Greener and facile synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s through a conventional heating procedure

Article abstract of DOI:10.1080/00397911.2020.1799014

A new catalytic application of tetraethylammonium L-prolinate for the facile and cleaner synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s is developed. This amino acid-based ionic liquid could be recycled up to five runs, and a neg

Full text of DOI:10.1080/00397911.2020.1799014

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Greener and facile synthesis of 4,4′-
(arylmethylene)bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s through a conventional heating
procedure
Nader Ghaffari Khaligh , Taraneh Mihankhah , Hayedeh Gorjian & Mohd
Rafie Johan
To cite this article: Nader Ghaffari Khaligh , Taraneh Mihankhah , Hayedeh Gorjian & Mohd
Rafie Johan (2020): Greener and facile synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s through a conventional heating procedure, Synthetic Communications, DOI:
10.1080/00397911.2020.1799014
To link to this article: https://doi.org/10.1080/00397911.2020.1799014
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2020.1799014
Greener and facile synthesis of 4,40-(arylmethylene)bis(3-
methyl-1-phenyl-1H-pyrazol-5-ol)s through a conventional
heating procedure
Nader Ghaffari Khaligha , Taraneh Mihankhahb , Hayedeh Gorjianc , and
Mohd Rafie Johana
aNanotechnology and Catalysis Research Centre, Institute of Postgraduate Studies, University of Malaya,
b
Kuala Lumpur, Malaysia; Environmental Research Laboratory, Department of Water and Environmental
Engineering, School of Civil Engineering, Iran University of Science and Technology, Tehran, Iran;
cDepartment of Food Science and Technology, Sari Agricultural Sciences and Natural Resources
University, Sari, Iran
ABSTRACT
ARTICLE HISTORY
Received 24 May 2020
A new catalytic application of tetraethylammonium L-prolinate for
the facile and cleaner synthesis of 4,40-(arylmethylene)bis(3-methyl-1-
phenyl-1H-pyrazol-5-ol)s is developed. This amino acid-based ionic
liquid could be recycled up to five runs, and a negligible reduction
of catalytic activity was detected within the experimental error. A
variety of substituted 4,40-(arylmethylene)bis(3-methyl-1-phenyl-1H-
pyrazol-5-ol)s were obtained in good to high yields under eco-
friendly conditions. Tetraethylammonium L-prolinate is easy to pre-
pare, as well as it shows moderate thermal stability and good solu-
bility in water. This work revealed that this amino acid-based ionic
liquid, containing L-prolinate anion, can catalyze the tandem
Knoevenagel-Michael condensation reaction due to hydrogen bond
donor and Lewis base moieties. The current methodology has other
advantages, including (a) wide substrate-scope, (b) relatively short
reaction times, (c) the use of a nontoxic, biocompatible, biodegrad-
able and metal-free ionic liquid, and (d) simple workup procedure.
KEYWORDS
Ionic liquid; heterocycles;
one-pot synthesis; multi-
component reaction;
waste prevention
GRAPHICAL ABSTRACT
CONTACT Nader Khaligh
ngkhaligh@gmail.com; ngkhaligh@um.edu.my
Nanotechnology and Catalysis Research
Centre, Institute of Postgraduate Studies, University of Malaya, Kuala Lumpur, Malaysia
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

2
N. G. KHALIGH ET AL.
Introduction
Bis(pyrazolyl)methanes have been widely investigated due to their broad spectrum of
biological activities, such as antimicrobial,[1] selective COX-2 inhibitors,[2] antiviral,[3]
antitumor,[4] antioxidant,[5] antibacterial,[6] anti-microbial and insecticides.[7]
Bis(pyrazolyl)methane copper complexes have been used as catalysts for Sonogashira
couplings.[8] Their derivatives have been applied as chelating and extracting agents for
various metal ions.[9,10]
These scaffolds have been prepared through pseudo-three or five-component
reactions. The catalyst-free methods for the preparation of 4,40-(arylmethylene)bis(1H-
pyrazol-5-ol)s have been reported through condensation of aldehydes and 3-methyl-1-
phenyl-2-pyrazolin-5-one.[11–13] Each of them had some drawbacks, for example, high
temperature (120 ꢀC),[11] reflux in ethanol,[12] or at 90 ꢀC in ethylene glycol.[13]
Although various catalysts and methods have been reported for the preparation of these
valuable compounds through pseudo-five-component reaction,[5,14–19] they have certain
advantages and some limitations/drawbacks.
Amino acid-based ionic liquids (AAILs) have received increasing attention in a var-
iety of fields, including catalysis, separation and extraction, cellulose dissolution, CO2
capture, and chemical transformations. They are superior to the conventional ionic
liquids and organic solvents due to their unique properties such as nontoxicity, low vis-
cosity, biodegradability, biocompatibility, and low cost of their production.[20] L-proline
and L-prolinates including metal complexes of L-prolinate, ionic liquids and supported-
catalysts containing L-prolinate anion have been employed as a catalyst in organic reac-
tions; for example, one-pot synthesis of pyrano[2,3-d] pyrimidinones,[21,22] enantioselec-
tive a-amination of aldehydes,[23,24] desymmetric aldolization,[25] asymmetric Michael
reactions,[26] pseudo-three component synthesis of 4,40-(arylmethylene)-bis-(1H-pyrazol-
5-ol)s.[27]
In continuing of our interest to perform organic reactions in cleaner and greener
conditions,[28–32] herein, the catalytic activity of tetraethylammonium L-prolinate
([N2222][pro]) is investigated for the one-pot synthesis of a series of 4,40-(arylmethyle-
ne)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s through pseudo-five-component reaction.
Results and discussion
One-pot pseudo-five-component synthesis of bis(pyrazolyl)methane derivatives
using tetraethylammonium L-prolinate
Tetraethylammonium L-prolinate was fabricated according to a modified method from
the literature.[33] The reaction involved neutralization of commercially available tetrae-
thylammonium hydroxide (TEAOH) (ꢁ40 wt. % in H2O) and L-proline (Scheme 1).
The tetraethylammonium L-prolinate [N2222][Pro] was isolated as an orange low viscous
liquid in 88% yield.
The one-pot pseudo-five-component reaction of 4-chlorobenzaldehyde (1a), ethyl ace-
toacetate, and phenylhydrazine was investigated as the model reactants to find the opti-
mal reaction conditions. Initially, a ratio of 1:2:2 equivalents of the model reactants per
1.0 mmol of 1a were stirred together in water as a green solvent at room and reflux

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SYNTHETIC COMMUNICATIONSV
3
O
O
N
+
+
N
OH
H2O
H2O, reflux, 3 days
N
O
N
OH
H
H
Scheme 1. Preparation of tetraethylammonium L-prolinate.
Table 1. Optimization of different parameters including [N2222][Pro] loading, temperature, stirring
time for the model reaction.a
Entry
Amount of [N2222][Pro] (mol%)
Solvent
Condition
Time (min)
Crude yield (%)b
1
2
3
4
5
6
7
8
–
–
10
10
10
8
10
10
10
10
H2O
H2O
H2O
H2O
r.t.
reflux
r.t.
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
60
60
60
60
60
60
50
40
30
60
–
A few spots
28
69
94
63
94
86
65
38
EtOH (ꢁ96%)
EtOH (ꢁ96%)
EtOH (~96%)
EtOH (ꢁ96%)
EtOH (ꢁ96%)
EtOH (ꢁ96%)
9
10
aReaction conditions: 4-chlorobenzaldehyde (72.5 mg, ꢁ0.5 mmol), ethyl acetoacetate (0.13 mL, 1.0 mmol), phenyl hydra-
bYields after trituration of the reaction mixture in water and before recrystallization from ethanol.
zine (0.10 mL, 1.0 mmol), solvent (1.0 mL).
temperature for 60 min under catalyst-free conditions (Table 1, entries 1 and 2). A few
spots, including a large amount of the unreacted aldehyde (1a), were detected on the
TLC at reflux condition. The yield of 2a was significantly increased by the addition of
[N2222][Pro] at reflux conditions (Table 1, entries 3 and 4). In the next experiment, we
conducted the model reaction in ethanol (ꢁ96%) as a green solvent, where the yield of
2a was improved (Table 1, entry 5). This fact can be attributed to the limited solubility
of 4-chlorobenzaldehyde in the water at room temperature and the refluxing water. The
difference in yield was meaningful when 8 mol% of [N2222][Pro] was used (Table 1,
entry 6). No significant drop in yield was observed by reducing the reaction time to 50
and 40 min (Table 1, entries 7 and 8). The yield of 2a decreased to 65% when the reac-
tion time was shortened to 30 min (Table 1, entry 9). These results show that this
multi-component reaction can be promoted in the presence of a catalyst in appropriate
solvent and temperature. Interestingly, the stirring of model reactants and [N2222][Pro]
in ethanol (ꢁ96%) at room temperature gave 2a in 38% yield after 60 min (Table 1,
entry 10).
Therefore, the scope and generality of the current protocol were investigated based
on the entry 7 in Table 1 as the optimized reaction conditions (Scheme 2).
Various benzaldehydes afforded the corresponding 4,40-(arylmethylene)bis(3-methyl-
1-phenyl-1H-pyrazol-5-ol)s in high yields under optimized reaction conditions (Table
2). As one can see in Table 2, the bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s were
obtained in high yields from the corresponding aldehydes bearing electron-donating
and electron-withdrawing substituents under optimal conditions. Also, a hetero-aryl
aldehyde viz. thiophene-2-carboxaldehyde and 2-furaldehyde, sensitive to acid medium,
gave the desired products in high yield by the current protocol. The results in Table 2
showed that the effect of nature and position of substituents in the yields and rates are
negligible within errors in experimental measurements. In general, the ortho-substituted
benzaldehydes gave lower yields, probably due to steric hindrance. Also, the reaction of

4
N. G. KHALIGH ET AL.
Ar
H3C
CH3
O
O
N
N
N
N
O
OEt
CH3
[N2222][Pro] (12 mg, 10 mol%)
OH HO
H
N
+
+
H
Ar
EtOH (96%), reflux, 50-65 min
NH2
X
X
X
1.0 mmol
0.5 mmol
1.0 mmol
Isolated yield 74-86%
1(a-p)
2(a-p)
X = H or Cl
Scheme 2. Synthesis of 4,40-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s under optimized
reaction conditions.
Table 2. The one-pot pseudo-five-component synthesis of bis(pyrazolyl)methane derivatives in the
presence of [N2222][Pro] under optimized reaction conditions.a
Bis(pyrazolyl)methanes
Reaction
time (min)
Isolated
yield (%)
Entry
Aldehydes 1(a-p)
X
2(a–p)
TON
TOF (minꢂ1
)
1
2
3
4
5
6
7
8
4-Cl–C6H4–CHO
4-CH3–C6H4–CHO
4-Br–C6H4–CHO
2-Br–C6H4–CHO
4-NO2–C6H4–CHO
2-NO2–C6H4–CHO
4-(CH3O)–C6H4–CHO
2-(CH3O)–C6H4–CHO
Thiophene-2-carboxalde
2-Furaldehyde
4-(HO)–C6H4–CHO
(CH2)5CH–CHO
4-Cl–C6H4–
4-CH3–C6H4–
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
50
55
50
60
50
65
55
65
65
60
65
60
55
60
55
65
85
85
82
77
83
80
82
81
78
78
74
77
86
83
84
82
8.33
8.33
8.04
7.55
8.14
7.84
8.04
7.94
7.65
7.65
7.25
7.55
8.43
8.14
8.24
8.04
0.17
0.15
0.16
0.13
0.16
0.12
0.15
0.12
0.12
0.13
0.11
0.13
0.15
0.14
0.15
0.12
9
10
11
12
11
12
13
14
4-Br–C6H4–
4-(CH3O)–C6H4–
aMethod A: aldehyde (0.5 mmol), ethyl acetoacetate (0.13 mL, ꢁ1.0 mmol), phenyl hydrazine (0.102 mL, ꢁ1.0 mmol) or
4-chlorophenyl hydrazine (142 mg, ꢁ1.0 mmol), [N2222][Pro] (12 mg, 0.051 mmol, 10 mol%), ethanol (1.0 mL), reflux.
cyclohexane carboxaldehyde with ethyl acetoacetate and phenyl hydrazine under optimal
conditions gave the corresponding product in 77% yield.
1
The known products were approved by comparing their melting point and H NMR
with authentic reports in the literature.[5,13–15,18,34] New products were characterized by
1
melting point, FTIR, H NMR and 13C NMR, Mass, and elemental analysis.
Two control experiments were also performed with the model reactants using
10 mol% of tetraethylammonium hydroxide and L-proline under optimized reaction
conditions, which afforded the desired product in 21% and 48% yields together with
unreacted reactants and by-products, respectively. Although the L-proline can be inter-
changed under appropriate conditions, [N2222][Pro] is preferred regarding high yield at
the same conditions.
The above results demonstrated the catalytic efficiency of [N2222][Pro] for the prepar-
ation of bis(pyrazolyl)methanes through a pseudo-five-component condensation by a
tandem Knoevenagel–Michael condensation reaction.
A schematic plausible reaction mechanism is illustrated in Scheme 3. The L-prolinate
can act simultaneously as a hydrogen bond donor and a Lewis base through the

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SYNTHETIC COMMUNICATIONSV
5
H C
3
O
EtO
H C
3
H
Et
O
N
N
N
N
N
H C
3
N
OH
H
O
O
H
H O
2
H
H
H
O
O
N
O
N
(I)
O
H C
3
H C
3
Ar
N
N
O
Ar
Ar
H C
3
CH
3
H C
3
CH
3
H C
3
Ar
H
N
N
H
N
N
N
N
N
N
N
N
H
N
N
O
O
H
N
H
H
OH
O
OH HO
O
O
H O
2
H
N
O
O
O
(II)
Scheme 3. A schematic reaction mechanism of the synthesis of bis(pyrazolyl)methanes through a
pseudo-five component condensation reaction in the presence of tetraehylammonium L-prolinate.
O
N
O
CH3
H3C
H3C
H
O
H
H3C
N
H2C CH2
+
+
N
N
OH
H
CH3
CH3
Scheme 4. Hofmann elimination reaction.
secondary amine and carboxylate groups, respectively, to activate the phenylhydrazine
and ethyl acetoacetate. A nucleophilic attack of phenylhydrazine to the activated ethyl
acetoacetate forms the intermediate (I), followed by dehydration, which gives the
Knoevenagel product, namely 3-methyl-l-phenyl-5-pyrazolone. The L-prolinate also
activates the carbonyl group of aldehyde for the Michael addition of the Knoevenagel
product, which affords the intermediate (II). Finally, the second molecule of 3-methyl-l-
phenyl-5-pyrazolone is added to intermediate II to give bis(pyrazolyl)methanes.
Although tetrabutylammonium L-prolinate failed the biodegradability closed bottle
test, it displayed slightly better biodegradability than the commercially available tetrabu-
tylammonium bromide or hydroxide.[33] We supposed that tetraethylammonium cation
could be decomposed in medium basic of [N2222][Pro] through Hofmann elimination.
This decomposition mechanism is shown in Scheme 4. Our group is working on the
investigation of this mechanism and reverse reaction, namely treatment of a mixture of
triethylamine and ethylene with L-proline at high temperature.
A scale-up experiment was also conducted for the model reaction through conven-
tional heating. A bottom round flask contains 20 mL ethanol (ꢁ96%) was charged with
7.2 g of 4-chlorobenzaldehyde, 10.2 mL of phenylhydrazine, 13.0 mL of ethyl acetoace-
tate, and 1.2 g of [N2222][Pro] (ꢁ10 mol%). The mixture was heated and stirred under
reflux conditions. After one hour, the mixture was concentrated by a rotary evaporator
under a vacuum, and the white solid was filtered on a Bu€chner funnel, which was
washed three times with 5 mL of deionized water. The purified product was obtained by
recrystallization from the hot ethanol (20 mL), which gave 18.84 g of 2a (ꢁ80%). After

6
N. G. KHALIGH ET AL.
removal of solvent from the filtrate, the recovered [N2222][Pro] was reused for the
mmole-scale reactions.
Easy separation and recyclability of [N2222][pro]
The separation of [N2222][Pro] and the crude products was conducted through the trit-
uration of the reaction mixture in water and subsequent filtration. The [N2222][Pro]
could be recovered through the solvent removing by rotary evaporator under a vacuum.
The recycling results demonstrated that the recovered [N2222][Pro] could be employed
for five subsequent runs, which gave 2a in the range of 85–80% isolated yield. Although
a 0.6 0.1 wt. % loss of [N2222][Pro] was detected during five runs of recovering process,
1H NMR analysis of retrieved [N2222][Pro] showed no detectable changes in the chem-
ical structure of [N2222][Pro] after the 5th run. The leaching of amino acid-based ionic
liquid into the product was also investigated by LC-MS analysis of 2a, which showed no
amount of [N2222][Pro] after each run.
Table 3 shows our results in comparison with some previous reports in the literature.
The reported methods have their merits and limitations, and numerous of them were
not employed for organic reactions. Some limitations of the previous reports can be
exemplified as the use of expensive chemicals and hazardous solvents and reagents to
prepare the catalysts along with tedious and multi-steps with multiple washes, which are
very time-consuming. These catalysts often required an activation step (Table 3, entries
2,4, and 7). Some of the catalysts could not be retrieved and reused (Table 3, entries 1
and 6). Some of the methods were applied for a limited range of substrates and required
long reaction times (Table 3, entries 1 and 6), or use a corrosive and hazardous strong
acid as well as volatile, and flammable liquid to the preparation of catalyst (Table 3,
entry 5).
Experiment
Synthetic procedure for tetraethylammonium L-prolinate
A mixture of L-proline (6.27 g, ꢁ55 mmol) and an aqueous solution of tetraethylammo-
nium hydroxide (TEAOH) (ꢁ40 wt. %, 18.41 g, ꢁ50 mmol) was stirred at refluxing con-
ditions for three days. The water was removed at 60 ꢀC under vacuum within 24 h.
Then, ethanol absolute (40 mL) was added to the crude product, and the unreacted L-
proline was separated by filtration. The 10.75 g of pure tetraethylammonium L-prolinate
was obtained as an orange low viscous liquid after removing of solvent by a rotary
evaporator, followed by drying at 60 ꢀC under vacuum overnight.
Tetraethylammonium L-prolinate ([N2222][pro]):[33]
1
Orange low viscous liquid; 10.75 g (Isolated yield 88%); H NMR (400 MHz, DMSO-d6)
d 3.45 (dd, J ¼ 12.1 and 7.2 Hz 1H), 3.12–3.09 (m, 1H), 3.21 (q, J ¼ 7.3 Hz, 8H),
2.99–2.74 (m, 1H), 2.17–2.03 (m, 1H), 1.72–1.61 (m, 3H), 1.14 (t, J ¼ 7.3 Hz, 12H) ppm;
13C NMR (100 MHz, DMSO-d6) d 180.3, 61.7, 52.1, 46.2, 30.8, 25.2, 6.9 ppm.

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7

8
N. G. KHALIGH ET AL.
Typical procedure for the synthesis of bis(pyrazolyl)methanes in the presence
of [N2222][pro]
A mixture of 4-chlorobenzaldehyde (72.46 mg, 0.5 mmol), ethyl acetoacetate (130 mg,
0.126 mL, 1.0 mmol), 4-chlorophenyl hydrazine (142 mg, ꢁ1.0 mmol), and [N2222][pro]
(12 mg, 0.051 mmol, 10 mol%) were stirred in the refluxing ethanol. After completion of
the reaction (monitored by TLC), the solvent was evaporated under vacuum by a rotary
evaporator, and the deionized water (2 mL) was added to the reaction mixture. The sus-
pension was stirred for 10 min, and ionic liquid was separated from the desired prod-
ucts by simple filtration. The catalyst was recovered after removing the solvent in
reduced pressure by a rotary evaporator. The pure products were obtained by recrystal-
lized from ethanol as a white solid in 86% yield (0.23 g).
4,40-((4-Chlorophenyl)methylene)bis(1-(4-chlorophenyl)-3-methyl-1H-pyrazol-5-
ol) (2k)
White solid, m.p. 202–203 ꢀC; ꢀmax (neat) 3432, 2891, 1601, 1490, 1305, 1078, 1014,
882, 716 cmꢂ1
;
1H NMR (400 MHz, DMSO-d6) d 7.72 (d, J ¼ 9.1 Hz, 4H), 7.66 (d,
J ¼ 9.1 Hz, 4H), 7.35 (d, J ¼ 8.6 Hz, 2H), 7.27 (d, J ¼ 8.4 Hz, 2H), 5.07 (s, 1H), 2.40 (s,
6H) ppm; 13C NMR (100 MHz, DMSO-d6) d 157.9, 157.8, 145.1, 135.2, 132.9, 131.8,
127.9, 123.7, 119.0, 113.7, 107.4, 34.6, 11.3 ppm; MS (ESþ, m/z): calcd for
[C27H21Cl3N4O2 þ Na]þ: 561.0628; found: 561.0625; Anal. Calcd for C27H21Cl3N4O2: C,
60.07; H, 3.92; N, 10.38%. Found: C, 60.05; H, 3.95; N, 10.41%.
Conclusion
In conclusion, the tetraethylammonium L-prolinate was used to catalyze a one-pot pseudo-
five-component condensation reaction under cost- and energy-effective conditions. The
catalytic efficiency of tetraethylammonium L-prolinate as a recyclable amino acid-based
ionic liquid was approved for the synthesis of a series of bis(pyrazolyl)methanes through
the conventional heating in the refluxing ethanol. The current protocol has advantages
such as using a green solvent, high yields and short reaction times, easy workup to separate
the product and catalyst followed by simple purification of products and recovering of cata-
lyst, low loading of catalyst, minimize generation of hazardous and corrosive waste. Also,
the commercial availability of chemicals and simple reaction for the fabrication of catalyst
along with its high recyclability make it an attractive catalyst for organic chemistry.
Full experimental detail along with physical and spectra data of tetraethylammonium
1
1
L-prolinate and new compounds 2(k–n), H NMR of known compounds, and H NMR
and 13C NMR copies of 2k–2n can be found via the “Supplementary Content” section
of this article’s webpage.
Acknowledgments
The authors are grateful to staff members in the Nanotechnology & Catalysis Research Center,
the University of Malaya and Sari Agricultural Sciences and Natural Resources University for
partial support of this work.

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9
Disclosure statement
There are no conflicts of interest to declare.
Funding
This work was supported by a Research Grant [NANOCAT RU001-2019] for Scientific Research
from the University of Malaya, Malaysia.
ORCID
Nader Ghaffari Khaligh
Taraneh Mihankhah
http://orcid.org/0000-0001-9585-9253
http://orcid.org/0000-0003-3104-5220
Hayedeh Gorjian
Mohd Rafie Johan
http://orcid.org/0000-0001-8932-5829
http://orcid.org/0000-0003-1133-9977
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