The catalyst-free syntheses of pyrazolo[3,4-b]quinolin-5-one and pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives by one-pot, three-component reactions

Article abstract of DOI:10.1016/j.tet.2017.10.004

Herein we report the syntheses of pyrazolo[3,4-b]quinolin-5-one and pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives by cyclocondensation of 1,3-diketones, 3-methyl-1-phenyl-1H-pyrazole-5-amine and arylglyoxals, under catalyst-free conditions in H₂O/EtOH at reflux in 65–98% and 73–96% yields respectively. This protocol provides mild reaction conditions, good to high yields, non-catalytic, simple procedures and easy isolation of products to structurally diverse tricyclic pyrazolo[3,4-b]quinolin-5-one and pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives, which may have biological and pharmacological activities.

Full text of DOI:10.1016/j.tet.2017.10.004

Accepted Manuscript
The catalyst-free syntheses of pyrazolo[3,4-b]quinolin-5-one and
pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives by one-pot, three-
component reactions
Mahnaz Ezzati, Jabbar Khalafy, Ahmad Poursattar Marjani, Rolf H. Prager
PII:
S0040-4020(17)31012-8
10.1016/j.tet.2017.10.004
TET 29007
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 June 2017
Revised Date: 21 September 2017
Accepted Date: 2 October 2017
Please cite this article as: Ezzati M, Khalafy J, Marjani AP, Prager RH, The catalyst-free syntheses of
pyrazolo[3,4-b]quinolin-5-one and pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives by one-
pot, three-component reactions, Tetrahedron (2017), doi: 10.1016/j.tet.2017.10.004.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
The catalyst-free syntheses of pyrazolo[3,4-b]quinolin-5-one
and pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidin-5,7-dione
Leave this area blank for abstract info.
derivatives by one-pot, three-component reactions
Mahnaz Ezzati,a Jabbar Khalafy,a Ahmad Poursattar Marjania and Rolf H. Pragerb
a Department of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia, Iran
b Department of Chemistry, Flinders University, G.P.O. Box 2100, Adelaide, Australia 5001

ACCEPTED MANUSCRIPT
The catalyst-free syntheses of pyrazolo[3,4-b]quinolin-5-one and
pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives by
one-pot, three-component reactions
Mahnaz Ezzati,a Jabbar Khalafy,a Ahmad Poursattar Marjania,* and Rolf H. Pragerb
a Department of Organic Chemistry, Faculty of Chemistry, Urmia University, Urmia, Iran
b Department of Chemistry, Flinders University, G.P.O. Box 2100, Adelaide, Australia 5001
*Corresponding author. e-mail: a.poursattar@gmail.com; a.poursattar@urmia.ac.ir
ABSTRACT
Herein we report the syntheses of pyrazolo[3,4-b]quinolin-5-one and pyrazolo[4',3':5,6]pyrido[2,3-
d]pyrimidin-5,7-dione derivatives by cyclocondensation of 1,3-diketones, 3-methyl-1-phenyl-1H-
pyrazole-5-amine and arylglyoxals, under catalyst-free conditions in H2O/EtOH at reflux in 65-98% and
73-96% yields respectively. This protocol provides mild reaction conditions, good to high yields, non-
catalytic, simple procedures and easy isolation of products to structurally diverse tricyclic pyrazolo[3,4-
b]quinolin-5-one and pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidin-5,7-dione derivatives, which may have
biological and pharmacological activities.
Keywords: Arylglyoxals, Pyrazolo[3,4-b]quinolines, Pyrido[2,3-d]pyrimidines, One-pot, Multi-
component reactions
Introduction
The green synthesis of nitrogen-containing heterocyclic compounds using environmentally friendly
chemical procedures has attracted much attention due to their various biological and pharmaceutical
activities. One-pot, multicomponent reactions (MCRs), which combine three or more substrates
concurrently or in sequential addition, lead to domino processes,1 without isolating intermediate species
or changing the solvent. MCRs offer benefits such as simple and convenient operation, facile automation
and minimized waste generation due to the decrease in the number of work-up, extraction and purification
stages. They play an important role in the synthesis of heterocyclic compounds through environmentally
and economically useful one-pot procedures.
Water is the ideal green solvent and the best alternative to organic solvents, because of being non-
flammable, non-hazardous, non-toxic, uniquely redox-stable, inexpensive, readily available and
environmentally benign.2 Pyrazoles are important because of their wide range of pharmacological effects3
and biological activities,4 such as antidepressant,5 antibacterial,6 antihyperglycemic,7 antimalarial,8

ACCEPTED MANUSCRIPT
antiinflammatory,9 antimicrobial,10 antitumor,11 anticancer,12 antiviral,13 and analgesic14 properties. They
also have a wide range of applications in the agrochemicals industry,15,16 but are relatively scarce in
nature.
Pyrazolo[3,4-b]quinolones have attracted more attention than other derivatives due to their
bioactivities,17 such as antimycobacterial,18 antimicrobial,19 and antiviral.20 Examples of their use are as
inhibitors of herpex simplex virus,21 oncogenic ras-inhibitors,22 cyclooxygenase inhibitors,23 replication,24
activators of caspases and inducers of apoptosis.25 Among the several methods available for the synthesis
of pyrazolo[3,4-b]quinolones,26-28 the one-pot, three-component reaction of 1,3-diketons, 5-
aminopyrazoles and aromatic aldehydes has received much attention.29
Pyrazolo[3,4-b]pyridines are present in numerous natural products and biologically active molecules,
such as the anxiolytic drugs cartazolate, etazolate and tracazolate.30
Several methods for the synthesis of pyrazoloquinoline derivatives have been reported by diverse
procedures,31-34 but some of the reported methods are limited by the use of expensive reagents, time-
consuming multi-step procedures, use of toxic solvents or catalysts. In continuation of our interests in the
synthesis of new heterocyclic compounds by one-pot, multi-component reactions,35-40 herein we report a
convenient and rapid method for the synthesis of novel pyrazolo[3,4-b]quinoline and
pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine derivatives via a one-pot, three-component reaction, involving
intramolecular cyclocondensation of arylglyoxals, 3-methyl-1-phenyl-1H-pyrazol-5-amine, 1,3-
dicarbonyl compounds such as cyclohexane-1,3-dione, dimedone (5,5-dimethylcyclohexane-1,3-dione)
and 1,3-dimethylbarbituric acid using H2O/EtOH as solvent, without any catalyst.
Results and discussion
In attempting to develop a simple, one-pot and short reaction route for the synthesis of various
heterocyclic compounds, we reported earlier the syntheses of arylquinoxalines, cinnolines, 1H-indol-
4(5H)-ones, acridinediones and diindenopyridine-10,12-diones starting from arylglyoxals.35-40
We found that reaction of arylglyoxals 1 with 1,3-diketones [(cyclohexane-1,3-dione (2a) and dimedone
o
(2b)] and 3-methyl-1-phenyl-1H-pyrazol-5-amine 3, in H2O/EtOH at 50 C afforded pyrazolo[3,4-
b]quinolone derivatives 4a-k by a one-pot, three-component reaction in good to excellent yields. When
the reaction was carried out under reflux conditions in the presence of air, the corresponding
pyrazolo[3,4-b]quinolones 5a-k were obtained in good to excellent yields (Scheme 1).
4

ACCEPTED MANUSCRIPT
Scheme 1. Synthesis of pyrazolo[3,4-b]quinolones 5a-k.
Similarly, the reaction of arylglyoxals 1 with 1,3-dimethylbarbituric acid (2c) and 3-methyl-1-phenyl-1H-
pyrazol-5-amine (3) in H2O/EtOH under reflux conditions gave the desired pyrazolo[4',3':5,6]pyrido[2,3-
d]pyrimidine-5,7(6H,8H)-diones 6a-e in 73-96% yields (Scheme 2).
Scheme 2. Synthesis of pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-diones 6a-e.
The reaction conditions were then applied to a range of different arylglyoxals. The results with various
arylglyoxals and product yields and melting points are summarized in Table 1, 2 and 3 (Entry 14).
Arylglyoxals with both electron-rich and electron-deficient substituents were well tolerated. Spectral data,
TLC and melting points were used to establish that only one product was formed in all cases.
5

ACCEPTED MANUSCRIPT
Table 1. Synthesis of 1,4,6,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-ones 4a-k.
Entry
Product
Yield (%)
M.p (oC )
67
149-150
1
63
167-168
2
96
197
3
66
148-149
4
84
188-189
5
83
159 (dec.)
6
6

ACCEPTED MANUSCRIPT
94
125-126
7
65
130
8
91
166-167
9
71
159-160
10
87
149
11
7

ACCEPTED MANUSCRIPT
Table 2. Synthesis of 1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one 5a-k.
Entry
Product
Yield (%)
M.p (oC )
76
170
1
75
176
2
95
183
3
98
210 (dec.)
4
89
159
5
8

ACCEPTED MANUSCRIPT
84
224
6
71
173
7
70
171-172
8
Cl
O
O
H3C
94
180
9
N
N
N
5i
95
179
10
83
165
11
* The isolated yields refer to the products recrystallized from EtOH.
9

ACCEPTED MANUSCRIPT
Table 3. Synthesis of 1,8-dihydro-5H-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-diones 6a-e.
Entry
Product
Yield (%)
M.p (oC )
73
241
1
75
96
75
230
256
263
2
3
4
90
233
5
* The isolated yields refer to the products recrystallized from EtOH.
A plausible mechanism for this reaction is shown in Scheme 3. It involves the initial Knoevenagel
condensation of arylglyoxals 1 and β-diketones 2a,b or 1,3-dimethylbarbituric acid (2c) to form the
10

ACCEPTED MANUSCRIPT
corresponding intermediates, followed by Michael addition of 3-methyl-1-phenyl-1H-pyrazol-5-amine (3)
to these intermediates to form the corresponding pyrazolo[3,4-b]quinoline and pyrazolo
[4',3':5,6]pyrido[2,3-d]pyrimidine derivatives through intermolecular cyclization followed by subsequent
tautomerization. The initial products were dehydrogenated to give the desired products 5a-k and 6a-e
under reflux conditions or treatment with ethanolic KOH in the presence of air.
Scheme 3. A plausible mechanistic pathway for formation of 5a-k and 6a-e.
11

ACCEPTED MANUSCRIPT
The substituted 4-aroyl-3-methyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]-5(4H)-ones 4a-k were
1
13
characterized using H-NMR, C-NMR and FT-TR spectral data and microanalysis. The characteristic
singlet at δ = 5.61-5.82 ppm was ascribed to the CH of the dihydropyridine ring, which was present in all
products, and a singlet at δ = 1.67-1.86 ppm which was due to the methyl group attached to the pyrazole
13
ring. In the C-NMR spectra of products 4a-k, signals located around δ = 200.4-202.9 and δ = 194.5-
195.7 ppm were attributed to the quinolone and aroyl carbonyl groups respectively. The characteristic
absorption bands at 1662-1695 and 1602-1624 cm-1 could be assigned to the vibrations of quinolone and
aroyl carbonyl groups respectively.
The characteristic singlets at around δ = 2.26-2.29 ppm was attributed to the methyl group attached to the
pyrazole moiety and were present in all new products. In the 13C-NMR spectra of the products 5a-k,
signals located around δ = 196.6-199.7 and 192.3-195.1 ppm were due to the quinolone and aroyl
carbonyl groups respectively. The absorption bands at around 1662-1679 cm-1 could be assigned to the
two different carbonyl groups.
In the 1H-NMR spectra of the products 6a-e, the singlets at around δ = 3.86-3.87, 3.39-3.42 and 2.26-2.27
ppm are attributed to the 3-methyl, 1-methyl and the methyl of pyrazole ring respectively and were
13
present in all new products. In the C-NMR spectra of products 6a-e, signals located around δ = 180.6-
192.1 and 159.6-173.5 ppm were due to aroyl and C-4 carbonyl groups respectively. In the FT-IR spectra,
the characteristic absorption bands at 1665-1707 cm-1 could be assigned to the vibrations of three
different carbonyl groups.
The structures of compound 4a and 4i were confirmed by single-crystal X-ray analysis (Fig. 1).
4a
4i
Fig. 1. ORTEP diagram of compounds 4a and 4i.

ACCEPTED MANUSCRIPT
The X-ray single crystal diffraction analysis showed that the carbonyl group of arylglyoxal and the
carbonyl group of 1,3-diketones and also the aryl ring of the arylglyoxal and pyrazole moieties are not
collimated together.
In the X-ray crystallographic data of compound 4a the bond lengths of N1-N2, C9-C10, C18-O2 were
1.381, 1.362, 1.222 ° respectively. The bond angles of N2-N1-C6, C7-C9-C17, C11-N3-C10 were 121.04
°, 121.86° and 117.37 °, respectively.
In the X-ray crystallographic data of compound 4i the bond lengths of C11-N3, C18-C11, C10-N1 were
1.349, 1.379, 1.344 ° respectively. The bond angles of C10-C9-C8, C10-C9-C19, C19-C20-C21 were
105.3 °, 120.7 ° and 121.1 °, respectively.
Conclusions
We have synthesized a new series of pyrazolo[3,4-b]quinolin-5-one and pyrazolo[4',3':5,6]pyrido[2,3-
d]pyrimidin-5,7-dione derivatives by one-pot, three-component reactions of arylglyoxals, 1,3-diketones
and pyrazoles under catalyst-free conditions. The reasonable reaction times, mild reaction conditions,
good to excellent yields, absence of any catalyst, easy work-up, and ready availability of the starting
materials are the merits of this method. Our method provides a new synthesis for pyrazoloquinolines,
pyrazolo[3,4-b]quinolin-5-ones, and pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidin-5,7-diones with different
substituents, which may have pharmaceutical and biological applications.
Experimental
The chemicals used in this work were obtained from Acros and Merck companies and were used without
purification. Melting points were measured on a Philip Harris C4954718 apparatus and are uncorrected.
The progress of the reaction was monitored by thin layer chromatography (TLC) on Merck’s silica plates.
Infrared spectra were recorded on a Thermo Nicolet Nexus 670 FT-IR instrument using KBr discs. 1H and
13C NMR spectra were recorded on a Bruker Avance AQS 300 MHz spectrometer at 300 and 75.5 MHz,
respectively. Chemical shifts were measured in CDCl3 as solvent relative to TMS as the internal standard.
Mass spectra were recorded on a Varian Matt 311 spectrometer and relative abundance of fragments are
quoted in parentheses after the m/z values. The arylglyoxals were prepared as their hydrates by oxidation
of the corresponding acetophenones with SeO2.41 The 3-methyl-1-phenyl-1H-pyrazole-5-amine 3 was
prepared according to the literature method.42
13

ACCEPTED MANUSCRIPT
General procedure for the synthesis of products:
A) 4-Aroyl-3-methyl-1-phenyl-1,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-5-one derivatives
4a-k:
A mixture of arylglyoxals 1 (1 mmol) and 1,3-diketones [(cyclohexane-1,3-dione (2a) or dimedone (2b)]
(1 mmol) in H2O (5 mL) was stirred at room temperature and monitored by TLC (CH2Cl2 : MeOH /
15:1). After completion of the intermediate formation, 3-methyl-1-phenyl-1H-pyrazol-5-amine 3 (1
mmol) in EtOH (2.5 mL) was added to the reaction mixture which was stirred at 50 oC for an appropriate
time (monitored by TLC, CH2Cl2 : Hexane : MeOH / 15:5:1), during which the precipitate was formed
and the solid was filtered and washed twice with 2×1 mL of cold H2O : EtOH (1:1). The desired products
were obtained in moderate to excellent yields (63-96%).
B) 4-Aroyl-3-methyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one derivatives 5a-
k:
Method (І): A mixture of arylglyoxals 1 (1 mmol) and 1,3-diketones [cyclohexane-1,3-dione (2a) or
dimedone (2b)] (1 mmol) in H2O (5 mL) was stirred and monitored by TLC (CH2Cl2 : MeOH / 15:1).
After completion of the intermediate formation, 3-methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol) in
EtOH (5 mL) was added and the reaction mixture was stirred under reflux while passing a fine stream of
air through the reaction for an appropriate time (monitored by TLC, CH2Cl2 : Hexane : MeOH / 15:5:1).
Half of the solvent was evaporated and the obtained precipitate was filtered, washed with cold water and
subsequently recrystallized from ethanol to obtain the desired products in high to excellent yields (71-
98%).
Method (II): Refluxing the products 4a-k (1 mmol) in EtOH (5 mL) in the presence of KOH (1 mmol),
while passing a fine stream of air over the surface of the solution, for 10-30 min led to the formation of 4-
aroyl-3-methyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quino lin-5(6H)-one derivatives 5a-k.
C)
4-Aroyl-3,6,8-trimethyl-1-phenyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]5,7(6H,8H)-dione
derivatives 6a-e:
A mixture of arylglyoxals 1 (1 mmol) and 1,3-dimethylbarbituric acid (2c, 1 mmol) in H2O (5 mL) was
stirred and monitored by TLC (CH2Cl2 : MeOH / 15:1). After completion of intermediate formation, 3-
methyl-1-phenyl-1H-pyrazol-5-amine (1 mmol) in EtOH (5 mL) was added to the mixture and it was
stirred under reflux for an appropriate time (monitored by TLC, CH2Cl2 : Hexane : MeOH / 15:5:1). After
completion of the reaction, half of the solvent was evaporated and the obtained precipitate was filtered,
14

ACCEPTED MANUSCRIPT
washed with cold water and recrystallized from ethanol to give the desired products in high to excellent
yields (73-96%).
4-Benzoyl-3-methyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-one (4a).
Yellow crystals, 67%, m.p. 149-150 ºC; νmax 3238, 3164, 3037, 2954, 2889, 1662, 1623, 1537, 1460,
1357, 1188, 1113, 1001, 914, 852, 758, 692, 649, 557 cm-1; δH (300 MHz, CDCl3) 8.18 (2 H, d, J 7.5 Hz,
Ar), 7.94 (1 H, bs, NH, exchanged by D2O addition), 7.61 (1 H, t, J 7.2 Hz, Ar), 7.51 (2 H, t, J 7.5 Hz,
Ar), 7.40-7.20 (5 H, m, Ar), 5.78 (1 H, s, CH), 2.58-2.40 (2 H, m, CH2), 2.36-2.21 (2 H, m, CH2), 1.95 (2
H, quin, J 6.3 Hz, CH2), 1.75 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 202.9, 195.6, 162.3, 1534.0, 153.9,
146.6, 137.7, 137.5, 136.6, 133.1, 129.6, 129.2, 128.5, 127.3, 122.9, 110.2, 100.2, 39.0, 36.3, 28.1, 21.2,
12.9; EIMS : m/z (%) 383 (M, 5), 382 (22), 381 (79), 353 (20), 352 (49), 325 (21), 324 (39), 279 (34),
278 (100), 106 (64), 77 (98), 51 (34); and HRMS m/z 383.1618 (C24H21N3O2 requires 383.1634).
4-(4-Fluorobenzoyl)-3-methyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-one
(4b).
Yellow crystals, 63%, m.p. 167-168 ºC; νmax 3232, 3162, 3048, 2957, 2891, 1668, 1610, 1537, 1467,
1358, 1220, 1115, 1005, 852, 760, 596, 522 cm-1; δH (300 MHz, CDCl3) 8.24 (2 H, t, J 7.8 Hz, Ar), 7.48-
7.26 (6 H, m, Ar + NH, exchanged by D2O addition), 7.19 (2 H, t, J 8.4 Hz, Ar), 5.77 (1 H, s, CH), 2.64-
2.45 (2 H, m, CH2), 2.38 (2 H, t, J 6.3 Hz, CH2), 2.03 (2 H, quin, J 6.3 Hz, CH2), 1.79 (3 H, s, CH3); δC
(75.5 MHz, CDCl3) 201.2, 195.6, 167.5, 164.1, 153.3, 146.6, 137.7, 136.4, 134.0, 131.8, 131.7, 129.7,
127.5, 123.0, 115.8, 115.5, 110.4, 100.2, 39.0, 36.4, 28.4, 21.2, 12.9; EIMS : m/z (%) 401 (M, 10), 400
(61), 399 (96), 371 (48), 370 (100), 343 (48), 342 (89), 278 (69), 123 (96), 95 (95), 77 (76), 75 (25), 51
(23); and HRMS m/z 401.1528 (C24H20FN3O2 requires 401.1540).
3-Methyl-4-(4-nitrobenzoyl)-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-one
(4c).
Orange crystals, 96%, m.p. 197 ºC; νmax 3217, 3137, 3028, 2939, 1695, 1604, 1527, 1462, 1350, 1194,
1116, 1000, 851, 769, 689 cm-1; δH (300 MHz, CDCl3) 8.38-8.22 (4 H, m, Ar), 7.50-7.30 (6 H, m, Ar +
NH, exchanged by D2O addition), 5.69 (1 H, s, CH), 2.62-2.44 (2 H, m, CH2), 2.42-2.22 (2 H, m, CH2),
2.03 (2 H, quin, J 6.3 Hz, CH2), 1.78 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 201.2, 195.7, 153.4, 150.1,
146.5, 142.7, 137.6, 136.2, 129.8, 127.8, 123.7, 123.1, 110.3, 99.5, 40.0, 36.2, 28.4, 21.2, 13.0; EIMS :
m/z (%) 428 (M, 13), 278 (100), 277 (98), 276 (37), 249 (99), 220 (36), 180 (77), 179 (60), 167 (41), 129
(46), 77 (97), 65 (49), 51 (45); and HRMS m/z 428.1471 (C24H20N4O4 requires 428.1485).
15

ACCEPTED MANUSCRIPT
4-(4-Methoxybenzoyl)-3-methyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-one
(4d).
Yellow crystals, 66%, m.p. 148-149 ºC; νmax 3328, 2955, 2623, 2452, 1680, 1606, 1524, 1459, 1351,
1331, 1232, 1172, 1122, 1046, 1024, 845, 756, 697, 599, 512 cm-1; δH (300 MHz, CDCl3) 8.21 (2 H, d, J
8.7 Hz, Ar), 7.89 (1 H, bs, NH, exchanged by D2O addition), 7.54-7.20 (5 H, m, Ar), 7.00 (2 H, d, J 8.7
Hz, Ar), 5.79 (1 H, s, CH), 3.91 (3 H, s, OCH3), 2.69-2.41 (2 H, m, CH2), 2.33 (2 H, t, J 6 Hz, CH2), 1.98
(2 H, quin, J 6.3 Hz, CH2), 1.80 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 201.2, 195.6, 163.7, 162.3, 153.8,
146.6, 137.7, 136.7, 131.6, 130.2, 129.5, 127.2, 122.9, 113.7, 110.3, 100.6, 55.5, 38.3, 36.4, 28.2, 21.2,
13.0; EIMS : m/z (%) 413 (M, 7), 336 (44), 277 (100), 249 (66), 217 (20), 135 (78), 77 (93), 51 (40); and
HRMS m/z 413.1720 (C25H23N3O3 requires 413.1739).
4-(3,4-Dimethoxybenzoyl)-3-methyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-
one (4e).
Pale yellow crystals, 84%, m.p. 188-189 ºC; νmax 3315, 3242, 2941, 1650, 1620, 1525, 1453, 1356, 1255,
1154, 1017, 884, 756, 633 cm-1; δH (300 MHz, CDCl3) 8.06 (1 H, d, J 8.4 Hz, Ar), 7.65 (2 H, bs, Ar +
NH, exchanged by D2O addition), 7.50-7.20 (5 H, m, Ar), 6.99 (1 H, d, J 8.1 Hz, Ar), 5.82 (1 H, s, CH),
3.99 (3 H, s, OCH3), 3.96 (3 H, s, OCH3), 2.54 (2 H, t, J 6 Hz, CH2), 2.36 (2 H, t, J 6 Hz, CH2), 2.00 (2 H,
quin, J 6 Hz, CH2), 1.85 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 201.0, 195.6, 153.6, 153.5, 148.9, 146.6,
137.7, 136.6, 130.3, 129.6, 127.3, 124.3, 122.9, 111.2, 110.4, 110.2, 100.6, 56.1, 56.0, 38.3, 36.4, 28.3,
21.2, 13.0; EIMS : m/z (%) 443 (M, 9), 442 (23), 441 (70), 426 (30), 425 (81), 410 (34), 382 (19), 278
(92), 277 (94), 249 (41), 212 (12), 166 (39), 165 (100), 139 (20), 129 (13), 77 (76), 51 (25); and HRMS
m/z 443.1859 (C26H25N3O4 requires 443.1845).
3-Methyl-4-(4-methylbenzoyl)-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-one
(4f).
Yellow crystals, 83%, m.p. 159-160 ºC (dec); νmax 3345, 3030, 2955, 1662, 1617, 1527, 1459, 1363,
1189, 1119, 1066, 1004, 847, 754, 694, 599, 521 cm-1; δH (300 MHz, DMSO-d6) 9.51 (1 H, bs, NH,
exchanged by D2O addition), 8.00 (2 H, d, J 8.1 Hz, Ar), 7.66-7.35 (5 H, m, Ar), 7.33 (d, J 7.8 Hz, 2H,
Ar), 5.61 (s, 1H, CH), 2.71-2.55 (2 H, m, CH2), 2.39 (3 H, s, CH3), 2.31-2.08 (2 H, m, CH2), 1.99-1.77 (2
H, m, CH2), 1.67 (3 H, s, CH3); δC (75.5 MHz, DMSO-d6) 200.8, 195.0, 155.2, 146.1, 143.4, 138.4,
137.5, 135.3, 129.9, 129.5, 129.2, 127.6, 123.9, 109.4, 99.9, 40.1, 39.9, 36.8, 27.6, 21.6, 13.2; EIMS : m/z
(%) 397 (M, 9), 396 (29), 395 (94), 366 (43), 354 (36), 338 (42), 277 (100), 249 (49), 180 (25), 129 (15),
16

ACCEPTED MANUSCRIPT
119 (91), 91 (96), 84 (68), 77 (71), 66 (91), 65 (35), 51 (27); and HRMS m/z 397.1782 (C25H23N3O2
requires 397.1790).
4-(4-Chlorobenzoyl)-3,7,7-trimethyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-
one (4g).
Pale yellow crystals, 94%, m.p. 124-125 ºC; νmax 3225, 3154, 3044, 2951, 2889, 1687, 1602, 1526, 1467,
1371, 1215, 1113, 993, 861, 813, 765, 642, 607, 546 cm-1; δH (300 MHz, CDCl3) 8.08 (2 H, d, J 8.4 Hz,
Ar), 7.57-7.24 (8 H, m, Ar + NH, exchanged by D2O addition), 5.67 (1 H, s, CH), 2.33 (2 H, s, CH2),
2.25-2.10 (2 H, m, CH2), 1.78 (3 H, s, CH3), 1.06 (3 H, s, CH3), 1.05 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 201.3, 195.5, 151.8, 146.7, 139.3, 137.6, 136.5, 136.1, 130.3, 129.8, 128.8, 127.6, 123.0, 109.0,
99.8, 50.1, 42.0, 39.2, 33.0, 28.4, 28.0, 13.0; EIMS : m/z (%) 447 (M+2, 1), 445 (M, 2), 443 (5), 305
(100), 249 (65), 193 (26), 139 (31), 77 (53), 51 (21); and HRMS m/z 445.1557 (C26H24ClN3O2 requires
445.1557).
4-(4-Fluorobenzoyl)-3,7,7-trimethyl-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-
one (4h).
Pale yellow crystals, 65%, m.p. 130 ºC; νmax 3249, 3172, 3053, 2954, 1681, 1605, 1530, 1464, 1372,
1220, 1156, 1125, 1062, 994, 759, 598 cm-1; δH (300 MHz, CDCl3) 8.30-8.12 (2 H, m, Ar), 7.59-7.25 (6
H, m, Ar + NH, exchanged by D2O addition), 7.17 (2 H, t, J 8.4 Hz, Ar), 5.70 (1 H, s, CH), 2.45-2.28 (2
H, m, CH2), 2.28-2.10 (2 H, m, CH2), 1.77 (3 H, s, CH3), 1.07 (3 H, s, CH3), 1.06 (3 H, s, CH3); δC (75.5
MHz, CDCl3) 200.9, 195.6, 167.4, 164.0, 146.7, 137.6, 136.6, 134.1, 131.7, 131.5, 129.8, 127.7, 123.1,
115.8, 115.5, 99.9, 50.1, 42.0, 39.1, 33.0, 28.3, 28.0, 13.0; EIMS : m/z (%) 429 (M, 2), 428 (6), 427 (19),
370 (11), 306 (89), 305 (100), 250 (29), 249 (98), 220 (26), 180 (56), 179 (42), 129 (31), 123 (40), 103
(17), 95 (23), 77 (82), 51 (27); and HRMS m/z 429.1840 (C26H24FN3O2 requires 429.1853).
3,7,7-Trimethyl-4-(4-nitrobenzoyl)-1-phenyl-6,7,8,9-tetrahydro-1H-pyrazolo[3,4-b]quinolin-5(4H)-
one (4i).
Yellow crystals, 91%, m.p. 166-167 ºC; νmax 3214, 3147, 3041, 2954, 1694, 1605, 1528, 1466, 1364,
1205, 1120, 1062, 997, 846, 764, 698, 646 cm-1; δH (300 MHz, CDCl3) 8.45-8.20 (4 H, m, Ar), 7.60-7.33
(5 H, m, Ar), 6.58 (1 H, s, NH, exchanged by D2O addition), 5.71 (1 H, s, CH), 2.58-2.37 (2 H, m, CH2),
2.35-2.14 (2 H, m, CH2), 1.82 (3 H, s, CH3), 1.12 (3 H, s, CH3), 1.10 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 200.7, 195.6, 151.1, 150.0, 146.7, 143.1, 137.6, 136.2, 130.0, 129.8, 128.0, 123.7, 123.1, 109.2,
99.4, 50.1, 42.3, 40.2, 33.1, 28.8, 27.6, 13.0; EIMS : m/z (%) 456 (M, 8), 455 (47), 454 (100), 435 (27),
17

ACCEPTED MANUSCRIPT
383 (14), 351 (26), 332 (13), 305 (49), 249 (24), 150 (15), 105 (30), 77 (64), 51 (14); and HRMS m/z
456.1773 (C26H24N4O4 requires 456.1798).
4-(4-Methoxybenzoyl)-3,7,7-trimethyl-1-phenyl-1,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-b]quinolin-
5-one (4j).
Yellow crystals, 71%, m.p. 159-160 ºC; νmax 3233, 3162, 3049, 2949, 1679, 1604, 1527, 1465, 1371,
1328, 1223, 1167, 1128, 1026, 760, 600, 558 cm-1; δH (300 MHz, CDCl3) 8.18 (2 H, d, J 8.7 Hz, Ar),
7.60-7.30 (5 H, m, Ar), 7.10-6.88 (3 H, m, Ar + NH, exchanged by D2O addition), 5.77 (1 H, s, CH), 3.90
(3 H, s, OCH3), 2.38 (2 H, s, CH2), 2.24 (2 H, s, CH2), 1.83 (3 H, s, CH3), 1.12 (3 H, s, CH3), 1.09 (3 H, s,
CH3); δC (75.5 MHz, CDCl3) 200.5, 195.4, 163.5, 151.2, 146.9, 137.8, 136.5, 131.4, 130.6, 129.8, 127.5,
123.0, 113.7, 109.5, 100.4, 55.4, 50.3, 42.3, 38.5, 33.0, 28.4, 28.1, 13.0; EIMS : m/z (%) 441 (M,1), 439
(3), 409 (5), 305 (9), 153 (57), 152 (100), 146 (70), 145 (98), 109 (41), 107 (69), 92 (86), 81 (48), 63 (56),
51 (26); and HRMS m/z 441.2069 (C27H27N3O3 requires 441.2052).
4-(3,4-Dimethoxybenzoyl)-3,7,7-trimethyl-1-phenyl-1,4,6,7,8,9-hexahydro-5H-pyrazolo[3,4-
b]quinolin-5-one (4k).
Pale yellow crystals, 87%, m.p. 149 ºC; νmax 3313, 3062, 2935, 1670, 1624, 1534, 1460, 1346, 1257,
1169, 1124, 1018, 757, 693 cm-1; δH (300 MHz, CDCl3) 8.00 (1 H, d, J 8.1 Hz, Ar), 7.62 (1 H, s, Ar),
7.58-7.29 (5 H, m, Ar), 6.97 (1 H, d, J 8.4 Hz, Ar), 6.85 (1 H, bs, NH, exchanged by D2O addition), 5.78
(1 H, s, CH), 3.97 (3 H, s, OCH3), 3.94 (3 H, s, OCH3), 2.39 (2 H, s, CH2), 2.25 (2 H, s, CH2), 1.86 (3 H,
s, CH3), 1.12 (3 H, s, CH3), 1.09 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 200.4, 195.5, 153.2, 151.2, 148.9,
146.9, 137.8, 136.5, 130.6, 129.8, 127.6, 123.9, 123.0, 111.1, 110.1, 109.5, 100.4, 56.0, 55.9, 50.3, 42.3,
38.4, 33.0, 28.6, 27.9, 13.1; EIMS : m/z (%) 471 (M, 7), 470 (32), 469 (100), 450 (14), 448 (17), 398
(12), 305 (33), 249 (13), 165 (46), 77 (64), 55 (17); and HRMS m/z 471.2139 (C28H29N3O4 requires
471.2158).
4-Benzoyl-3-methyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (5a).
White crystals, 76%, m.p. 170 ºC; νmax 3059, 2946, 2347, 1676, 1571, 1484, 1431, 1332, 1221, 1129,
1018, 909, 838, 752, 685, 604, 556, 521 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.1 Hz, Ar), 7.81 (2
H, d, J 7.5 Hz, Ar), 7.67-7.39 (5 H, m, Ar), 7.35 (1 H, t, J 7.5 Hz, Ar), 3.35 (2 H, t, J 6.3 Hz, CH2), 2.75-
2.61 (2H, m, CH2), 2.24 (2 H, bt, J 6.3 Hz, CH2), 2.26 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 196.7, 195.1,
164.7, 151.0, 146.0, 144.5, 138.8, 136.5, 133.6, 129.1, 128.9, 128.5, 126.4, 121.3, 120.7, 113.9, 38.8,
34.1, 21.7, 13.9; EIMS : m/z (%) 381 (M, 23), 380 (53), 352 (37), 338 (29), 306 (55), 305 (100), 249 (92),
18

ACCEPTED MANUSCRIPT
220 (24), 180 (44), 129 (26), 105 (65), 77 (96), 51 (35); and HRMS m/z 381.1464 (C24H19N3O2 requires
381.1477).
4-(4-Fluorobenzoyl)-3-methyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (5b).
White crystals, 75%, m.p. 176 ºC; νmax 3078, 2954, 1677, 1599, 1575, 1508, 1480, 1420, 1323, 1232,
1187, 1160, 860, 759, 691, 614 cm-1; δH (300 MHz, CDCl3) 8.27 (2 H, d, J 8.1 Hz, Ar), 7.92-7.78 (2 H,
m, Ar), 7.55 (2 H, t, J 7.8 Hz, Ar), 7.35 (1 H, t, J 7.2 Hz, Ar), 7.15 (2 H, t, J 8.4 Hz, Ar), 3.35 (2 H, t, J
6.3 Hz, CH2), 2.82-2.60 (2 H, m, CH2), 2.28 (2 H, t, J 6.3 Hz, CH2), 2.26 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 196.8, 193.5, 167.7, 164.7, 151.0, 145.4, 144.3, 138.7, 133.1, 131.1, 129.1, 126.5, 121.4, 120.7,
116.3, 113.7, 38.8, 34.0, 21.7, 13.8; EIMS : m/z (%) 399 (M, 14), 370 (7), 342 (6), 101 (44), 100 (93), 77
(100), 55 (98), 45 (95); and HRMS m/z 399.1396 (C24H18FN3O2 requires 399.1383).
4-(4-Chlorobenzoyl)-3-methyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (5c).
White crystals, 95%, m.p. 183 ºC; νmax 2942, 1678, 1574, 1484, 1422, 1225, 1088, 1015, 848, 756, 688,
539 cm-1; δH (300 MHz, CDCl3) 8.27 (2 H, d, J 8.1 Hz, Ar), 7.74 (2 H, d, J 8.1 Hz, Ar), 7.55 (2 H, t, J 7.8
Hz, Ar), 7.45 (2 H, d, J 8.1 Hz, Ar), 7.36 (1 H, t, J 7.2 Hz, Ar), 3.35 (2 H, t, J 6 Hz, CH2), 2.82-2.58 (2 H,
m, CH2), 2.26 (3 H, s, CH3), 2.24 (2 H, bt, J 6 Hz, CH2); δC (75.5 MHz, CDCl3) 196.8, 192.3, 164.7,
145.2, 144.3, 140.1, 138.7, 134.9, 129.8, 129.3, 129.1, 126.5, 121.3, 121.2, 120.6, 112.0, 38.7, 34.0, 21.7,
13.9; EIMS : m/z (%) 417 (M+2, 2), 415 (M, 3), 399 (9), 279 (18), 278 (85), 218 (38), 217 (100), 175
(10), 139 (17), 111 (23), 91 (11), 77 (20), 55 (21), 51 (11); and HRMS m/z 415.1062 (C24H18FN3O2
requires 415.1088).
3-Methyl-4-(4-nitrobenzoyl)-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (5d).
White crystals, 98%, m.p. 216 ºC (dec); νmax 3098, 2943, 1679, 1574, 1520, 1422, 1343, 1263, 1220,
1128, 1018, 864, 757, 606, 538 cm-1; δH (300 MHz, CDCl3) 8.42-8.16 (4 H, m, Ar), 7.96 (2 H, d, J 8.7
Hz, Ar), 7.56 (2 H, t, J 7.8 Hz, Ar), 7.38 (1 H, t, J 7.2 Hz, Ar), 3.38 (2 H, t, J 6 Hz, CH2), 2.89-2.59 (2 H,
m, CH2), 2.30 (2 H, t, J 6 Hz, CH2), 2.27 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 197.0, 193.3, 164.8, 151.1,
150.5, 144.2, 143.9, 140.9, 138.6, 129.2, 129.1, 126.7, 124.2, 121.4, 120.7, 113.6, 38.6, 33.9, 21.7, 13.9;
EIMS : m/z (%) 427 (M+1, 34), 426 (M, 100), 397 (29), 369 (24), 351 (32), 304 (13), 150 (14), 104 (29),
92 (12), 77 (52), 51 (13); and HRMS m/z 426.1311 (C24H18N4O4 requires 426.1328).
3-Methyl-4-(4-methylbenzoyl)-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (5e).
19

ACCEPTED MANUSCRIPT
White crystals, 89%, m.p. 159 ºC; νmax 3044, 2943, 2886, 1675, 1572, 1504, 1426, 1229, 1179, 1126,
1027, 907, 842, 752, 685, 609, 564 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.4 Hz, Ar), 7.70 (2 H, d, J
7.5 Hz, Ar), 7.55 (2 H, t, J 7.8 Hz, Ar), 7.35 (1 H, t, J 7.2 Hz, Ar), 7.26 (2 H, d, J 7.5 Hz, Ar), 3.35 (2 H,
t, J 6.3 Hz, CH2), 2.82-2.60 (2 H, m, CH2), 2.43 (3 H, s, CH3), 2.26 (3 H, s, CH3), 2.23 (2 H, bt, J 6.3 Hz,
CH2); δC (75.5 MHz, CDCl3) 196.6, 194.7, 172.5, 164.7, 151.0, 146.2, 144.6, 138.8, 134.1, 129.6, 129.1,
128.7, 126.4, 121.4, 120.6, 113.8, 55.8, 38.8, 34.1, 22.0, 13.9; EIMS : m/z (%) 396 (M+1, 36), 395 (M,
100), 369 (21), 368 (46), 352 (37), 119 (49), 91 (55), 77 (24), 65 (21); and HRMS m/z 395.1655
(C25H21N3O2 requires 395.1634).
4-(4-Hydroxy-3-methoxybenzoyl)-3,7,7-trimethyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-
b]quinolin-5-one (5f).
White crystals, 84%, m.p. 224 ºC; νmax 3150, 2948, 2355, 1662, 1576, 1505, 1434, 1392, 1272, 1176,
1130, 1029, 827, 752, 680, 635, 552 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.1 Hz, Ar), 7.77 (1 H,
bs, Ar), 7.54 (2 H, t, J 7.8 Hz, Ar), 7.34 (1 H, t, J 7.5 Hz, Ar), 7.05-6.69 (2 H, m, Ar), 6.30 (1 H, bs, OH,
exchanged by D2O addition), 4.01 (3 H, s, OCH3), 3.24 (2 H, s, CH2), 2.62 (2 H, s, CH2), 2.28 (3 H, s,
CH3), 1.17 (3 H, s, CH3), 1.15 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 196.7, 193.7, 163.4, 151.3, 147.3,
145.5, 144.6, 138.8, 129.6, 129.4, 129.1, 126.3, 124.9, 121.3, 119.6, 114.1, 113.9, 109.1, 56.1, 52.4, 47.8,
32.8, 28.4, 28.0, 13.8; EIMS : m/z (%) 456 (M+1, 38), 455 (M, 100), 426 (26), 384 (19), 331 (22), 151
(98), 123 (29), 108 (16), 77 (49), 65 (20), 51 (26); and HRMS m/z 455.1825 (C27H25N3O4 requires
455.1845).
4-Benzoyl-3,7,7-trimethyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one (5g).
White crystals, 71%, m.p. 173 ºC; νmax 3068, 2946, 2874, 1678, 1570, 1489, 1426, 1345, 1230, 1130,
1020, 903, 879, 846, 759, 685, 550, 516, 462 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.1 Hz, Ar), 7.79
(2 H, d, J 7.2 Hz, Ar), 7.72-7.41 (5 H, m, Ar), 7.35 (1 H, t, J 7.2 Hz, Ar), 3.25 (2 H, s, CH2), 2.60-2.35 (2
H, m, CH2), 2.26 (3 H, s, CH3), 1.18 (3 H, s, CH3), 1.16 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 196.6,
195.1, 163.4, 151.4, 145.4, 144.5, 138.8, 136.5, 133.7, 129.1, 128.9, 128.5, 126.4, 121.3, 119.7, 113.8,
52.2, 47.8, 32.9, 28.4, 28.0, 13.9; EIMS : m/z (%) 410 (M+1, 38), 409 (M, 100), 381 (21), 380 (51), 352
(33), 338 (26), 332 (16), 326 (15), 255 (14), 105 (63), 77 (98), 51 (19); and HRMS m/z 409.1778
(C26H23N3O2 requires 409.1790).
4-(4-Fluorobenzoyl)-3,7,7-trimethyl-1-phenyl-1,6,7,8-tetrahydro-5H-pyrazolo[3,4-b]quinolin-5-one
(5h).
20

ACCEPTED MANUSCRIPT
White crystals, 70%, m.p. 171-172 ºC; νmax 2930, 2860, 1674, 1580, 1492, 1463, 1427, 1253, 1168, 1022,
842, 756, 692, 618, 555 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.1 Hz, Ar), 7.75 (2 H, d, J 8.1 Hz,
Ar), 7.63-7.47 (2 H, m, Ar), 7.34 (1 H, t, J 8.1 Hz, Ar), 6.94 (2 H, d, J 9.0 Hz, Ar), 3.86 (2 H, s, CH2),
3.33-3.14 (2 H, m, CH2), 2.27 (3 H, s, CH3), 1.17 (3 H, s, CH3), 1.15 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 196.6, 193.7, 164.0, 163.4, 151.4, 145.6, 144.6, 138.9, 130.8, 129.7, 129.1, 122.0, 121.2, 120.4,
119.6, 114.2, 52.3, 47.8, 32.8, 28.4, 28.0, 13.8; EIMS : m/z (%) 427 (M, 5), 410 (24), 408 (8), 382 (15),
368 (13), 343 (11), 305 (24), 249 (11), 136 (22), 135 (100), 107 (33), 92 (35), 77 (98), 51 (14); and
HRMS m/z 427.1680 (C26H22FN3O2 requires 427.1696).
4-(4-Chlorobenzoyl)-3,7,7-trimethyl-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one
(5i).
White crystals, 94%, m.p. 180 ºC; νmax 3067, 2940, 2880, 1679, 1573, 1484, 1417, 1226, 1094, 1017, 876,
823, 745, 679, 621, 544 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.1 Hz, Ar), 7.73 (2 H, d, J 8.1 Hz,
Ar), 7.55 (2 H, t, J 7.8 Hz, Ar), 7.44 (2 H, d, J 8.4 Hz, Ar), 7.35 (1 H, t, J 7.2 Hz, Ar), 3.25 (2 H, s, CH2),
2.63-2.50 (2 H, m, CH2), 2.27 (3 H, s, CH3), 1.18 (3 H, s, CH3), 1.16 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 196.8, 193.8, 163.4, 151.4, 144.2, 140.1, 138.6, 134.9, 129.7, 129.3, 129.1, 126.5, 121.3, 120.9,
119.7, 113.6, 52.2, 47.7, 32.9, 28.4, 28.0, 13.9; EIMS : m/z (%) 445 (M+2, 22), 443 (M, 18), 307 (100),
306 (93), 300 (25), 249 (34), 195 (29), 140 (27), 139 (70), 111 (55), 77 (65), 51 (18); and HRMS m/z
443.1423 (C26H22ClN3O2 requires 443.1401).
3,7,7-Trimethyl-4-(4-nitrobenzoyl)-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one
(5j).
White crystals, 95%, m.p. 179 ºC; νmax 3064, 2949, 2876, 1678, 1570, 1464, 1338, 1226, 1133, 1019, 882,
832, 754, 689, 551 cm-1; δH (300 MHz, CDCl3) 8.40 (1 H, d, J 8.4 Hz, Ar), 8.28 (2 H, d, J 7.8 Hz, Ar),
8.21 (1 H, d, J 8.4 Hz, Ar), 7.91 (2 H, t, J 9.3 Hz, Ar), 7.55 (2 H, t, J 7.2 Hz, Ar), 7.45-7.30 (1 H, m, Ar),
3.26 (2 H, s, CH2), 2.71-2.47 (2 H, m, CH2), 2.29 (3 H, s, CH3), 1.18 (3 H, s, CH3), 1.17 (3 H, s, CH3); δC
(75.5 MHz, CDCl3) 196.7, 193.9, 163.4, 151. 5, 147.3, 144.3, 139.1, 138.8, 136.7, 129.1, 129.0, 126.4,
123.2, 121.4, 119.8, 113.6, 52.1, 47.7, 32.9, 28.4, 28.1, 13.9; EIMS : m/z (%) 455 (M+1, 11), 454 (M,
36), 424 (56), 395 (13), 379 (15), 367 (14), 331 (44), 120 (100), 92 (41), 77 (52), 65 (26), 51 (12); and
HRMS m/z 454.1662 (C26H22N4O4 requires 454.1641).
3,7,7-Trimethyl-4-(4-methylbenzoyl)-1-phenyl-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one
(5k).
21

ACCEPTED MANUSCRIPT
White crystals, 83%, m.p. 165 ºC; νmax 3033, 2939, 2871, 1678, 1572, 1484, 1421, 1230, 1176, 1128,
1023, 881, 817, 752, 679, 614, 548 cm-1; δH (300 MHz, CDCl3) 8.28 (2 H, d, J 8.1 Hz, Ar), 7.68 (2 H, d, J
7.5 Hz, Ar), 7.54 (2 H, t, J 7.8 Hz, Ar), 7.34 (1 H, t, J 7.8 Hz, Ar), 7.17-7.30 (2 H, m, Ar), 3.24 (2 H, s,
CH2), 2.51-2.48 (2 H, m, CH2), 2.42 (3 H, s, CH3), 2.27 (3 H, s, CH3), 1.17 (3 H, s, CH3), 1.16 (3 H, s,
CH3); δC (75.5 MHz, CDCl3) 196.6, 194.7, 163.4, 151.4, 145.6, 144.6, 138.8, 134.1, 129.7, 129.1, 128.6,
126.3, 121.3, 119.7, 116.7, 113.8, 52.3, 47.8, 32.9, 28.4, 28.0, 21.8, 13.8; EIMS : m/z (%) 423 (M, 23),
305 (100), 249 (62), 180 (28), 83 (41), 77 (32), 51 (13); and HRMS m/z 423.1926 (C27H25N3O2 requires
423.1947).
4-Benzoyl-3,6,8-trimethyl-1-phenyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-
dione (6a).
White crystals, 73%, m.p. 241 ºC; νmax 3054, 2948, 1689, 1592, 1503, 1454, 1374, 1272, 1116, 1003, 756,
687 cm-1; δH (300 MHz, CDCl3) 8.25 (2H, d, J 8.1 Hz, Ar), 7.86 (2 H, d, J 7.2 Hz, Ar), 7.74-7.43 (5 H, m,
Ar), 7.37 (1 H, t, J 8.1 Hz, Ar), 3.86 (3 H, s, CH3), 3.40 (3 H, s, CH3), 2.26 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 191.1, 173.5, 164.8, 163.8, 158.4, 150.8, 144.5, 136.1, 134.2, 129.2, 129.1, 128.8, 127.7, 126.5,
120.9, 114.6, 109.4, 53.7, 28.6, 13.7. and HRMS m/z 425.1462 (C24H19N5O3 requires 425.1488).
4-(4-Fluorobenzoyl)-3,6,8-trimethyl-1-phenyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-
5,7(6H,8H)-dione (6b).
White crystals, 75%, m.p. 230 ºC; νmax 3082, 2948, 1691, 1680, 1593, 1509, 1470, 1375, 1235, 1166,
1005, 834, 753, 691, 509 cm-1; δH (300 MHz, CDCl3) 8.42-8.17 (2 H, m, Ar), 7.98-7.75 (1 H, m, Ar),
7.69-7.47 (2 H, m, Ar), 7.38 (1 H, t, J 7.5 Hz, Ar), 7.38-7.23 (2 H, m, Ar), 7.18 (1 H, t, J 8.4 Hz, Ar), 3.86
(3 H, s, CH3), 3.41 (3 H, s, CH3), 2.26 (3 H, s, CH3); δC (75.5 MHz, CDCl3) 191.9, 168.4, 155.3, 151.3,
144.4, 131.5, 129.2, 129.1, 128.9, 128.7, 126.5, 126.5, 120.9, 116.6, 116.3, 115.5, 115.2, 30. 5, 28.6,
13.7; EIMS : m/z (%) 444 (M+1, 33), 443 (M, 100), 415 (56), 414 (44), 398 (14), 329 (13), 263 (12), 123
(84), 95 (46), 77 (27), 51 (10); and HRMS m/z 443.1380 (C24H18FN5O3 requires 443.1394).
3,6,8-Trimethyl-4-(4-nitrobenzoyl)-1-phenyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-
5,7(6H,8H)-dione (6c).
White crystals, 96%, m.p. 256 ºC; νmax 3072, 2938, 2875, 1706, 1666, 1585, 1520, 1416, 1359, 1276,
1236, 1157, 1117, 1075, 1024, 975, 876, 833, 799, 753, 690, 585 cm-1; δH (300 MHz, CDCl3) 8.35 (2 H,
d, J 8.7 Hz, Ar), 8.24 (2 H, d, J 7.8 Hz, Ar), 8.02 (2 H, d, J 8.4 Hz, Ar), 7.58 (2 H, t, J 7.8 Hz, Ar), 7.39 (1
H, t, J 7.5 Hz, Ar), 3.87 (3 H, s, CH3), 3.39 (3 H, s, CH3), 2.27 (3 H, s, CH3); δC (75.5 MHz, CDCl3)
22

ACCEPTED MANUSCRIPT
191.8, 160.8, 151.1, 150.9, 150.7, 150.6, 145.8, 144.0, 140.4, 138.5, 129.5, 129.2, 126.7, 124.3, 121.0,
111.6, 103.5, 30.5, 28.6, 13.8; EIMS : m/z (%) 471 (M+1, 32), 470 (M, 100), 442 (15), 395 (15), 348
(17), 263 (16), 150 (13), 104 (19), 77 (25), 51 (10); and HRMS m/z 470.1343 (C24H18N6O5 requires
470.1339).
4-(4-Methoxybenzoyl)-3,6,8-trimethyl-1-phenyl-1,8-dihydro-5H-pyrazolo[4',3':5,6]pyrido[2,3-
d]pyrimidine-5,7(6H)-dione (6d).
White crystals, 75%, m.p. 263 ºC; νmax 3066, 2940, 2868, 1665, 1580, 1497, 1420, 1368, 1254, 1159,
1069, 1016, 973, 899, 844, 755, 674, 582, 496, 416 cm-1; δH (300 MHz, CDCl3) 8.25 (2 H, d, J 8.1 Hz,
Ar), 7.82 (2 H, d, J 6.9 Hz, Ar), 7.56 (2 H, t, J 8.1 Hz, Ar), 7.37 (1 H, t, J 7.2 Hz, Ar), 6.97 (2 H, d, J 8.4
Hz, Ar), 3.89 (3 H, s, OCH3), 3.86 (3 H, s, CH3), 3.41 (3 H, s, CH3), 2.27 (3 H, s, CH3); δC (75.5 MHz,
CDCl3) 192.0, 164.4, 160.6, 151.3, 150.7, 148.1, 144.6, 138.7, 131.1, 129.4, 129.3, 129.2, 126.4, 120.9,
114.4, 111.8, 103.3, 55.6, 30.4, 28.6, 13.7; EIMS : m/z (%) 456 (M+1, 29), 455 (M, 91), 437 (12), 426
(25), 319 (14), 263 (10), 135 (100), 107 (20), 92 (17), 77 (46); and HRMS m/z 455.1578 (C25H21N5O4
requires 455.1594).
4-(3,4-Dimethoxybenzoyl)-3,6,8-trimethyl-1-phenyl-1,8-dihydro-5H-pyrazolo[4',3':5,6]pyrido [2,3-
d]pyrimidine-5,7(6H)-dione (6e).
White crystals, 90%, m.p. 233 ºC; νmax 3068, 2929, 2857, 1707, 1667, 1584, 1505, 1419, 1377, 1269,
1140, 1068, 1021, 756, 576, 492 cm-1; δH (300 MHz, CDCl3) 8.26 (2 H, d, J 7.8 Hz, Ar), 7.80 (1 H, bs,
Ar), 7.57 (2 H, t, J 7.8 Hz, Ar), 7.37 (1 H, t, J 7.5 Hz, Ar), 7.06 (1 H, d, J 7.2 Hz, Ar), 6.79 (1 H, d, J 8.4
Hz, Ar), 4.02 (3 H, s, OCH3), 3.94 (3 H, s, OCH3), 3.87 (3 H, s, CH3), 3.42 (3 H, s, CH3), 2.27 (3 H, s,
CH3); δC (75.5 MHz, CDCl3) 180.6, 159.6, 154.3, 151.3, 150.7, 149.8, 148.0, 145.1, 144.7, 129.6, 129.2,
126.4, 122.0, 119.0, 117.8, 114.0, 111.3, 110.2, 109.1, 65.2, 56.1, 40.5, 24.6, 13.7; EIMS : m/z (%) 486
(M+1, 35), 485 (M, 100), 457 (27), 455 (31), 348 (16), 319 (20), 263 (17), 252 (16), 200 (28), 166 (29),
165 (97), 137 (27), 91 (15), 86 (20), 78 (25), 77 (67), 51 (15); and HRMS m/z 485.1681 (C26H23N5O5
requires 485.1699).
Acknowledgments
The authors gratefully acknowledge the financial assistance from Urmia University.
23

ACCEPTED MANUSCRIPT
References
1. (a) Alba, A. N.; Company´ X.; Viciano, O. M.; R´ıos, R. Curr. Org. Chem., 2009, 13, 1432;
(b) Tietze, L. F.; D¨ufert, A. In Catalytic Asymmetric Conjugate Reactions, ed. Cordova, A.
Wiley-VCH, Weinheim, Germany, 2010, pp. 321-350; (c) Grondal, C.; Jeanty, M.; Enders,
D. Nat. Chem., 2010, 2, 167.
2. Ahluwalia, V. K.; Varma, R. S. Green Solvents for Organic Synthesis, Alpha Science
International, Abingdon, UK, 2009.
3. (a) Barcelo, M.; Ravina, E.; Masaguer, C. F.; Dominuez, E.; Areias, F. M.; Brea, J.; Loza,
M. I. Bioorg. Med. Chem. Lett., 2007, 17, 4873; (b) Said, A. S.; Abd El-Galil, E. A.;
Nermien, M. S.; Mohamed, M. Eur. J. Med. Chem., 2009, 44, 4787; (c) Karthikeyan, M. S.;
Holla, B. S.; Kumari, N. S. Eur. J. Med. Chem., 2007, 42, 30. (d) Mitchell, R. E.;
Greenwood, D. R.; Sarojini, V. Phytochemistry., 2008, 69, 2704.
4. a) Pandey, G.; Bhowmik, S.; Batra, S. Org. Lett., 2013, 15, 5044. (b) Bassoude, I.;
Berteina-Raboin, S.; Leger, J.-M.; Jarry, C.; Essassi E. M.; Guillaumet, G. Tetrahedron.,
2011, 67, 2279. (c) Taliani, S.; Pugliesi, I.; Barresi, E.; Salerno, S.; Marchand, C.; Agama,
K.; Simorini, F.; La Motta, C.; Marini, A. M.; Di Leva, F. S.; Marinelli, L.; Cosconati, S.;
Novellino, E.; Pommier, Y.; Di Santo, R.; Da Settimo, F. J. Med. Chem., 2013, 56, 7458
5. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.;
Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A.; Zhang, W. Y. Y.; Isakson, P. C. J. Med.
Chem., 1997, 40, 1347.
6. Srivastava, S. K.; Tripathi R. P.; Ramachandran, R. J. Biol. Chem., 2005, 280, 30273.
7. Liu, X. -H.; Cui, P.; Song, B. -A.; Bhadury, P. S.; Zhu H. -L.; Wang, S. -F. Bioorg. Med.
Chem., 2008, 16, 4075.
8. Stein, R. G.; Biel, J. H.; Singh, T. J. Med. Chem., 1970, 13, 153.
9. Shrivastava, B.; Sharma, V.; Lokwani, P. Pharmacologyonline., 2011, 1, 236.
10. Selvi, S. T.; Nadaraj, V.; Sellappan, M.; Sasi, R.; Hema, M. Bioorg. Med. Chem., 2006, 14,
3896.
11. Singh, S. K.; Reddy, P. G.; Rao, K. S.; Lohray, B. B.; Misra, P.; Rajjak, S. A.; Rao, Y. K.;
Venkatewarlu, A. Bioorg. Med. Chem. Lett., 2004, 14, 499.
12. Gioranni A.; Ezio, B. Tetrahedron Lett., 1996, 37, 7836; [Chem. Abstr. 1997, 126, 19064r].
13. Arif, J. M.; Kunhi, M.; Subramanian, M. P.; Bekhit, A. A.; El-Sayed, O. A.; Al-Hussein,
K.; Aboul-Enein, H. Y.; Al-Khodairy, F. M. Int. J. Biomed. Sci., 2007, 3, 194.
14. Faurun, C.; Turin M. G.; Pourrias, B. Chem. Abstr., 1976, 84, 59477y.
15. Marcic, D. Exp. Appl. Acarol., 2005, 36, 177.
16. Kim, M.; Sim, C.; Shin, D.; Suh, E.; Cho, K. Crop Prot., 2006, 25, 542.
17. Li, A. M.; Ouyang, Y.; Wang, Z. Y.; Cao, Y. Y.; Liu, X. Y.; Ran, L.; Li, C.; Li, L.; Zhang,
L.; Qiao, K. J. Med. Chem., 2013, 56, 3593.
18. Quiroga, J.; Diaz, Y.; Bueno, J.; Insuasty, B.; Abonia, R.; Ortiz, A.; Nogueras, M.; Cobo, J.
Eur. J. Med. Chem., 2014, 74, 216.
19. Selvi, S. T.; Nadaraj, V.; Mohan, S.; Sasi, R.; Hema, M. Bioorg. Med. Chem., 2006, 14,
3896.
24

ACCEPTED MANUSCRIPT
20. Rádl, S.; Zikán, V. Collect. Czech. Chem. Commun., 1987, 52, 788.
21. El-Sayed, O. A.; Aboul-Enein, H. Y. Weinheim., 2001, 334, 117.
22. Quiroga, J.; Insuasty, B.; Hormaza, A.; Saitz, C.; Jullian, C. J. Heterocycl. Chem., 1998, 35,
575.
23. Ghosh, P.; Mandal, A. Catal Commun., 2011, 12, 744.
24. Bekhit, A.; El-Sayed, O. A.; Aboul-Enein, H. Y.; Siddiqui, Y. M.; Al-Ahdal, M. N. J.
Enzyme. Inhib. Med. Chem., 2004, 19, 33.
25. Thamarai Selvi, S.; Nadaraj, V.; Mohan, S.; Sasi, R.; Hema, M. Bioorg. Med. Chem., 2006,
14, 3896.
26. Zhang, X.; Li, D.; Fan, X.; Wang, X.; Li, X.; Qu, G.; Wang, J. Mol. Divers., 2010, 14, 159.
27. a) Gondek, E.; Danel, A.; Kwiecien, B.; Niziol, J.; Kityk, A. V. Mater. Chem. Phys., 2010,
119, 140; (b) Afghan, A.; Baradarani, M. M.; Joule, J. A. ARKIVOC., 2009, ii, 20; (c) Mali,
J. R.; Pratap, U. R.; Jawale, D. V.; Mane, R. A. Tetrahedron Lett., 2010, 51, 3980.
28. a) Karnakar, K.; Murthy, S. N.; Ramesh, K.; Satish, G.; Nanubolu, J. B.; Nageswar, Y. V.
D. Tetrahedron Lett., 2012, 53, 2897; (b) Wang, H.; Shi, D. J. Heterocycl. Chem., 2012, 49,
212; (c) Hao, Y.; Xu, X.; Chen, T.; Zhao, L.; Ji, S. Org. Biomol. Chem., 2012, 10, 724; (d)
Yin, Z.; Yang, L.; Wu, L. J. Chem. Sci., 2013, 125, 601; (e) De, K.; Bhaumik, A.; Banerjee,
B.; Mukhopadhyay, C. Tetrahedron Lett., 2015, 56, 1614.
29. Cappelli, A.; Nannicini, C.; Gallelli, A.; Giuliani, G.; Valenti, S.; Mohr, G. P.; Anzini, M.;
Mennuni, L.; Ferrari, F.; Caselli, G.; Giordani, A.; Pereis, W.; Makovec, F.; Giorgi, G.;
Vomero, S. J. Med. Chem., 2008, 51, 2137.
30. Danel, A.; Chaczatrian, K.; Tomasik, P. ARKIVOC., 2000, i, 51.
31. Yu, J.; Moon, H. R.; Lim, J. W.; Kim, J. N. Bull. Korean Chem. Soc., 2015, 36, 203.
32. Gondek, E.; Kityk, I. V.; Danel, A. Z. Naturforsch., 2009, 64a, 632.
33. El-Aal, H. A. K. A.; Khalaf, A. A. Aust. J. Chem., 2016, 69, 652.
34. Poursattar Marjani, A.; Khalafy, J.; Salami, F.; Mohammadlou, M. Synthesis 2015, 47,
1656.
35. Khalafy, J., Poursattar Marjani, A., Haghipour, M., Curr. Chem. Lett., 2013, 2, 21.
36. Khalafy, J.; Ezzati, M.; Rimaz, M.; Poursattar Marjani, A.; Yaghoobnejad Asl, H. J. Iran.
Chem. Soc., 2014, 11, 1067.
37. Khalafy, J.; Etivand, N.; Dilmaghani, S.; Ezzati, M.; Poursattar Marjani, A. Tetrahedron
Lett., 2014, 55, 3781.
38. Poursattar Marjani, A.; Khalafy, J.; Mahmoodi, S. ARKIVOC., 2016, iii, 262.
39. Poursattar Marjani, A.; Khalafy, J.; Chitan, M.; Mahmoodi, S. Iran. J. Chem. Chem. Eng.,
2017, 36, 1.
40. Poursattar Marjani, A.; Khalafy, J.; Haghi, A. J. Heterocycl. Chem., 2017, in press. DOI:
10.1002/jhet.2949.
41. Riley, H. A.; Gray, A. R. Organic Syntheses; Wiley & Sons: New York, NY, 1943; Collect.
Vol. II, p 509.
42. Ganesan, A.; Heathcock, C. H. J. Org. Chem., 1993, 58, 6155.
25