Object-oriented synthetic approach toward angular and linear fused pyrazoloquinolines of biological importance with InCl3 catalyst

Article abstract of DOI:10.1080/00397911.2015.1133827

A simple and short approach for the synthesis of pyrazolo[3,4-b]quinoline (3a-3p) and pyrazolo[4,3-c]quinoline (6a-6 h) using various Lewis acid catalysts was developed. InCl₃ was found to be more effective in providing greater yield of product

Full text of DOI:10.1080/00397911.2015.1133827

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Object-Oriented Synthetic Approach toward
Angular and Linear Fused Pyrazoloquinolines of
Biological Importance with InCl3 Catalyst
Thangaraj Arasakumar, Sadasivam Mathusalini, Krishnasamy Lakshmi,
Palathurai Subramaniam Mohan, Athar Ata & Chia-Her Lin
To cite this article: Thangaraj Arasakumar, Sadasivam Mathusalini, Krishnasamy
Lakshmi, Palathurai Subramaniam Mohan, Athar Ata & Chia-Her Lin (2015): An Object-
Oriented Synthetic Approach toward Angular and Linear Fused Pyrazoloquinolines
of Biological Importance with InCl3 Catalyst, Synthetic Communications, DOI:
10.1080/00397911.2015.1133827
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Date: 15 January 2016, At: 12:07

An object-oriented synthetic approach toward angular and linear fused
pyrazoloquinolines of biological importance with InCl3 catalyst
Thangaraj Arasakumar1,2, Sadasivam Mathusalini1, Krishnasamy Lakshmi1, Palathurai
Subramaniam Mohan1,, Athar Ata2, Chia-Her Lin3
1School of Chemical Sciences, Bharathiar University, Coimbatore, Tamil Nadu, India
2Department of Chemistry, Richardson College for the Environmental Science Complex,
The University of Winnipeg, Winnipeg, Manitoba, Canada
3Department of Chemistry, Chung Yuan Christian University, Chung-Li, Taiwan
Corresponding author: Palathurai Subramaniam Mohan . Email: psmohan59@gmail.com,
ps_mohan_in@yahoo.com
Abstract
A simple and short-cut approach for the synthesis of pyrazolo[3,4-b]quinoline (3a-3p)
and pyrazolo[4,3-c]quinoline (6a-6h), using various Lewis acid catalysts was developed.
InCl3 was found to be more effective in providing higher yield of products compared to
Yb(OTf)3, Sc(OTf)3, SnCl4, AlCl3, TiCl4, ZnCl2, FeCl3 and BF3.Et2O. More over a
comparison of conventional and microwave method has revealed that the latter method is
more efficient compared to former one. Structures were confirmed by FT-IR, mass
1
spectrometry, H, 13C NMR, X-ray crystallography and elemental analyses. All of the
synthesized compounds were evaluated for α-glucosidase inhibitory activity and
compounds 3a, 3p, 3i, 3h, 3k, 3o and 3g exhibited anti α-glucosidase inhibitory activity,
IC50 values of 57.5, 60.3, 65.9, 71.9, 80.8, 123.7, 126.4 µM, respectively, which is quite
comparable to standard drug, acarbose (IC50 = 115.8 µM).
1

KEYWORDS: Enolizable 3-acyl quinolin-2-one; InCl3; Angular and linear
pyrazoloquinolines; Microwave irradiation; α-Glucosidase Inhibitory
INTRODUCTION
A method of convenience is followed in the design of a new synthesis of azahetero-fused
quinoline as it attracts considerable, importance in organic and medicinal chemistry
research for the last several decades, [1–7] due to structural and functional complexity as
well as diversity with remarkable biological properties.[8–12] Pyrazolo[3,4-b]quinoline and
pyrazolo[4,3-c]quinoline are two important core structures of this group and among them
pyrazolo[3,4-b]quinoline derivatives have shown diverse biological activities such as
anticancer,[13] anti-mycobacterial,[14,15] antiviral,[16-18] anti-inflammatory and antimalarial
activities[19] and also exhibits antimicrobial,[14,20] TSPO modulators,[21] PDE10A
inhibitors,[22,23] Oncogenic Ras[24] and Interferon inducing activities.[25] Pyrazolo-
incorporated heterocyclic structure is also found in the core moiety in natural products
and numerous biological active compounds such as analgium, celebrex, fipronil, WYE-
2

354, viagra (1), BAY 41-2272 (2) and IND-2 (3)[26–29] (Fig.1) etc. Similarly, L-α-Amino-
β-(pyrazolyl-N)-propanoic acid (4) is reported to be the first example of pyrazolo
containing natural products with anti-diabetic activity [30] and during past decades, many
pyrazole containing analogs were developed, specifically fluorinated pyrazolo analogs
that showed potential diabetic activity [31]
.
Though, several routes for the synthesis of linear pyrazolo[3,4-b]quinoline scaffolds
were appeared to date,[32–35] they encounter draw backs like low yields, multistep
procedures, formation of by-products, long reaction times, harsh reaction condition, high
temperature etc. Our present efforts are directed towards the development of new,
efficient and selective synthetic strategies for the construction of highly substituted linear
pyrazoloquinoline. Indeed, enolizable 3-acyl quinolin-2-one 1(a-f) (Scheme 1) is well
known versatile intermediates for the preparation of highly substituted heterocycles and
angular pyrazolo[4,3-c]quinolines.[36–38] However, when both hydroxyl group at C-2 and
C-4 position are exposed and reacted with phenyl hydrazine, angular isomer is
predominantly formed.[37,38] In order to get only linear isomer, we adopted different
strategy to prepare compound containing phenyl or methyl group at C-4 position that
would enhance for nucleophilic attack at C-2 position by phenyl hydrazine via the
nucleophilic substitution reaction and finally leads to aromatized heterocycles.
In our endeavour to adopt green chemistry approach, we describe herein for the first time
an conventional and microwave assisted convenient, one pot synthesis of a series of
pyrazolo[3,4-b]quinoline and pyrazolo[4,3-c]quinoline derivatives thought a usual
3

condensation, followed by cyclization reaction of 3-acyl quinolin-2-one with phenyl
hydrazine in ethanol by Lewis acids. These compounds were first time evaluated for their
α-glucosidase inhibitory activity and compounds 3a, 3p, 3i, 3h, 3k, 3o and 3g were found
to be active against the enzyme.
RESULTS AND DISCUSSION
To initiate our experiment, 1a was selected as the model substrate to react with phenyl
hydrazine 2b in ethanol in the presence of 10 mol % of Lewis acid at reflux conditions
that afforded the desired pyrazolo quinoline in high yields (3b) (Table 1). The results
from table 1 shows that InCl3 was found to be an optimal one that delivered 3b in 85%
yield (entry 10, Table 1). Notably, the reaction was carried out with 20% of ZnCl2 at
reflux, resulting to afford the product 3b in 84% yield (entry 7, Table 1). Encouraged by
this result, we have optimized the reaction conditions including solvents, temperature and
catalyst loading has been carried out with InCl3. The results are listed in table 2. Different
solvents were investigated such as methanol, glycol, acetonitrile and toluene to make use
of this reaction of 1a (60-70% yields, entries 2-5, Table 2).While THF, CH2Cl2, and
CHCl3 were failed to yield the desired product 3b, due to poor solubility even at higher
temperature (entry 6,7,8, Table 2). However, moderate yields (30% yield, entry 9, Table
2) were obtained when the reaction was carried out in ethanol under room temperature
and fairly good yields (85% yield, entry 1, Table 2) were obtained under reflux condition.
In addition, the same reaction was carried out under microwave irradiation (MWI) at a
maximum power of 110 W at 70 ⁰ C and the product 3b obtained 84% (entry 10, Table
4

2) in yield. Higher yield was obtained upon the increase of catalyst loadings from 5 mol%
to 20 mol % (entry 12, Table 2). We found the yield of product 3b was improved and
reaction duration was shortened when the temperature was increased to 80 ⁰ C (94%
yield, entry 13, Table 2). Further increase of the reaction temperature to 90 ⁰ C led to a
slightly drop in yield to 90% (entry 14, Table 2). With optimized reaction conditions,
various substituted 3-acyl quinolin-2-one 1(a-f) and phenyl hydrazine 2(a-f) were
examined to test the generality of this Lewis acid-catalysed reaction under conventional
and microwave conditions (Scheme 1). It can be observed that the process permits both
electron-donating and electron-withdrawing substituents on the 3-acyl quinolin-2-one on
reaction with phenyl hydrazine. In all cases, the corresponding pyrazolo[3,4-b]quinolines
were obtained in good yields (80-94%, 3a-3p, Table 3), simple work-up procedures and
short reaction time period in microwave assisted synthesis.
To explore further synthetic potential of this reaction, we use 4-hydroxy-3-acyl quinolin-
2-one 1e and 1f instead of 3-acyl quinolin-2-one 1(a-d), which was treated with phenyl
hydrazine 2(a-f) derivatives under conventional as well as microwave conditions, the
reaction proceed regioselectively to afford pyrazolo[4,3-c]quinoline (6a-6h) (Scheme
1)as the sole product in good yields under microwave conditions (Table 3).
With the literature support,[39] we presume that InCl3 catalyzes the reaction as a mild
lewis acid. The mechanism is proposed as shown in scheme 2. The 3-acyl quinolin-2-one
condense with phenyl hydrazine to form schiff base I which was immediately activated
by InCl3 to form intermediate II, followed by an intramolecular cyclization to give III.
5

The subsequent dehydration of III results in pyrazolo[3,4-b]quinoline IV. The structures
of all the products were confirmed by IR, Mass as well as 1H, 13C NMR spectroscopic
data (Supplementary Data). Finally, the structure of product 3i is confirmed by single
crystal X-ray analysis as shown in Figure 1.[40]
Α-GLUCOSIDASE INHIBITION ASSAY
All synthesized compounds were evaluated for the α-glucosidase inhibitory activities
according to the literature procedure.[41] IC50 value of tested compounds (3a-3p) and (6a-
6h) on α-glucosidase are showed in table 4 and Acarbose was chosen as control. Among
the tested compounds 3a, 3g, 3h, 3i, 3k, 3p and 3o emerged as a potent inhibitor of α-
glucosidase enzyme. The fluorinated pyrazolo[3,4-b]quinoline 3a (R=H, R1=Ph, R2=H,
R3=F) and 3i (R=H, R1=Ph, R2=Cl, R3=F) exhibited potent activity due to the presence of
fluorine atom at R3 position. Compounds 3h (R=H, R1=Ph, R2=Cl, R3=H) shows better
activity than 3k (R=H, R1=Ph, R2=NO2, R3=H).The enhanced activity of compound 3h
may be due to the electron releasing group (Cl) at R2 position which may be responsible
for its binding with enzyme. The decreased activity of compound 3k may be due to the
presence of electron withdrawing group (NO2) group at R2 position. The compound 3p
(R=H, R1=CH3, R2=H, R3=Br) shows 2 folds stronger activity than that of compound 3o
(R=H, R1=CH3, R2=H, R3=OCH3). While compound 3p, 3o which contains bromine and
methoxy group at R3 position, the brominated one exhibits promising activity compare to
methoxy group. Compound 3g (R=H, R1=Ph, R2=Cl, R3=CF3) having chlorine and
fluorine group at R2, R3 position that showed a significant activity. The activity order of
6

above discussed compounds are 3a>3p>3i>3h>3k>3o>3g. At the same time
pyrazolo[4,3-c]quinoline analogs (6a-6h) were found to be inactive.
CONCLUSION
In conclusion, we have developed a target oriented synthesis of pyrazolo[3,4-b]quinoline
and pyrazolo[4,3-c]quinoline derivatives via enolizable 3-acyl quinolin-2-one with
phenyl hydrazine derivatives using InCl3 as a catalyst. The mild reaction conditions, good
to excellent yields, easy workup and easily available substrates make the reactions
attractive for the preparation of compounds 3a-3p and 6a-6h under microwave
conditions. The synthesized compounds were evaluated as inhibitors of α-glucosidase.
Compounds 3a, 3p, 3i, 3h, 3k, 3o, 3g shows a significant inhibition with IC50 values
between 57.5 and 126.43 µM. The fluorinated compounds 3a and 3i exhibits potential
inhibition activity.
EXPERIMENTAL
General procedure for the synthesis of pyrazoloquinolines (3a-3p) and (6a-6h)
Method 1: (Microwave Irradiation)
A mixture of 3-acyl quinolin-2-one 1 (0.30 mmol), phenylhydrazine 2 (0.60 mmol) and
InCl3 (0.03mmol) in ethanol 5 mL was sealed and subjected to microwave irradiation,
programmed at 80 °C and 110 W for 3-7 mins. The completion of the reaction was
monitored by TLC. The reaction mixture was cooled to room temperature, and the crude
product recrystallized from ethanol to obtain pure products.
7

Method 2: (Conventional)
To a mixture of 3-acyl quinolin-2-one 1 (0.30 mmol) and phenylhydrazine 2 (0.60
mmol), InCl3 (0.03) ethanol 5 mL was refluxed using a water bath 1-3h. The reaction was
monitored by TLC (MeOH : CHCl3 = 1:9). After completion of reaction, the mixture
bring to the room temperature, the solid was appeared and filtered off, subsequently
washed with methanol and crude product recrystallized from ethanol to obtained pure
products.
3-Methyl-4-Phenyl-1-(4-Chlorophenyl)-1H-Pyrazolo[3,4-B]Quinoline (3b)
Pale yellow solid, mp 210 ⁰ C; IR (KBr) υmax 3054, 1584, 1492, 1439, 1380 cm-1; 1H
NMR (400 MHz, CDCl3): δ 8.50 (d, 2H, J = 8.8 Hz, ArH), 8.18 (d, 1H J = 10 Hz, ArH),
7.71-7.68 (m, 2H, ArH), 7.63 (t, 3H, J = 3.2 Hz, ArH), 7.60 (t, 2H, J = 7.2 Hz, ArH),
7.48-7.46 (m, 2H), 7.33 (t, 1H, J = 7.6 Hz, ArH), 2.15 (S, 3H, CH3); 13C (100 MHz,
CDCl3): δ 150.0, 146.7, 143.8, 143.7, 139.7, 134.2, 131.3, 130.5, 129.6, 129.0, 128.4,
125.3, 125.2, 124.1, 120.4, 116.7, 14.8; Mass (ESI) m/z; 369.1 [M+H]+; Anal. Calcd for
C23H16ClN3: C, 74.69; H, 4.36; N, 11.36 %; Found. C, 74.64; H, 4.39; N, 11.41 %.
1-(4-Bromophenyl)-1,5-Dihydro-3,5-Dimethyl-4H-Pyrazolo[4,3-C]Quinolin-4-One (6h)
Brown solid, mp 210⁰ C; IR (KBr) υmax 2924, 1656, 1490, 1340 cm-1; 1H NMR (400
MHz, CDCl3): δ 7.75 (d, 2H, J = 8.8 Hz, ArH), 7.54 (t, 1H, J = 8.4 Hz, ArH), 7.46 (d,
3H, J = 8.4 Hz, ArH), 7.33 (d, 1H, J = 7.6 Hz, ArH), 7.05 (t, 1H, J = 7.2 Hz, ArH), 3.77
(s, 3H, N-CH3), 2.77 (s, 3H, CH3); 13C (100 MHz, CDCl3): δ 159.5, 149.8, 140.4, 139.8,
139.5, 132.9, 130.1, 128.7, 123.5, 123.0, 121.6, 115.7, 111.9, 111.6, 29.1, 13.2; Mass
8

(ESI) m/z; 367.0 [M+H]+; Anal. Calcd for C18H14BrNO3: C, 58.71; H, 3.83; N, 11.41 %;
Found. C, 58.67; H, 3.87; N, 11.42 %.
ACKNOWLEDGEMENTS
Funding provided by Natural Sciences and Engineering Research Council of Canada is
gratefully acknowledged.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
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13

Table 1 Evaluation of Lewis acids
Entrya
Lewis acid
Yb(OTf)3
Sc(OTf)3
SnCl4
Time (h)
Yieldb (%)
1
3
60
62
68
70
65
74
84
63
75
85
2
3
3
3
4
AlCl3
2.5
3
5
TiCl4
6
ZnCl2
2.5
2.5
3
7c
8
ZnCl2
FeCl3
9d
10
BF3.Et2O
InCl3
2
2
aReaction conditions: 1a (0.3mmol), 2b (0.6 mmol), Lewis acid (0.03 mmol) in ethanol
(20 mL) at reflux.
bIsolated yield. cWith 20 mol% of Lewis acid. dWith 100 mol% of Lewis acid.
14

Table 2 Optimization of reaction conditions
Entrya
1
x (mol%)
10
Solvent
Time
2h
Yieldb (%)
Ethanol
Methanol
Ethylene Glycol
Acetonitrile
Toluene
THF
85
70
68
65
60
-
2
10
2h
3
10
2h
4
10
3h
5
10
3h
6
10
5h
7
10
CH2Cl2
5h
-
8
10
CHCl3
5h
-
9c
10
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
12h
5min
10min
5min
4min
4min
30
84
80
90
94
90
10d
11d
12d
13e
14f
10
5
20
10
10
aReaction Conditions: 1a (0.3mmol), 2b (0.6mmol), InCl3 (0.03mmol) in solvent.
bIsolated yield.
cRT with stirring.
15

dUnder MWI at 70 ⁰ C.
eUnder MWI at 80 ⁰ C.
fUnder MWI at 90 ⁰ C
16

Table 3 Time and yield of synthesized of compounds (3a-3p) and (6a-6h)
Compound code
Conventional Method
Microwave Irradiation Method
Time (h)
Yield (%)
Time (min) Power (W) Yield (%)
3a
3b
3c
3d
3e
3f
2
82
85
80
80
79
78
75
82
84
80
82
75
76
83
80
78
87
80
81
83
4
4
4
4
5
5
7
5
4
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
90
94
91
92
88
90
80
86
90
84
85
88
80
86
87
86
95
93
94
94
2
3
2.5
2
2
3g
3h
3i
2
2
2
3j
2.5
2
6
3k
3l
6
5
7
5
6
6
3
3
3
3
3
3m
3n
3o
3p
6a
6b
6c
6d
3
2.5
3
2
1.5
1
1
1.5
17

6e
6f
1
2
1
1
85
75
83
82
3
4
3
3
110
110
110
110
92
88
90
95
6g
6h
18

Table 4 α-Glucosidase inhibitory activity of compounds (3a-3p) and (6a-6h)
a
S.No.
Compound
IC50a (µM)
S.No.
Compound
IC50 (µM)
code
3a
3b
3c
3d
3e
3f
code
1
57.5
NA
14
15
16
17
18
19
20
21
22
23
24
3n
NA
123.7
60.32
NA
2
3o
3
NA
3p
4
NA
6a
5
238.0
NA
6b
NA
6
6c
NA
7
3g
3h
3i
126.43
71.95
65.97
NA
6d
NA
8
6e
NA
9
6f
NA
10
11
12
13
3j
6g
NA
3k
3l
80.80
NA
6h
NA
Acarboseb
115.8
3m
187.5
aData is mean of three independent experiments, each done with duplicate. Standard
deviations were below ±20%.
bStandard Inhibitor. NA, not active.
19

Fig. 1 Crystal Structure of 3i
20

Scheme 1 Synthesis of pyrazoloquinolines
21

Scheme 2 Mechanism of formation of product 3b
22