Choline hydroxide promoted sustainable one-pot three-component synthesis of 1H-pyrazolo[1,2-a]pyridazine-2-carbonitriles under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2020.1720736

A sustainable one-pot three-component synthesis of novel 1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile derivatives employing a highly efficient, biodegradable, and recyclable choline hydroxide catalyst under solvent-free conditions is demonstrated. The salient features of this protocol are simple workup, mild reaction conditions, short reaction time (10 min), excellent yields (up to 97%), high atom economy, column chromatography-free protocol, and eco-friendliness. Interestingly, the choline hydroxide was recycled up to five cycles without any considerable loss of efficiency. The structures of the products were deduced by their ¹H NMR, ¹³C NMR, and HRLC-MS spectra.

Full text of DOI:10.1080/00397911.2020.1720736

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Choline hydroxide promoted sustainable one-pot
three-component synthesis of 1H-pyrazolo[1,2-
a]pyridazine-2-carbonitriles under solvent-free
conditions
Shailesh N. Vajekar & Ganapati S. Shankarling
To cite this article: Shailesh N. Vajekar & Ganapati S. Shankarling (2020): Choline
hydroxide promoted sustainable one-pot three-component synthesis of 1H-pyrazolo[1,2-
a]pyridazine-2-carbonitriles under solvent-free conditions, Synthetic Communications, DOI:
10.1080/00397911.2020.1720736
To link to this article: https://doi.org/10.1080/00397911.2020.1720736
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https://doi.org/10.1080/00397911.2020.1720736
Choline hydroxide promoted sustainable one-pot three-
component synthesis of 1H-pyrazolo[1,2-a]pyridazine-2-
carbonitriles under solvent-free conditions
Shailesh N. Vajekar
and Ganapati S. Shankarling
Department of Dyestuff Technology, Institute of Chemical Technology, Mumbai, India
ABSTRACT
ARTICLE HISTORY
Received 6 November 2019
A sustainable one-pot three-component synthesis of novel 1H-pyra-
zolo[1,2-a]pyridazine-2-carbonitrile derivatives employing a highly
efficient, biodegradable, and recyclable choline hydroxide catalyst
under solvent-free conditions is demonstrated. The salient features
of this protocol are simple workup, mild reaction conditions, short
reaction time (10 min), excellent yields (up to 97%), high atom econ-
omy, column chromatography-free protocol, and eco-friendliness.
Interestingly, the choline hydroxide was recycled up to five cycles
without any considerable loss of efficiency. The structures of the
products were deduced by their 1H NMR, 13C NMR, and HRLC-MS
spectra.
KEYWORDS
Choline hydroxide; 1H-
pyrazolo[1,2-a]pyridazine-2-
carbonitrile; one-pot three-
component; solvent-free;
sustainable
GRAPHICAL ABSTRACT
Introduction
Green chemistry for chemical synthesis addresses the problems pertaining to environ-
mental pollution experienced worldwide. In this context, multi-component reactions
(MCRs) under solvent-free conditions have proven to be a valuable asset in organic and
medicinal chemistry. This eco-friendly protocol minimizes the number of steps in the
synthesis of various biologically important derivatives. Since products are synthesized in
CONTACT Ganapati S. Shankarling
gsshankarling@gmail.com
Department of Dyestuff Technology, Institute of
Chemical Technology, N. P. Marg, Matunga, Mumbai, Maharashtra 400019, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
S. N. VAJEKAR AND G. S. SHANKARLING
one-pot, the structural diversity can be achieved directly by varying the reacting
components.[1–3]
Nitrogen-containing heterocycles are important skeletons owing to their tremendous
application in biologically active pharmaceuticals, agrochemicals, and functional materi-
als.[4–7] 1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile derivatives have been reported to
have analgesic, anti-hypoxic, anti-inflammatory, and antipyretic activities.[8,9] Hence, the
development of new synthetic methods for the efficient synthesis of 1H-pyrazolo[1,2-
a]pyridazine-2-carbonitrile derivatives is a fascinating challenge in green synthesis.
In recent years, the surge in environmental consciousness in chemical research and
industry compelled practicing environmentally benign and sustainable methods involv-
ing eco-friendly catalysts and lacking harmful organic solvents. Ionic liquids (ILs) are
getting significant worldwide consideration and are being employed comprehensively in
chemical transformations as green solvents and/or catalysts owing to their unique prop-
erties such as low volatility, tunable solubility, non-flammability, good catalytic activity,
and excellent recyclability.[10–13]
Choline chloride (ChCl), belonging to the vitamin B class, is a naturally occurring
biocompatible compound. It is used as a chicken feed additive and commercially pro-
duced on a large scale.[14,15] Choline chloride-based ionic liquid i.e., ChOH is a non-
toxic ionic liquid with a number of benefits such as biodegradability, recyclability,
solvation power, ready availability, high water solubility, and good catalytic activity in
numerous organic transformations.[16–26]
In continuation of our efforts to develop new green methodologies in organic synthe-
sis,[27–32] we herein present a sustainable one-pot three-component synthesis of novel
1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile derivatives employing choline hydroxide
catalyst under solvent-free conditions.
Results and discussion
In this protocol, we have used 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione, 4-nitro-
benzaldehyde, and malononitrile as model substrates for the optimization of the reac-
tion conditions. We have thoroughly investigated the effect of different organic bases
such as DBU, piperidine, triethylamine, pyridine, tetramethylammonium hydroxide and
inorganic bases such as KOH, NaOH, Cs2CO3, K2CO3, and Na2CO3, which gave the
desired product yields around 47–86% (Table 1, entries 2–11). However, with choline
hydroxide as a catalyst, we achieved the desired product in excellent yield (97%)
(Table 1, entry 15). To determine the optimum catalyst loading, the model reaction was
carried out with different mol % of ChOH. The reaction happened efficiently with
10 mol % of ChOH giving a single product in 97% yield (Table 1, entry 15). Increasing
the quantity of ChOH further, displayed no significant enhancement in the yield or
reaction rate.
In order to screen the effect of solvent on the reaction rate as well as yield of the
product, the model reaction was carried out using ChOH in different solvents (Table 2).
In aprotic solvents such as toluene, tetrahydrofuran, chloroform, dichloromethane, and
1,2-dichloroethane, the reaction was very slow and resulted in a lower yield of the prod-
uct (Table 2, entries 4–8). Conducting the reaction in protic solvents such as methanol

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3
Table 1. Effect of different bases on the synthesis of 1H-pyrazolo[1,2-a]pyridazine-2-carbonitriles.
Entry
Catalyst
Catalyst loading (mol %)
Reaction time (min)
Yield (%)a
1
2
3
4
5
6
7
8
Without catalyst
KOH
–
100
15
15
15
20
20
20
40
50
55
60
40
30
20
10
10
18
86
84
78
82
74
69
61
59
52
47
61
70
81
97
98
10
10
10
10
10
10
10
10
10
10
04
06
08
10
12
NaOH
(CH3)4NþOHꢁ
Cs2CO3
K2CO3
Na2CO3
DBU
Piperidine
Et3N
Pyridine
ChOH
ChOH
ChOH
ChOH
ChOH
9
10
11
12
13
14
15
16
aIsolated yields.
Reaction conditions: Reaction of 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione (1 mmol), 4-nitrobenzaldehyde (1 mmol),
and malononitrile (1 mmol) under solvent-free conditions at 80 ꢀC.
The bold values indicate the optimized parameters giving the highest yield.
Table 2. Effect of solvent and temperature on model reaction.a
Temperature
(ꢀC)
Reaction time
(min)
Isolated yield
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
Water
Methanol
Ethanol
100
65
79
84
40
61
66
111
40
60
25
20
20
30
30
30
35
45
60
40
20
10
15
67
84
81
72
69
63
60
58
51
70
81
97
97
1,2-Dichloroethane
Dichloromethane
Chloroform
Tetrahydrofuran
Toluene
Solvent-free
Solvent-free
Solvent-free
Solvent-free
Solvent-free
9
10
11
12
13
70
80
100
aReaction conditions: Reaction of 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione (1 mmol), 4-nitrobenzaldehyde (1 mmol),
malononitrile (1 mmol), solvent (5 mL), and ChOH catalyst (10 mol %).
The bold values indicate the optimized parameters giving the highest yield.
and ethanol improved both the reaction rates as well as yield of the product (Table 2,
entries 2 and 3). Comparatively low reaction rate, as well as yield of the product, is
observed in water as a solvent (Table 2, entry 1), it may be owing to less solubility of
reactants in water. Moreover, we also conducted this model reaction under a
solvent-free condition at 80 ꢀC. As shown in Table 2, entry 12, the reaction time under
solvent-free condition was shorter and the yield of the product was also higher than
under solvent conditions. The excellent yield of the product formation under solvent-
free condition could be explained by uniform dissemination of reactants, which are in
close vicinity to react with each other. To optimize the reaction temperature, the same
model reaction was studied at different temperatures. An enhanced reaction rate and
yield of the product were observed on rising the reaction temperature from 40 ꢀC to
80 ꢀC (Table 2, entries 9–12). The best conversion was achieved with 10 mol % of
ChOH at 80 ꢀC and 10 min under solvent-free condition (Table 2, entry 12). However,

4
S. N. VAJEKAR AND G. S. SHANKARLING
97
93
100
91
87
90
80
70
60
50
40
30
20
10
0
81
1
2
3
4
5
Run
Figure 1. Recyclability study of choline hydroxide.
no more increase was found in the reaction rate and yield of the product when the
reaction temperature was raised from 80 ꢀC to 100 ꢀC.
In order to demonstrate the industrial applicability of this protocol, the reaction of
4,5-diphenyl-1,2-dihydropyridazine-3,6-dione, 4-nitrobenzaldehyde, and malononitrile
catalyzed by ChOH was carried out on a larger scale (25 mmol). To our delight, the
outcomes were reproducible with 97% yield of the product as obtained in smaller scale
(1 mmol). On the same scale, the recyclability study of the catalyst was investigated
using the above model reaction. Upon the completion of the reaction (monitored using
TLC), water was added to the reaction mass; the product was isolated by filtration.
ChOH being soluble in water was recovered by evaporation of water under vacuum
from the filtrate. Recovered choline hydroxide was reused without further purification.
As depicted in Figure 1, ChOH could be reused for at least five times without any sub-
stantial loss in its activity.
FT-IR analysis
FT-IR is a powerful tool for ascertaining types of chemical bonds in a molecule by gen-
erating an infrared absorption spectrum that is like a molecular “fingerprint.” The wave-
length of light absorbed is characteristic of the chemical bond as can be seen in
Figure 2. The Fresh and recycled (after 5th run) choline hydroxide have been character-
ized by FT-IR spectroscopy. The comparative study of the fresh and recycled ChOH
proves that there is no significant change observed in the IR spectra of ChOH. The
broad absorption peak around 3297 cmꢁ1 is a characteristic of O–H stretching vibration.
The aliphatic C–H stretching vibration observed around 2959 cmꢁ1. The methyl bend-
ing vibration was observed at 1472 cmꢁ1. The band near 1357 cmꢁ1 corresponds to the
stretching vibration of the C–N bond. The band at 1081 cmꢁ1 corresponds to C–O
stretch in a primary alcoholic group. The C–H bending vibrations of –CH2– group was
observed near 947 and 877 cmꢁ1
.
Based on the current investigational observations and literature reports,[22,23] the pro-
posed reaction mechanism for the synthesis of 1H-pyrazolo[1,2-a]pyridazine-2-carboni-
triles is showed in Figure 3. The initial step involves the Knoevenagel condensation of
an aromatic aldehyde with malononitrile catalyzed by ChOH to produce an intermedi-
ate arylidenemalononitrile (vi). ChOH catalyst deprotonates the malononitrile to

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5
Figure 2. FT-IR spectra of fresh and recycled ChOH.
Figure 3. Proposed mechanism for 1H-pyrazolo[1,2-a]pyridazine-2-carbonitriles formation catalyzed by
choline hydroxide.
generate a resonance stabilized carbanion (ii). This carbanion attacks the electrophilic
carbonyl group which is already activated via hydrogen bonding with ChOH.
Subsequently, phthalhydrazide (vii) gets deprotonated by ChOH to generate an anion
(viii), which undergoes the Michael-type addition to arylidenemalononitrile (vi),

6
S. N. VAJEKAR AND G. S. SHANKARLING
followed by intramolecular cyclization and tautomerism to afford the final product 1H-
pyrazolo[1,2-a]pyridazine-2-carbonitrile (xi). The hydrogen bonding interaction of
ChOH with the nitrogen of nitrile group in (ix) is responsible for increasing electrophi-
licity of nitrile group thereby facilitating the intramolecular cyclization.
Experimental
Materials and methods
All the solvents and reagents were purchased from S D Fine-Chem Limited and used
without further purification. The progress of all reactions was monitored using alumi-
num TLC plate, silica gel coated with fluorescent indicator F254 (Merck) detecting the
1
spots by means of UV light as a visualizing agent. H NMR and 13C NMR spectra were
obtained with 500 MHz instrument (Agilent NMR spectrometer) in (CD3)2SO at ambi-
ent temperature. The chemical shifts values are stated as d value (ppm) relative to an
internal standard tetramethylsilane (Si(CH3)4 ¼ 0.00 ppm). Mass spectra (HRLC-MS)
were recorded on Model: 1290 Infinity UHPLC System, 1260 infinity Nano HPLC with
Chipcube, 6550 iFunnel Q-TOFs (Make: Agilent Technologies, USA). All synthesized
1
compounds were analyzed using HRLC-MS, H NMR, and 13C NMR spectra. Infrared
spectra were recorded on a JASCO-FT/IR 4100 LE ATR PRO450-S spectrometer.
Melting points were found out by standard melting point device procured from Sunder
Industrial Product, Mumbai and are uncorrected.
General procedure for the synthesis of choline hydroxide (ChOH)
The ChOH was prepared according to the literature.[2,4,23,33] Choline chloride
(10 mmol) and KOH (10 mmol) in methanol (15 mL) were heated at 60 ꢀC for 12 h with
constant stirring. After cooling to room temperature, the reaction mixture was filtered
to remove solid KCl and the obtained solution was concentrated under vacuum to
remove methanol. The residue was used without further purification (Scheme 1).
Synthesis of 2,3-diphenyl maleic anhydride (3)
A mixture of benzoyl formic acid 1 (5.0 g, 33 mmol), phenylacetic acid 2 (4.53 g,
33 mmol) and acetic anhydride (50 mL) was reflux at 150 ꢀC for 5 h. Later the reaction
mixture was allowed to cool and poured over ice-cubes. Subsequently the solid was fil-
tered off, washed with water, and dried. On crystallization from ethanol, 2,3-diphenyl-
maleic anhydride was obtained as pale yellow needles (6.024 g, 72.36%, mp 151–152 ꢀC,
lit.[29] mp 148 ꢀC) (Scheme 2).[30,31]
Scheme 1. Synthesis of Choline hydroxide (ChOH).

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7
Scheme 2. Preparation of 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione.
Scheme 3. One-pot three-component synthesis of 1H-pyrazolo[1,2-a]pyridazine-2-carbonitriles.
Synthesis of 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione (4)
2:1 Mixture (5.0 g) of hydrazine hydrate and water was added drop-wise to a mixture of
2,3-diphenylmaleic anhydride (2.40 g, 10 mmol) in acetic acid (10 mL). Sodium acetate
anhydrous (0.88 g, 10 mmol) was added and the reaction mixture was heated to reflux
for 2 h. After cooling, the suspension was poured into water (20 mL), and the precipitate
was filtered, delivering 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione (2.164 g, 81.97%,
mp 218 ꢀC, lit.[29] mp 216–217 ꢀC) (Scheme 2).[17,24]
General procedure for the synthesis of 1H-pyrazolo[1,2-a]pyridazine-2-
carbonitriles
In a general procedure, a mixture of 4,5-diphenyl-1,2-dihydropyridazine-3,6-dione 4
(1.0 mmol), aromatic aldehyde 5 (1.0 mmol), malononitrile 6 (1.0 mmol) and choline
hydroxide (10 mol %) was stirred at 80 ꢀC for 10 min. After completion of the reaction
(monitored using TLC), water (5 mL) was added, and the 1H-pyrazolo[1,2-a]pyridazine-
2-carbonitrile was filtered off and washed with water. It is then recrystallized from
hexane:ethyl acetate (3:1) solvent system to afford the corresponding 1H-pyrazolo[1,2-
a]pyridazine-2-carbonitrile derivative (Scheme 3; Table 3).
Characterization data for selected 1H-pyrazolo[1,2-a]pyridazine-2-
carbonitrile
7a: 3-amino-5,8-dioxo-1,6,7-triphenyl-5,8-dihydro-1H-pyrazolo[1,2-a]pyridazine-2-
carbonitrile
Yield: 81% (0.339 g, 0.8 mmol); Yellow powder; m.p. 280–282 ꢀC.

8
S. N. VAJEKAR AND G. S. SHANKARLING
Table 3. Yields of the synthesized novel 1 H-pyrazolo1,2-apyridazine-2-carbonitriles.
Entry
1
Notation
7a
Structure of product
Time (min)
15
Isolated yield (%)
81
2
7b
10
97
3
7c
10
93
4
7d
10
91
5
7e
10
89
(continued)

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SYNTHETIC COMMUNICATIONSV
9
Table 3. Continued.
Entry
6
Notation
7f
Structure of product
Time (min)
10
Isolated yield (%)
87
7
7g
20
79
8
7h
20
76
9
7i
20
74
The bold values indicate the optimized parameters giving the highest yield.
1H NMR (500 MHz, DMSO-d6) d 8.236 (2 H, s, NH2), 7.791–7.817 (4 H, m, C8’,
C12’, C14’, and C18’-H), 7.298–7.379 (9 H, m, C2’ to C6’, C9’, C11’, C15’, and C17’-H),
7.236 (2 H, t, J ¼ 7.5 Hz, C10’, and C16’-H), 6.180 (1H, s, C1-H).
13C NMR (125 MHz, DMSO-d6): d 61.23 (C1), 63.97 (C2), 116.51 (-CN), 126.97
(C4’), 127.51 (C2’ and C6’), 128.47 (C10’ and C16’), 129.02 (C3’ and C5’), 130.09 (C8’,
C12’, C14’ and C18’), 131.08 (C9’, C11’, C15’ and C17’), 136.28 (C7’ and C13’), 137.57
(C6 and C7), 139.81 (C1’), 158.12 (C3), 161.97 (C5), 164.23 (C8).
HRLC-MS m/z (ESI): Calcd for C26H19N4O2 (M þ H)þ: 419.1503, found: 419.1501

10
S. N. VAJEKAR AND G. S. SHANKARLING
Conclusion
In summary, novel 1H-pyrazolo[1,2-a]pyridazine-2-carbonitrile derivatives substituted
with electron donating or withdrawing groups were designed and synthesized by an effi-
cient, green, and sustainable one-pot three-component methodology. The biocompatibil-
ity, inexpensiveness, and recyclability of the choline hydroxide catalyst, mild reaction
conditions, operational simplicity, lower loading of catalyst, solvent-free condition, short
reaction time, high atom economy, column chromatography-free protocol, and excellent
yields make this strategy a green alternative to the existing protocols.
Full experimental details and data pertaining to the characterization of the
1
compounds 7a to 7i using H NMR, 13C MNR spectra and HRLC-MS are given in the
Supplementary information which can be seen via the “Supplementary Content” section
of this article’s webpage.
Acknowledgments
The authors cordially thank the Department of Dyestuff Technology, Institute of Chemical
Technology, Mumbai, India for 1HNMR, 13CNMR, and FT-IR analysis. The authors are also
grateful to SAIF IIT Bombay, India for HRLC-MS analysis.
Disclosure statement
All authors declare that they have no conflict of interest to disclose.
ORCID
Shailesh N. Vajekar
Ganapati S. Shankarling
http://orcid.org/0000-0003-0321-3864
http://orcid.org/0000-0002-1727-7941
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