Lewis acid–catalyzed green synthesis and biological studies of pyrrolo[3,4-c]pyrazoles in aqueous medium

Article abstract of DOI:10.1002/jhet.3740

An environmentally benign approach in aqueous medium by means of Lewis acid catalyst affords a wide spectrum of pyrazoline derivatives in satisfactory yields. [3+2] cycloaddition reactions of substituted azomethine-N-imines to maleimide in aqueous medium at relatively high concentrations of Lewis acid catalyst have emerged as an environment friendly alternative to conventional solvents. Promising catalytic activity has been revealed by Lewis acid like Cu (NO₃)₂ in aqueous medium. The obvious features of this synthetic protocol were short reaction time, high efficiency, less hazardous synthesis by benign solvent, catalysis, modest workup, and a clean reaction methodology.

Full text of DOI:10.1002/jhet.3740

Received: 22 March 2019
DOI: 10.1002/jhet.3740
Revised: 21 August 2019
Accepted: 26 August 2019
A R T I C L E
Lewis acid–catalyzed green synthesis and biological studies of
pyrrolo[3,4-c]pyrazoles in aqueous medium
Manpreet Kaur1
| Baldev Singh1 | Anania Arjuna2
1Department of Chemistry, Punjabi University,
Patiala, India
Abstract
2Faculty of Applied Medical Sciences, Lovely
Professional University, Jalandhar, India
An environmentally benign approach in aqueous medium by means of Lewis acid cat-
alyst affords a wide spectrum of pyrazoline derivatives in satisfactory yields. [3+2]
cycloaddition reactions of substituted azomethine-N-imines to maleimide in aqueous
medium at relatively high concentrations of Lewis acid catalyst have emerged as an
environment friendly alternative to conventional solvents. Promising catalytic activity
has been revealed by Lewis acid like Cu (NO3)2 in aqueous medium. The obvious fea-
tures of this synthetic protocol were short reaction time, high efficiency, less hazard-
ous synthesis by benign solvent, catalysis, modest workup, and a clean reaction
methodology.
Correspondence
Manpreet Kaur, Department of Chemistry,
Punjabi University, Patiala 147002, Punjab,
India.
Email: manpreet21044@gmail.com
antipyretic,[44,45] antifilarial,[46] immunosuppressive,[47] antineoplastic,
hypoglycemic, and antidiabetic activities.[48–50] Broggini et al[51]
1
| INTRODUCTION
Aqueous organic reactions are inexpensive, nonhazardous, and
nontoxic[1–10] in the green chemistry approach.[11] Organic reactions
in water have high environmental acceptability and availability.[12,13]
However, the reactivity and selectivity cannot be achieved in case of
traditional organic solvents.[14]
reported the use of promoter Ag2CO3. Afterwards, Bonini et al[52]
used Ag2CO3 with Sc (OTf)3 for the 1,3-dipolar cycloaddition reac-
tions of in situ generated nitrilimines with functionalized acetylenes.
In current years, hydrotalcites (HTs) served as a better approach in
the reactions with Lewis base, Brønsted base, or acid-base sites.[53]
HTs have been reported in base-catalyzed cycloaddition reactions for
the synthesis of isoxazoles and tetrazoles.[54] Synthesis of
1,4,2-dioxazoles in aqueous media by employing β-cyclodextrin
nanoreactor and 2-amino-4H-chromene derivatives using MOF-5 as
catalyst under solvent-free conditions has been developed as a green
alternative method for producing most important class of heterocyclic
compounds.[55,56] A considerable number of methods towards the for-
mation of heterocyclics using green catalysts and solvent-free condi-
tions under microwave and ultrasonic irradiations have also been
reported in recent years.[57,58] One-pot synthesis of propanamide
derivatives in aqueous solvent under catalyst-free environment using
ultrasonic irradiations has been reported as a successful method in
achieving the green chemistry objectives.[59] Eco-friendly synthesis of
efficient and recyclable nanocatalysts and their usage in heterocyclic
synthesis have been investigated successfully.[60,61] 1,3-Dipolar cyclo-
addition reactions of nitrilimine with N-benzylmaleimide in conven-
tional solvents using base has been reported by our group
previously.[62] Vinyltriphenylphosphonium salts on the Michael
The endorsement of catalytic chemical reactions contributes to
the progress of unconventional mechanisms by allowing the substitu-
tion of organic solvents with water.[15–19] In recent years, eco-green
features have recognized [3+2] cycloaddition reactions in aqueous
medium, as an innovative green alternative to conventional solvents
in scientific research.[17–23] Micellar catalysts in basic medium have
been used for in situ generation of 1,3-dipoles,[24] which possess a
variety of pharmacological activities such as antidepressant,[25–28]
anticonvulsant,[27,28] antitumor,[29] protein kinase
C
inhibitor,[30]
anticancer,[31,32] anti-inflammatory,[33] antiepileptic, antimicrobial,[34]
inhibitors of alkaline phosphatase,[35] antiamoebic[36] and
antiandrogenic,[37] antibiotic,[38] and antioxidant.[39] Oxidized low-
density lipoproteins (LDLs) have a major role in the development of
atherosclerosis.[40] Treatment of hypoxic-ischemic encephalopathy[41]
in neonates and paraquat poisoning[42] using pyrazolin-5-one deriva-
tives have been reported. Fipronil and zaleplon are widely used as
pesticides and sedatives, respectively.[43] Many pyrazole derivatives
have exhibited remarkable biological activities like analgesic,
J Heterocyclic Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

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KAUR ET AL.
addition lead to the formation of stabilized phosphorus ylides that
produce various heterocyclic compounds to take part in intramolecu-
lar Wittig reaction.[63] A green procedure for the synthesis of biologi-
cally important quinoxaline derivatives in the presence of two novel
heterogeneous Lewis acid catalysts at ambient temperature has been
reported in literature.[64] Lewis acid-promoted chemical reactions
appreciably contribute to the development of new reaction strategies
by allowing the replacement of hazardous organic solvents with envi-
ronmentally safe and inexpensive solvents such as water to reduce
the generation of toxic waste.[65,66] Benzopyrano[3,2-c]chromene-
6,8-dione derivatives have been synthesized through an eco-friendly
approach using Cu (II)-Schiff base/SBA-15 in solvent-free conditions,
and 2,4,5-trisubstituted imidazoles have been synthesized using
CoFe2O4 magnetic nanoparticles as benign catalyst.[67,68]
SCHEME 1 Schematic diagram describing the synthesis of
hydrazonyl bromides 1a-m
whereas proton of the cyclohexyl ring directly attached to nitrogen
atom shows multiplet in the range of δ 3.83-3.89 owing to coupling
with the neighboring protons, while a multiplet in the range of δ
2.02-1.09 (10H) and a singlet at δ 2.59 (3H) has been assigned to ali-
phatic protons of cyclohexyl moiety and methyl protons, respectively.
Compound 3e displays characteristic signals at δ 166.72 and 166.70
(C═O of succinimide moiety), δ 141.40 (C3 of C═N), δ 137.06 (C-10 of
2
| RESULTS AND DISCUSSION
2.1 | Chemistry
The present scheme is a convenient and facile approach for the in situ
generation of nitrilimines by treating the respective hydrazonyl bro-
mides 1a-m (Scheme 1) and N-cyclohexyl maleimide 2 (Scheme 2)
with an excess of triethylamine in different solvents as reported in lit-
erature.[69] Table 1 shows that no reaction has been observed in the
absence of Lewis acid catalyst in aqueous medium and that poor yield
has been obtained on heating the reactants in solvent-free and cata-
lyst-free conditions. However, lower yields have been obtained with
cosolvents under catalyst-free conditions consuming more time, while
on adding varied quantities of Cu (II) salts as catalyst, the reactions
occurred smoothly on mild heating consuming less time and providing
higher yields. It has been found that yield obtained with Cu (NO3)2 in
water was quite high and promoted the Lewis acid–catalyzed cycload-
dition reactions in aqueous medium (Scheme 3, Table 2). The pro-
posed structure of compounds 3a-m has been characterized through
spectroscopic techniques IR, 1H-NMR, [13]C-NMR, 1H,1H correlation
spectroscopy (COSY) (Figure 1), and electrospray ionization–mass
spectrometry (ESI-MS).
the dibromophenyl ring),
δ δ δ
132.57 (C-30), 126.45 (C-200),
124.36-110.93 (aromatic carbons), δ 56.55 (carbon atom of N-
cyclohexyl moiety directly attached to the nitrogen atom of
succinimide moiety), δ 49.66 (C5-pyrazoline), δ 47.26 (C4-pyrazoline),
δ 18.10 (CH3), and δ 23.48-19.57 (carbon atoms of cyclohexyl
moiety).
2.2 | Biology
2.2.1 | In vitro inhibition of advanced glycation end-
product formation activity
Synthesized compounds 3a-m were tested for their in vitro inhibition
of advanced glycation end-product formation activity.[72] It was
suggested that compounds 3b, 3c, and 3d having strong electron-
withdrawing nitro groups (−M and −I effects) on the C-phenyl ring
were more potent (Table 3). Among these compounds, compound 3c
having m-NO2 substitution on C-phenyl moiety was more potent
owing to strong electron-withdrawing power. 3m and 3k with p-
OCH3 and o-OCH3 group on C-phenyl moiety were least active owing
to weaker electron-withdrawing power of the methoxy group at para
All the stereoisomers exhibited an analogous trend in their IR
spectra. However, as a representative case, the IR spectrum of com-
pound 3e shows two absorption bands owing to the symmetric and
asymmetric carbonyl stretching vibrations of succinimide moiety.[70,71]
In IR spectrum, two carbonyl bands of succinimide moiety coupled
with each other and hence redistributed their energies, showing the
appearance of one strong band in the region of 1703 cm−1
νsym.(C═O)
and another shoulder band in the region of 1774 cm−1
νasymm.(C═O).
Absorption bands at 1603 cm−1 (C═N stretching vibrations of the
pyrazole ring) and 1575 cm−1 (aromatic C═C double-bond skeletal
stretching vibrations) confirm the cycloaddition between nitrilimine
and N-cyclohexyl maleimide. 1H-NMR spectra compound 3e shows
aromatic multiplets in the range of δ 7.19-7.81 (7H), and doublets at δ
5.78 (C6a-H, J = 10.08 Hz) and δ 4.89 (C3a-H, J = 10.04 Hz), respec-
tively, on mutual coupling of protons C3a-H and C6a-H. Downfield
shift appeared in C6a-H owing to electronegative nitrogen atom,
SCHEME 2 Schematic diagram describing the synthesis of N-
cyclohexyl maleimide 2

KAUR ET AL.
3
TABLE 1 Optimization of the reaction conditiona for 1, 3-dipolar
cycloaddition reaction of 1a with N-cyclohexyl maleimide 2
Entry
1
Catalyst
Solvent
THF
Yield,b
58
48
53
55
72
69
63
84
72
63
58
80
65
53
45
72
69
64
58
70
NRc
7d
%
Time, h
(C2H5)3N
5
6
7
6
4
6
6
2
6
6
6
3
7
8
8
5
6
7
7
4
-
2
CH2Cl2
1,4-Dioxane
H2O
3
4
5
Cu (NO3)2
CuCl2ꢀ2H2O
Cu (OAc)2
CuCO3
THF
6
CH2Cl2
SCHEME 3 Schematic diagram describing the Lewis acid–
catalyzed synthesis of variously substituted compounds 3a-m in
aqueous media
7
1,4-Dioxane
H2O
8
9
THF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
CH2Cl2
2.2.2 | Antioxidant activity
1,4-Dioxane
H2O
The radical scavenging activity (RSA) (%) at various concentrations (0.25,
0.54, 0.88, 1.37, 2.50, 5.00, and 7.50 μg/mL) and IC50 of synthesized
compounds 3a-m are depicted in Table 4.[73] All tested compounds 3a-
m have shown remarkable in vitro antioxidant activity as than did stan-
dard antioxidant (butylated hydroxytoluene [BHT]) (Figures 3 and 4). It
was very clear from our present findings that the highest scavenging
activity was observed in compound 3c (electron-withdrawing group
[EWG] at the meta position) and the least scavenging activity was
observed in compound 3g (electron-donating group [EDG] at the para
position), whereas compounds 3b, 3c, and 3d with nitro substitution
were more active than their unsubstituted counterparts. The moderate
activity has been shown by compounds 3h, 3i, and 3j having hydroxy
group in the aromatic ring. It was interesting to note that the C-phenyl
ring of pyrazoline having EWG showed maximum antioxidant activity.
THF
CH2Cl2
1,4-Dioxane
H2O
THF
CH2Cl2
1,4-Dioxane
H2O
No catalyst
H2O
-
-
-
-
-
-
9
8
9
10
9
H2O/t-BuOHe
EtOH/AcOHe
CH2Cl2/AcOHe
CH3CN/AcOHe
25
32
18
15
3
| EXPERIMENTAL
Abbreviation: THF, tetrahydrofuran.
aReaction condition: 1a (5 mmol), 2 (30 mmol), solvent (100 mL).
bIsolated yield after recrystallization.
cNo reaction was observed.
Melting points reported are uncorrected. IR spectra were obtained
using PerkinElmer RXIFT infrared spectrophotometer (manufactured
at Buckinghamshire, England). 1H-NMR, 13C-NMR spectra, and
1H,1H-COSY spectra were obtained at 400 MHz on BRUKER spec-
trometer (manufactured at Fallanden, Switzerland). Waters Micromass
Q-T of Micro (ESI) spectrometer (manufactured at Vernon Hills, IL,
USA) was used to obtain electrospray ionization mass spectra.
Elementar Vario MICRO cube CHN analyzer (Frankfurt, Germany) was
used for elemental analysis. Glass plates coated with silica gel-G and
silica gel (100-200 mesh, Loba Chemie Pvt Ltd Mumbai, Maharashtra,
India) suspended in methanol-chloroform (1:2) were used for thin-
layer chromatography (TLC) and column chromatography.
dReflux/solvent-free.
eCosolvent (20 mL)/reflux, Et3N (3.3 mmol), other Lewis acid catalyst
(0.05 mmol).
and ortho positions (owing to +M effect along with −I effect). The
methoxy group at the meta position on the C-phenyl ring 3l that
exhibited that strong electron-withdrawing power (−I effect) was also
an active antiglycating agent, and the potency was comparable with
that of aminoguanidine. Compounds 3h, 3i, and 3j with strong elec-
tron-donating hydroxyl group (+M and −I effects) at the ortho and
para positions on the C-phenyl ring were less active (owing to +M
effect along with −I effect). Compounds 3e, 3f, and 3g having moder-
ate electron-donating methyl group on the C-phenyl ring and
unsubstituted compound 3a were reasonable antiglycating agents,
while compounds 3m and 3k with high electron-donating power, viz,
p-OCH3 and o-OCH3, were found to be the least potent among all
synthesized compounds 3a-m. The graphical representation of the
data and IC50 values in μM is also shown in Figure 2.
3.1 | General procedure for synthesis of substituted
benzaldehyde-20,40-dibromophenyl hydrazonyl
bromide 1a-m
The reaction mixture of phenyl hydrazone (0.1 mol) in cold glacial
acetic acid (100 mL) and acetous bromine (0.3 mol/30 mL of glacial
acetic acid) on continuous stirring for 3 to 4 hours gave hydrazonyl
bromide derivatives 1a-m in good yield.

4
KAUR ET AL.
TABLE 2 Synthesis of cycloadducts 3a-m by 1,3-dipolar cycloaddition reactions of 1a-m with N-cyclohexyl maleimide 2 using Cu (NO3)2
Compound
X
mp,ꢁC
Time, h
Yield,a %
3a
3b
3c
3d
3e
3f
H
168-169
240-243
210-215
172-173
162-163
142-144
185-187
225-227
192-193
200-203
212-214
182-184
185-187
2
84
78
82
75
83
67
78
84
71
77
82
70
76
2-NO2
2
3-NO2
4-NO2
2-CH3
3-CH3
4-CH3
2-OH
1.5
2
3
3
3g
3h
3i
2.5
1.5
2.5
2
3-OH
3j
4-OH
3k
3l
2-OCH3
3-OCH3
4-OCH3
2
3
3m
2.5
Note. 1a-m (5 mmol), 2 (30 mmol), and catalyst (10 mol %).
aIsolated yield of pure compound after recrystallization.
TABLE 3 Advanced glycation end-product formation inhibitory
activity of synthesized compounds 3a-m
Compound
X
IC50, μM
3a
H
65.19 2.20
16.60 1.52
10.66 0.90
14.56 0.24
52.85 1.10
94.30 3.91
68.67 2.61
122.67 5.23
107.67 3.61
135.67 4.65
235.67 5.23
37.53 0.83
266.37 5.65
40.54 2.04
3b
2-NO2
3-NO2
4-NO2
2-CH3
3-CH3
4-CH3
2-OH
3c
3d
3e
3f
3g
3h
3i
3-OH
3j
4-OH
3k
2-OCH3
3-OCH3
4-OCH3
-
3l
3m
FIGURE 1 1H,1H-COSY spectrum of compound 3e. COSY,
correlation spectroscopy
Aminoguanidine

KAUR ET AL.
5
FIGURE 2 Graphical representation of IC50 values (μM) for the advanced glycation end-product formation inhibitory activity of synthesized
compounds 3a-m relative to the standard drug aminoguanidine [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 4 Percentage of in vitro radical scavenging activity of
synthesized compounds (3a-m)
3.4 | General procedure for Lewis acid–catalyzed
cycloaddition in water
Concentration, μg/mL
Cu (NO3)2 was allowed to dry by heating under vacuum. The reaction
mixture of 5 mmol of corresponding hydrazonyl bromides 1a-m, 30 mmol
of N-cyclohexyl maleimide 2 in 100 mL of deionized water, and
0.05 mmol of dried Cu (NO3)2 was placed in a round-bottom flask set in
an oil bath for 1.5 to 2.0 hours under an inert atmosphere of nitrogen.
Stir the reaction mixture on magnetic stirrer till completion, as directed
by TLC. After removal of the solvent under reduced pressure dic-
hloromethane was added to the reaction mixture. Remove undissolved
catalyst by filtration. Cycloadducts 3a-m were obtained by column chro-
matography on silica gel using hexane-ethyl acetate mixture as eluent.
Compound 0.25 0.54 0.88 1.37 2.50 5.00 7.50 IC50
3a
3b
3c
3d
3e
3f
17.04 23.02 30.05 44.04 55.04 65.03 74.03 0.48
11.04 23.06 31.03 41.07 56.04 64.01 76.00 0.46
0.56 18.09 26.05 35.02 44.03 53.03 76.03 0.44
9.05 24.08 36.07 53.08 65.08 78.09 83.04 0.45
2.07 17.05 28.07 45.03 59.04 62.09 83.04 0.52
12.02 21.06 33.07 45.09 59.08 76.06 86.08 0.56
15.07 24.08 36.09 49.08 62.04 77.03 89.05 0.59
7.05 18.04 27.05 41.03 54.07 62.04 86.04 0.49
18.05 22.02 31.05 40.04 54.04 66.03 78.03 0.48
7.09 19.04 33.01 43.06 52.04 67.03 79.02 0.49
11.04 16.07 32.09 36.04 53.04 63.05 81.06 0.51
9.04 16.04 30.09 41.03 52.07 67.07 77.04 0.52
15.06 28.07 39.05 42.04 53.02 66.03 79.03 0.52
3g
3h
3i
3.4.1 | 20,40-Dibromophenyl-5-cyclohexyl-3-phenyl-
3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]pyrazole-
4,6-dione (3a)
3j
3k
3l
3m
BHTa
Compound obtained as white solid, yield 84%; mp 168-169ꢁC; IR (KBr
pellets, ʋmax/cm−1): 1709 (C═O), 1781 (C═O), 1609 (C═N), 1565
(C═C); 1H-NMR (400 MHz, DMSO-d6): δ 5.82 (d, 1H, J = 10.28 Hz,
H6a), 4.87 (d, 1H, J = 10.24 Hz, H3a), 7.81-7.19 (m, 8H, Ar–H),
3.74-3.68 (m, 1H, CH cyclohexyl), 2.20-1.09 (m, 10H, 5CH2
-
4.62 11.56 23.12 30.11 44.71 55.22 5.37
Note. - indicates no activity.
aButylated hydroxytoluene as standard substance.
cyclohexyl); 13C-NMR (100 MHz, DMSO-d6):
δ 172.46, 172.08,
3.2 | General procedure for synthesis of N-
cyclohexyl maleimide 2
149.65, 145.55, 135.02, 134.69, 131.62, 130.26, 129.87, 128.07,
117.20, 116.08, 113.48, 52.60, 50.45, 41.28, 28.87, 28.80, 23.66,
20.53, 20.19; MS (ESI): m/z = 531(M)+; Anal Calcd (%) for C23H21N3O2
Br2: C, 51.98; H, 3.95; N, 7.90. Found: C, 52.17; H, 3.93; N, 7.92.
N-Cyclohexyl maleanilic acid was obtained by stirring 20 mmol of mal-
eic anhydride in 25 mL of diethyl ether and cyclohexyl aniline in 5 mL
of diethyl ether at room temperature, which was refluxed with a solu-
tion of anhydrous sodium acetate (0.65 g, 8 mmol) in acetic anhydride
(6.7 mL) for 1.5 hours afforded N-cyclohexyl maleimide 2.
3.4.2 | 20,40-Dibromophenyl-5-cyclohexyl-3-(200-
nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3b)
3.3 | General procedure for cycloaddition in
triethylamine
Compound obtained as brownish solid, yield 78%; mp 240-243ꢁC; IR
(KBr, ʋmax/cm−1): 1706 (C═O), 1778 (C═O), 1604 (C═N), 1563 (C═C);
1H-NMR (400 MHz, CDCl3): δ 5.72 (d, 1H, J = 10.20 Hz, H6a), 4.71 (d,
1H, J = 10.20 Hz, H3a), 7.88-7.19 (m, 7H, Ar–H), 3.89-3.83 (m, 1H, CH
cyclohexyl), 1.92-1.02 (m, 10H, 5CH2 cyclohexyl); 13C-NMR
(100 MHz, CDCl3): δ 172.63, 172.42, 148.72, 146.87, 144.90, 136.07,
135.28, 132.68, 131.28, 130.46, 126.12, 123.34, 118.26, 117.18,
Triethylamine (3.3 mmol) was added dropwise to the cold reaction mixture
of substituted benzaldehyde-20,40-dibromophenyl hydrazonyl bromide
derivatives 1a-m (5 mmol) and N-cyclohexyl maleimides 2 (30 mmol) in
100 mL of solvent. The reaction mixture was stirred at room temperature
till completion as evidenced by TLC to give cycloadducts 3a-m.

6
KAUR ET AL.
FIGURE 3 Graphical presentation of in vitro DPPH radical scavenging activity of compounds 3a-m relative to the standard antioxidant BHT.
BHT, butylated hydroxytoluene [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 4 Graphical presentation of the IC50 values (μg/mL) for the antioxidant activity of compounds 3a-m measured at various
concentrations [Color figure can be viewed at wileyonlinelibrary.com]
114.29, 52.64, 50.98, 40.05, 29.73, 29.71, 26.85, 26.45, 24.39; MS
(ESI): m/z = 576 (M)+; Anal Calcd (%) for C23H20N4O4 Br2: C, 47.92; H,
3.47; N, 9.72. Found: C, 47.88; H, 3.45; N, 9.70.
(100 MHz, CDCl3): δ 171.80, 171.62, 149.72, 147.87, 145.90, 135.07,
134.88, 133.66, 130.48, 129.72, 125.14, 123.33, 117.56, 116.78,
113.22, 52.44, 50.77, 42.15, 28.74, 28.65, 25.64, 25.45, 21.42; MS
(ESI): m/z = 576(M)+; Anal Calcd (%) for C23H20N4O4 Br2: C, 47.92; H,
3.47; N, 9.72. Found: C, 47.75; H, 3.46; N, 9.76.
3.4.3 | 20,40-Dibromophenyl)-5-cyclohexyl-3-(300-
nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3c)
3.4.4 | 20,40-Dibromophenyl-3-(400-nitrophenyl)-
5-cyclohexyl-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3d)
Compound obtained as brownish solid, yield 82%; mp 210-215ꢁC; IR
(KBr, ʋmax/cm−1): 1705 (C═O), 1781 (C═O), 1608 (C═N), 1562 (C═C);
1H-NMR (400 MHz, DMSO-d6): δ 5.79 (d, 1H, J = 10.48 Hz, , H6a),
5.32 (d, 1H, J = 10.48 Hz, H3a), 7.89-7.17 (m, 7H, Ar–H), 3.87-3.78 (m,
1H, CH cyclohexyl), 2.00-1.00 (m, 10H, 5CH2 cyclohexyl); 13C-NMR
Compound obtained as white solid, yield 75%; mp 172-173ꢁC; IR
(KBr, ʋmax/cm−1): 1699 (C═O), 1771 (C═O), 1609 (C═N), 1577 (C═C);
1H-NMR (400 MHz, CDCl3): δ 5.74 (d, 1H, J = 10.40 Hz, H6a), 4.75 (d,

KAUR ET AL.
7
1H, J = 10.36 Hz, H3a), 8.02-7.15 (m, 7H, Ar–H), 3.79-3.62 (m, 1H, CH
cyclohexyl), 1.98-1.08 (m, 10H, 5CH2 cyclohexyl); 13C-NMR
(100 MHz, CDCl3): δ 173.18, 172.32, 150.23, 149.24, 144.53, 141.16,
135.59, 131.26, 129.68, 122.12, 117.25, 116.28, 113.28, 52.78,
50.44, 42.02, 28.75, 28.71, 25.35, 24.95, 21.33; MS (ESI): m/z = 576
(M)+; Anal Calcd (%) for C23H20N4O4 Br2: C, 47.92; H, 3.47; N, 9.72.
Found: C, 47.72; H, 3.42; N, 9.80.
MS (ESI): m/z = 545(M)+; Anal Calcd (%) for C24H23N3O2Br2: C,
52.84; H, 4.22; N, 7.70. Found: C, 53.02; H, 4.30; N, 7.62.
3.4.8 | 20,40-Dibromophenyl-5-cyclohexyl-3-(200-
hydoxyphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3h)
Compound obtained as white solid, yield 84%; mp 225-227ꢁC; IR
(KBr, ʋmax/cm−1): 1700 (C═O), 1780 (C═O), 1601 (C═N), 1575 cm−1
(C═C); 1H-NMR (400 MHz, DMSO-d6): δ 5.81 (d, 1H, J = 10.24 Hz,
3.4.5 | 20,40-Dibromophenyl-5-cyclohexyl-3-(200-
methylphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3e)
H6a), 4.79 (d, 1H, J = 10.24 Hz, H3a), 7.92-7.10 (m, 7H, Ar–H),
Compound obtained as white solid, yield 83%; mp 162-163ꢁC; IR
(KBr, ʋmax/cm−1): 1703 (C═O), 1774 (C═O), 1603 (C═N), 1575 (C═C);
1H-NMR (400 M Hz, DMSO-d6): δ 5.78 (d, 1H, J = 10.08 Hz, H6a),
4.89 (d, 1H, J = 10.04 Hz, H3a), 7.81-7.19 (m, 7H, Ar–H), 3.83-3.89 (m,
1H, CH cyclohexyl), 2.02-1.1.09 (m, 10H, 5CH2 cyclohexyl), 2.59 (s,
3H, CH3); 13C-NMR (100 MHz, DMSO-d6): δ 166.72, 166.70, 141.40,
137.06, 132.57, 130.50, 126.45, 126.09, 124.36, 124.00, 123.41,
120.50, 120.48, 112.91, 110.93, 56.55, 49.66, 47.26, 23.48, 23.28,
20.44, 20.39, 19.57, 18.10; MS (ESI): m/z = 545(M)+; Anal Calcd (%)
for C24H23N3O2Br2: C, 52.84; H, 4.22; N, 7.70. Found: C, 52.90; H,
4.20; N, 7.66.
3.83-3.79 (m, 1H, CH cyclohexyl), 2.00-1.02 (m, 10H, 5CH2
cyclohexyl), 9.02 (s, 1H, OH); 13C-NMR (100 MHz, DMSO-d6): δ
173.04, 172.78, 159.50, 148.77, 144.34, 135.52, 132.80, 131.10,
129.80, 122.56, 119.93, 117.25, 116.98, 116.52, 113.81, 52.32,
50.62, 42.18, 28.62, 28.58, 23.32, 23.98, 20.82; MS (ESI): m/z = 547
(M)+; Anal Calcd (%) for C23H21N3O3Br2: C, 50.46; H, 3.84; N, 7.68.
Found: C, 50.17; H, 3.85; N, 7.62.
3.4.9 | 20,40-Dibromophenyl-5-cyclohexyl-3-(300-
hydroxyphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3i)
3.4.6 | 20,40-Dibromophenyl-5-cyclohexyl-3-(300-
methylphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3f)
Compound obtained as white solid, yield 71%; mp 192-193ꢁC; IR
(KBr, ʋmax/cm−1): 1702 (C═O), 1775 (C═O), 1603 (C═N), 1572 (C═C);
1H-NMR (400 MHz, CDCl3): δ 5.67 (d, 1H, J = 10.40 Hz, H6a), 4.89 (d,
1H, J = 10.40 Hz, H3a), 7.77-6.88 (m, 7H, Ar–H), 3.89-3.83 (m, 1H, CH
cyclohexyl), 2.10-1.04 (m, 10H, 5CH2 cyclohexyl), 9.01 (s, 1H, OH);
13C-NMR (100 MHz, DMSO-d6): δ 172.44, 171.82, 158.80, 149.87,
143.24, 136.58, 135.70, 130.78, 129.65, 121.68, 118.73, 117.55,
116.78, 114.32, 112.61, 52.38, 50.52, 41.48, 28.52, 28.35, 23.12,
Compound obtained as white solid, yield 67%; mp 142-144ꢁC; IR
(KBr, ʋmax/cm−1): 1706 (C═O), 1782 cm−1 (C═O), 1603 (C═N), 1575
(C═C); 1H-NMR (400 MHz, DMSO-d6): δ 5.68 (d, 1H, J = 10.00 Hz,
H6a), 5.17 (d, 1H, J = 10.00 Hz, H3a), 8.01-7.02 (m, 7H, Ar–H),
3.79-3.64 (m, 1H, CH cyclohexyl), 1.99-1.00 (m, 10H, 5CH2
cyclohexyl), 2.56 (s, 3H, CH3); 13C-NMR (100 MHz, CDCl3): δ 172.72,
172.60, 149.45, 145.65, 137.50, 135.35, 132.45, 130.45, 130.20,
128.37, 127.20, 125.54, 117.25, 116.28, 113.18, 52.67, 50.23, 44.29,
24.40, 24.24, 20.47, 20.36, 19.70, 18.20; MS (ESI): m/z = 545(M)+;
Anal Calcd (%) for C24H23N3O2Br2: C, 52.84; H, 4.22; N, 7.70.
Found: C, 53.05; H, 4.20; N, 7.72.
23.08, 20.92; MS (ESI): m/z
23H21N3O3Br2: C, 50.46; H, 3.84; N, 7.68. Found: C, 50.49; H,
3.83; N, 7.60.
=
547(M)+; Anal Calcd (%) for
C
3.4.10 | 20,40-Dibromophenyl-5-cyclohexyl-3-(400-
hydroxyphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3j)
3.4.7 | 20,40-Dibromophenyl-5-cyclohexyl-3-(400-
methylphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3g)
Compound obtained as white solid, yield 77%; mp 202-203ꢁC; IR
(KBr, ʋmax/cm−1): 1700 (C═O), 1777 (C═O), 1603 (C═N), 1574 (C═C);
1H-NMR (400 MHz, CDCl3): δ 5.72 (d, 1H, J = 10.34 Hz, H6a), 4.79 (d,
1H, J = 10.34 Hz, H3a), 7.89-7.03 (m, 7H, Ar–H), 3.82-3.74 (m, 1H, CH
cyclohexyl), 1.92-0.90 (m, 10H, 5CH2 cyclohexyl), 9.09 (s, 1H, OH);
13C-NMR (100 MHz, DMSO-d6): δ 172.74, 172.38, 160.20, 148.97,
143.94, 135.32, 131.60, 130.04, 125.90, 117.35, 116.66, 116.27,
113.85, 52.63, 50.82, 41.59, 27.93, 27.88, 23.20, 23.18, 18.82; MS
(ESI): m/z = 547(M)+; Anal Calcd (%) for C23H21N3O3Br2: C, 50.46; H,
3.84; N, 7.68. Found: C, 50.47; H, 3.73; N, 7.65.
Compound obtained as white solid, yield 78%; mp 185-187ꢁC; IR
(KBr, ʋmax/cm−1): 1706 (C═O), 1781 (C═O), 1597 (C═N); 1572 (C═C);
1H-NMR (400 MHz, DMSO-d6): δ 5.76 (d, 1H, J = 10.40 Hz, H6a), 4.67
(d, 1H, J = 10.38 Hz, H3a), 8.00-7.10 (m, 7H, Ar–H), 3.84-3.77 (m, 1H,
CH cyclohexyl), 2.01-1.00 (m, 10H, 5CH2 cyclohexyl), 2.53 (s, 3H,
CH3); 13C-NMR (100 MHz, CDCl3): δ 172.04, 171.68, 148.50, 143.72,
140.64, 135.58, 131.90, 131.09, 129.22, 129.12, 117.75, 116.72,
113.11, 52.53, 50.12, 42.28, 23.68, 23.44, 20.98, 20.56, 19.92, 18.32;

8
KAUR ET AL.
3.4.11 | 20,40-Dibromophenyl-5-cyclohexyl-3-(200-
methoxyphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3k)
catalytic conditions without using volatile organic solvents. The vital
role of these cycloadducts as aldose reductase inhibitors and antioxi-
dants is prejudiced by the relative positions of electron-withdrawing/
electron-donating substituents on the C-phenyl ring. The compounds
with less activated rings are more significant as potent aldose reduc-
tase inhibitors.
Compound obtained as white solid, yield 82%; mp 212-214ꢁC; IR
(KBr, ʋmax/cm−1): 1704 (C═O), 1777 (C═O), 1598 (C═N); 1576 (C═C);
1H-NMR (400 MHz, CDCl3): δ 5.28 (d, 1H, J = 10.40 Hz, H6a), 4.35 (d,
1H, J = 10.38 Hz, H3a), 8.20-7.62 (m, 7H, Ar–H), 3.79-3.66 (m, 1H, CH
cyclohexyl), 2.00-1.08 (m, 10H, 5CH2 cyclohexyl), 3.63 (s, 3H, OCH3);
13C-NMR (100 MHz, CDCl3): δ 173.10, 172.68, 160.20, 149.97,
144.44, 135.72, 132.62, 131.70, 130.04, 122.34, 117.98, 117.15,
116.56, 114.28, 112.83, 56.43, 52.17, 50.28, 40.68, 29.42, 29.07,
27.32, 24.62, 24.48; MS (ESI): m/z = 561(M)+; Anal Calcd (%) for
ACKNOWLEDGMENTS
The authors are grateful to the University Grants Commission, New
Delhi, for financial support as Basic Scientific Research Fellowship
(F 4-1/2006(BSR)/7-185/2007, award number 6373/Research). The
authors are thankful to the Department of Chemistry, Punjabi Univer-
sity, Patiala, and Sophisticated Analytical Instrumentation Facility
(SAIF), Panjab University, Chandigarh, for spectral analysis.
C
24H23N3O3Br2: C, 51.34; H, 4.10; N, 7.49. Found: C, 51.36; H,
4.12; N, 7.46.
3.4.12 | 20,40-Dibromophenyl-5-cyclohexyl-3-(300-
methoxyphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo
[3,4-c]pyrazole-4,6-dione (3l)
ORCID
Manpreet Kaur
https://orcid.org/0000-0003-1621-8875
Compound obtained as white solid, yield 70%; mp 182-184ꢁC; IR
(KBr, ʋmax/cm−1): 1703 (C═O), 1779 (C═O), 1600 (C═N), 1566 (C═C);
1H-NMR (400 MHz, CDCl3): δ 5.67 (d, 1H, J = 10.00 Hz, H6a), 4.79 (d,
1H, J = 10.02 Hz, H3a), 7.78-7.12 (m, 7H, Ar–H), 3.88-3.81 (m, 1H, CH
cyclohexyl), 2.02-0.92 (m, 10H, 5CH2 cyclohexyl), 3.62 (s, 3H, OCH3);
13C-NMR (100 MHz, CDCl3): δ 172.70, 172.48, 159.26, 149.77,
144.24, 135.92, 135.32, 131.92, 129.84, 122.44, 117.28, 116.35,
116.26, 113.08, 112.92, 56.63, 52.57, 50.38, 41.78, 29.32, 29.09,
26.52, 23.62, 23.28; MS (ESI): m/z = 561(M)+; Anal Calcd (%) for
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| CONCLUSIONS
The contemporary reassessment of Diels-Alder reactions in aqueous
medium is a new synthetic approach for [3+2] cycloaddition reactions
of hydrazonyl bromides and substituted maleimides under Cu (II) salts'

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How to cite this article: Kaur M, Singh B, Arjuna A. Lewis
acid–catalyzed green synthesis and biological studies of
pyrrolo[3,4-c]pyrazoles in aqueous medium. J Heterocyclic
Chem. 2019;1–9. https://doi.org/10.1002/jhet.3740
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