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

Article abstract of DOI:10.1002/jhet.4113

A new catalytic application of 4,4′-trimethylenedipiperidine for the efficient synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s is developed. According to the principles of green chemistry, the reaction was performed by conventiona

Full text of DOI:10.1002/jhet.4113

Greener and practical synthesis of ‎4,4′-(arylmethylene)bis(3-
methyl-1-phenyl-1H-pyrazol-5-ol)s through a conventional
heating and a mechanochemical procedure
Nader Ghaffari Khaligh*1, Taraneh Mihankhah2
1Nanotechnology and Catalysis Research Center, Institute of Postgraduate Studies,
University of Malaya, 50603 Kuala ‎Lumpur, Malaysia Address
2Environmental Research Laboratory, Department of Water and Environmental Engineering,
School of Civil Engineering, Iran U‎ niversity of Science and Technology, 16765-163, Tehran,
Iran
*Corresponding author, e-mail: ngkhaligh@gmail.com and also ngkhaligh@um.edu.my
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2
Abstract
A new catalytic application of 4,4'-trimethylenedipiperidine‎for the efficient synthesis of
4‎,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s is developed. According to the
principles of green chemistry, the reaction was performed by conventional and non-
conventional processes: a) in the refluxing ethanol using a catalytic amount of organocatalyst
b) at room temperature in the presence of organocatalyst in a planetary ball mill under
solvent-free conditions. The organocatalyst could be reused up to ten runs, and a negligible
reduction of catalytic activity was detected.
A
variety of substituted 4‎,4′-
(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s were obtained in good to excellent
yields under eco-friendly conditions. 4,4'-Trimethylenedipiperidine is commercially available
and easy to handle and storage, less toxic, non-flammable, as well as it shows high thermal
stability and good solubility in water. The current methodology has merits include a) wide
substrate-scope and high yields of the desired products in the short reaction times, b) avoid
the use of hazardous solvents and acidic and metal-containing catalysts, c) minimize the
generation of hazardous waste, and d) simple workup process. Based on great potential as a
promising organocatalyst, we hope it can be used as a greener alternative to piperidine for
other organic transformations.
Keywords: Organocatalyst; Heterocycles; One-pot synthesis; Three-component reaction;
Waste prevention
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3
Introduction
Bis(pyrazolyl)methanes have been extensively investigated due to their broad spectrum of
biological activities. They have been shown antimicrobial,[1] antiviral,[2] antitumor,[3]
antioxidant,[4] antibacterial,[5] activities and they were used as selective COX-2 inhibitors[6]
and insecticides.[7] Bis(pyrazolyl)methane copper complexes used as catalyst for Sonogashira
couplings.[8] Their derivatives have been applied as extracting or chelating agents for a variety
of metal ions.[9,10]
These scaffolds have been prepared through pseudo-three or five-component reactions.
The catalyst-free preparation of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s have been reported
through pseudo-three component condensation of aldehydes and 3-methyl-1-phenyl-2-
pyrazolin-5-one.[11-13] Although the synthesis of these valuable heterocycles has also been
reported using various catalysts and methods through pseudo-five-component reaction,[5,14-19]
numerous of the reported methods were not employed owing to their limitations/drawbacks in
practical processes.
In recent years, the unconventional processes attract more attention in academic and
industry chemical reactions. The mechanochemical processes have been applied in a variety
of fields, including organic,[20] inorganic,[21] material and nanomaterial engineering,[22] and
organometallic synthesis.[23] This process has been widely applied for the greener and cleaner
synthesis of organic compounds especially heterocycles through multi-component reactions
under solvent-free conditions.[24]
Although mortar and pestle are the easiest tools to accomplish a mechanochemical reaction
in a laboratory, it is a tedious and imprecise process that often leads the unreproducible
results. More reliable and reproducible results can be achieved by a planetary ball mill can or
mixer ball mill.[25] In continuing of our application of planetary ball mill process to preform
organic reactions in cleaner and greener conditions,[26-28] and exploring the promising
properties ‎and new applications of ‎4,4'-trimethylenedipiperidine ‎ (TMDP);[29,30]‎ herein, we
encouraged to investigate the catalytic activity of TMDP‎ for the one-pot multicomponent
synthesis of a series of 4‎ ,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s via
pseudo-five-component reaction by the conventional and non-conventional methods.
Experimental
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4
Typical procedure for the synthesis of bis(pyrazolyl)methanes using TMDP in refluxing
ethanol
A mixture of aromatic aldehyde (0.5 mmol), ethyl acetoacetate (130 mg, 0.125 mL, 1.0
mmol), and phenylhydrazine (102 μL, ~1.0 mmol) or 4-chlorophenyl hydrazine (142 mg, ~1.0
mmol), and TMPD (11 mg, 0.05 mmol, 10 mol%) was stirred in the refluxing ethanol. After
50 minutes, the solvent was removed by a rotary evaporator under vacuum. Then 1.0 mL of
deionized water was added to the residue, and the suspension was stirred for 10 minutes. The
TMDP was separated from the desired product by simple filtration. The catalyst was
recovered after removing the water by a rotary evaporator. The pure products were obtained
by recrystallized from ethanol.
Typical procedure for the synthesis of bis(pyrazolyl)methanes in the presence of TMDP using
a planetary ball mill
A mixture of aromatic aldehyde (5 mmol), ethyl acetoacetate (1.30 g, 1.25 mL, 10 mmol),
and phenylhydrazine (1.02 mL, 10 mmol) or 4-chlorophenyl hydrazine (1.42 g, ~10 mmol),
and TMPD (0.11 g, 0.5 mmol, 10 mol%) were ground at room temperature in a milling jar (12
mL) at rotational frequency 10 Hz. After one hour, the water was added to the reaction
mixture, and organocatalyst was separated from the desired product by a simple filtration. The
catalyst could be recovered through the removing of solvent in reduced pressure by a rotary
evaporator. The pure products were obtained by recrystallized from ethanol.
Results and discussion
One-pot multicomponent synthesis of bis(pyrazolyl)methane derivatives in the presence of
TMDP
The one-pot pseudo-five-component condensation of 4-chlorobenzaldehyde (1a), ethyl
acetoacetate, and phenyl hydrazine was chosen as the model reaction to investigate different
parameters to optimize the reaction conditions. Initially, a ratio 1:2:2 equivalents of the model
reactants per 1.0 mmol of 1a were stirred together in the deionized water, a green solvent, at
room and reflux temperature for 60 min in the absence of catalyst (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 TMDP at
reflux condition (Table 1, entries 3 and 4). In the next experiment, we conducted the model
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5
reaction in ethanol (~96%) as green solvent, where the yield of 2a was improved probably
due to the limited solubility of 4-chlorobenzaldehyde in water (Table 1, entry 5). The
solubility of 4-chlorobenzaldehyde in water is only 935 mg L−1 at 25 °C [Chemical Book
data]. The difference in yield was negligible within the experimental error ‎wlo‎-hwt ‎ ‎ehw‎
r e t et‎r ‎ eP‎h e‎meto‎N lt‎rt‎t e j‎l)a‎(w‎ tu a lt‎o wi‎r ‎jrtlo was observed by
reducing the reaction time to 40 min (Table 1, entries 7 and 8), however, the yield of 2a
decreased to 62% within 30 min (Table 1, entry 9). These results demonstrate that this multi-
component reaction can be catalyzed in the presence of TMDP, as well as an appropriate
solvent and temperature. Interestingly, a manual mixing of model reactants and TMDP in a
bottom-round flask at room temperature gave 2a in 38% yield after 60 min (10 min intervals)
(Table 1, entry 10). The manual mixing has some significant drawbacks, including a) this
method is not safe due to the open reactor conditions, b) large scale experiments are
problematic and manual mixing for a long-time reactions is not practical, c) the results often
are not reproducible and dependence to the strength and tenacity of the operator. Furthermore,
handling and stirring of the mixture are often troublesome under solvent-free conditions, and
mixing efficiency diminished due to sticky substrates can be stuck to the wall of the flask over
the reaction duration. A way of overcoming some of the disadvantages is the use of a
planetary ball mill which gives more reproducible results and is operator independent.
TABEL 1 Optimization of different parameters including TMDP loading, reaction
temperature, stirring time for the model reactiona
Entry
Amount of TMDP/mol%
Solvent
H2O
Condition
Stirring, r.t.
Stirring, reflux
Stirring, r.t.
Stirring, reflux
Stirring, reflux
Stirring, reflux
Stirring, reflux
Stirring, reflux
Stirring, reflux
Manual mixing, r.t.
Time/min
Crude yield/%b
1
2
3
4
5
6
7
8
-
-
60
60
60
60
60
60
50
40
30
60
-
H2O
H2O
H2O
A few spots
10
10
10
20
10
10
10
10
28
69
94
95
94
86
65
38
EtOH (~96%)
EtOH (~96%)
EtOH (~96%)
EtOH (~96%)
EtOH (~96%)
Solvent-free
9
10
a
Reaction conditions: 4-chlorobenzaldehyde (72.5 mg, ~0.5 mmol), ethyl acetoacetate
(0.13 mL, 1.0 mmol), phenyl hydrazine (0.10 mL, 1.0 mmol), Solvent (1 mL).
b
Yields after trituration of the reaction mixture in water and before recrystallization from
ethanol.
The yield of 2a was enhanced to 51% when the model reaction was carried out into a
planetary ball mill for the length of time 60 (Table 2, entry 1). Then, the influence of
planetary ball mill mechanical parameters on the yield of the desired product was
investigated. The diameter and number of milling balls, rotation frequency, and milling time
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6
are crucial parameters that affect the yield of the product. It was indicated that higher rotation
frequency, milling balls with a larger diameter and higher milling ball filling degree are
advantageous for the reaction.[31] Although both friction and heat dissipation cause a raise the
reaction temperature over the course of milling, the direct control of the temperature cannot
be recorded for planetary ball milling. The results showed that the ball milling has a notable
effect on the yields, which can be due to severe mixing of the reactants, the generation a
higher surface contacts of reactants, and direct input of energy by collision and friction. The
highest yield of 2a was observed at 600 rpm with eight milling balls, diameter 10 mm, within
60 min (Table 2, entry 8).
TABLE 2 Optimization of mechanical parameters on the tandem Knoevenagel-Michael
condensation of the model reaction in a planetary ball milla
b
Entry
Rotational speed
Milling ball diameter
Milling ball number ΦMB
Time
/min
60
60
60
60
60
60
60
Crude yield
/rpm
450
450
450
500
550
600
600
600
/mm
5
5
10
10
10
10
10
10
/%c
51
54
69
76
81
85
94
78
1
2
3
4
5
6
7
8
30
50
5
5
5
5
8
8
0.092
0.153
0.122
0.122
0.122
0.122
0.196
0.196
50
a
Reaction conditions: Grinding jar 12 mL, 4-chlorobenzaldehyde (0.725 g, 5 mmol), ethyl
acetoacetate (1.3 mL, ~10 mmol), phenyl hydrazine (1.02 mL, ~10 mmol), TMDP (0.11 g, 0.5
mmol, 10 mol%)
b
Milling ball filling degree is defined as the volumetric ratio of the overall milling ball
volume to the total volume of the milling jar (Schmidt‎et al. 2015)
c
Yields after trituration of the reaction mixture in water and before recrystallization from
ethanol.
The entries 7 and 8 in Table 1 and 2, respectively, were chosen as the optimal conditions to
investigate scope and generality of the conventional and non-conventional protocols (Scheme
1).
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7
Ar
H3C
CH3
O
O
N
N
N
N
O
OEt
CH3
TMDP (0.11 g, 10 mol%)
EtOH, reflux, 50 min
OH HO
H
+
+
Ar
H
N
NH2
R
R
R
1.0 mmol
0.5 mmol
1.0 mmol
Isolated yield 77-86%
1(a-n)
2(a-n)
R = H or Cl
Conventional method
Ar
H3C
CH3
O
N
N
N
N
O
OEt
TMDP (0.11 g, 10 mol%)
Ball milling, r.t., 60 min
OH HO
H
+
+
Ar
H
N
CH3
O
NH2
R
R
R
10 mmol
5 mmol
10 mmol
Isolated yield 73-85%
1(a-n)
2(a-n)
R = H or Cl
Non-conventional method
SCHEME 1 Synthesis of 4,4′-(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s using
TMDP by conventional and non-conventional processes.
Various benzaldehydes and heteroaryl aldehydes afforded the corresponding 4,4′-
(arylmethylene)bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s in moderate to high isolated yields
under conventional and non-conventional optimized reaction conditions (Table 3).
TABLE 3 The one-pot multicomponent synthesis of bis(pyrazolyl)methane‎derivatives in the
presence of TMDP under conventional and non-conventional optimized reaction conditions
Entry
Aldehydes
1(a-j)
R
bis(pyrazolyl)methanes
2(a-j)
Melting point/°C
Isolated yield/%a
Method Ab
85
Method Bc
83
Found
Reported[Ref.]
1
4-Cl-C6H4-CHO
H
2a
169-170
171-173[13]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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
Cinnamaldehyde
(CH2)5CH-CHO
4-Cl-C6H4-
4-CH3-C6H4-
4-Br-C6H4-
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
85
82
77
83
80
82
81
78
78
73
75
86
83
84
82
85
80
74
83
78
82
79
73
74
72
72
83
81
81
76
198-199
184-185
251-252
230-231
220-221
175-176
220-221
186-187
189-190
218-219
150-151
202-203
178-179
219-220
208-209
197-199[14]
185‐186[4]
252-254[14]
228-230[14]
220-222[14]
172-174[13]
222-224[13]
189‐190[4]
188-190[32]
220-222[33]
152-154[18]
-
-
-
-
4-(CH3O)-C6H4-
a Isolated yield.
b
Method ‎A: Conventional heating, aldehyde (0.5 mmol), ethyl acetoacetate (0.13 mL, 1.0
mmol), phenyl hydrazine (0.102 mL, 1.0 mmol) or 4-chlorophenyl hydrazine (0.142 g, 1.0
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8
mmol), TMDP (11 mg, 0.05 mmol, 10 mol%), ethanol (~96%) (2 mL), reflux, reaction time
(50 min)
c Method B: Grinding jar 12 mL, aldehyde (5 mmol), ethyl acetoacetate (1.3 mL, ~10 mmol),
phenyl hydrazine (1.02 mL, ~10 mmol) or 4-chlorophenyl hydrazine (1.42 g, ~10 mmol),
TMDP (0.11 g, 0.5 mmol, 10 mol%), eight milling ball (diameter 10 mm), rotational
frequency (10 Hz), room temperature, reaction time (60 min)
As one can see in Table 3, high yields of the corresponding bis(pyrazolyl)methanes were
isolated from the benzaldehydes bearing electron-withdrawing and electron-donating
substituents under both optimal conditions. Also,
a
hetero-aryl aldehyde viz.
thiophene‐2‐carboxaldehyde 2-furaldehyde, sensitive to acid medium, gave the desired
product in high yield by the current protocols. The results in Table 2 showed that the effect of
nature and position o‎ f substituents in the yields and rates are negligible within the
experimental error. In general, the ortho-substituted benzaldehydes gave lower yields
probably due to steric hindrance. α,β-Unsaturated benzaldehyde such as cinnamaldehyde gave
the corresponding product in 73% yield and the carbon-carbon double bond remains intact in
the current method. Also, the reaction of cyclohexanecarboxaldehyde with ethyl acetoacetate
and phenyl hydrazine gave the corresponding product in 75% yield under optimal conditions.
1
The known products were approved by comparing their melting point and H NMR with
authentic reports in the literature.[4,13,14,32,33] New products were characterized by melting
point, FTIR, 1H NMR and 13C NMR, and MS analysis.
The model reaction was also carried out using 40 µL (~20 mol%) of piperidine under
optimized conventional and non-conventional conditions, and the desired product 2a was
isolated in 61% and 88% yields, respectively. Although the two organocatalysts, TMDP and
piperidine, can be interchanged under appropriate conditions, TMDP is preferred ‎regarding
high toxicity and unsafe handling/storage of piperidine.‎ Also, there is a limitation of
piperidine availability in some ‎institutions or countries due to use of piperidine as a substrate
for illegal psychotropic drugs. This fact can cause administrative problems for purchasing
piperidine.[34]
The above mentioned results demonstrate the catalytic efficiency of TMDP for the
synthesis of bis(pyrazolyl)methanes as a typical one-pot multicomponent reaction.
A schematic plausible reaction mechanism was proposed, as shown in Scheme 2.[35] The
TMDP can act simultaneously as a hydrogen bond donor and a Lewis base through the
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9
nitrogen atom of second piperidine moiety to promote the condensation of phenylhydrazine
and ethyl acetoacetate which gives 3-methyl-l-phenyl-5-pyrazolone. The TMDP also activates
the carbonyl group of aldehyde for the Knoevenagel condensation, 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.
H-bond from
TMDP
Ar
H3C
N
H3C
N
H3C
H
N
Knoevenagel
Condensation
H
O
H3C
Ar
N
N
Condensation
N
H
H
H
N
N
N
N
m
O
O
H
o
r
f
O
d
CH3
H2O
n
P
H2O
O
o
D
H
EtO
b
M
-
T
H
EtOH
O
O
H-bond from
TMDP
(I)
H-bond from
TMDP
(II)
H-bond from
TMDP
Ar
Ar
H3C
CH3
H3C
CH3
H
N
N
N
N
N
N
N
N
OH
O
OH HO
H-bond from
TMDP
SCHEME 2 A schematic reaction mechanism
A large scale trial of the model reaction was conducted through conventional heating to
investigate the practicality of the current protocol. A bottom round flask contains 20 mL of
ethanol (~96%) was charged with 7.2 g of 4-chlorobenzaldehyde, 10.2 mL of
phenylhydrazine, 13 mL of ethyl acetoacetate, and 1.1 g of TMDP (~10 mol%) ‎ wt‎uriem t‎‎a
‎ah e‎wt eto‎ o‎eer to‎m ot ‎ t lmi‎ew orerw eAfter one hour, mixture was concentrated by a
rotary evaporator under a vacuum. The residue was triturated by 5 mL of the deionized water,
and the white solid was filtered on a Büchner funnel, followed by three times washing with 5
mL of deionized water. The purified product was obtained by recrystallization from the hot
ethanol (20 mL), which gave 18.13 g of 2a (~78%). After removing of solvent from the
filtrate, the recovered TMDP was reused for the mmole-scale reactions.
Easy separation and recyclability of TMDP
The separation of TMDP and the crude products were conducted through the trituration of
the reaction mixture in water and subsequent filtration. The TMDP was recovered through the
This article is protected by copyright. All rights reserved.

10
solvent removing by rotary evaporator under a vacuum. The recycling results demonstrated
that the recovered TMDP could be employed for five subsequent runs, which gave 2a in the
range of 83-80% isolated yield. Although a 0.6 wt. % loss of TMDP was detected during five
1
runs of recovering process, H NMR analysis of retrieved TMDP showed no detectable
changes in the chemical structure of TMDP after the 5th run (see Supplementary Information,
Figure S). The leaching of TMDP into the product was also investigated by an LC-MS
analysis of 2a, which showed a negligible amount of TMDP after each run.
Table 4 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 limits/disadvantages are exemplified as the use of hazardous
solvents and reagents to fabricate the catalysts; as well as require tedious, multi-steps, long-
time duration at high temperature, and an activation step of the catalyst before catalyst reusing
(Table 4, entries 2,4, and 7). Furthermore, retrieving and reusability of some reported
catalysts were not reported (Table 4, entries 1 and 6). Some of the methods were applied for a
limited range of substrates and required long reaction times (Table 4, entries 1 and 6) or use a
corrosive and hazardous strong acid along with volatile and flammable liquid to the
fabrication of catalyst (Table 4, entry 5).
TABEL 4 A comparative table for the synthesis bis(pyrazolyl)methanes through pseudo five-
component condensation using previous reported catalysts and the current protocols
Catalyst
loadin/mol%
50
Reaction
time/min
6-7 h
Entry
Catalyst
Solvent
Temp./°C
Yiel/% [Ref.]
1
2
HOAc
MCM-41@
Pd(0)
-
-
90
80
74-83
84-95
[4]
guanidine-
0.1
10
15-30
10-80
[14]
2-Hydroxy
3
-
90
86-96
[15]
ethylammonium propionate
4
5
6
7
DCDBTSDa
10
10
50
10 mg
-
-
80
90
r.t.
80
35-100
30-45
1-4.5 h
3-25
71-85
82-97
56-93
88-98
78-85
[16]
[17]
[18]
[32]
[Et3NH][HSO4]
K2CO3
MeCN
-
EtOH (~96%)
Fe3O4@SiO2-NDISb
TMDP
Reflux
50
8
a
[Planetary ball mill (10 10
Hz)]
This work
-
r.t.
60
73-85
DCDBTSD:
N,2-dibromo-6-chloro-3,4-‎dihydro-‎2H-benzo[e][1,2,4]thiadiazine‎-7-
sulfonamide 1,1-dioxide
b
Fe3O4@SiO2-NDIS: Brønsted acidic dicationic ionic liquid immobilized on Fe3O4@SiO2
nanoparticles.
Conclusions
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11
In conclusion, the TMDP was employed to catalyze a one-pot pseudo-five-component
reaction by the conventional and non-conventional protocols. The catalytic efficiency of
TMDP as a safe and recyclable organocatalyst was approved for the preparation of a series of
4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s through a) stirring in the refluxing ethanol and b)
grinding in a planetary ball mill at room temperature under solvent-free conditions. The
current protocols has advantages such as minimize the generation of hazardous waste, facile
separation of the catalyst along with an easy purification of the product, low catalyst loading,
negligible leaching of catalyst in product or environment, a broad substrate scope, high yields
and short reaction times. The commercial availability and high recyclability of TMDP, one
molecule containing two piperidine rings and less hazardous than piperidine, make it an
attractive organocatalyst for the organic reactions. Our group is currently performing further
research to investigate promising applications of TMDP for other organic reactions.
Disclosure statement
There are no conflicts of interest to declare.
Acknowledgments
The authors are grateful to the University of Malaya and Iran University of Science and
Technology for partial support of this work.
Supplementary data
1
Full experimental detail along with H NMR of known compounds, physical and spectra
1
13
data of new compounds 2(k-n), and H NMR and C NMR copies of 2k-2n can be found in
the online version of this paper (DOI: xxxxxxxxxx).
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