Alcohol participates in the synthesis of functionalized coumarin-fused pyrazolo[3,4-b]pyridine from a one-pot three-component reaction

Article abstract of DOI:10.3390/molecules24152835

A concise and efficient approach to synthesizing coumarin-fused pyrazolo[3,4-b]pyridine via silica sulfuric acid (SSA) catalyzed three-component domino reaction under microwave irradiation has been demonstrated. Participation of various alcohols in construction of coumarin derivatives has been described for the first time. Short reaction time, high yields, one-pot procedure, usage of eco-friendly catalyst, and solvent are the key features of this method.

Full text of DOI:10.3390/molecules24152835

molecules
Article
Alcohol Participates in the Synthesis of
Functionalized Coumarin-Fused
Pyrazolo[3,4-b]Pyridine from a One-Pot
Three-Component Reaction
Wei Lin 1,
* *
, Cangwei Zhuang 1, Xiuxiu Hu 1, Juanjuan Zhang 2 and Juxian Wang 3,
1
School of Chemistry and Environmental Engineering, Jiangsu University of Technology,
Changzhou 213001, China
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical
College, Beijing 100050, China
2
3
*
Correspondence: linwei@jsut.edu.cn (W.L.); imbjxwang@163.com (J.-W.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Derek J. McPhee and Roman Dembinski
Received: 10 July 2019; Accepted: 2 August 2019; Published: 4 August 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A concise and efficient approach to synthesizing coumarin-fused pyrazolo[3,4-b]pyridine
via silica sulfuric acid (SSA) catalyzed three-component domino reaction under microwave irradiation
has been demonstrated. Participation of various alcohols in construction of coumarin derivatives
has been described for the first time. Short reaction time, high yields, one-pot procedure, usage of
eco-friendly catalyst, and solvent are the key features of this method.
Keywords: coumarin; pyrazolo[3,4-b]pyridine; synthesis; silica sulfuric acid
1. Introduction
As one of the most important heterocyclic compounds, coumarin was widely found in nature
products [
C-3, C-4, and C-7 positions have been intensively screened for various biological activities like
AChE inhibitors [ ], anticancer [ ], anticoagulant [10 11], anti-HIV [12 14], antitubercular [15 16],
anti-inflammatory [17 18], antioxidant [19], antibacterial [20], antihypertensive [21], anticonvulsant [22],
1,2], and several synthetic coumarins [3] with a variety of pharmacophoric groups at
4–
6
7–9
,
–
,
,
antifungal [23], and antihyperglycemic [24]. A recent literature survey suggests quite a few coumarin
derivatives have been patented for their biological properties (Figure 1). Besides the high biological
activity, coumarin is also considered to be a functional material [25
,26] such as receptors [27–29],
signaling units in sensors and biosensors, as well as in advanced photophysical systems [30,31].
Among various nitrogen-containing heterocyclic compounds, pyrazolo[3,4-b]pyridine is
recognized as important drug molecular skeleton in recent years due to a wide varieties of biological
activities (Figure 2), such as antimicrobial [32,33], anti-inflammatory [34,35], anti-proliferative [36,37],
and many other [38,39] important effects.
Molecules 2019, 24, 2835; doi:10.3390/molecules24152835
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2835
2 of 17
Figure 1. General structures of coumarin molecules possessing biological activity.
Figure 2. Biologically active compounds having pyrazolo[3,4-b]pyridine unit.
Therefore, development and introduction of a convenient, efficient method for the synthesis of
coumarin-fused pyrazolo[3,4-b]pyridine is highly desirable for their immense pharmacological potential.
As a part of our research on the synthesis of novel functionalized heterocyclic derivatives [40–46], in the
current paper, we report a novel three-component domino reaction for the synthesis of functionalized
coumarin-fused pyrazolo[3,4-b]pyridine derivatives using silica sulfuric acid as the catalyst. It worth
mentioning that participation of alcohols in construction of coumarin derivatives is described for the
first time.
2. Results and Discussion
In the early literature reports of our group [44], the coumarino[4,3-d]pyrazolo[3,4-b]pyridine
derivative (3a) was synthesized by the reaction of 3-a◦cylcoumarin (1a) with 5-aminopyrazole (2a
catalyzed by silica sulfuric acid (SSA) in EtOH at 90 C for 20 min under microwave irradiation
(Scheme 1).
)

Molecules 2019, 24, 2835
3 of 17
Scheme 1. Synthesis of coumarino[4,3-d]pyrazolo[3,4-b]pyridine derivative 3a.
According to our previously reported synthetic procedure, we speculate that the coumarin
derivative 6a could be obtained from the 2-butyryl-3H-benzo[f]chromen-3-one (4a) and 3-methyl-1-
phenyl-1H-pyrazol-5-amine (2a) used as the starting materials. However, product 6a was not available
as expect (Scheme 2-1). Considering the steric hindrance effect of the reaction, when ethanol and
ethylene glycol (EG) as mixed solvent (volume ratio of EG/EtOH = 1:1) was added to the reaction,
and further increasing the temperature (120 ◦C), a new product 7a formed unexpectedly (Scheme 2-2),
which was identified by 1H-NMR, 13C-NMR, HRMS analysis. Moreover, we also obtained the single
crystal of 7a suitable for X-ray analysis (Figure 3) [47]. To our surprise, the solvent ethanol also
participated in this reaction and a novel coumarin derivative was constructed.
Scheme 2. New multicomponent domino reactions.
Figure 3. Crystal structure of 7a.
In order to achieve the optimal conditions of three-component reaction, a series of catalysts,
solvents, and temperature were screened, as shown in Table 1. Some other acid catalysts such as
p-TsOH, HClO3S, H2SO4, SiO2-H2SO4 (Table 1. entries 1, 3–5) and base catalysts such as K2CO3,
NaOH, Cs2CO3 (Table 1, entries 6–8) were tested. However, none of them gave better results, lead to
the identification of SSA as the most effective catalyst (Table 1. entry 2). To further increase the yield

Molecules 2019, 24, 2835
4 of 17
of desired product 7a, different solvents were evaluated. The results revealed that EtOH and EG as
mixed solvents greatly improved the transformation, in control to EtOH, PEG, glycerol, and DMF as a
single solvent (Table 1, entries 2, 9–12). When the volume ratio of EG/EtOH = 3:1, the yield of 7a could
further increase to 68% (Table 1, entry 15). Much to our delight, we observed that increasing of the
temperature to 140 ◦C resulted in affording 7a in 84% yield (Table 1, entry 20).
Table 1. Optimizing the reaction conditions for the synthesis of 7a under microwave a.
Yield (%) b
Entry
Catalyst
Solvent (v/v)
Temperature (◦C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
p-TsOH (20 mol%)
SSA (0.25 g)
EG/EtOH=1:1
EG/EtOH=1:1
EG/EtOH=1:1
EG/EtOH=1:1
EG/EtOH=1:1
EG/EtOH=1:1
EG/EtOH=1:1
EG/EtOH=1:1
EtOH
120
120
120
120
120
120
120
120
110
120
120
120
120
120
120
120
100
110
130
140
150
trace
58
36
-
-
-
HClO3S (5 mol%)
SiO2-H2SO4 (0.25 g)
H2SO4 (20 mol%)
K2CO3 (20 mol%)
NaOH (20 mol%)
Cs2CO3 (20 mol%)
SSA (0.25 g)
-
-
20
45
32
24
21
55
68
57
trace
trace
78
84
76
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
SSA (0.25 g)
PEG/EtOH = 1:1
Glycerol/EtOH = 1:1
DMF/EtOH = 1:1
EG/EtOH=1:2
EG/EtOH = 2:1
EG/EtOH = 3:1
EG/EtOH = 4:1
EG/EtOH = 3:1
EG/EtOH = 3:1
EG/EtOH = 3:1
EG/EtOH = 3:1
EG/EtOH = 3:1
a Reaction conditions: 4a (0.5 mmol), 2a (0.5 mmol), 5a (1.0 mL), 45 min; b GC yield of 7a determined using tridecane
as internal standard.
With optimal conditions in hand, the corresponding novel coumarin-fused pyrazolo[3,4-b]pyridine
derivatives 7 were synthesized (Scheme 3).
As illustrated in Scheme 3, the substrate scope of the transformation was examined using
arylbenzo[f]chromen-3-one 4, enaminone 2, and alkyl alcohol 5 as staring materials. Notably, electronic
effects had an important impact on this reaction. When the substituent R3 was electron-donating group,
such as Me, the desired products could not be obtained at all (7e, 7f).
To further expand the scope of substrates, aryl alcohols (8) instead of alkyl alcohols (5) were also
tested. It was found that aryl alcohols were well tolerated under the optimal reaction conditions,
the corresponding products were afforded in moderate to good yields. When substituent R3 was
electron-withdrawing groups (Ph), the yields were good and no more than 1 h cost (Table 2, entries
1–19). However, the substituents R3 was electron-donating groups (CH3) (Table 2, entries 20–22), the
yields were lower and the reaction time was longer. Unfortunately, When R3 and R4 was electron rich
group, such as Me, the reaction could not proceed successfully (Table 2, entry 23).

Molecules 2019, 24, 2835
5 of 17
Table 2. Synthesis of coumarin-fused pyrazolo[3,4-b]pyridine derivatives 9 a.
Entry Product
R1
R2
R3
R4
Ar
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
9o
9p
9q
9r
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
C6H5
1
1
0.75
0.75
0.75
1
1
1
1
1
69
74
77
76
71
70
76
62
70
72
68
70
74
72
67
70
60
56
58
55
50
45
trace
4-CH3C6H4
4-OCH3C6H4
3-OCH3C6H4
4-BrC6H4
Pyridine-4-yl
Furan-2-yl
C6H5
4-CH3C6H4
4-OCH3C6H4
C6H5
4-CH3C6H4
4-OCH3C6H4
3-OCH3C6H4
4-CH3C6H4
4-OCH3C6H4
C6H5
OCH3 Ph
OCH3 Ph
OCH3 Ph
H
H
H
H
OCH3 Ph
OCH3 Ph
OCH3 Ph
H
H
H
Ph
Ph
Ph
Ph
1
1.25
1.25
1.25
1.25
1.25
1.25
1.5
1.5
2
Ph
Ph
CH3
C6H5
4-OCH3C6H4
C6H5
C6H5
4-OCH3C6H4
4-OCH3C6H4
9s
9t
9u
9v
9w
CH2CH3
CH3
CH3
OCH3 CH3
OCH3 CH3
H
Ph
Ph
2
2
2.5
CH2CH3
CH3 CH3
a
Reaction conditions: arylbenzo[f]chromen-3-one
EG (3 mL) and SSA (0.25 g), 140 ◦C.
4 (0.5 mmol), enaminone 2 (0.5 mmol), aryl alcohols 8 (1.0 mL),
To gain insight into the mechanism of this one-spot three-component reaction process, some
additional experiments were performed. When benzaldehyde (10) was added to the reaction instead of
phenylmethanol (8a) under standard conditions, 73% yield of desired product (9a) could be obtained,
and reaction time reduced from 1 h to 15 min (Scheme 4A), and when butyraldehyde (11) was added
to the reaction 50% yield of desired product (7c) could be obtained (Scheme 4B). The reaction did
◦
not proceed successfully without SSA catalyzed. Just phenylmethanol (8a) was heated to 140 C,
directly with the catalyst of SSA, benzaldehyde (10) and benzoic acid (12) could be detected by GC-MS
(Scheme 4C). We speculated that the benzaldehyde was most likely the key intermediate in this protocol.

Molecules 2019, 24, 2835
6 of 17
a
Scheme 3. Synthesis of coumarin-fused pyrazolo[3,4-b]pyridine derivatives 7 a
arylbenzo[f]chromen-3-one (0.5 mmol), enaminone (0.5 mmol), alkyl alcohol
and SSA (0.25 g), 140 ◦C,45 min; b Isolated yield; c 2 h.
.
Reaction conditions:
5 (1.0 mL), EG (3 mL)
4
2
Scheme 4. Preliminary mechanistic studies. (
derivatives 9a. ( ) Synthesis of coumarin-fused pyrazolo[3,4-b]pyridine derivatives 7c. (
phenylmethanol with the catalyst of SSA.
A
) Synthesis of coumarin-fused pyrazolo[3,4-b]pyridine
B
C
) Reaction of
Herein, we propose the following mechanism for the reaction (Scheme 5). SSA catalyzed alkyl
alcohol to afford the corresponding aldehyde, then the intermediate is formed by means of a
5
A

Molecules 2019, 24, 2835
7 of 17
Knoevenagel condensation of aldehyde and arylbenzo[f]chromen-3-one (
4
). The intermediate
) via attack of
, which transformed to more-stable
tautomerizes to intermediate , which undergoes intramolecular
nucleophilic addition to form intermediate . In the last step, loss of H2O affords the desired product.
A is
activated by SSA, which subsequently undergoes Michael addition with enaminone (
the nucleophilic C-4 of the intermediate to give intermediate
intermediate . Then, intermediate
2
A
B
C
C
D
E
Scheme 5. Proposed mechanism for this reaction.
3. Conclusions
In conclusion, we have developed a protocol for the facile synthesis of various potentially
biologically active coumarin-fused pyrazolo[3,4-b]pyridine derivatives, based on a novel three-
component domino reaction under microwave irradiation. Using this method, coumarin derivatives
could be rapidly constructed in moderate-to-good yields with short reaction time. Further study to
deeply understand the reaction mechanism is currently underway in our lab.
4. Experimental Section
4.1. General
All reagents were purchased from commercial suppliers (Aladdin, Shanghai, China) and used
without further purification. Microwave irradiation was carried out with Initiator 2.5 Microwave
Synthesizers from Biotage, Uppsala, Sweden. The reaction temperatures were measured by infrared
detector during microwave heating. Melting points are uncorrected. IR spectra were recorded on a
1
Tensor 27 spectrometer (Bruker Corp., Karlsruhe, Germany) in KBr with absorptions in cm−1. H-NMR
(400 MHz) and 13C-NMR (75 MHz or 100 MHz) spectra were recorded on a Varian Inova-400 MHz or
Varian Inova-300 MHz (Varian, CA, America) in CDCl3, DMSO-d6 or CF3COOD as solution. J values
are in hertz. Chemical shifts are expressed in parts per million downfield from interal standard TMS.
High-resolution mass spectra (HRMS) for all the compounds were determined on Bruker MicrOTOF-QII

Molecules 2019, 24, 2835
8 of 17
mass spectrometer (Bruker Corp., Karlsruhe, Germany) with ESI resource. X-ray diffraction analysis
was recorded on a Smart-1000 diffractometer (PANalytical B.V., Holland).
4.2. General Procedure for the Synthesis of Products 4 Are Represented as Follows
Typically, 2-hydroxy-1-naphthaldehyde (5 mmol), ethyl 3-oxopentanoate or ethyl 3-oxohexanoate
or ethyl acetoacetate (5 mmol) and piperidine (0.5 mmol) were introduced in a 20 mL vial with ethanol
(10 mL) as solution. Subsequently, the reaction vial was closed and then prestirred for 10 s. The mixture
was irradiated at 90 ◦C for 10 min. After the completion, the reaction mixture was then cooled to room
temperature and concentrated in vacuo to remove the solvent. The residue was then washed with
water, filtered, dried, and the precipitate was purified by recrystallization from 95% EtOH to give the
1
products of
4
. The analytical data for represent compounds are shown below. H-NMR and 13C-NMR
spectra of compounds 4 in Supplementary Materials.
4.2.1. 2-Butyryl-3H-benzo[f]chromen-3-one (4a)
Yellow solid; yield 89%; m.p.: 127–129 ◦C; IR (KBr):
ν ;
1734, 1626, 1557, 1513, 1383, 1109, 864 cm−1
1H-NMR (CDCl3, 400 MHz)
δ (ppm): 9.21 (s, 1H, ArH), 8.91 (s, 1H, ArH), 8.06 (d, J = 8.8 Hz, 1H, ArH),
7.83 (d, J = 8.8 Hz, 1H, ArH), 7.57–7.56 (m, 1H, ArH), 7.20 (d, J = 9.2 Hz, 1H, ArH), 7.12 (dd, J1 = 8.8 Hz,
J2 = 2.0 Hz, 1H, ArH), 3.00 (t, J = 7.2 Hz, 2H, CH2), 1.63–1.58 (m, 2H, CH2), 0.93 (t, J = 7.2 Hz, 3H, CH3);
13C-NMR (100 MHz, DMSO-d6)
δ (ppm): 197.5, 159.1, 158.9, 156.4, 142.8, 136.6, 132.1, 131.5, 124.6, 121.9,
118.6, 113.0, 111.4, 104.8, 43.9, 17.3, 14.1;
4.2.2. 2-Butyryl-9-methoxy-3H-benzo[f]chromen-3-one (4b)
Yellow solid, yield 88%; m.p.: 125–128 ◦C; IR (KBr)
836 cm−1; 1H-NMR (CDCl3, 400 MHz)
(ppm): 9.01 (s, 1H, ArH), 7.86 (d, J = 8.8 Hz, 1H, ArH), 7.68 (d,
J = 8.8 Hz, 1H, ArH), 7.40 (s, 1H, ArH), 7.14 (t, J = 8.4 Hz, 2H, ArH), 3.94 (s, 3H, CH3O), 3.12 (t, J = 8.4
Hz, 2H, CH2); 1.76–1.70 (m, 2H, CH2), 1.00 (t, J = 8.4 Hz, 3H, CH3); 13C-NMR (100 MHz, CDCl3)
ν: 1730, 1667, 1601, 1556, 1513, 1386, 1365, 1196, 948,
δ
δ
(ppm): 197.6, 159.9, 158.7, 156.0, 142.5, 135.3, 131.2, 130.2, 124.7, 121.1, 117.9, 113.1, 111.4, 100.7, 55.5,
44.0, 16.9, 13.3.
4.2.3. 2-Propionyl-3H-benzo[f]chromen-3-one (4c)
Yellow solid, yield 87%; m.p.: 134–136 ◦C; IR (KBr):
823 cm−1; 1H-NMR (CDCl3, 400 MHz)
(ppm): 9.15 (s, 1H, ArH), 8.74 (s, 1H, ArH), 7.90 (d, J = 8.8 Hz,
ν 1732, 1662, 1601, 1556, 1524, 1387, 1365, 1196, 945,
δ
1H, ArH), 7.66 (d, J = 8.8 Hz, 1H, ArH), 7.41–7.40 (m, 1H, ArH), 7.04 (d, J = 8.8 Hz, 1H, ArH), 6.95 (dd,
J1 = 8.8 Hz, J2 = 2.0 Hz, 1H, ArH), 3.14–3.08 (m, 2H, CH2), 1.08 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (100
MHz, CDCl3)
δ (ppm): 198.4, 159.9, 159.4, 156.7, 143.3, 135.9, 131.9, 130.8, 125.3, 121.8, 118.7, 113.7,
112.1, 102.0, 35.2, 10.7.
4.2.4. 9-Methoxy-2-propionyl-3H-benzo[f]chromen-3-one (4d)
Yellow solid, yield 87%; m.p.: 125–128 ◦C; IR (KBr):
836 cm−1; 1H-NMR (DMSO-d6, 400 MHz)
(ppm): 9.19 (s, 1H, ArH), 8.14 (d, J = 9.2 Hz, 1H, ArH), 7.90
ν 1730, 1667, 1601, 1556, 1513, 1386, 1365, 1196, 948,
δ
(d, J = 9.2 Hz, 1H, ArH), 7.79 (s, 1H, ArH), 7.32 (t, J = 8.8 Hz, 1H, ArH), 7.21 (dd, J1 = 8.8 Hz, J2 = 2.0
Hz, 1H, ArH), 3.98 (s, 3H, CH3O), 3.10–3.05 (m, 2H, CH2), 1.09 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (100
MHz, DMSO-d6) δ (ppm): 198.7, 160.4, 158.8, 156.1, 143.0, 136.2, 131.9, 131.2, 125.4, 122.8, 118.6, 113.9,
112.1, 102.4, 56.2, 35.4, 8.4.
4.2.5. 2-Acetyl-3H-benzo[f]chromen-3-one (4e)
Yellow solid, yield 88%; m.p.: 189–190 ◦C [48]; IR (KBr):
857 cm−1
ν 2959, 1696, 1622, 1562, 1384, 1227, 1206,
.

Molecules 2019, 24, 2835
9 of 17
4.3. General Procedure for the Synthesis of Products 7 and 9 Are Represented as Follows
Typically, benzo[f]chromen-3-one
or aryl alcohols
4
(0.5 mmol), enaminone
2
(0.5 mmol), alkyl alcohol
5
(1.0 mL)
8
(1.0 mL) and SSA (0.25 g) were introduced in a 5 mL vial with ethylene glycol (3 mL)
as solution. Subsequently, the reaction vial was closed and then prestirred for 10 s. The mixture
◦
was irradiated at 140 C. The reaction was monitored by TLC. After the completion, the reaction
mixture was then cooled to room temperature and diluted with cold water (30 mL), and extracted with
CH2Cl2 (3
×
30 mL). The extracts were washed with water (3
×
50 mL) and dried over anhydrous
Na2SO4. After evaporation of the solvent under reduced pressure, the precipitate was collected and
purified by recrystallization from 95% EtOH or by flash column chromatography (petroleum ether:ethyl
acetate = 8:1) to give the products
7 or 9. The analytical data for represent compounds are shown
1
below. H-NMR and 13C-NMR spectra of compounds 7 and 9 in Supplementary Materials.
4.3.1. 2-(5-Ethyl-3,4-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (7a)
White solid, m.p.: 258–260 ◦C; IR (KBr, cm−1
1248, 1211, 1096, 989, 906, 815, 787, 713, 691, 605; 1H-NMR (400 MHz, DMSO-d6)
ArH), 8.58 (d, J = 8.0 Hz, 1H, ArH), 8.23 (t, J = 8.0 Hz, 3H, ArH), 8.08 (d, J = 8.0 Hz, 1H, ArH), 7.69–7.61
(m, 3H, ArH), 7.44 (t, J = 8.0 Hz, 2H, ArH), 7.20 (t, J = 7.2 Hz, 1H, ArH), 2.78–2.66 (m, 8H, 2 CH3 +
CH2), 1.05 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
(ppm): 156.0, 148.8, 146.2, 145.4,
)
ν: 2960, 1722, 1629, 1572, 1507, 1415, 1387, 1315, 1290,
δ
(ppm): 9.07 (s, 1H,
×
δ
140.5, 139.1, 135.6, 134.1, 132.6, 132.0, 131.2, 130.8, 130.2, 129.4, 128.5, 126.5, 122.3, 121.3, 116.7, 116.2,
22.7, 17.0, 14.3, 13.4; HRMS: m/z cacld. for C29H24N3O2 [M + H]+ 446.1869, Found 446.1853.
4.3.2. 2-(4,5-Diethyl-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (7b)
White solid, m.p.: >300 ◦C; IR (KBr, cm−1
1413, 1357, 1204, 1071, 909, 817, 752, 694, 676, 589; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2974, 1719, 1688, 1656, 1628, 1596, 1628, 1571, 1546, 1506,
δ
(ppm): 9.16 (s, 1H,
ArH), 8.66 (d, J = 8.4 Hz, 1H, ArH), 8.29 (d, J = 9.2 Hz, 1H, ArH), 8.21 (d, J = 7.6 Hz, 2H, ArH), 8.11 (d, J
= 8.0 Hz, 1H, ArH), 7.73–7.63 (m, 3H, ArH), 7.47 (t, J = 8.0 Hz, 2H, ArH), 7.23 (t, J = 7.6 Hz, 1H, ArH),
3.51–3.48 (m, 2H, CH2), 3.17–3.14 (m, 2H, CH2), 2.79 (s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3), 1.09 (t,
J = 7.6 Hz, 3H, CH3); 13C-NMR (75 MHz, DMSO-d6)
δ (ppm): 160.2, 154.3, 153.8, 149.4, 148.1, 142.4,
139.6, 134.1, 130.5, 130.3, 129.6, 129.0, 128.3, 126.8, 125.7, 123.2, 120.5, 117.2, 115.9, 113.5, 100.0, 22.2, 21.6,
16.6, 16.2, 15.5; HRMS: m/z cacld. for C30H25N3O2 (M)+ 459.1947, Found 459.1946.
4.3.3. 2-(5-Ethyl-3-methyl-1-phenyl-4-propyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (7c
White solid, m.p.: 242–245 ◦C; IR (KBr, cm−1
: 2974, 2880, 2703, 2545, 1789, 1722, 1665, 1573, 1503,
1439, 1414, 1389, 1359, 1320, 1288, 1248, 1217, 1155, 1091, 915, 858, 813, 792, 745, 695, 641, 610; 1H-NMR
(400 MHz, DMSO-d6) (ppm): 9.14 (s, 1H, ArH), 8.63 (d, J = 8.8 Hz, 1H, ArH), 8.26 (d, J = 8.8 Hz, 1H,
)
)
ν
δ
ArH), 8.22 (d, J = 8.0 Hz, 2H, ArH), 8.09 (d, J = 8.0 Hz, 1H, ArH), 7.70–7.63 (m, 3H, ArH), 7.46 (t, J
= 7.6 Hz, 2H, ArH), 7.22 (t, J = 7.6 Hz, 1H, ArH), 3.07–3.06 (m, 2H, CH2), 2.76–2.73 (m, 5H, CH3 +
CH2), 1.72–1.69 (m, 2H, CH2), 1.13 (s, 3H, CH3), 1.07 (s, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ
(ppm): 165.7, 155.9, 148.1, 146.2, 145.9, 140.8, 139.1, 135.0, 134.1, 132.6, 131.9, 131.2, 130.7, 130.2, 129.3,
128.5, 126.5, 121.6, 121.3, 116.3, 33.4, 26.2, 22.2, 14.5, 13.7; HRMS: m/z cacld. for C31H28N3O2 [M + H]+
474.2182, Found 474.2210.
4.3.4. 2-(5-Ethyl-3,4-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-3H-benzo[f]chromen-
3-one (7d)
White solid, m.p.: >300 ◦C; IR (KBr, cm−1
917, 840, 794, 751, 686, 610; 1H-NMR (400 MHz, DMSO-d6)
3H, ArH), 8.01–7.96 (m, 2H, ArH), 7.50–7.45 (m, 3H, ArH), 7.27–7.21 (m, 2H, ArH), 3.90 (s, 3H, OCH3),
2.80–2.79 (m, 8H, CH2 + 2 (ppm):
CH3), 1.07 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (75 MHz, DMSO-d6)
160.3, 160.1, 154.4, 154.0, 149.0, 143.1, 142.4, 140.0, 139.7, 133.8, 131.4, 131.0, 129.5, 127.5, 125.6, 125.5,
)
ν: 2975, 2026, 1795, 1728, 1628, 1574, 1509, 1230, 1091, 989,
δ
(ppm): 9.21 (s, 1H, ArH), 8.24–8.17 (m,
×
δ

Molecules 2019, 24, 2835
10 of 17
120.3, 118.7, 116.9, 114.3, 102.6, 56.3, 22.4, 16.1, 15.4, 15.0; HRMS: m/z cacld. for C30H26N3O3 [M + H]+
476.1974, Found 476.1980.
4.3.5. 2-(5-Ethyl-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (9a)
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1
588; 1H-NMR (400 MHz, CF3COOD)
(ppm): 10.16 (s, 1H, ArH), 9.15–9.14 (m, 2H, ArH), 8.88–8.87 (m,
1H, ArH), 8.65–8.64 (m, 1H, ArH), 8.59–8.55 (m, 4H, ArH), 8.51–8.47 (m, 6H, ArH), 8.38–8.37 (m, 2H,
ArH), 3.77–3.76 (m, 2H, CH2), 3.05 (s, 3H, CH3), 1.91 (s, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
) ν: 3032, 2978, 2888, 2763, 1725, 1049, 958, 815, 756, 699, 679,
δ
δ
(ppm): 163.7, 156.1, 149.4, 146.8, 146.4, 140.8, 139.1, 135.8, 134.3, 132.8, 132.6, 132.0, 131.6, 131.2, 130.8,
130.2, 129.9, 129.5, 128.5, 127.8, 126.5, 121.9, 121.4, 116.8, 116.3, 113.6, 22.9, 14.3, 12.5; HRMS: m/z cacld.
for C34H26N3O2 [M + H]+ 508.2025, Found 508.2025.
4.3.6. 2-(5-Ethyl-3-methyl-1-phenyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-
one (9b)
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1) ν: 2968, 1972, 1779, 1572, 1505, 1413, 1360, 1207, 1088, 961,
898, 806, 758, 728, 690, 642; 1H-NMR (400 MHz, CF3COOD)
δ (ppm): 10.13 (s, 1H, ArH), 9.15–9.09 (m,
2H, ArH), 8.87–8.84 (m, 1H, ArH), 8.63–8.60 (m, 1H, ArH), 8.54–8.40 (m, 9H, ArH), 8.25–8.24 (m, 2H,
ArH), 3.76–3.74 (m, 2H, CH2), 3.37 (s, 3H, CH3), 3.06 (s, 3H, CH3), 1.88–1.87 (m, 3H, CH3); 13C-NMR
(75 MHz, CF3COOD) δ (ppm): 162.8, 155.1, 148.6, 145.6, 145.4, 142.0, 139.8, 138.2, 135.0, 133.3, 131.7,
131.1, 130.3, 129.9, 129.6, 129.3, 128.7, 128.5, 127.6, 126.9, 125.6, 121.0, 120.4, 115.9, 115.4, 112.7, 21.9, 19.5,
13.4, 11.7; HRMS: m/z cacld. for C35H28N3O2 [M + H]+ 522.2182, Found 522.2180.
4.3.7. 2-(5-Ethyl-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]
chromen-3-one (9c)
◦
Yellow solid, m.p.: >300 C; IR (KBr, cm−1
)
ν
: 2967, 1711, 1597, 1571, 1505, 1412, 1286, 1249, 1211,
(ppm): 9.29 (s, 1H, ArH),
1048, 982, 897, 849, 806, 758, 690, 641, 587; 1H-NMR (400 MHz, CF3COOD)
δ
8.28–8.23 (m, 2H, ArH), 7.99 (d, J = 8.4 Hz, 1H, ArH), 7.76 (t, J = 7.6 Hz, 1H, ArH), 7.69–7.56 (m, 7H,
ArH), 7.50 (d, J = 8.4 Hz, 2H, ArH), 7.35 (d, J = 8.4 Hz, 2H, ArH), 4.06 (s, 3H, OCH3), 2.93–2.88 (m, 2H,
CH2), 2.23 (s, 3H, CH3), 1.02 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 162.9,
160.9, 160.5, 155.2, 148.4, 145.8, 145.7, 140.0, 138.3, 135.3, 133.5, 131.8, 131.2, 130.4, 130.0, 129.4, 129.2,
128.7, 127.7, 125.8, 125.3, 121.3, 120.6, 116.0, 115.5, 114.9, 112.8, 55.1, 22.1, 13.4, 12.0; HRMS: m/z cacld.
for C35H28N3O3 [M + H]+ 538.2131, Found 538.2111.
4.3.8. 2-(5-Ethyl-4-(3-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]
chromen-3-one (9d)
Yellow solid, m.p.: >300 ◦C;.IR (KBr, cm−1
1136, 1046, 782, 759, 712, 689, 588; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2965, 2023, 1785, 1712, 1573, 1504, 1382, 1357, 1285, 1158,
δ
(ppm): 9.23 (s, 1H, ArH), 8.66 (d,
J = 8.4 Hz, 1H, ArH), 8.29–8.23 (m, 3H, ArH), 8.10 (d, J = 8.0 Hz, 1H, ArH), 7.73–7.62 (m, 3H, ArH),
7.54–7.47 (m, 3H, ArH), 7.25 (t, J = 7.6 Hz, 1H, ArH), 7.14–7.12 (m, 1H, ArH), 7.03–7.01 (m, 2H, ArH),
3.84 (s, 3H, OCH3), 2.58–2.56 (m, 2H, CH2), 1.96 (s, 3H, CH3), 0.89 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR
(75 MHz, DMSO-d6)
δ (ppm): 160.2, 159.6, 154.2, 153.9, 148.7, 145.3, 142.9, 140.1, 139.6, 137.3, 134.3,
130.5, 130.4, 130.1, 129.6, 129.5, 129.4, 129.0, 127.8, 126.8, 125.9, 123.1, 121.4, 120.6, 117.2, 115.8, 114.6,
113.5, 55.8, 22.5, 16.0, 14.2; HRMS: m/z cacld. for C35H27N3O3 (M)+ 537.2052, Found 537.2053.
4.3.9. 2-(4-(4-Bromophenyl)-5-ethyl-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]
chromen-3-one (9e)
Yellow solid, m.p.: >300 ◦C;.IR (KBr, cm−1
782, 759, 712, 681, 588; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2968, 2032, 1775, 1721, 1574, 1385, 1357, 1285, 1166, 1047,
δ
(ppm): 10.19 (s, 1H, ArH), 8.57–8.53 (m, 2H,
ArH), 8.43 (d, J = 9.2 Hz, 1H, ArH), 8.06 (d, J = 8.0 Hz, 1H, ArH), 7.86 (t, J = 7.6 Hz, 1H, ArH), 7.78–7.23
(m, 10H, ArH), 2.79 (s, 2H, CH2), 2.54(s, 3H, CH3), 1.35 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR (75 MHz,

Molecules 2019, 24, 2835
11 of 17
DMSO-d6) δ (ppm): 165.7, 159.3, 157.7, 152.3, 151.4, 144.7, 141.6, 138.9, 134.8, 132.3, 131.0, 129.7, 126.7,
125.2, 121.4, 118.1, 113.1, 111.4, 111.3, 109.6, 107.5, 21.9, 17.0, 14.6; HRMS: m/z cacld. for C34H24BrN3O2
(M)+ 585.1052, Found 585.1057.
4.3.10. 2-(5-Ethyl-3-methyl-1-phenyl-4-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]
chromen-3-one (9f):
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1
805, 758, 693, 642; 1H-NMR (400 MHz, CF3COOD)
8.80 (d, J = 8.0 Hz, 1H, ArH), 8.60–8.35 (m, 10H, ArH), 8.21–8.19 (m, 2H, ArH), 3.72–3.70 (m, 2H, CH2),
3.01 (s, 3H, CH3), 1.83 (t, J = 6.8 Hz, 3H, CH3);13C-NMR (75 MHz, CF3COOD)
(ppm): 162.8, 155.0,
)
ν: 2965, 1972, 1783, 1573, 1505, 1413, 1362, 1089, 961, 898,
δ
(ppm): 10.09 (s, 1H, ArH), 9.11–9.05 (m, 2H, ArH),
δ
148.5, 145.5, 145.4, 142.0, 139.7, 138.1, 135.0, 133.3, 131.6, 131.0, 130.2, 129.8, 129.5, 129.2, 128.7, 128.5,
127.5, 126.8, 125.5, 121.0, 120.4, 115.8, 115.3, 112.6, 21.8, 13.3, 11.6; HRMS: m/z cacld. for C33H25N4O2
[M + H]+ 509.1978, Found 509.1963.
4.3.11. 2-(5-Ethyl-4-(furan-2-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-
3-one (9g):
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1
797, 766, 724, 691, 640, 617; 1H-NMR (400 MHz, CF3COOD)
)
ν
: 2966, 1720, 1629, 1566, 1412, 1383, 1264, 1084, 959, 852,
δ
(ppm): 9.24 (s, 1H, ArH), 8.21 (d, J = 9.2
Hz, 1H, ArH), 7.95 (d, J = 8.8 Hz, 1H, ArH), 7.65–7.63 (m, 2H, ArH), 7.62–7.55 (m, 6H, ArH), 7.46 (d, J
= 9.2 Hz, 1H, ArH), 7.39 (m, 3H, ArH), 2.93–2.87 (m, 2H, CH2), 2.21 (s, 3H, CH3), 1.03 (t, J = 7.6 Hz,
3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 163.0, 160.2, 156.0, 148.7, 145.7, 142.1, 140.0, 137.9,
135.2, 133.5, 131.9, 131.5, 130.7, 130.5, 129.8, 129.0, 127.1, 126.9, 125.8, 121.2, 118.0, 115.4, 113.7, 112.2,
22.1, 13.6, 11.8; HRMS: m/z cacld. for C32H24N3O3 [M + H]+ 498.1818, Found 498.1831.
4.3.12. 2-(5-Ethyl-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-3H-benzo[f]chromen-
3-one (9h)
White solid, m.p.: 248–250 ◦C; IR (KBr, cm−1
1281, 1241, 1135, 1105, 980, 960, 905, 827, 789, 758, 705, 692, 636; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2968, 1724, 1631, 1573, 1507, 1434, 1414, 1384, 1354,
δ
(ppm):
9.32 (s, 1H, ArH), 8.24 (d, J = 8.0 Hz, 2H, ArH), 8.17 (d, J = 9.2 Hz, 1H, ArH), 8.00–7.97 (m, 2H, ArH),
7.61–7.57 (m, 3H, ArH), 7.51–7.46 (m, 5H, ArH), 7.27–7.24 (m, 2H, ArH), 3.91 (s, 3H, OCH3), 2.54–2.53
(m, 2H, CH2), 1.89 (s, 3H, CH3), 0.86 (t, J = 7.6 Hz, 3H, CH3); 13C-NMR (75 MHz, DMSO-d6)
δ (ppm):
160.3, 160.2, 154.5, 154.4, 148.7, 145.5, 142.8, 140.6, 139.5, 135.9, 134.0, 131.5, 131.0, 130.5, 129.6, 129.1,
129.0, 128.9, 127.0, 125.9, 125.7, 120.6, 118.7, 115.8, 114.3, 112.8, 102.7, 56.3, 22.5, 15.8, 14.2; HRMS: m/z
cacld. for C35H28N3O3 [M + H]+ 538.2131, Found 538.2122.
4.3.13. 2-(5-Ethyl-3-methyl-1-phenyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-3H-benzo[f]
chromen-3-one (9i)
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1
832, 796, 761, 725, 691, 678, 640, 602; 1H-NMR (400 MHz, CF3COOD)
)
ν
: 2966, 1720, 1628, 1570, 1417, 1383, 1264, 1084, 959, 904,
δ
(ppm): 9.24 (s, 1H, ArH), 8.20
(d, J = 9.2 Hz, 1H, ArH), 7.95 (d, J = 8.8 Hz, 1H, ArH), 7.65–7.54 (m, 8H, ArH), 7.46 (d, J = 9.2 Hz, 1H,
ArH), 7.39 (d, J = 7.6 Hz, 3H, ArH), 4.04 (s, 3H, OCH3), 2.92–2.87 (m, 2H, CH2), 2.52 (s, 3H, CH3), 2.20
(s, 3H, CH3), 1.02 (t, J = 7.6 Hz, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 162.9, 160.1, 155.9,
148.6, 145.6, 145.5, 142.0, 139.8, 137.8, 135.1, 133.4, 131.8, 131.4, 130.6, 130.4, 129.6, 128.9, 127.0, 126.8,
125.7, 121.1, 117.9, 115.3, 113.6, 112.1, 55.3, 22.0, 19.6, 13.5, 11.8; HRMS: m/z cacld. for C36H30N3O3 [M +
H]+ 552.2287, Found 552.2246.
4.3.14. 2-(5-Ethyl-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-
3H-benzo[f]chromen-3-one (9j)
White solid, m.p.: 256–258 ◦C; IR (KBr, cm−1
1227, 1077, 960, 887, 884, 805, 691, 604, 567; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2965, 2145, 1735, 1717, 1629, 1572, 1463, 1381, 1286,
δ
(ppm): 9.33 (s, 1H, ArH),

Molecules 2019, 24, 2835
12 of 17
8.23 (d, J = 8.0 Hz, 2H, ArH), 8.19 (d, J = 8.8 Hz, 1H, ArH), 8.01–7.99 (m, 2H, ArH), 7.52–7.48 (m, 3H,
ArH), 7.39–7.38 (m, 2H, ArH), 7.28–7.25 (m, 2H, ArH), 7.16 (d, J = 8.8 Hz, 2H, ArH), 3.92 (s, 3H, OCH3),
2.87 (s, 3H, OCH3), 2.56–2.55 (m, 2H, CH2), 1.95 (s, 3H, CH3), 0.87 (t, J = 7.2 Hz, 3H, CH3); 13C-NMR
(75 MHz, DMSO-d6)
δ (ppm): 160.3, 160.2, 159.7, 154.6, 154.4, 148.8, 145.5, 142.9, 140.6, 139.6, 134.0,
131.5, 131.0, 130.9, 130.4, 129.7, 127.8, 127.1, 125.9, 125.7, 120.6, 118.8, 116.2, 114.3, 112.8, 102.7, 56.4, 55.7,
22.5, 15.8, 14.5; HRMS: m/z cacld. for C36H30N3O4 [M + H]+ 568.2236, Found 568.2248.
4.3.15. 2-(3,5-Dimethyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (9k)
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1
692, 651, 633, 585; 1H-NMR (400 MHz, CF3COOD)
8.00–7.97 (m, 1H, ArH), 7.72–7.61 (m, 11H, ArH), 7.48–7.47 (m, 2H, ArH), 2.42 (s, 3H, CH3), 2.22 (s,
3H, CH3); 13C-NMR (75 MHz, CF3COOD)
(ppm): 155.3, 148.3, 146.2, 145.8, 139.9, 138.5, 133.5, 132.4,
)
ν
: 2934, 2173, 1710, 1598, 1572, 1438, 1278, 965, 909, 820, 791,
(ppm): 9.33 (s, 1H, ArH), 8.29–8.24 (m, 2H, ArH),
δ
δ
131.8, 131.1, 130.8, 130.4, 130.0, 129.4, 129.3, 129.0, 128.7, 127.7, 126.9, 125.7, 120.6, 120.4, 115.9, 115.5,
112.9, 14.5, 12.0; HRMS: m/z cacld. for C33H24N3O2 [M + H]+ 494.1869, Found 494.1887.
4.3.16. 2-(3,5-Dimethyl-1-phenyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (9l
Yellow solid, m.p.: 286–290 ◦C; IR (KBr, cm−1
: 3078, 2187, 1719, 1626, 1606, 1575, 1507, 1447, 1380,
1212, 1093, 963, 813, 790, 741, 685; 1H-NMR (400 MHz, CF3COOD)
(ppm): 9.35 (s, 1H, ArH), 8.31 (d, J
)
)
ν
δ
= 9.2 Hz, 1H, ArH), 8.27 (d, J = 7.6 Hz, 1H, ArH), 8.02 (d, J = 8.4 Hz, 1H, ArH), 7.79 (t, J = 7.2 Hz, 1H,
ArH), 7.72–7.57 (m, 9H, ArH), 7.39 (d, J = 7.6 Hz, 2H, ArH), 2.55 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.29 (s,
3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 154.3, 147.5, 145.2, 144.5, 141.3, 138.9, 137.5, 132.5,
130.8, 130.2, 129.4, 129.0, 128.8, 128.4, 128.3, 128.1, 127.7, 126.7, 126.0, 124.7, 119.6, 119.5, 114.9, 114.4,
18.6, 14.0, 10.9; HRMS: m/z cacld. for C34H26N3O2 [M + H]+ 508.2025, Found 508.2020.
4.3.17. 2-(4-(4-Methoxyphenyl)-3,5-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo
[f]chromen-3-one (9m)
White solid, m.p.: 258–260 ◦C; IR (KBr, cm−1
1158, 1103, 1061, 849, 818, 759, 712, 668, 589; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2904, 2342, 1735, 1631, 1574, 1427, 1367, 1240, 1200,
δ
(ppm): 9.20 (s, 1H, ArH),
8.66 (d, J = 8.4 Hz, 1H, ArH), 8.28 (t, J = 7.6 Hz,3H, ArH), 8.11 (d, J = 8.0 Hz, 1H, ArH), 7.75–7.63 (m,
3H, ArH), 7.50 (t, J = 8.0 Hz, 2H, ArH), 7.37 (d, J = 8.4 Hz, 2H, ArH), 7.26 (t, J = 7.2 Hz, 1H, ArH), 7.16
(d, J = 8.4 Hz, 2H, ArH), 3.87 (s, 3H, OCH3), 2.13 (s, 3H, CH3), 2.02 (s, 3H, CH3); 13C-NMR (75 MHz,
DMSO-d6) δ (ppm): 159.8, 159.6, 154.2, 154.0, 149.0, 145.3, 142.7, 140.3, 139.6, 134.3, 130.6, 130.5, 129.6
129.5, 128.1, 126.7, 125.8, 124.9, 123.1, 120.6, 117.1, 115.9, 114.4, 113.6, 55.7, 16.3, 14.7; HRMS: m/z cacld.
for C34H26N3O3 [M + H]+ 524.1974, Found 524.1978.
4.3.18. 2-(4-(3-Methoxyphenyl)-3,5-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]
chromen-3-one (9n)
White solid, m.p.: 260–263 ◦C; IR (KBr, cm−1
1142, 1054, 1019, 988, 970, 877, 815, 786, 744, 714, 670, 586; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2970, 2372, 1718, 1573, 1505, 1410, 1362, 1279, 1239,
δ
(ppm):
9.19 (s, 1H, ArH), 8.66 (d, J = 8.4 Hz, 1H, ArH), 8.29–8.25 (m, 3H, ArH), 8.10 (d, J = 8.0 Hz, 1H, ArH),
7.75–7.63 (m, 3H, ArH), 7.52–7.48 (m, 3H, ArH), 7.25 (t, J = 7.6 Hz, 1H, ArH), 7.13–7.11 (m, 1H, ArH),
7.00–6.98 (m, 2H, ArH), 3.84 (s, 3H, OCH3), 2.13 (s, 3H, CH3), 2.00 (s, 3H, CH3); 13C-NMR (75 MHz,
DMSO-d6) δ (ppm): 159.7, 159.6, 154.3, 154.0, 148.9, 145.2, 142.7, 140.4, 139.6, 137.6, 134.3, 130.5, 130.3,
129.6, 129.5, 129.4, 129.0, 128.1, 126.8, 125.9, 124.5, 123.1, 121.3, 120.6, 117.1, 115.5, 114.7, 114.6, 113.6,
55.8, 16.2, 14.4; HRMS: m/z cacld. for C34H26N3O3 [M + H]+ 524.1974, Found 524.1978.
4.3.19. 2-(3,5-Dimethyl-1-phenyl-4-(p-tolyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-3H-benzo[f]
chromen-3-one (9o)
Yellow solid, m.p.: 288–290 ◦C; IR (KBr, cm−1
1125, 1019, 852, 827, 795, 749, 690, 643, 606; 1H-NMR (400 MHz, CF3COOD)
)
ν
: 2929, 1718, 1631, 1600, 1346, 1239, 1204, 1173, 1149,
(ppm): 9.28 (s, 1H, ArH),
δ

Molecules 2019, 24, 2835
13 of 17
8.22 (d, J = 8.8 Hz, 1H, ArH), 7.96 (d, J = 8.8 Hz, 1H, ArH), 7.65–7.62 (m, 6H, ArH), 7.56–7.54 (m, 2H,
ArH), 7.46 (d, J = 8.8 Hz, 1H, ArH), 7.41–7.35 (m, 3H, ArH), 4.04 (s, 3H, OCH3), 2.52 (s, 3H, CH3), 2.44
(s, 3H, CH3), 2.26 (s, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 159.0, 158.9, 155.0, 147.4, 145.2,
144.4, 141.2, 138.8, 137.0, 132.4, 130.7, 130.4, 129.6, 129.4, 128.8, 128.2, 128.1, 126.0, 125.8, 124.6, 119.4,
116.6, 115.2, 114.1, 112.5, 54.2, 18.5, 14.0, 10.9; HRMS: m/z cacld. for C35H28N3O3 [M + H]+ 538.2131,
Found 538.2130.
4.3.20. 9-Methoxy-2-(4-(4-methoxyphenyl)-3,5-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-
benzo[f]chromen-3-one (9p)
Yellow solid, m.p.: 287–289 ◦C; IR (KBr, cm−1
1033, 960, 832, 795, 754, 691; 1H-NMR (400 MHz, CF3COOD)
Hz, 1H, ArH), 7.56 (d, J = 8.8 Hz, 1H, ArH), 7.65–7.63 (m, 6H, ArH), 7.48–7.42 (m, 3H, ArH), 7.39–7.35 (m,
3H, ArH), 4.07–4.05 (m, 6H, 2
OCH3), 2.46 (s, 3H, CH3), 2.30 (s, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
)
ν
: 1716, 1630, 1611, 1571, 1513, 1464, 1385, 1246, 1107,
(ppm): 9.29 (s, 1H, ArH), 8.23 (d, J = 8.8
δ
×
δ
(ppm): 159.6, 159.0, 155.0, 147.2, 145.1, 144.6, 138.9, 137.0, 132.4, 130.7, 130.4, 129.6, 129.3, 128.3, 128.1,
125.8, 124.6, 116.6, 114.0, 112.5, 54.3, 54.0, 14.0, 11.1; HRMS: m/z cacld. for C35H28N3O4 [M + H]+
554.2080, Found 554.2093.
4.3.21. 2-(3,5-Dimethyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-3H-benzo[f]chromen-3-
one (9q)
Yellow solid, m.p.: 252–254 ◦C; IR (KBr, cm−1
1250, 1219, 1196, 999, 906, 819, 797, 753, 695, 625; 1H-NMR (400 MHz, DMSO-d6)
)
ν
: 2961, 1725, 1629, 1582, 1557, 1435, 1397, 1335, 1290,
(ppm): 9.29 (s, 1H,
δ
ArH), 8.28–8.26 (m, 2H, ArH), 8.17 (d, J = 9.2 Hz, 1H, ArH), 8.01–7.98 (m, 2H, ArH), 7.62–7.57 (m, 3H,
ArH), 7.52–7.43 (m, 5H, ArH), 7.28–7.25 (m, 2H, ArH), 3.92 (s, 3H, OCH3), 2.11 (s, 3H, CH3), 1.95 (s, 3H,
CH3); 13C-NMR (75 MHz, DMSO-d6)
δ (ppm): 160.2, 159.7, 154.6, 154.5, 148.9, 145.3, 142.6, 140.8, 139.6,
136.2, 134.0, 131.5, 131.1, 129.7, 129.2, 129.1, 127.4, 125.9, 125.7, 124.5, 120.7, 118.7, 115.5, 114.3, 112.9,
102.8, 56.3, 16.2, 14.5; HRMS: m/z cacld. for C34H26N3O3 [M + H]+ 524.1974, Found 524.1988.
4.3.22. 2-(3-Methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (9r)
Yellow solid, m.p.: 268–270 ◦C; IR (KBr, cm−1
657, 631, 585; 1H-NMR (400 MHz, CF3COOD)
)
δ
ν
: 2935, 2355, 1729, 1667, 1553, 1092, 891, 818, 746, 694,
(ppm): 10.22 (s, 1H, ArH), 8.61–8.57 (m, 2H, ArH), 8.46
(d, J = 9.2 Hz, 1H, ArH), 8.09 (d, J = 8.0 Hz, 1H, ArH), 7.90 (t, J = 7.6 Hz, 1H, ArH), 7.82–7.76 (m, 11H,
ArH), 7.70 (d, J = 8.8 Hz, 1H, ArH), 2.58 (s, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ
(ppm): 163.5, 159.1,
155.0, 147.5, 145.0, 144.8, 140.3, 138.7, 132.9, 132.4, 131.1, 130.4, 130.3, 130.0, 129.8, 128.8, 128.3, 127.9,
127.4, 127.3, 122.6, 120.1, 114.3, 114.1, 113.5, 11.9; HRMS: m/z cacld. for C32H22N3O2 [M + H]+ 480.1712,
Found 480.1726.
4.3.23. 2-(4-(4-Methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-
one (9s)
Yellow solid, m.p.: >300 ◦C; IR (KBr, cm−1
765, 689, 654, 633, 599; 1H-NMR (400 MHz, CF3COOD)
)
ν
: 2988, 2355, 1987, 1730, 1512, 1089, 1066, 959, 810, 809, 788,
(ppm): 11.03 (s, 1H, ArH), 9.43 (d, J = 8.4 Hz,
δ
1H, ArH), 9.34–9.30 (m, 2H, ArH), 8.94 (d, J = 8.0 Hz, 1H, ArH), 8.75 (t, J = 7.6 Hz, 1H, ArH), 7.66–7.63
(m, 8H, ArH), 8.54 (t, J = 9.2 Hz, 1H, ArH), 8.23 (d, J = 8.8 Hz, 2H, ArH), 4.95 (s, 3H, OCH3), 3.50 (s, 3H,
CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 164.3, 159.2, 155.9, 148.2, 145.7, 145.3, 141.1, 139.8, 133.6,
131.3, 130.9, 130.6, 129.7, 128.8, 128.2, 126.6, 123.5, 120.9, 117.1, 115.1, 114.6, 55.1, 13.1; HRMS: m/z cacld.
for C33H24N3O3 [M + H]+ 510.1818, Found 510.1835.
4.3.24. 2-(5-Ethyl-1-methyl-3,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-benzo[f]chromen-3-one (9t)
Yellow solid, m.p.: 285–288 ◦C; IR (KBr, cm−1
810, 803, 704; H-NMR (400 MHz, CF3COOD)
)
ν
: 2396, 1732, 1574, 1353, 1099, 1515, 1088, 1076, 959,
1
δ (ppm): 10.26 (s, 1H, ArH), 9.25 (d, J = 8.8 Hz, 2H,
ArH), 8.95 (d, J = 8.0 Hz, 1H, ArH), 8.73 (t, J = 7.6 Hz, 1H, ArH), 8.63 (t, J = 7.6 Hz, 1H, ArH), 8.46 (d,

Molecules 2019, 24, 2835
14 of 17
J = 7.6 Hz, 1H, ArH), 8.26 (t, J = 7.6 Hz, 1H, ArH), 8.21–8.14 (m, 3H, ArH), 8.09–8.02 (m, 4H, ArH),
7.94 (d, J = 7.6 Hz, 2H, ArH), 5.31 (s, 3H, CH3), 3.87–3.85 (m, 2H, CH2), 1.84 (t, J = 7.2 Hz, 3H, CH3);
13C-NMR (75 MHz, CF
3COOD)
δ (ppm): 162.9, 155.3, 150.3, 146.0, 145.4, 140.3, 138.2, 134.3, 131.2, 131.1,
130.2, 129.9, 129.5, 129.3, 128.5, 128.3, 127.9, 127.8, 127.6, 127.1, 120.5, 119.3, 116.3, 115.5, 34.9, 21.8, 13.1;
HRMS: m/z cacld. for C34H26N3O2 [M + H]+ 508.2025, Found 508.2027.
4.3.25. 2-(1,5-Dimethyl-3,4-diphenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-9-methoxy-3H-benzo[f]chromen-3-
one (9u)
Yellow solid, m.p.: 260–262 ◦C; IR (KBr, cm−1
1387, 1330, 1218, 1149, 1017, 976, 898, 845, 796, 756, 725, 702, 601; 1H-NMR (400 MHz, CF3COOD)
) ν: 2697, 2551, 1783, 1708, 1628, 1567, 1511, 1469, 1441,
δ
(ppm): 10.10 (s, 1H, ArH), 9.03 (d, J = 9.2 Hz, 1H, ArH), 8.76 (d, J = 8.8 Hz, 1H, ArH), 8.66–8.65 (m,
1H, ArH), 8.28 (d, J = 8.8 Hz, 1H, ArH), 8.20 (d, J = 9.2 Hz, 1H, ArH), 8.12 (d, J = 7.6 Hz, 1H, ArH),
8.05–7.99 (m, 3H, ArH), 7.91–7.87 (m, 4H, ArH), 7.81 (d, J = 7.6 Hz, 2H, ArH), 5.18 (s, 3H, OCH3), 4.85
13C-NMR (75 MHz, CF
(s, 3H, CH3), 3.21 (s, 3H, CH3).
3COOD) δ (ppm): 162.3, 160.0, 156.0, 150.1, 146.1,
145.8, 140.3, 138.0, 131.5, 131.4, 130.6, 130.3, 129.5, 128.5, 128.3, 128.2, 128.0, 127.9, 127.2, 126.7, 117.5,
113.5, 112.2, 112.1, 103.0, 55.2, 34.8, 15.1. HRMS: m/z cacld. for C34H26N3O3 [M + H]+ 554.2080, Found
554.2093.
4.3.26. 9-Methoxy-2-(4-(4-methoxyphenyl)-1,5-dimethyl-3-phenyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-3H-
benzo[f]chromen-3-one (9v)
Yellow solid, m.p.: 240–244 ◦C; IR (KBr, cm−1
1289, 1249, 1208, 1173, 1025, 970, 902, 836, 801, 698, 664, 607; 1H-NMR (400 MHz, CF3COOD)
)
ν
: 2932, 1720, 1624, 1608, 1564, 1512, 1463, 1383, 1353,
(ppm):
δ
10.15 (s, 1H, ArH), 9.09 (d, J = 9.2 Hz, 1H, ArH), 8.82 (d, J = 9.2 Hz, 1H, ArH), 8.72–8.71 (m, 1H, ArH),
8.34 (d, J = 9.2 Hz, 1H, ArH), 8.26 (d, J = 9.2 Hz, 1H, ArH), 8.17–8.13 (m, 1H, ArH), 8.02–7.95 (m, 4H,
ArH), 7.89–7.87 (m, 2H, ArH), 7.69–7.66 (m, 2H, ArH), 5.23 (s, 3H, OCH3), 4.90 (s, 3H, OCH3), 4.72 (s,
3H, CH3), 3.31 (s, 3H, CH3); 13C-NMR (75 MHz, CF3COOD)
δ (ppm): 162.4, 160.3, 156.1, 150.0, 146.0, 145.9,
140.3, 138.1, 131.5, 130.4, 129.4, 128.7, 128.1, 128.0, 127.6, 126.8, 125.1, 117.5, 114.2, 113.5, 55.2, 55.1, 34.9,
15.1; HRMS: m/z cacld. for C35H28N3O4 [M + H]+ 524.1974, Found 524.1972.
Supplementary Materials: The following are available online, Crystal date of compound 7a [
47], 1H NMR and
13C NMR Spectra of all compounds and GC-MS spectra of Scheme 4B.
Author Contributions: W.L. conceived the synthetic route, supervised the project and wrote the paper; J.Z. and
J.W. designed the experiments; C.Z. and X.H. performed all synthetic work in the laboratory.
Funding: This research was supported financially by the Natural Science Foundation of China (no. 21502074),
Qing Lan Project of Jiangsu Province, Postgraduate Research & Practice Innovation Program of Jiangsu Province
(SJCX18_0985 and SJCX19_0766) and CAMS lnitiative for Innovative Medicine (2016-I2M-3-014).
Conflicts of Interest: The authors declare no conflict of interest.
References and Note
1.
2.
3.
Revankar, H.M.; Bukhari, S.N.A.; Kumar, G.B.; Qin, H.L. Coumarins scaffolds as COX inhibitors. Bioorg.
Chem. 2017, 71, 146–159. [CrossRef] [PubMed]
Dandriyal, J.; Singla, R.; Kumar, M.; Jaitak, V. Recent developments of C-4 substituted coumarin derivatives
as anticancer agents. Eur. J. Med. Chem. 2016, 119, 141–168. [CrossRef] [PubMed]
Ibrar, A.; Shehzadi, S.A.; Saeed, F.; Khan, I. Developing hybrid molecule therapeutics for diverse enzyme
inhibitory action: Active role of coumarin-based structural leads in drug discovery. Bioorg. Med. Chem. 2018
26, 3731–3762. [CrossRef] [PubMed]
,
4.
5.
Singla, S.; Piplani, P. Coumarin derivatives as potential inhibitors of acetylcholinesterase: Synthesis, molecular
docking and biological studies. Bioorg. Med. Chem. 2016, 24, 4587–4599. [CrossRef] [PubMed]
Hamulakova, S.; Janovec, L.; Soukup, O.; Jun, D.; Kuca, K. Synthesis, in vitro acetylcholinesterase inhibitory
activity and molecular docking of new acridine-coumarin hybrids. Int. J. Biol. Macromol. 2017, 104, 333–338.
[CrossRef]

Molecules 2019, 24, 2835
15 of 17
6.
Lan, J.S.; Ding, Y.; Liu, Y.; Kang, P.; Hou, J.W.; Zhang, X.Y.; Xie, S.S.; Zhang, T. Design, synthesis and biological
evaluation of novel coumarin-N-benzyl pyridinium hybrids as multi-target agents for the treatment of
Alzheimer’s disease. Eur. J. Med. Chem. 2017, 139, 48–59. [CrossRef] [PubMed]
Emami, S.; Dadashpour, S. Current developments of coumarin-based anti-cancer agents in medicinal
chemistry. Eur. J. Med. Chem. 2015, 102, 611–630. [CrossRef]
Kaur, M.; Kohli, S.; Sandhu, S.; Bansal, Y.; Bansal, G. Coumarin: A promising scaffold for anticancer agents.
Anti Cancer Agents Med. Chem. 2015, 15, 1032–1048. [CrossRef]
Klenkar, J.; Molnar, M. Natural and synthetic coumarins as potential anticancer agents. J. Chem. Pharm. Res.
2015, 7, 1223–1238.
7.
8.
9.
10. Poole, S.K.; Poole, C.F. Thin-layer chromatographic method for the determination of the principal polar
aromatic flavour compounds of the cinnamons of commerce. Analyst 1994, 119, 113–120. [CrossRef]
11. Riveiro, M.E.; De Kimpe, N.; Moglioni, A.; Vazquez, R.; Monczor, F.; Shayo, C.; Davio, C. Coumarins:
Old compounds with novel promising therapeutic perspectives. Curr. Med. Chem. 2010, 17, 1325–1338.
[CrossRef] [PubMed]
12. Patil, A.D.; Freyer, A.J.; Eggleston, D.S.; Haltiwanger, R.C.; Bean, M.F.; Taylor, P.B.; Caranfa, M.J.; Breen, A.L.;
Bartus, H.R. The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the malaysian
tree, calophyllum inophyllum linn. J. Med. Chem. 1993, 36, 4131–4138. [CrossRef] [PubMed]
13. Spino, C.; Dodier, M.; Sotheeswaran, S. Anti-HIV coumarins from calophyllum seed oil. Bioorg. Med. Chem.
Lett. 1998, 8, 3475–3478. [CrossRef]
14. Kostova, I.; Mojzis, J. Biologically active coumarins as inhibitors of HIV-1. Future HIV Ther. 2007, 1, 315–329.
[CrossRef]
15. Shin, E.; Choi, K.M.; Yoo, H.S.; Lee, C.K.; Hwang, B.Y.; Lee, M.K. Inhibitory effects of coumarins from the
stem barks of Fraxinus rhynchophylla on adipocyte differentiation in 3T3-L1 cells. Biol. Pharm. Bull. 2010
33, 1610–1614. [CrossRef] [PubMed]
,
16. Keri, R.S.; Sasidhar, B.S.; Nagaraja, B.M.; Santos, M.A. Recent progress in the drug development of coumarin
derivatives as potent antituberculosis agents. Eur. J. Med. Chem. 2015, 100, 257–269. [CrossRef] [PubMed]
17. Piller, N.B. A comparison of the effectiveness of some anti-inflammatory drugs on thermal oedema. Br. J.
Exp. Pathol. 1975, 56, 554–560. [PubMed]
18. Bansal, Y.; Sethi, P.; Bansal, G. Coumarin: A potential nucleus for anti-inflammatory molecules. Med. Chem.
Res. 2013, 22, 3049–3060. [CrossRef]
19. Whang, W.K.; Park, H.S.; Ham, I.; Oh, M.; Namkoong, H.; Kim, H.K.; Hwang, D.W.; Hur, S.Y.; Kim, T.E.;
Park, Y.G. Natural compounds, fraxin and chemicals structurally related to fraxin protect cells from oxidative
stress. Exp. Mol. Med. 2005, 37, 436–446. [CrossRef]
20. Rosselli, S.; Maggio, A.M.; Faraone, N.; Spadaro, V.; Morris-Natschke, S.L.; Bastow, K.F.; Lee, K.H.; Bruno, M.
The cytotoxic properties of natural coumarins isolated from roots of ferulago campestris (Apiaceae) and of
synthetic ester derivatives of aegelinol. Nat. Prod. Commun. 2009, 4, 1701–1706. [CrossRef]
21. Crichton, E.G.; Waterman, P.G. Dihydromammea C/OB: A new coumarin from the seed of mammea Africana.
Phytochemistry 1978, 17, 1783–1786. [CrossRef]
22. Baek, N.I.; Ahn, E.M.; Kim, H.Y.; Park, Y.D. Furanocoumarins from the root of Angelica dahurica. Arch.
Pharm. Res. 2000, 23, 467–470. [CrossRef] [PubMed]
23. Teng, M.C.; Lin, H.; Ko, F.N.; Wu, T.S.; Huang, T.F. The relaxant action of osthole isolated from Angelica
pubescens in guinea-pig trachea. Naunyn Schmiedeberg’s. Arch. Pharmacol. 1994, 349, 202–208. [CrossRef]
[PubMed]
24. Fort, D.; Rao, K.; Jolad, S.; Luo, J.; Carlson, T.; King, S. Antihyperglycemic activity of teramnus labialis
(fabaceae). Phytomedicine 2000, 6, 465–467. [CrossRef]
25. Liu, Y.H.; Xu, J.R.; Wang, Q.; Li, M. Coupling coumarin to gold nanoparticles by DNA chains for sensitive
detection of DNase I. Anal. Biochem. 2018, 555, 50–54. [CrossRef] [PubMed]
26. Chesterman, J.P.; Hughes, T.C.; Amsden, B.G. Reversibly photo-crosslinkable aliphatic polycarbonates
functionalized with coumarin. Eur. Polym. J. 2018, 105, 186–193. [CrossRef]
27. Sarkar, N.; Datta, A.; Das, S.; Bhattacharyya, K. Solvation dynamics of coumarin 480 in micelles. J. Phys.
Chem. 1996, 100, 15483–15486. [CrossRef]
28. Arzhantsev, S.; Ito, N.; Heitz, M.; Maroncelli, M. Solvation dynamics of coumarin 153 in several classes of
ionic liquids: Cation dependence of the ultrafast component. Chem. Phys. Lett. 2003, 381, 278–286. [CrossRef]

Molecules 2019, 24, 2835
16 of 17
29. Lang, B.; Angulo, G.; Vauthey, E. Ultrafast solvation dynamics of coumarin 153 in imidazolium-based ionic
liquids. J. Phys. Chem. A 2006, 110, 7028–7034. [CrossRef]
30. Birau, M.M.; Wang, Z.Y. A dual-mode molecular switch based on a chiral binaphthol-coumarin compound.
Tetrahedron Lett. 2000, 41, 4025–4028. [CrossRef]
31. Deng, G.W.; Xu, H.J.; Kuang, L.; He, C.C.; Li, B.K.; Yang, M.; Zhang, X.L.; Li, Z.H.; Liu, J.L. Novel nonlinear
optical chromophores based on coumarin: Synthesis and properties studies. Opt. Mater. 2019, 88, 218–222.
[CrossRef]
32. Goda, F.E.; Abdel-Azizb, A.A.M.; Attef, O.A. Synthesis, antimicrobial activity and conformational analysis
of novel substituted pyridines: BF3-promoted reaction of hydrazine with 2-alkoxy pyridines. Bioorg. Med.
Chem. 2004, 12, 1845–1852. [CrossRef] [PubMed]
33. Foks, H.; Pancechowska-Ksepko, D.; Ke˛dzia, A.; Zwolska, Z.; Janowiec, M.; Augustinowicz-Kopec´, E.
Synthesis and antibacterial activity of 1H-pyrazolo[3,4-b] pyrazine and-pyridine derivatives. Farmaco 2005,
60, 513–517. [CrossRef] [PubMed]
34. Bharate, S.B.; Mahajan, T.R.; Gole, Y.R.; Nambiar, M.; Matan, T.T.; Kulkarni-Almeida, A.; Balachandran, S.;
Junjappa, H.; Balakrishnan, A.; Vishwakarma, R.A. Synthesis and evaluation of pyrazolo[3,4-b] pyridines and
its structural analogues as TNF-α and IL-6 inhibitors. Bioorg. Med. Chem. 2008, 16, 7167–7176. [CrossRef]
[PubMed]
35. De Mello, H.; Echevarria, A.; Bernardino, A.M.; CantoCavalheiro, M.; Leon, L.L. Antileishmanial
pyrazolopyridine derivatives: Synthesis and structure-activty relationship analysis. J. Med. Chem. 2004, 47,
5427–5432. [CrossRef] [PubMed]
36. Misra, R.N.; Rawlins, D.B.; Xiao, H.; Shan, W.; Bursuker, I.; Kellar, K.A.; Mulheron, J.G.; Sack, J.S.; Tokarski, J.S.;
Kimball, S.D.; et al. 1H-Pyrazolo[3,4-b] pyridine inhibitors of cyclin-dependent kinases: Highly potent
2,6-difluorophenacyl analogues. Bioorg. Med. Chem. Lett. 2003, 13, 2405–2408. [CrossRef]
37. Lin, R.; Connolly, P.J.; Lu, Y.; Chiu, G.; Li, S.; Yu, Y.; Huang, S.; Li, X.; Emanuel, S.L.; Middleton, S.A.; et al.
Synthesis and evaluation of pyrazolo[3,4-b] pyridine CDK1 inhibitors as anti-tumor agents. Bioorg. Med.
Chem. Lett. 2007, 17, 4297–4302. [CrossRef] [PubMed]
38. Parker, W.B. Enzymology of purine and pyrimidine antimetabolites used in the treatment of cancer. Chem.
Rev. 2009, 109, 2880–2893. [CrossRef]
39. Miliutina, M.; Janke, J.; Hassan, S.; Zaib, S.; Iqbal, J.; Lecka, J.; Sévigny, J.; Villinger, A.; Friedrich, A.;
Lochbrunner, S.; et al. A domino reaction of 3-chlorochromones with aminoheterocycles. Synthesis of
pyrazolopyridines and benzofuropyridines and their optical and ecto-50-nucleotidase inhibitory effects. Org.
Biomol. Chem. 2018, 16, 717–732. [CrossRef]
40. Lin, W.; Hu, X.X.; Song, S.; Cai, Q.; Wang, Y.; Shi, D.Q. Microwave-assisted synthesis of novel hetero[5]
helicene-like molecules and coumarin derivatives. Org. Biomol. Chem. 2017, 15, 7909–7916. [CrossRef]
41. Wang, H.Y.; Liu, X.C.; Feng, X.; Huang, Z.B.; Shi, D.Q. GAP chemistry for pyrrolyl coumarin derivatives: A
highly efficient one-pot synthesis under catalyst-free conditions. Green Chem. 2013, 15, 3307–3311. [CrossRef]
42. Wang, H.Y.; Shi, D.Q. Efficient synthesis of functionalized dihydro-1H-indol-4(5H)-ones via one-pot
three-component reaction under catalyst-free conditions. ACS Comb. Sci. 2013, 15, 261–266. [CrossRef]
[PubMed]
43. Liu, X.C.; Lin, W.; Wang, H.Y.; Huang, Z.B.; Shi, D.Q. Improved and efficient synthesis of chromeno
[4,3-d]pyrazolo[3,4-b]pyridine-6(3H)-ones and their fluorescence properties. J. Heterocycl. Chem. 2014, 51,
1036–1044. [CrossRef]
44. Wang, J.X.; Lin, W.; Liu, H.T.; Hu, M.H.; Feng, X.; Ren, J.F.; Huang, Z.B.; Shi, D.Q. An efficient synthesis
of coumarino[4,3-d]pyrazolo[3,4-b]-pyridine derivatives catalyzed by silica sulfuric acid under microwave
irradiation. Chin. J. Org. Chem. 2015, 35, 927–933. [CrossRef]
45. Lin, W.; Cai, Q.; Zheng, C.Z.; Zheng, Y.X.; Shi, D.Q. Synthesis of functionalized coumarino[4,3-d]pyrazolo
[3,4-b]pyridine derivatives and their selective recognition for Zn2+. Chin. J. Org. Chem. 2017, 37, 2392–2398.
[CrossRef]
46. Lin, W.; Zheng, Y.X.; Wang, Y.Z.; Shi, D.Q. An efficient synthesis of functionalized chromeno[4,3-d]pyrazolo
[3,4-b]pyridine derivatives. Heterocycles 2016, 92, 2235–2243.

Molecules 2019, 24, 2835
17 of 17
47. Crystallographic Data for 7a Have been Deposited at the Cambridge Crystallographic Data Centre (CCDC
1881623). Available online: www.ccdc.cam.ac.uk/conts/retrieving.html (accessed on 30 July 2019).
48. Bogdal, D. Coumarins: Fast synthesis by knoevenagel condensation under microwave irradiation. J. Chem.
Res. Synop. 1998, 12, 468–469. [CrossRef]
Sample Availability: Samples of the compounds 4 and 7 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).