(18)
112.97(17)
110.84(17)
104.21(18)
113.56(17)
110.61(17)
130.14(18)
121.01(13)
121.14(14)
pyrazole OH bond length (1.331(2) Å).10 N5 atom of the pyrazolyl rings is oriented away
from the pyridine N3, in order to reduce the nitrogen lone pairs of the electronic repulsion.
The individual molecule 3a fully exploits their H-bonding ability as depicted in
Figure S1 (see supplemental materials). The O(1) atom is an acceptor in two fairly strong
intermolecular hydrogen bonds (Table S1). A strong one (O(1) H(1)···N(1)) forming
dimmers linked through a weaker H-bond interaction (N(2) H(2)···N(5)) that gives rise to
independent layers parallel to the (1 0 0) plane.
The molecular structures of compounds 4–7 are presented in Figures 2–5, respec-
tively. In the crystalline phase of compound 4, crystallographic asymmetric units contain
two compound 4 molecules, together with one water molecule, in the crystalline phase
of compound 5 and 6, crystallographic asymmetric units contain one compound 5 or 6
molecules and one water molecule. In the crystalline phase of compound 7, crystallographic

SYNTHESIS, X-RAY CRYSTAL STRUCTURE, AND COMPUTATIONAL STUDY OF NOVEL 679
Figure 2 The molecular structures of 4·H2O showing 30% probability displacement ellipsoids.
asymmetric units contain one compound 7 molecules. Selected geometric parameters de-
rived from the structure refinement are listed in Table 2 (4 and 6) and Table 3 (5 and 7,
as well as those obtained from quantum chemical calculations). Structural data for these
substituted pyrazolo[3,4-b]pyridine heterocycles, which formally differ from sulfonyl and
acylated of the 1H−pyrazolo[3,4−b]pyridine ring, are summarized in Table 2 and Ta-
ble 3. The difference has been observed in the geometric parameters for the compounds
4−7 when the crystal structure is compared. For example, the dihedral angles between the
pyrazolo[3,4−b]pyridine plane and the pyrazole plane are 16.1◦, 2◦, 20◦, and 9.2◦ for 4−7,
Figure 3 The molecular structures of 5·H2O showing 30% probability displacement ellipsoids.

680
L.-Q. SHEN ET AL.
Figure 4 The molecular structures of 6·H2O showing 30% probability displacement ellipsoids.
respectively. Their C C bond lengths, as well as its C N (147 pm) and C N (128 pm)
bond distances are to a large extent averaged. The exocyclic C N bond distance is 1.421(3)
Å, 1.411(2) Å, 1.414(2) Å, and 1.407 (2) Å for 4−7, respectively, the nearly identical bond
length is found in a similar system.11 The S O bond distance is 1.619(2) Å, 1.604(1) Å,
Figure 5 The molecular structures of 7 showing 30% probability displacement ellipsoids.

SYNTHESIS, X-RAY CRYSTAL STRUCTURE, AND COMPUTATIONAL STUDY OF NOVEL 681
Table 3 Experimental and calculated selected geometric parameters (Å and ◦) of compounds 5 and 7
Parameters 5
Parameters 7
Experimental
Experimental
difference
Calculated
difference
Calculated
Bond lengths
(Å)
S1− O3
1.412(2)
1.628
2.010
1.860
1.344
1.355
1.370
1.408
1.401
1.400
1.006
1.379
1.437
1.382
1.344
1.379
1.338
1.396
0.216
0.406
0.11
C1 – N3
C1–N4
N4–N5
C2–N5
C2–C3
C2–O2
O2–C14
O1–C14
C14–C15
N2–C6
N2–N1
N4–C7
C7–O3
C7–C8
C22–C24
C24–C25
C22–C23
1.334(2)
1.392(2)
1.391(2)
1.300(2)
1.420(2)
1.384(2)
1.373(2)
1.192(2)
1.475(2)
1.407(2)
1.379(2)
1.408(2)
1.210(2)
1.486(3)
1.394(3)
1.367(3)
1.498(3)
1.333
1.393
1.378
1.305
1.430
1.376
1.380
1.209
1.484
1.409
1.373
1.435
1.211
1.489
1.421
1.376
1.497
−0.001
0.001
−0.013
0.005
0.01
S1− O2
1.604(1)
1.750(2)
1.392(2)
1.310(3)
1.364(2)
1.411(2)
1.376(2)
1.373(4)
0.860
1.345(2)
1.405(3)
1.392(3)
1.317(2)
1.352(2)
1.323(3)
1.375(2)
S1− C6
O2 − C7
−0.048
0.045
0.006
−0.003
0.025
0.027
0.146
0.034
0.032
−0.01
0.027
0.027
0.015
0.021
N1− C7
N1−N2
−0.008
0.007
0.017
0.009
0.002
−0.006
0.027
0.001
0.003
0.027
0.009
−0.001
N4−C11
N4−N5
C1−C2
N2−H2
N3−C12
C7−C8
C16−C17
N3−C11
N2−C12
N5−C17
N4−C15
Bond angles
O3−S1−O2
O4−S1−C6
C7−N1−N2
C15−N4−N5
C15−N4−C11
N3−C11−N4
N3−C12−N2
C15−C16−C17
S1–O2–C7
108.63(9)
110.19(10)
104.60(16)
111.16(16)
130.25(17)
115.86(16)
125.17(17)
107.2(2)
105.15
109.53
105.29
111.35
130.50
116.06
126.69
107.10
113.40
−3.48
−0.66
0.69
0.19
0.25
N3–C1–N4
C1–N4–C7
N4–C7–O3
C3–C2–O2
C2–C3–C4
O2–C14–O1
126.39(15) 126.80
128.05(14) 130.90
119.30(17) 119.62
127.04(16) 128.21
137.68(16) 138.31
126.30(19) 122.72
0.41
2.85
0.32
1.17
0.63
−3.58
−0.66
−0.11
−0.79
0.79
0.2
1.52
O2–C14–C15 112.29(15) 111.63
−0.1
C4–C5–N2
N4–C7–C8
N3–C6–N2
C6–N2–N1
119.89(16) 119.78
118.25(15) 117.46
116.14(15) 116.93
117.38(15) 118.16
118.51(12)
−5.11
0.78
1.610(2) Å for 4−6, respectively. The C O bond in 7 is directed inward to their parent
heterocyclic moiety (toward pyridine ring), the amide C O bond distance is 1.210 (2) Å
and the ester C O bond distance is 1.192 (2) Å. The C O bond distance is 1.397(3) Å,
1.392(2) Å, 1.383(4) Å, and 1.384(2) Å for 4−7, respectively, the C−O bond length is
slightly longer than the pure C(sp2) O single bond (average length for such a bond is 1.34
Å).12
The crystal structure of the compounds 4−6 shows the presence of water molecules
in the crystal packing diagram, which plays an important role in the crystal packing as
they act as mediator and in stabilization of the network of weak interactions by involving
N H . . . O and O H . . . N donor−acceptor interactions (Table S1, Figures S2–S4). The
compounds 4−6 and water molecules can be linked through the intermolecular hydrogen
bond interactions to form a one-dimensional structure.
In order to rationalize the observed geometric structure determined by X-ray diffrac-
tion analysis, we studied the compounds 5 and 7 as the representative theoretically by
density functional theory (DFT) calculations. Selected geometric parameters of 5 and
7 derived from those calculated theoretically using B3LYP functional with a 6-31+G∗

682
L.-Q. SHEN ET AL.
basis set are listed in Table 3. For the compound 5, the largest difference between cal-
culated bond lengths and bond angles and X-ray values are about 0.406 Å at S1−O2
and −3.48◦ at O3−S1−O2, respectively. In contrast, the compound 7 shows a maximum
difference between X-ray values and calculated bond lengths and bond angles, which is
about 0.027 Å at N4–C7 and C22–C24 and −3.58◦ at O2–C14–O1, respectively. The
discrepancy between calculated for an isolated molecule in the gas and the value deter-
mined from X-ray diffraction data may be partly attributed to crystal packing effects.
In addition, in the theoretical optimized single molecule, the intermolecular interactions
are absent, and the intramolecular ones are stronger than those in crystals. Therefore,
taking into account the difference in the physical state of the substance, there is, in gen-
eral, an agreement between the theoretical and the experimental data obtained for the two
compounds.
We carried out DFT(B3LYP) with the 6−31+G∗ calculations to determine the en-
ergies of the three molecules of Scheme 1. The minimum is 3a (−814.1027756 hartree)
followed by 3b (24.23 kJ mol−1), and the least stable is 3c (79.28). Here, the tautomer 3a
is the most stable according to the calculations in accord with the X-ray.
We investigated the distributions and energy levels of highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals computed
with B3LYP/6−31+G∗ level for the compound 3a. The HOMO (Figure S5) was found
to be contributed mainly from p-orbitals of the nitrogen and oxygen atoms forming the
1H−pyrazolo ring and substituent hydroxy (20.59% for the pivotal atom N1, 19.92% for
N2, and 11.82% for O1; for numbering, see Figure 1). On the other hand, the LUMO
(Figure S5) is more delocalized with major contributions from p-orbitals of the carbon
and nitrogen atoms forming the pyridine ring (20.44% for the pivotal atom C4, 18.35%
for C7, and 15.88% for N3; for numbering, see Figure 1). The energy difference be-
tween the HOMO and LUMO, being 4.72 eV, showed that the molecule is in the steady
state.
The molecular electrostatic potential (MESP) is a method of mapping electrostatic
potential onto the electron density surface and is a very useful descriptor in understand-
ing sites for electrophilic attack and nucleophilic reactions as well as hydrogen-bonding
Figure 6 Total electron density mapped with electrostatic potential surface of the compound 3a.

SYNTHESIS, X-RAY CRYSTAL STRUCTURE, AND COMPUTATIONAL STUDY OF NOVEL 683
interactions.13,14 To visually consider the most probable sites of the compound 3a for
an interaction with electrophilic and nucleophilic species, MESP was calculated at the
B3LYP/6−31+G∗ optimized geometry (Figure 6). The color scheme for the MESP surface
is red, electron rich, partially negative charge; blue, electron deficient, partially positive
charge; light blue, slightly electron deficient region; yellow, slightly electron-rich region;
green, neutral, respectively. Domain with the most negative MESP is located on the nitrogen
atom of pyrazole ring (N5,N1, for numbering, see Figure 1), while the domain with the
most positive MESP is localized at the OH and NH moiety.
CONCLUSIONS
New 6-(pyrazol-1-yl)pyrazolo[3,4-b]pyridin-3-ol and its sulfonyl and acylated
1
derivatives were synthesized and characterized by FT IR, H NMR spectroscopy, and
high-resolution mass spectra (HRMS). Single crystals were successfully grown from
solution by slow evaporation technique at room temperature using ethanol as a solvent.
The single crystal X-ray diffraction and energies’ calculations show the compound 3a
as a predominant tautomer structure. The single crystal X-ray diffraction revealed herein
allowed the identification of the chemical structures of the O-versus or N-versus upon
treatment with different sulfonyl and acyl halide reagents. Such structural identification is
of very importance to further apply these compounds in the drug design research. From
supramolecular point of view, the crystal packing of these compounds is similar. The
hydrogen-bonding networks are mainly responsible for supramolecular packing, each
molecule uses all the donor/acceptor moieties to form layer with similar patterns. The
theoretical calculations of the compounds 3a, 5, and 7 have been performed by using the
DFT(B3LYP) with the 6–31+G∗ basis set. The calculated bond lengths and bond angles
of the compounds 5 and 7 are generally closer to X-ray diffraction.
EXPERIMENTAL AND COMPUTATIONAL SECTION
Methods
All commercially available reagents were used without further purification. All sol-
vents were dried and distilled before use. Column chromatography was conducted by
using 200–300 mesh silica gel (Qingdaohaiyang, China). Melting points were determined
using a WRS-1B apparatus (Shanghai Precise Science Instrument Co., China) and were
uncorrected. The IR spectra were recorded in the range of 400–4000 cm−1 with a Magna
1
550 FT-IR spectrometer using KBr pellets (Thermo Fisher Nicolet, USA). The H and
13C NMR spectra were recorded on a Bruker AV600 spectrometer (Bruker, Switzerland).
HRMS were obtained in ESI mode on a Finnigan MAT95XP HRMS system (Thermo
Electron Corporation, USA).
Synthesis
2,6-Dichloro-4-Methylnicotinamide 115. A solution of 2,6-dichloro-4-
methylnicotinonitrile (5.0 g, 26.7 mmol) in concentrated H2SO4 (25 mL) was heated at
◦
◦
80 C for 4 h, then the resulting solution was cooled to 25 C, and poured into ice water
(100 mL). The suspension was filtered and the filter cake was washed thoroughly with
water. The filter cake recrystallized from acetone to give the product (4.05 g, 80.9%) as a
white solid.

684
L.-Q. SHEN ET AL.
mp: 173.5◦C–175 ◦C (lit 169 ◦C–173 ◦C). 1H NMR ((CD3)2SO): δ 8.10 (s, 1H), 7.93
(s, 1H), 7.55 (s, 1H), 2.31 (s, 3H). IR (KBr): 3444, 3343, 3169, 1682, 1577, 1081, 917,
848 cm−1
.
6-Hydrazino-4-Methyl-1-H-Pyrazolo[3,4-b]Pyridine-3-ol 216
A solution of 2,6-dichloro-4-methylnicotinamide (1, 5.000 g, 4.9 mmol) in 80%
hydrazine hydrate (5 mL) was heated at 100◦C for 5 h, then the resulting solution was
cooled to room temperature, and a yellow solid formed. The yellow solid product was
isolated by filtration and the filter was washed with 95% ethanol to give 2 (3.44 g, 71.8%).
mp > 300 ◦C. 1H NMR (600 MHz, (CD3)2SO): δ 11.56 (s, 1H), 10.35 (s, 1H), 7.97 (s, 1H),
6.09 (s, 1H), 4.2 (brs, 2H), 2.37 (s, 3H). IR (KBr): 3395, 3325, 3207, 1619, 1505, 1306,
1015,747 cm−1. The product was used without further purification.
6-(3,5-Dimethyl-Pyrazol-1-yl)-4-Methyl-1H-Pyrazolo[3,4-b]Pyridin-3-ol
3a16. To a solution of 6-hydrazino-4-methyl-1-H-pyrazolo[3,4-b]pyridine-3-ol (0.9 g,
5.0 mmol) in ethanol (10 mL) was added 2,4-pentanedione (1 mL, 9.7 mmol). The reaction
mixture was stirred at room temperature for 30 min, then was heated to 80◦C for 3h.
The yellow solution was evaporated in vacuum, the residue was isolated by filtration and
the filter was washed with cold methanol. The filter cake recrystallized from ethanol to
1
obtain 3a as a white solid (1.0 g, 75.8%). mp: 270.1◦C–271.9◦C. H NMR (600 MHz,
(CD3)2SO): δ 11.89 (s, 1H), 10.94 (s, 1H), 7.32 (s, 1H), 6.11 (s, 1H), 2.61 (s, 3H), 2.49
(s, 3H), 2.19 (s, 3H). 13C NMR (150 MHz, (CD3)2SO): δ 13.5, 14.5, 17.8, 102.3, 107.9,
109.3, 141.2, 146.2, 149.0, 151.8, 153.0, 157.1. IR (KBr) 3638, 3141, 3089, 2929, 1602,
1567, 1553, 1390, 1289, 903, 827 cm−1. HRMS (m/z): Calcd. for C12H13N5O: 243.1120.
Found: 243.1117.
Methanesulfonic 6-(3,5-Dimethyl-Pyrazol-1-yl)-4-Methyl-1H-Pyrazolo[3,
4-b]Pyridine-3-yl Ester 4. To a solution of 6-(pyrazol-1-yl)pyrazolo[3,4-b]pyridin-3-
ol (3a) (0.5086 g, 2.1 mmol) in pyridine (5 mL) at 0◦C was added dropwise methylsulfonyl
chloride (0.5120 g, 4.5 mmol), and the reaction mixture was stirred at 5 ◦C for 8 h. Then,
the mixture was poured into ice water (50 mL). The solid was collected and washed with
water to give the compound 4 (0.5365 g, 79.9%). Recrystallization from aqueous ethanol
gave needles, mp: 201.5 ◦C–203 ◦C IR (KBr): 3152, 3030, 1609, 1564, 1524, 1447, 1367,
1195, 801 cm−1.1H NMR ((CD3)2SO): δ 13.58 (s, 1H), 7.63 (s, 1H), 6.17 (s, 1H), 3.65
(s, 3H), 2.67 (s, 3H), 2.66 (s, 3H), 2.22 (s, 3H). HRMS (m/z): Calcd. for C13H15N5O3S:
321.0896. Found: 321.0901.
Benzenesulfonic Acid 6-(3,5-Dimethyl-Pyrazol-1-yl)-4-Methyl-1H-Pyraz
olo[3,4-b]Pyridine-3-yl Ester 5. Under the reaction conditions described above,
6-(pyrazol-1-yl)pyrazolo[3,4-b]pyridin-3-ol (3a) (1.0001 g, 4.1 mmol) and benzene-
sulfonyl chloride (1.8030 g, 10.2 mmol) gave the product 5 (1.4841 g, 94.2%). mp:
203.0 ◦C–204.3 ◦C IR (KBr): 3154, 3037, 1612, 1571, 1536, 1449, 1366, 1180, 837 cm−1
.
1H NMR ((CD3)2SO): δ 13.45 (s, 1H), 8.00 (d, J = 7.8, 2H), 7.87 (t, J = 7.8 2H, 1H), 7.73
(d, J = 7.8, 2H), 7.61 (s, 1H), 6.15 (s, 1H), 2.64 (s, 3H), 2.59 (s, 3H), 2.21 (s, 3H). 13C
NMR (150 MHz, (CD3)2SO): δ 13.4, 14.7, 18.0, 103.7, 110.0, 110.9, 128.5, 129.9, 135.0,
135.0, 141.6, 143.6, 145.3, 149.6, 149.7, 153.1. HRMS (m/z): Calcd. for C18H17N5O3S:
383.1052. Found: 383.1056.

SYNTHESIS, X-RAY CRYSTAL STRUCTURE, AND COMPUTATIONAL STUDY OF NOVEL 685
Toluene-4-Sulfonic Acid 6-(3,5-Dimethyl-Pyrazol-1-yl)-4-Methyl-1H-Pyr
azolo[3,4-b]Pyridine-3-yl Ester 6. Under the reaction conditions described above,
6-(pyrazol-1-yl)pyrazolo[3,4-b]pyridin-3-ol (3a) (0.5027 g, 2 mmol) and p-toluenesulfonyl
chloride (0.9000 g, 4.7 mmol) gave the product 6 (0.7266 g, 88.5%). mp: 204 ◦C–204.5 ◦C.
IR (KBr): 3167, 3113, 1612, 1564, 1449, 1364, 1192, 810 cm−1. 1H NMR ((CD3)2SO): δ
13.43 (s, 1H), 7.87 (d, J = 8.4, 2H), 7.61 (s, 1H), 7.52 (d, J = 8.4, 2H), 6.16 (s, 1H), 2.65
(s, 3H), 2.60 (s, 3H), 2.45 (s, 3H), 2.22 (s, 3H). HRMS (m/z): Calcd. for C19H19N5O3S:
397.1209. Found: 397.1203.
Benzoic Acid-1-Benzoyl-6-(3,5-Dimethyl-Pyrazol-1-yl)-4-Methyl-1H-Pyr
azolo[3,4-b]Pyridine-3-yl Ester 7. To a solution of 6-(pyrazol-1-yl)pyrazolo[3,4-
b]pyridin-3-ol (3a) (0.5027 g, 2.1 mmol) in pyridine (5 mL) at 0◦C was added dropwise
benzoyl chloride (0.6463 g, 4.6 mmol), and the reaction mixture was stirred at 0 ◦C for 8 h.
Then, the mixture was poured into ice water (50 mL). The solid was collected and washed
with water to give the compound 7 (0.7166 g, 76.9%). Recrystallization from aqueous
ethanol gave needles, mp: 185.5◦C–187◦C. IR (KBr): 3166, 3020, 2950, 1758, 1609, 1564,
1456, 1251, 1022, 816, 716 cm−1. 1H NMR ((CD3)2SO): δ 8.55–8.54 (m, 1H), 8.23–8.21
(m, 2H), 7.95–7.92 (m, 1H), 7.70–7.66 (m, 3H), 7.61–7.56 (m, 3H), 7.40–7.35 (m, 1H),
6.16 (s, 1H), 2.66 (s, 3H), 2.54 (s, 3H), 2.43 (s, 3H). 13C NMR (150 MHz, (CD3)2SO):
δ 13.5, 14.7, 17.8, 104.0, 107.4, 109.8, 110.3, 124.0, 127.6, 128.3, 128.6, 129.4, 130.2,
132.7, 134.9, 136.2, 141.5,142.5, 143.5, 144.9, 149.5, 149.7, 150.1, 150.5, 152.9, 164.8.
HRMS (m/z): Calcd. for C26H21N5O3: 451.1644. Found: 451.1666.
X-Ray Crystallography
Diffraction experiments for 3a and 4–7 were carried out with Mo Ka radiation (λ =
0.71073 Å) using a Bruker SMART APEX CCD diffractometer at 296 K. Raw frame data
were integrated with the SAINT program. The structures were solved by direct methods
and refined with full-matrix least squares on F2 using SHELXS-97 and SHELXL-97.17 All
the non-hydrogen atoms were refine anisotropically. The hydrogen atoms were set in the
calculated positions and refined by riding model.
Computational Methods
All quantum chemical calculations were performed with the GAUSSIAN 03 program
package. All geometries were optimized using DFT(B3LYP)18,19 with the 6-31+G∗20 basis
set. The HOMO and LUMO energy was also calculated at DFT(B3LYP)/6-31+G∗ level of
theory, and the single point frequency calculations were based on the optimized geometries
in order to ensure the energy minimum structure.
SUPPLEMENTARY MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
Crystallographic data for compound 3a, 4−7 in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication number CCDC
888113, CCDC 902436, CCDC 902437, CCDC 902438, and CCDC 936727. Copies of the
data can be obtained, free of charge, on application to CCDC, 12 Union Road, CB2 1EZ,
UK [fax: +44(1223)336033 or E-mail: deposit@ccdc.cam.ac.uk].

686
L.-Q. SHEN ET AL.
REFERENCES
1. Sckikawa, I.; Nishie, J.; Tono-oka, S.; Tanaka, Y.; Kakimoto, S. J. Heterocycl. Chem. 1973, 10,
931-932.
2. Ho˝ehn, H.; Denzel, T.; Janssen, W. J. Heterocycl. Chem. 1972, 9, 235-253.
3. Patel, M.; Rodgers, J. D.; McHugh, R. J.; Johnson, B. L.; Cordova, B. C.; Klabe, R. M.; Bacheler,
L. T.; Erickson-Viitanen, S.; Ko, S. S. Bioorg. Med. Chem. Lett.1999, 9,3217-3220.
4. Elnagdi, M. H.; Al-Awadi, N.; Erian, A. W.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.
Comprehensive Heterocyclic Chemistry II: A Review of the Literature 1982–1995. Pergamon,
Oxford, UK, 1996.
5. Desenko, S. M.; Komykhov, S. A.; Orlov, V. D.; Meier, H. J. Heterocycl. Chem. 1998, 35,
989-990.
6. Khalil, A. K.; Hassan, M. A.; Mohamed, M. M.; El-Sayed, A. M. Indian J. Chem. 2006, 45B,
2485-2490.
7. Urban´czyk-Lipkowska, Z.; Krajewski, J. W.; Gluzin´ski, P. Acta Cryst., 1979, B35, 2753-2755.
8. Calderazzo, F.; Englert, U.; Hub, C.; Marchetti, F.; Pampaloni, G.; Passarelli, V.; Romano, A.;
Santi, R. Inorg. Chim. Acta. 2003, 344, 197-206.
9. Claramunt, R. M.; Sanz, D.; Lo´pez, C.; Elena, P.; Torres, M. R.; Elguero, P.; Nioche, P.; Raman,
C. S. Helv. Chim. Acta. 2009, 92, 1952-1962.
10. Shen, L. Q.; Huang, S. Y.; Diao, K. S.; Lei, F. H. J. Mol. Struct. 2012, 1021, 167-173.
11. Kimberly, A. B.; Garner, C. M.; Klausmeyer, K. K.; Feazell, R. J. Chem. Crystallogr. 2005, 35,
875-883.
12. Smith, M. B.; March, J. March’s Advanced Organic Chemistry Reactions, Mechanisms, and
Structure, 6th ed.; John Wiley & Sons, Hoboken, New Jersey, USA, 2007.
13. Scrocco, E.; Tomasi, J. Adv. Quantum Chem. 1978, 11, 115-121.
14. Okulik, N.; Jubert, A. H. Internet Electron. J. Mol. Des. 2005, 4, 17-30.
15. Grozinger, K. G.; Hargrave, K. D.; Adams, J. US Patent 5, 200, 522, 1993.
16. Wu, A. Q.; Tong, Y.; Huang, S. Y.; Shen, L. Q. Res. Chem. Intermed. 2012, DOI:10.1007/s11164-
012-0958-2. Published online December 8, 2012.
17. Sheldrick, G. M. Acta Cryst. 2008, A64, 112-122.
18. Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.
19. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. 1988, B37, 785-789.
20. Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724-728.