Novel uric acid-based nano organocatalyst with phosphorous acid tags: Application for synthesis of new biologically-interest pyridines with indole moieties via a cooperative vinylogous anomeric based oxidation

Article abstract of DOI:10.1016/j.mcat.2021.111549

In this study, we have designed, synthesized and full characterized a novel biological based acidic nano organocatalyst via condensations reaction of uric acid and phosphorous acid. The obtained compound was named theacrine tetrakis(phosphonic acid) (TTPA) and prepared under refluxing ethanol. This new nano organocatalyst was applied as an efficient and recyclable catalyst for the preparation of novel pyridines with indole moieties via a cooperative vinylogous anomeric based oxidation with good to excellent yields.

Full text of DOI:10.1016/j.mcat.2021.111549

Molecular Catalysis 507 (2021) 111549
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.journals.elsevier.com/molecular-catalysis
Novel uric acid-based nano organocatalyst with phosphorous acid tags:
Application for synthesis of new biologically-interest pyridines with indole
moieties via a cooperative vinylogous anomeric based oxidation
,
,
Sima Kalhora, Mahmoud Zareia *, Hassan Sepehrmansouriea, Mohammad Ali Zolfigola *,
Hu Shib *, Jinping Wangc, Jalal Arjomandid, Masoumeh Hasanie, Romana Schirhaglf
,
a Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, PO Box 6517838683, Hamedan, Iran
b School of Chemistry and Chemical Engineering, Institute of Molecular Science, Shanxi University, Taiyuan, 030006, China
c Institute of Surface Analysis and Chemical Biology, University of Jinan, Jinan, Shandong, 250022, China
d Department of Physical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, 65178, Hamedan, Iran
e Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
f University Medical Center Groningen, Groningen University, Antonius Deusinglaan 1, 9713 AV, Groningen, Netherlands
A R T I C L E I N F O
A B S T R A C T
Keywords:
In this study, we have designed, synthesized and full characterized a novel biological based acidic nano orga-
nocatalyst via condensations reaction of uric acid and phosphorous acid. The obtained compound was named
theacrine tetrakis(phosphonic acid) (TTPA) and prepared under refluxing ethanol. This new nano organocatalyst
was applied as an efficient and recyclable catalyst for the preparation of novel pyridines with indole moieties via
a cooperative vinylogous anomeric based oxidation with good to excellent yields.
(2-Methyl-1H-indol-3-yl)-pyrazolo[3,4-b]
pyridine
Phosphorous acid
theacrine tetrakis (phosphonic acid) (TTPA)
Uric acid
Vinyligous anomeric based oxidation
1. Introduction
and treatment. Therefore, this compound has different applications in
chemical and biochemical processes [14]. Among different properties of
In recent years, the design and application of biological-
basedcatalysts in organic synthesis and functional groups trans-
formation have attracted intensive attention in the science and industry
because of their unique properties, such as biodegradable ability, effi-
ciency, reusability, reactivity, stability, selectivity, and easy separation
of the catalyst [1–8]. The application of biological-based acidic orga-
nocatalysts in chemical processes has already been fully investigated
[9]. The development of biological-based compounds with acidic groups
(SO3H and PO3H2) as solid acids has been the subject of enormous in-
terest because of their interesting features such as nano-structures,
thermal stability, and environmental friendliness [10–12]. Recent ad-
vances in organocatalytic cascade reactions toward the formation of
quaternary stereocenters has been also comprehensively reviewed [13].
Uric acid (7,9-dihydro-1H-purine-2,6,8(3H)-trione), as a biological
urea like structure, is known of having free-radical-scavenging property
in human serum and blood and antioxidant activity. Different electro-
chemical, optical sensors and biosensors have been developed for sen-
sitive and selective detection of uric acid in the field of disease diagnosis
uric acid one can point to capability of increasing serum antioxidant
capacity, adsorption of concomitant macromolecules particularly pro-
teins, being a diagnostic marker of neurodegenerative diseases, and
lowering blood glucose level [15].
Phosphorus as essential mineral for all living things, is naturally
found in the body. In conjunction with calcium, phosphorus contributes
to the formation of healthy bones and teeth [16]. Furthermore, it is an
important nutrient for biochemical reactions in plants which are needed
for plant’s growth and puberty. It also plays an important role in
photosynthesis, cell division, respiration, energy transfer and storage
[17,18]. Recently, catalysts with phosphorous acid tags have been pre-
pared and applied in organic synthesis [19].
Pyridine and its corresponding derivatives are unique heterocycles
with worthwhile chemical and pharmaceutical importance, both in na-
ture and synthesis plans. It has widely been used as key scaffold for
design and preparation of novel drug candidate materials [20–25], su-
pramolecular structures [26,27], polymers [28], and catalysts [29–31].
The essential vitamin B6, nicotine, redox NADP-NADPH2 coenzymes and
* Corresponding authors.
E-mail addresses: mahmoud8103@yahoo.com (M. Zarei), zolfi@basu.ac.ir (M.A. Zolfigol), hshi@sxu.edu.cn (H. Shi).
https://doi.org/10.1016/j.mcat.2021.111549
Received 14 January 2021; Received in revised form 21 March 2021; Accepted 24 March 2021
Available online 20 April 2021
2468-8231/© 2021 Elsevier B.V. All rights reserved.

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 1. The molecular structure of four drugs with indole moieties.
subset of stereoelectronic effects is the preference of certain substituents
bonded to anomeric carbon for the axial position of the pyranose ring.
The more stable axial configuration is explained by an orbital interac-
tion. Anomeric effect as an oldest part of stereoelectronic effects is
particularly important because it is a foundational concept that provides
a basis for understanding reactivity of many organic, organometallic,
and inorganic functional groups. It is a complicated effect because, as
any other chemical phenomenon, it is related to molecular energies,
conformations, and reactivity and depends on combination of factors, of
which electrostatics and delocalization competition is of key importance
[41–44]. In this phenomenon (i.e., AE), which is a kind of negative
hyperconjugation, the electron density is delocalized from the lone-pair
in a nonbonding orbital to the empty anti-bonding sigma orbital (n→σ*)
(Fig. 2).
AE has been divided into different types including geminal (Endo,
exo and reverse), vinylogous (Endo and exo) and so on (Fig. 3) [12]. This
paper attempts to describe the role of vinylogous AE in the course of
synthesis of target molecules for the first time [45]. Recently, we have
introduced and developed the new term “anomeric based oxidation”
(ABO) as a recent mechanistic viewpoint in the course of special re-
actions [46–52]. Cooperative geminal and vinylogous ABO has been
well reviewed (Schemes 1 and 2) [53]. Due to this immensity, we wish to
develop the application of the concept of ABO in new organic synthesis
(Fig. 4).
Fig. 2. Anomeric effect leads to the abnormal conformational preference.
many other natural products possess pyridine ring in their structures so
it is quite rational that pyridine-containing compounds continue to
receive great synthetic attention in organic chemistry [32–35]. On the
other hand, indole derivatives, which are another important class of
nitrogen containing heterocyclic compounds, also play notable role as
targets in synthesis of a variety of drugs such as zolmitriptan (migraine:
1), sumatriptan (migraine:2), tadalafil (erectile dysfunction: 3) and
indomethacin (anti-inflammatory :4). The structure of these
indole-containing drugs is shown in Fig. 1 [36]. The application of in-
doles in multicomponent reactions [37] and the various synthetic stra-
tegies for synthesis of bis and tris indolyl methane’s have been
previously reviewed [38].
In continuation of our investigation for developing biological based
catalysts, we wish to introduce a novel uric acid-based organoctalyst
with methylene phosphonic acid moieties as a derivative of theacrine
namely theacrine tetrakis(phosphonic acid) (TTPA). Theacrine is a pu-
rine alkaloid which has been also known as 1,3,7,9-tetramethyluric acid.
Theacrine is alike to caffeine molecule with additional methyl and
carbonyl groups at
9 and 8-positions respectively [56]. This
According to the alabugine’s theory the stereoelectronic effects is a
bridge between structure and reactivity and it has implications for many
reactions, from classic to new [39,40]. The anomeric effect (AE) as a
nano-organphosphorous acid was applied in the synthesis of novel
3-methyl-6-(2-methyl-1H-indol-3-yl)-1,4-diphenyl-1H-pyrazolo[3,4-b]
Fig. 3. Geminal anomeric effect versus the vinylogous anomeric effect.
Scheme 1. A cooperative geminal anomeric based oxidation mechanism in the synthesis of 2-sbstituted benz-(imida, oxa and othia)-zoles [54].
2

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Scheme 2. A cooperative vinylogous anomeric based oxidation mechanism in the synthesis of 1,4-dihydropyrano-[2,3-c]-pyrazoles [55].
Fig. 4. Prepared aromatized molecules through a cooperative vinylogous anomeric based oxidation mechanism [5353b].
pyridine-5-carbonitrile and 6-(5-methoxy-2-methyl-1H-indol-3-yl)-
recorded on a Perkin Elmer PE-1600-FTIR spectrometer. SEM was per-
formed using a scanning electron microscope. The curves of thermog-
ravimetric (TG), differential thermogravimetric (DTG) were recorded on
Perkin Elmer Pyris 1 thermogravimetric analyzer at a temperature range
of 25–600 ◦C and a heating rate of 10 ◦C/min. X-ray photoelectron
spectroscopy (XPS) was carried out using Kratos Axis Ultra Spectrom-
eter, equipped with an Al- Ka X-ray source (hn ¼ 1486.7 eV).
3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
by
reaction of various aromatic aldehydes, 3-methyl-1-phenyl-1H-pyr-
azol-5-amine and 3-(1H-indol-3-yl)-3-oxopropanenitrile derivatives
under solvent-free at 110 ◦C (Scheme 3).
2. Experimental
2.1. Materials and methods
2.2. General procedure for the preparation of Theacrine tetrakis
(phosphonic acid) (TTPA)
All chemicals were purchased from Merck Chemical Company. Silica
gel SIL G/UV 254 plates were used for monitoring the progress of the
reactions and purity tests. 1H NMR and 13C NMR spectra were recorded
on a BRUKER Ultrashield FT-NMR spectrometer in DMSO-d6 at fre-
quencies of 600 or 400 MHz for proton and 151 or 101 MHz for carbon.
Melting points were obtained on a Buchi B-545 apparatus using open
capillary tubes. The infrared spectra of the synthesized compounds were
According to our previously reported procedures [48,49], in a 50 mL
round-bottomed flask, a mixture of uric acid (1 mmol, 0.17 g), para-
formaldehyde (4 mmol, 0.12 g), phosphorous acid (4 mmol, 0.32 g),
p-TSA (10 mol%, 0.017 g) and 25 mL of ethanol were refluxed for 18 h.
After this time, the resulting white precipitate was filtered off and dried
under vacuum to give theacrine tetrakis(phosphonic acid) (Scheme 4).
3

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Scheme 3. Preparation of mono and bis-pyridines using theacrinete trakis(phosphonic acid) (TTPA) as a novel nano organocatalyst.
Scheme 4. Preparation of theacrine tetrakis(phosphonic acid) (TTPA).
Scheme 5. Preparation of 3-(1H-indol-3-yl)-3-oxopropanenitrile derivatives.
2.3. General procedure for the synthesis of (2-methyl-1H-indol-3-yl)-
pyrazolo[3,4-b]pyridine derivatives using TTPA as catalyst
H), 7.46 (d, J =7.8 Hz, 2 H), 7.42 (d, J =7.8 Hz, 1 H), 7.34 (t, J =7.4 Hz,
1 H), 7.15 (t, J =7.4 Hz, 1 H), 7.09 (t, J =7.8 Hz, 1 H), 2.59 (s, 3 H), 2.47
(s, 3 H), 2.12 (s, 3 H).13C NMR (101 MHz, DMSO-d6) δ 156.7, 152.2,
150.1, 143.8, 139.5, 138.4, 137.4, 135.0, 130.8, 129.1, 129.1, 129.0,
126.9, 126.2, 121.3, 120.6, 119.8, 118.8, 117.6, 112.3, 111.1, 111.0,
102.8, 20.9, 14.5, 13.2.
Initially,3-(1H-indol-3-yl)-3-oxopropanenitrile derivatives were
synthesized according to the previously reported literature (Scheme 5)
[47,57]. Then, a mixture of 3-methyl-1-phenyl-1H-pyrazol-5-amine
(1 mmol, 0.174 g), aryl aldehyde (1 mmol), 3-(2-methyl-1-
H-indol-3-yl)-3-oxopropanenitrile derivatives (1 mmol) and theacrine
tetrakis(phosphonic acid) (10 mol%, 0.0054 g) as the reaction catalyst
were stirred under solvent-free condition at 110 ◦C in a 25 mL
round-bottomed flask. After completion of the reaction [monitored by
TLC (n-hexane: ethyl acetate 1:1)] the catalyst was separated by
centrifugation (2000 rpm) after adding polyethylene glycol (PEG, 5 mL)
for 5 min. Finally, the mixture was filtered off and washed with ethanol
(3 × 10 mL) and the desired pure product was obtained (Scheme 3).
2.3.1.2. 4-(4-Bromophenyl)-3-methyl-6-(2-methyl-1H-indol-3-yl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2a). White solid; Mp:
298ꢀ 300 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3213, 3184, 2926, 2211, 1666, 1571,
1546. 1H NMR (600 MHz, DMSO-d6) δ 11.70 (s, 1 H), 8.25 (d, J =7.9 Hz,
2 H), 7.95 (s, 1 H), 7.87 (d, J =8.3 Hz, 2 H), 7.71 (d, J =8.3 Hz, 2 H), 7.68
(d, J =8.0 Hz, 1 H), 7.55 (t, J =7.9 Hz, 2 H), 7.42 (d, J =8.0 Hz, 1 H),
7.35 (t, J =7.4 Hz, 1 H), 7.15 (t, J =7.5 Hz, 1 H), 7.09 (t, J =7.4 Hz, 1 H),
2.60 (s, 3 H), 2.12 (s, 3 H).13C NMR (151 MHz, DMSO-d6) δ 162.7,
157.2, 151.2, 150.6, 144.1, 138.8, 138.0, 135.5, 133.5, 132.01 131.8,
129.7, 127.3, 126.7, 124.1, 121.8, 121.1, 120.3, 119.3, 117.9, 112.7,
111.5, 103.2, 40.3, 40.2, 40.1, 39.9, 39.8, 39.6, 39.5, 36.2, 31.2, 15.0,
13.7.
2.3.1. Spectral data
2.3.1.1. 3-Methyl-6-(2-methyl-1H-indol-3-yl)-1-phenyl-4-(p-tolyl)-1H-
pyrazolo [3,4-b]pyridine-5-carbonitrile (1a). White solid; Mp: 255ꢀ 257
◦C; IR (KBr):
υ
(cmꢀ 1) = 3294, 3064, 2926, 2854, 2224, 1583, 1551. 1H
2.3.1.3. 4-(4-Chlorophenyl)-3-methyl-6-(2-methyl-1H-indol-3-yl)-1-
NMR (600 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.26 (d, J =7.9 Hz, 2 H),
7.67 (d, J =7.9 Hz, 1 H), 7.61 (d, J =7.8 Hz, 2 H), 7.55 (t, J =7.9 Hz, 2
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (3a). White solid; Mp:
272-275 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3428, 3298, 3082, 2912, 2226, 1594,
4

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 5. FT-IR spectrum of TTPA.
Fig. 6. Mass spectrum of TTPA.
5

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 7. XRD pattern of TTPA.
2.3.1.6. 4-(4-(Diethylamino) phenyl)-3-methyl-6-(2-methyl-1H-indol-3-
Table 1
yl)-1-phenyl-1H-pyrazolo
[3,4-b]pyridine-5-carbonitrile
(6a). White
solid; Mp: 274ꢀ 276 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3357, 3061, 2974, 2220,
XRD data of TTPA.
1602, 1522, 1478. 1H NMR (600 MHz, DMSO-d6) δ 11.65 (s, 1 H), 8.26
(d, J =8.0 Hz, 2 H), 7.67 (d, J =7.9 Hz, 1 H), 7.53 (dd, J = 13.2, 8.1 Hz, 4
H), 7.41 (d, J =8.0 Hz, 1 H), 7.33 (t, J =7.4 Hz, 1 H), 7.14 (t, J =7.5 Hz, 1
H), 7.09 (t, J =7.4 Hz, 1 H), 6.87 (d, J =8.6 Hz, 2 H), 3.45 (q, J =6.9 Hz,
4 H), 2.59 (s, 3 H), 2.26 (s, 3 H), 1.17 (t, J =7.0 Hz, 6 H).13C NMR (151
MHz, DMSO-d6) δ 157.4, 153.3, 150.9, 149.0, 144.5, 139.0, 137.8,
135.5, 131.6, 129.6, 127.5, 126.5, 121.7, 121.1, 120.2, 119.6, 119.4,
118.9, 112.8, 111.8, 111.48, 110.8, 102.9, 44.1, 15.7, 13.8, 12.9.
Entry
2θ
Peak width (degree)
Size [nm]
Inter planer distance[nm]
1
2
3
4
5
6
13.58
18.03
23.08
27.28
28.93
41.43
0.6
13.23
13.31
15.78
14.76
14.04
15.34
0.65
0.49
0.38
0.32
0.31
0.22
0.6
0.51
0.55
0.58
0.55
1573. 1H NMR (600 MHz, DMSO-d6) δ 11.70 (s, 1 H), 8.26 (d, J =8.1 Hz,
2 H), 7.79 (d, J =8.3 Hz, 2 H), 7.74 (d, J =8.3 Hz, 2 H), 7.68 (d, J =7.9
Hz, 1 H), 7.55 (t, J =7.8 Hz, 2 H), 7.42 (d, J =8.0 Hz, 1 H), 7.35 (t, J =7.4
Hz, 1 H), 7.15 (t, J =7.5 Hz, 1 H), 7.09 (t, J =7.5 Hz, 1 H), 2.60 (s, 3 H),
2.12 (s, 3 H).13C NMR (151 MHz, DMSO-d6) δ 157.2, 151.2, 150.6,
144.1, 138.8, 138.0, 135.5, 135.3, 133.1, 131.6, 129.7, 129.1, 127.3,
126.7, 121.8, 121.1, 120.3, 119.3, 117.9, 112.7, 111.5, 103.3, 40.3,
40.2, 40.1, 39.9, 39.8, 39.6, 39.5, 15.0, 13.7.
2.3.1.7. 4-(4-Methoxyphenyl)-3-methyl-6-(2-methyl-1H-indol-3-yl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (7a). White solid; Mp:
246ꢀ 248 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3418, 3058, 2929, 2215, 1579, 1549.
1H NMR (600 MHz, DMSO-d6) δ 11.67 (s, 1 H), 8.26 (d, J =8.1 Hz, 2 H),
7.68 (d, J =8.1 Hz, 3 H), 7.55 (t, J =7.8 Hz, 2 H), 7.42 (d, J =8.0 Hz, 1
H), 7.34 (t, J =7.4 Hz, 1 H), 7.20 (d, J =8.4 Hz, 2 H), 7.14 (t, J =7.5 Hz, 1
H), 7.09 (t, J =7.5 Hz, 1 H), 3.89 (s, 3 H), 2.59 (s, 3 H), 2.16 (s, 3 H).13
C
NMR (151 MHz, DMSO-d6) δ 160.9, 157.3, 152.5, 150.6, 144.3, 138.9,
137.8, 135.5, 131.4, 129.6, 127.4, 126.6, 126.2, 121.8, 121.1, 120.3,
119.3, 118.2, 114.3, 113.0, 111.6, 111.4, 103.5, 55.8, 40.3, 40.2, 40.1,
39.9, 39.8, 39.6, 39.5, 15.2, 13.7.
2.3.1.4. 3-Methyl-6-(2-methyl-1H-indol-3-yl)-1-phenyl-4-(o-tolyl)-1H-
pyrazolo[3,4-b]pyridine-5-carbonitrile (4a). White solid; Mp: 255ꢀ 258
◦C; IR (KBr):
υ
(cmꢀ 1) = 3412, 3061, 2923, 2215, 1601, 1567, 1507. 1H
NMR (600 MHz, DMSO-d6) δ 11.69 (s, 1 H), 8.29 – 8.27 (m, 2 H), 7.66 (d,
J =7.9 Hz, 1 H), 7.57 – 7.49 (m, 4 H), 7.48 (d, J =1.4 Hz, 1 H), 7.45 (dd, J
= 7.4, 1.6 Hz, 1 H), 7.44 – 7.41 (m, 1 H), 7.37 – 7.31 (m, 1 H), 7.18 –
7.13 (m, 1 H), 7.12 – 7.07 (m, 1 H), 2.59 (s, 3 H), 2.20 (s, 3 H), 1.97 (s, 3
H).13C NMR (151 MHz, DMSO-d6) δ 157.2, 152.1, 150.6, 144.3, 138.9,
137.9, 135.6, 135.5, 134.0, 130.7, 130.2, 129.7, 129.1, 127.4, 126.6,
126.5, 121.9, 121.0, 120.4, 119.2, 117.6, 113.0, 111.5, 103.5, 40.5,
40.3, 40.2, 40.1, 39.9, 39.8, 39.6, 39.5, 19.7, 13.7, 13.7
2.3.1.8. 4-(4-fluorophenyl)-3-methyl-6-(2-methyl-1H-indol-3-yl)-1-
phenyl-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile (8a). White solid; Mp:
1
198ꢀ 200 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3323, 3050, 2920, 2220, 1597. H
NMR (400 MHz, DMSO-d6) δ 11.71 (s, 1 H), 8.26 (d, J =7.7 Hz, 2 H),
7.95 (s, 1 H), 7.81 (dd, J = 8.6, 5.4 Hz, 2 H), 7.69 (d, J =7.8 Hz, 1 H),
7.56 – 7.47 (m, 4 H), 7.43 (d, J =7.9 Hz, 1 H), 7.34 (t, J =7.4 Hz, 1 H),
7.15 (t, J =7.0 Hz, 1 H), 7.09 (t, J =7.0 Hz, 1 H), 2.61 (s, 3 H), 2.10 (s, 3
H).13C NMR (101 MHz, DMSO-d6) δ 164.2, 162.3, 161.7, 156.7, 151.0,
150.1, 143.7, 138.3, 137.5, 135.0, 131.7, 131.6, 130.1, 130.1, 129.1,
126.9, 126.2, 121.3, 120.6, 119.8, 118.8, 117.5, 115.6, 115.4, 112.4,
111.0, 111.0, 103.0, 39.8, 39.6, 39.4, 39.2, 39.0, 35.7, 30.7, 14.4, 13.2.
2.3.1.5. 4-(4-Isopropylphenyl)-3-methyl-6-(2-methyl-1H-indol-3-yl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (5a). White solid; Mp:
300ꢀ 302 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3360, 3061, 2962, 2223, 1573, 1550.
1H NMR (600 MHz, DMSO-d6) δ 11.68 (s, 1 H), 8.26 (d, J =8.0 Hz, 2 H),
7.67 (d, J =7.9 Hz, 1 H), 7.64 (d, J =7.9 Hz, 2 H), 7.57 – 7.50 (m, 4 H),
7.42 (d, J =8.0 Hz, 1 H), 7.34 (t, J =7.4 Hz, 1 H), 7.15 (t, J =7.5 Hz, 1 H),
7.09 (t, J =7.4 Hz, 1 H), 3.05 (h, J =6.9 Hz, 1 H), 2.59 (s, 3 H), 1.31 (d, J
=6.9 Hz, 6 H).13C NMR (151 MHz, DMSO-d6) δ 148.5, 148.3, 146.0,
146.0, 138.7, 137.6, 137.3, 135.5, 134.8, 130.9, 129.7, 129.6, 127.4,
127.3, 123.6, 123.5, 122.6, 122.6, 122.4, 121.69, 121.4, 121.1, 120.2,
119.0, 111.4, 106.1, 101.0, 84.1, 84.1, 56.4, 40.2, 40.0, 39.9, 39.8, 39.6,
19.0.
2.3.1.9. 4-(2-Bromo-4-methoxyphenyl)-3-methyl-6-(2-methyl-1H-indol-3-
yl)-1-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile (9a). White solid;
Mp: 172ꢀ 175 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3388, 3326, 2926, 2840, 2222,
1600, 1555, 1458. 1H NMR (600 MHz, DMSO-d6) δ 11.72 (s, 1 H), 8.27
(d, J =7.7 Hz, 2 H), 7.68 – 7.64 (m, 2 H), 7.56 (t, J =8.0 Hz, 2 H), 7.52 (d,
J =2.5 Hz, 1 H), 7.43 (d, J =8.0 Hz, 1 H), 7.35 (t, J =7.4 Hz, 1 H), 7.24
(dd, J = 8.5, 2.5 Hz, 1 H), 7.16 (t, J =7.2 Hz, 1 H), 7.10 (t, J =7.4 Hz, 1
H), 3.92 (s, 3 H), 2.59 (s, 3 H), 2.08 (s, 3 H).13C NMR (151 MHz, DMSO-
d6) δ 161.3, 157.1, 150.9, 150.6, 144.1, 138.8, 138.0, 135.6, 131.9,
6

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 8. (a) Energy dispersive X-ray spectroscopy (EDX) and (b) SEM-elemental mapping of TTPA.
129.7, 127.3, 127.2, 126.7, 122.6, 121.9, 121.1, 120.4, 119.2, 118.1,
117.4, 114.6, 113.2, 111.6, 111.4, 104.2, 56.3, 40.3, 40.2, 40.1, 39.9,
39.8, 39.6, 39.5, 13.9, 13.7.
154.6, 152.7, 150.7, 144.3, 140.0, 139.0, 138.4, 131.4, 130.5, 129.6,
129.6, 129.5, 128.0, 126.7, 121.1, 118.2, 112.8, 112.1, 111.9, 111.7,
103.1, 101.3, 55.6, 21.5, 15.0, 14.1.
2.3.1.10. 4-(4-fluorophenyl)-6-(5-methoxy-2-methyl-1H-indol-3-yl)-3-
2.3.1.12. 4-(5-cyano-6-(5-methoxy-2-methyl-1H-indol-3-yl)-3-methyl-1-
phenyl-1H-pyrazolo [3,4-b]pyridin-4-yl)benzoic acid(3b). White solid;
Mp: >300 ◦C; 1H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1 H), 11.56 (s, 1
H), 8.30 (d, J =7.7 Hz, 2 H), 8.20 (d, J =8.2 Hz, 2 H), 7.86 (d, J =8.2 Hz,
2 H), 7.57 (d, J =7.5 Hz, 2 H), 7.39 – 7.28 (m, 4 H), 6.79 (dd, J = 8.7, 2.2
Hz, 1 H), 3.73 (s, 3 H), 2.89 (s, 3 H), 2.08 (s, 3 H). 13C NMR (101 MHz,
DMSO-d6) δ 166.8, 156.7, 154.1, 151.1, 150.1, 143.6, 138.4, 138.0,
132.0, 130.0, 129.5, 129.3, 129.1, 127.5, 126.3, 120.7, 117.4, 112.0,
111.6, 111.4, 102.3, 100.9, 55.1, 14.3, 13.6.
methyl-1-phenyl-1H-pyrazolo
[3,4-b]pyridine-5-carbonitrile(1b). White
solid; Mp: 280ꢀ 282 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3332, 2967, 2221, 1604,
1560. 1H NMR (600 MHz, DMSO-d6) δ: 11.55 (s, 1 H), 8.30 (d, 2 H), 7.84
– 7.78 (m, 2 H), 7.57 – 7.49 (m, 4 H), 7.37 – 7.28 (m, 3 H), 6.79 (dd, J =
8.7, 2.5 Hz, 1 H), 3.72 (s, 3 H), 2.56 (s, 3 H), 2.11 (s, 3 H).13C NMR (101
MHz, DMSO-d6) δ 164.2, 161.7, 156.7, 154.1, 151.1, 150.1, 143.7,
138.4, 138.0, 131.6, 131.6, 130.2, 130.0, 129.1, 127.5, 126.2, 120.6,
117.5, 115.7, 115.4, 112.4, 111.6, 111.4, 111.1, 102.7, 100.9, 55.1,
40.0, 39.8, 39.6, 39.4, 39.2, 39.0, 38.8, 14.4, 13.6.
2.3.1.13. 6-(5-Methoxy-2-methyl-1H-indol-3-yl)-3-methyl-1-phenyl-4-(o-
2.3.1.11. 6-(5-Methoxy-2-methyl-1H-indol-3-yl)-3-methyl-1-phenyl-4-(p-
tolyl)-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile(4b). White solid; Mp:
tolyl)-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile(2b). White solid; Mp:
223ꢀ 225 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3295, 2961, 2924, 2220, 1622, 1589,
291ꢀ 293 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3315, 3003, 2921, 2220, 1622, 1590,
1574. 1H NMR (600 MHz, DMSO-d6) δ 11.55 (s, 1 H), 8.32 (d, J =7.7 Hz,
2 H), 7.58 – 7.51 (m, 4 H), 7.49 – 7.44 (m, 2 H), 7.35 (t, J =7.4 Hz, 1 H),
7.31 (d, J =8.7 Hz, 1 H), 7.26 (s, 1 H), 6.79 (dd, J = 8.7, 2.4 Hz, 1 H),
3.73 (s, 3 H), 2.55 (s, 3 H), 2.22 (s, 3 H), 1.97 (s, 3 H).13C NMR (151
MHz, DMSO-d6) δ 157.2, 154.6, 152.2, 150.7, 144.3, 139.0, 138.4,
135.5, 134.1, 130.7, 130.5, 130.2, 129.6, 129.1, 128.0, 126.6, 126.5,
1574. 1H NMR (600 MHz, DMSO-d6) δ 11.53 (s, 1 H), 8.30 (d, J =7.7 Hz,
2 H), 7.61 (d, J =8.0 Hz, 2 H), 7.55 (t, J =8.0 Hz, 2 H), 7.47 (d, J =7.9
Hz, 2 H), 7.35 (t, J =7.4 Hz, 1 H), 7.30 (d, J =8.7 Hz, 1 H), 7.27 (d, J
=2.4 Hz, 1 H), 6.78 (dd, J = 8.7, 2.4 Hz, 1 H), 3.73 (s, 3 H), 2.55 (s, 3 H),
2.47 (s, 3 H), 2.12 (s, 3 H).13C NMR (151 MHz, DMSO-d6) δ 157.3,
7

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 9. Scanning electron microscopy (SEM) images TTPA.
121.0, 117.7, 113.0, 112.2, 111.9, 111.6, 103.2, 101.2, 55.5, 40.5, 40.3,
40.2, 40.1, 39.9, 39.8, 39.6, 39.5, 19.6, 14.1, 13.7.
solid; Mp: 272ꢀ 275 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3332, 2998, 2929, 2219,
1622, 1592, 1573. 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1 H), 8.30
(d, J =7.7 Hz, 2 H), 7.80 – 7.72 (m, 4 H), 7.55 (t, J =8.0 Hz, 2 H), 7.38 –
7.27 (m, 3 H), 6.79 (dd, J = 8.7, 2.4 Hz, 1 H), 3.72 (s, 3 H), 2.56 (s, 3 H),
2.12 (s, 3 H).
2.3.1.14. 4-(4-(Diethylamino) phenyl)-6-(5-methoxy-2-methyl-1H-indol-
3-yl)-3-methyl-1-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile(5b).
White solid; Mp: 272ꢀ 275 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3332, 2967, 2826,
2221, 1604, 1560, 1522. 1H NMR (600 MHz, DMSO-d6) δ 11.68 (s, 1 H),
8.26 (d, J =8.0 Hz, 2 H), 7.67 (d, J =7.9 Hz, 1 H), 7.64 (d, J =7.9 Hz, 2
H), 7.57 – 7.50 (m, 4 H), 7.42 (d, J =8.0 Hz, 1 H), 7.34 (t, J =7.4 Hz, 1
H), 7.15 (t, J =7.5 Hz, 1 H), 7.09 (t, J =7.4 Hz, 1 H), 3.05 (h, J =6.9 Hz, 1
H), 2.59 (s, 3 H), 1.31 (d, J =6.9 Hz, 6 H).13C NMR (151 MHz, DMSO-d6)
δ 157.5, 154.5, 153.3, 151.0, 149.1, 144.4, 139.1, 138.2, 131.6, 130.5,
129.5, 128.1, 126.5, 121.1, 119.6, 119.0, 112.7, 112.1, 111.8, 111.8,
110.8, 102.7, 101.3, 55.6, 44.1, 15.7, 14.1, 12.9.
2.3.1.17. 4-(2-Bromo-4-methoxyphenyl)-6-(5-methoxy-2-methyl-1H-
indol-3-yl)-3-methyl-1-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile
(8b). White solid; Mp: 230ꢀ 234 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3291, 3009,
2929, 2223, 1599, 1575, 1505. 1H NMR (600 MHz, DMSO-d6) δ 11.59 (s,
1 H), 8.30 (d, J =7.9 Hz, 2 H), 7.65 (d, J =8.5 Hz, 1 H), 7.56 (t, J =7.9
Hz, 2 H), 7.53 (d, J =2.4 Hz, 1 H), 7.36 (t, J =7.4 Hz, 1 H), 7.31 (d, J
=8.7 Hz, 1 H), 7.24 (dd, J = 8.4, 2.3 Hz, 2 H), 6.79 (dd, J = 8.7, 2.3 Hz, 1
H), 3.92 (s, 3 H), 3.73 (s, 3 H), 2.56 (s, 3 H), 2.08 (s, 3 H).13C NMR (151
MHz, DMSO-d6) δ 161.3, 157.1, 154.6, 151.0, 150.7, 144.1, 138.9,
138.5, 131.9, 130.5, 129.7, 127.8, 127.2, 126.7, 122.7, 121.0, 118.2,
117.5, 114.7, 113.1, 112.2, 112.0, 111.5, 103.9, 101.1, 56.34, 55.5,
14.0, 13.9.
2.3.1.15. 4-(4-Bromophenyl)-6-(5-methoxy-2-methyl-1H-indol-3-yl)-3-
methyl-1-phenyl-1H-pyrazolo
[3,4-b]pyridine-5-carbonitrile(6b). White
solid; Mp: 200ꢀ 202 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3315, 3003, 2921, 2220,
1622, 1590, 1574. 1H NMR (600 MHz, DMSO-d6) δ 11.55 (s, 1 H), 8.30 –
8.29 (m, 2 H), 7.88 (d, J =8.4 Hz, 2 H), 7.71 (d, J =8.4 Hz, 2 H), 7.56 (m,
3 H), 7.36 (s, 1 H), 7.30 (d, J =8.7 Hz, 1 H), 7.28 (d, J =2.5 Hz, 1 H), 6.79
2.3.1.18. 6-(5-Methoxy-2-methyl-1H-indol-3-yl)-4-(4-methoxyphenyl)-3-
methyl-1-phenyl-1H-pyrazolo
[3,4-b]pyridine-5-carbonitrile(9b). White
(dd, J = 8.7, 2.5 Hz, 1 H), 3.72 (s, 3 H), 2.56 (s, 3 H), 2.13 (s, 3 H).13
C
solid; Mp: 200ꢀ 202 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3316, 3001, 2929, 2221,
NMR (151 MHz, DMSO-d6) δ 157.2, 154.6, 151.3, 150.6, 144.1, 138.9,
138.5, 133.5, 132.0, 131.8, 130.5, 129.7, 128.0, 126.7, 124.1, 121.1,
118.0, 112.6, 112.1, 111.9, 111.6, 102.9, 101.4, 55.64, 15.0, 14.1.
1608, 1576, 1555. 1H NMR (600 MHz, DMSO-d6) δ 11.52 (s, 1 H), 8.30
(d, J =7.7 Hz, 2 H), 7.67 (d, J =8.6 Hz, 2 H), 7.55 (t, J =7.9 Hz, 2 H),
7.35 (t, J =7.4 Hz, 1 H), 7.30 (d, J =8.7 Hz, 1 H), 7.27 (d, J =2.3 Hz, 1
H), 7.21 (d, J =8.7 Hz, 2 H), 6.78 (dd, J = 8.7, 2.4 Hz, 1 H), 3.90 (s, 3 H),
3.73 (s, 3 H), 2.56 (s, 3 H), 2.16 (s, 3 H).13C NMR (151 MHz, DMSO-d6) δ
160.9, 157.3, 154.6, 152.6, 150.7, 144.3, 139.0, 138.4, 131.4, 130.5,
2.3.1.16. 4-(4-chlorophenyl)-6-(5-methoxy-2-methyl-1H-indol-3-yl)-3-
methyl-1-phenyl-1H-pyrazolo
[3,4-b]pyridine-5-carbonitrile(7b). White
8

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
(d, J =8.3 Hz, 1 H), 8.30 (d, J =7.7 Hz, 2 H), 8.08 (dd, J = 7.5, 1.1 Hz, 1
H), 8.00 – 7.97 (m, 1 H), 7.93 (dd, J = 7.6, 1.2 Hz, 1 H), 7.57 (d, J =8.4
Hz, 2 H), 7.37 (d, J =7.4 Hz, 1 H), 7.31 (d, J =8.7 Hz, 1 H), 7.21 (s, 1 H),
6.79 (dd, J = 8.7, 2.4 Hz, 1 H), 3.73 (s, 3 H), 2.53 (s, 3 H), 2.01 (s, 3
H).13C NMR (151 MHz, DMSO-d6) δ 154.6, 150.7, 147.7, 143.8, 138.8,
138.5, 135.2, 132.3, 130.5, 129.7, 128.9, 127.8, 126.9, 125.8, 121.1,
112.3, 112.1, 111.4, 102.4, 55.5, 13.9, 13.9.
2.3.1.20. 4,4′-(1,3-Phenylene)bis(3-methyl-6-(2-methyl-1H-indol-3-yl)-1-
phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile)(1c). White solid; Mp:
282ꢀ 284 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3323, 3058, 2920, 2220, 1597, 1505.
1H NMR (600 MHz, DMSO-d6) δ 11.70 (s, 2 H), 8.26 (d, J =7.9 Hz, 4 H),
7.96 (s, 1 H), 7.70 (d, J =8.0 Hz, 2 H), 7.58 – 7.52 (m, 6 H), 7.42 (d, J
=7.9 Hz, 2 H), 7.35 (d, J =4.9 Hz, 2 H), 7.15 (d, J =4.7 Hz, 2 H), 7.08 (d,
J =4.7 Hz, 2 H), 2.61 (s, 6 H), 2.17 (s, 6 H).
2.3.1.21. 4-(3-(5-Cyano-6-(4-methoxy-2-methyl-1H-indol-3-yl)-3-methyl-
1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)phenyl)-6-(5-methoxy-2-methyl-
1H-indol-3-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carbon-
itrile(2c). White solid; Mp: 200ꢀ 202 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3219,
3161, 2978, 2194, 1616, 1534, 1348. 1H NMR (600 MHz, DMSO-d6) δ
11.55 (s, 1 H), 8.30 (d, J =7.9 Hz, 2 H), 7.96 (d, J =3.2 Hz, 1 H), 7.58 –
7.53 (m, 3 H), 7.35 (d, J =7.2 Hz, 2 H), 7.32 (s, 1 H), 7.31 (d, J =3.2 Hz,
1 H), 6.79 (dd, J = 8.7, 2.1 Hz, 1 H), 3.72 (s, 3 H), 2.57 (s, 3 H), 2.17 (s, 3
H).13C NMR (151 MHz, DMSO-d6) δ 157.1, 151.8, 150.5, 144.4, 138.9,
138.0, 135.6, 135.0, 129.7, 127.4, 121.9, 121.2, 120.3, 113.1, 111.5,
103.6, 14.6, 13.7.
Fig. 10. Transmission electron microscopy (TEM) images TTPA.
2.4. Cytotoxicity studies
129.6, 128.1, 126.6, 126.3, 121.1, 118.3, 114.3, 112.9, 112.1, 111.9,
111.7, 103.2, 101.3, 55.8, 55.6, 15.2, 14.1.
Hela cells were cultured in dulbecco’s modified eagle medium,
supplemented with fetal bovine serum (10 %) and penicillin-
streptomycin mixture (100 U/mL and 100 mg/mL) in humidified air
containing 5% CO2 at 37 ◦C. Hela cells were seeded on a 24-well plate,
cultured for 12–24 hours, and then treated with 6a and 5b with different
2.3.1.19. 6-(5-Methoxy-2-methyl-1H-indol-3-yl)-3-methyl-4-(2-nitro-
phenyl)-1-phenyl-1H-pyrazolo [3,4-b]pyridine-5-carbonitrile(10b). White
solid; Mp: 241ꢀ 244 ◦C; IR (KBr):
υ
(cmꢀ 1) = 3295, 3071, 3003, 2221,
concentrations (0, 5, 10, 25, 50, 100 and 200
μM) for 72 h. Thereafter,
1622, 1593, 1577. 1H NMR (600 MHz, DMSO-d6) δ 11.60 (s, 1 H), 8.47
the entire medium and cells from one well of the 24-well plate were
Fig. 11. X-ray photoelectron spectroscopy (XPS) of TTPA (a) C 1s, (b) O 1s, (c) N 1s and (d) P 2p spectra for the * film on metal.
9

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 12. Thermal gravimetric (TG) and derivative thermal gravimetric (DTG) of TTPA.
Table 2
Effect of different amounts of catalysts, temperature and solvent (5 mL) in the synthesis of (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives.
Entry
Solvent
Catalyst (mol%)
Temp. (◦C)
Time (min)
Yield (%)
1
2
H2O
10
10
10
10
10
10
10
10
10
10
10
15
20
–
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
110
120
120
120
120
120
120
120
120
120
120
20
–
CH3CN
10
–
3
n-Hexane
4
CHCl3
–
5
Toluene
15
20
48
35
–
6
MeOH
7
DMF
8
EtOH
Reflux
Reflux
Reflux
110
9
CH2Cl2
10
11
12
13
14
15
16
17
EtOAc
–
–
–
–
–
–
–
–
83
82
80
–
110
20
110
20
110
120
40
10
10
10
90
73
48
25
70
40
25
120
collected into a micro centrifuge tube. Cell viability was quantified by
cell counting kit 8 (Beyotime Shanghai, China) assay in microplate
approved by FT-IR, Mass spectra, X-ray diffraction analysis (XRD), en-
ergy dispersive X-ray spectroscopy (EDX), SEM-elemental mapping,
scanning electron microscope (SEM), transmission electron microcopy
(TEM), XPS, thermal gravimetric (TG) and derivative thermal gravi-
metric (DTG). Then, the presented catalyst was used for the synthesis of
novel (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives as
biological active candidates.
¨
reader (Model Spark, TECAN, Mannedorf, Switzerland) according to the
manufacturer’s instruction.
3. Results and discussion
With the idea to show how stereoelectronic concepts can help
chemists to build a conceptual bridge between structure and reactivity
the synthesis of biological based uric acid (UA) with phosphorous acid
functional groups was carried out. The structure of theacrine tetrakis
(phosphonic acid) (TTPA) as nano-organocatalyst was thoroughly
FT-IR spectrum of TTPA is shown in Fig. 5. The bands at 3000 and
2824 cmꢀ 1 are assigned to aromatic C–H stretching vibrations. Besides,
the broad peak at 2800ꢀ 3400 cm-1 is related to OH of PO3H2 functional
–
groups. The absorption bands at 992 and 1055 cmꢀ 1 are related to P
O
bond stretching and the band at 1123 cm-1 is related to P O bond. Mass
–
–
10

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Table 3
Synthesis of 3-methyl-6-(2-methyl-1H-indol-3-yl)-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
derivatives by TTPA as a catalyst.
spectrum of TTPA is shown in Fig. 6. The mass spectrum of the catalyst
gave the molecular ion peak at 545 m/z corresponding to its molecular
formula.
one double bond with oxygen and two bonds with nitrogen. The peaks
with lower binding energy (284.8 eV) corresponds to the carbon making
one double bond with oxygen, one bond with nitrogen and one bond
with carbon, respectively [58]. Two broad O 1s peaks at 532.7 and 531.1
eV (Fig. 11b) indicate the different chemical states of oxygen. The peak
at 531.1 eV is due to oxygen making a double bond with carbon and the
other one at higher binding energy (532.7 eV) is attributed to the oxygen
in phosphategroups [59]. The peaks at 400.1 and 402.1 eV (Fig. 11c)
The particle size of TTPA was examined by X-ray diffraction analysis
(XRD) pattern in the 10–70 degrees (2θ) range. (Fig. 7). Debye-Scherrer
formula D = Kλ/(β cosθ) and Bragg equation: dhkl = λ/(2 s in.) were used
for calculating crystal sizes in the nanometer range (13ꢀ 16 nm)
(Table 1). The results of XRD analysis revealed a regular structure in
close agreement with the SEM images.
–
correspond to N 1s. Three C N bonds are formed from overlap of ni-
The elemental analysis and element distribution images of TTPA
were obtained by methods of energy dispersive X-ray spectroscopy
(EDX) and SEM-elemental mapping. The energy dispersive X-ray spec-
troscopy (EDX) was confirmed the existence of C, N, O and P atoms
(Fig. 8a). Then, SEM-elemental mapping revealed uniformly distribution
of elements throughout the sample C, N, O and P (Fig. 8b).
Morphology and particle size of TTPA were also studied by scanning
electron microscopy (SEM) and transmission electron microscopy (TEM)
images (Figs. 9 and 10). As shown, according to the obtained images
from TTPA its particles size is in nano scale which are regularly arranged
and not completely stacked.
trogen sp2 hybride orbital with three carbon sp2 orbitals (401.1–402.1
eV) [60]. The broad P 2p peak at 133.5 eV (Fig. 11d) is attributed to the
phosphate group [61]. The XPS and FT-IR spectra were in good agree-
ment for showing functional groups on the surface of the TTPA.
Thermal stability and structural of TTPA were also studied by ther-
mal gravimetric (TG) and derivative thermal gravimetric (DTG)
◦
(Fig. 12). The first step of weight loss was found at 441 C (includes
about 60 % weight loss), which was linked to breaking the bond of N-C-
PO3H2 in the structure of TTPA. This weight loss was related to removal
of P4O12 in the catalyst structure.
After the design, synthesis and identification of TTPA as an acidic
organocatalyst, it was tested for the synthesis of new N-heterocycle
derivatives such as (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine
derivatives. The synthesis of (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]
pyridine was selected as a model compound for optimization of reaction
by applying 4-methyl benzaldehyde (1 mmol, 0.151 g), 3-methyl-1-
phenyl-1H-pyrazol-5-amine (1 mmol, 0.174 g) and 3-(1H-indol-3-yl)-3-
oxopropanenitrile (1 mmol, 0.198 g). The optimized reaction conditions
are listed in Table 2. As shown, the best reaction conditions for the
The chemical composition of the TTPA was also confirmed by X-ray
photoelectron spectroscopy (XPS). The XPS spectra showed the presence
of carbon, oxygen, nitrogen, and phosphorus in the synthesized catalyst
and peaks corresponding to C 1s (a); O 1s (b); N 1s (c) and P 2p (d) were
detected (Fig. 11).
The broad C 1s peak (Fig. 11a) is divided into four peaks centered at
290.8, 288.4, 287.1 and 284.8 eV, separately. The peak at the higher
binding energy (290.8, 288.4 and 287.1 eV) is due to the carbon making
11

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Table 4
Synthesis of 6-(5-methoxy-2-methyl-1H-indol-3-yl)-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
derivatives by TTPA as a catalyst.
synthesis of (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine was
achieved in the presence of 10 mol% TTPA under solvent free condition
at 110 ◦C (entry 11, Table 2). As seen from Table 2, the other experi-
mental conditions used for the model reaction (i.e. different amounts of
catalyst and various temperatures) resulted in no better improvement in
reaction yield and time (entries 12–17, Table 2). The model reaction
was also studied in the several solvents such as H2O, CH3CN, n-Hexane,
CHCl3, Toluene, MeOH, DMF, EtOH, CH2Cl2, EtOAc (10 mL) (entries
1–10, Table 2). Considering the obtained reaction yield and time, we
chose the solvent-free condition in the presence of 10 mol% of the
acrinetetrakis(phosphonic acid) as optimal experimental condition.
In the next step, TTPA was used as a nano heterogeneous organo-
catalyst, in the reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1
mmol, 0.174 g), aryl aldehyde (1 mmol) and 3-(2-methyl-1H-indol-3-
yl)-3-oxopropanenitrile derivatives (1 mmol). As exposed in Table 3, the
results show that this method is suitable for the synthesis of novel (2-
methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives such as 3-
methyl-6-(2-methyl-1H-indol-3-yl)-1,4-diphenyl-1H-pyrazolo[3,4-b]
pyridine-5-carbonitrile and 6-(5-methoxy-2-methyl-1H-indol-3-yl)-3-
methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in high
to excellent yields (82–95 %) in relatively short reaction time (4ꢀ 20
min). As shown in Tables 3–5, all aldehydes including benzaldehyde as
well as other aromatic aldehydes possessing electron-releasing sub-
stituents, electron withdrawing substituents, basic groups or halogens
afforded the desired novel (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]
pyridine derivatives with good to excellent yields. Also, bis aromatic
aldehydes (terphetaldehyde and iso-terphetaldehyde) produced their
corresponding bis (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridines
12

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Table 5
Synthesis of bis (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives by
TTPA as a catalyst.
Scheme 6. Proposed mechanism for the synthesis (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives using TTPA.
(Table 5).
reaction was achieved under both nitrogen and argon atmosphere and in
In the proposed mechanism, aldehyde is activated with acidic func-
the absence of any molecular oxygen. It was found that, the reaction
proceeded under inert atmospheres (nitrogen and argon). These evi-
dences attributed to the conversion of intermediate (III) to (IV by un-
usual hydride transfer and release of molecular hydrogen (H2) by using
tional groups of TTPA and intermediate (I) is prepared by reaction of 3-
(1H-indol-3-yl)-3-oxopropanenitrile with the loss of one molecule of
H2O. In the second step, 3-methyl-1-phenyl-1H-pyrazol-5-amine reacts
with intermediate (I) to give intermediate (II) after tautomerization.
Then, intermediate (II) gives intermediate (III) after intramolecular
cyclization and loss of one molecule of H2O. We have recently intro-
duced "cooperative vinylogous anomeric-based oxidations" based on the
use of the vinylogous anomeric effect [53b] for the removal of hydride, a
step needed to complete the final oxidation/aromatization in the syn-
thesis of described pyridines. To approve the above-mentioned idea,
–
TTPA. The C H bond is weakened via a cooperative vinylogous
anomeric supporting of the nitrogen lone pairs into the vacant
anti-bonding of C–H (
σ
*
orbital) which can further react with a
C–H
proton to provide molecular hydrogen (Scheme 6). The results obtained
for the model reaction under argon and nitrogen atmospheres verified
our suggestion for the final step.
The efficiency of TTPA for the synthesis of (2-methyl-1H-indol-3-yl)-
13

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
pyrazolo[3,4-b]pyridine was compared with many other catalysts in the
reaction of 4-methyl benzaldehyde (1 mmol, 0.151 g), 3-methyl-1-
phenyl-1H-pyrazol-5-amine (1 mmol, 0.174 g) and 3-(1H-indol-3-yl)-3-
oxopropanenitrile (1 mmol, 0.198 g) under the above mentioned opti-
mized reaction conditions. Various organic and inorganic acidic cata-
lysts were also tested (Table 6). As Table 6 indicates, TTPA is the best
choice for the synthesis of (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]
pyridine derivatives; regarding the shorter reaction times, higher yields
and the amount of applied catalyst.
Table 6
Evaluation of various catalysts for the synthesis of (2-methyl-1H-indol-3-yl)-
pyrazolo[3,4-b]pyridine in comparison with TTPA.
Entry
Catalyst
(mol
%)
Time
Yield
(%)
(min)
1
CF3SO3H
10
30
45
30
60
15
60
30
30
60
60
60
60
45
25
–
2
NaHSO4
10
3
p-TSA
10
25
–
4
Al(HSO4)3
TTPA
10
5
10
85a
15
65
72
20
trace
–
The reusability of the TTPA as catalyst for the preparation of (2-
methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives was exam-
ined in the model reaction by using 4-methyl benzaldehyde (1 mmol,
0.151 g), 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol, 0.174 g) and
3-(1H-indol-3-yl)-3-oxopropanenitrile (1 mmol, 0.198 g). The results
showed that the TTPA catalyst has the potential to be reused up to 5
times without significant decrease in its catalytic activity (Fig. 13). The
recovered TTPA after the fifth run was also characterized by FT-IR and
energy dispersive X-ray spectroscopy (EDX). These spectra were the
same as those of the fresh catalyst (Figs. 14 and 15).
6
FeCl3
10
7
[Py-SO3H]Cl [62]
[PVI-SO3H]Cl [63]
Et3N
10
8
10 mg
20
9
10
11
12
13
UA
10
Mg(NO3)2.6H2O
TrBr [64]
10
10
trace
40
[Fe3O4@SiO2@(CH2)3-DABCO-
SO3H]Cl2 [65]
SSA [66]
10 mg
14
15
16
10 mg
10 mg
10
30
30
60
36
53
45
APVPB [67]
H3PO2
a
This work.
Fig. 13. Recyclability of TTPA at the synthesis (2-methyl-1H-indol-3-yl)-pyrazolo[3,4-b]pyridine derivatives.
Fig. 14. FT-IR spectrum of fresh and recovered catalyst (TTPA).
14

S. Kalhor et al.
Molecular Catalysis 507 (2021) 111549
Fig. 15. Energy dispersive X-ray spectroscopy (EDX) of recyclability of TTPA.
Fig. 16. Viability of Hela cells after being exposed to 6a(a) and 5b(b).
3.1. Cytotoxicity studies
Acknowledgements
Hela cells were incubated with 6a and 5b under the experimental
condition mentioned in Section 2.4 to investigate the cytotoxicity and
potential bio-applications of the compounds. As shown in Fig. 16a, after
exposing Hela cells to 6a with the concentrations of 5, 10, 25, 50, 100
We thank the Bu-Ali Sina University and Iran National Science
Foundation (INSF) (Grant Number: 98020070) for financial support.
Appendix A. Supplementary data
and 200 μM for 72 h, the viability of Hela cells was about 78.78 % for all
concentrations, implying a low cytotoxicity of 6a. Similarly, the viability
of Hela cells is greater than 81.3 % after being treated with 5b (5, 10, 25,
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2021.111549.
50, 100 and 200 μM) for 72 h (in Fig. 16b), indicating the biocompati-
bility of 5b is even higher than that of 6a. Consequently, it can be
deemed that both biocompatible 6a and 5b can be further applied in
biological assays.
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