A Facile and Solvent-Free Silica-Supported Route for the Preparation of Pyrazolium Salts and Its Catalytic Responses

Article abstract of DOI:10.1002/jhet.2885

Synthesis of di/trimeric substituted pyrazolium salts was carried out under a conventional/solvent-free silica-supported muffle furnace method. The solid phase method observed remarkable response compared with the conventional method for the preparation of pyrazolium salts. Di/trimeric substituted pyrazolium salts acted as a very good catalyst for benzilic acid preparation while compared with existing literatures.

Full text of DOI:10.1002/jhet.2885

Month 2017
A Facile and Solvent-Free Silica-Supported Route for the Preparation of
Pyrazolium Salts and Its Catalytic Responses
*
Tamilarasan Ramalingam and Ganesan Kilivelu
PG and Research Department of Chemistry, Presidency College (Autonomous), Chennai, India
*
E-mail: kiliveluganesan@yahoo.co.in
Additional Supporting Information may be found in the online version of this article.
Received September 2, 2016
DOI 10.1002/jhet.2885
Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of di/trimeric substituted pyrazolium salts was carried out under a conventional/solvent-free
silica-supported muffle furnace method. The solid phase method observed remarkable response compared
with the conventional method for the preparation of pyrazolium salts. Di/trimeric substituted pyrazolium
salts acted as a very good catalyst for benzilic acid preparation while compared with existing literatures.
J. Heterocyclic Chem., 00, 00 (2017).
INTRODUCTION
functionalized imidazolium salts, which are used as
catalyst for Heck reaction [16].
Ionic liquids (ILs) have several interesting applications
in the area of greener synthesis [1] because they are
nontoxic, have better catalytic behaviors, and are
environmental friendly in organic reaction medium. They
also acted as better Lewis acid [2]. The properties of
imidazolium/pyridinium salt varied with different counter
anions, which can enhance or suppress the catalytic
activities [3]. Pyrazole and its derivatives have emerged
to play an important role among the other heterocyclic
compounds due to their medicinal aspects like anticancer
[4], analgesic [5], antiviral [6], antimicrobial [7],
antipyretic [8], anti-anxiety [9], and anti-inflammatory
behaviors [10]. Some of the reports proved that adding
other materials like nitrogen containing ligands [11] and
phosphane [12] to imidazolium [13] and pyrazolium/
pyridinium [14] can give more stability to the compound,
which is a recyclable catalytic moiety. Shirin et al.
reported regioselective synthesis of pyrazole derivatives
under mild condition using interesting Bronsted acidic
type of ILs [15]. Wang and coworkers reported solvent-
free method for the preparation of pyrazolyl
Mesomorphic material based on long flexible alkyl
chain with substituted pyrazolium salts showed different
physical behaviors based on counter anions [17]. Diaryl
glycolic acid (DAGA) and its derivatives are very
important because of their medicinal application. They
have good analgesic properties and also used as precursor
for the production of nonsteroidal anti-inflammatory
medicines [18] and preparation of pharmacological drugs
like antispasmodic, antidepressant, and anticholinergic
drugs [19]. The DAGA is a potential precursor due to its
bifunctional optically active chiral carbon and some
photophysical behavior [20].
Herein, we wish to report the synthesis of flexible
di/trimeric pyrazolium salts under conventional/solvent-
free silica-supported conditions as well as its catalytic
behaviors. We have examined one-pot preparation of
DAGA with optimized concentration of our synthesized
pyrazolium salts under conventional/solid phase method.
To the best of our knowledge with available literature,
the preparation of DAGA with our catalyst and method is
much more effective.
© 2017 Wiley Periodicals, Inc.

T. Ramalingam and G. Kilivelu
Vol 000
RESULTS AND DISCUSSION
prepared the DAGA with nontoxic catalyst under
ordinary condition with shorter reaction time (Scheme 2).
Preparation of DAGA with optimized concentration of
pyrazolium catalyst at ambient reaction condition
(0.0000694 mmol) showed excellent performance, and
results are summarized in (Tables 1–3).
Hence, silica-supported muffle furnace reactions are
nearly 40 times faster than the conventional method.
Substituted di/trimeric pyrazolium bromide 1a/2a/3a is
dissolved in minimum amount of water and calculated
amount of inorganic salts like NaBF4/K4PF6/LiCF3SO3 at
room temperature with stirring for about 1 h to afford
N-alkylation reaction between substituted pyrazole with
various dibromides under refluxing condition in the
presence of 20 mL of 1:1 ratio of dry CH3CN:MeOH
solvents was carried out for about 19–28 h to afford the
pyrazolium bromide 1a/2a/3a in 82–85% yield. To
reduce the toxicity, reaction time, we examined the same
reaction with solvent-free silica-supported muffle furnace
condition at 100°C. These reactions are completed within
30–90 min with 90–92% yield (Scheme 1).
CATALYTIC ACTIVITY
Scheme 2. One-pot synthesis of diaryl glycolic acid from different routes.
[Color figure can be viewed at wileyonlinelibrary.com]
More numbers of reports are available in the literature
for the preparation of DAGA by using different catalytic
conditions. Yongjun et al. reported the preparation of
benzion from benzophenone using Sm/TMSCl as a
catalyst which is very expensive for 10 h at 90°C to
afford benzion [21]. DAGAs were prepared from various
aryl aldehydes in the presence of 20 mol% of [Bmim]
BF4 along with KOH at 70°C for 3–4 h to afford poor
yield [15]. Craig and coworkers examined the benzil-
benzilic acid rearrangement under very high temperature
(300–380°C) [22]. So, based on the literature, we
Scheme 1. Synthesis of flexible di/trimeric pyrazolium salts under conventional/muffle furnace route. [Color figure can be viewed at wileyonlinelibrary.
com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2017
Solid Phase Synthesis of Pyrazolium Salt
Table 1
One-pot preparation of DAGA with low concentration of flexible dimeric pyrazolium salts 1(a–d).
Concentration of flexible pyrazolium salts
0.0000361 mmol
0.0000722 mmol
0.000108 mmol
DAGA
S. no
Catalyst
derivative
Time (h:m) Yield (%) Time (h:m)
Yield (%) Time (h:m) Yield (%)
1
2
3
4
Dimeric pyrazolium
cation with
BrÀ 1a
PFÀ6 1b
BFÀ4 1c
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
4a
2.15
1.30
1.45
1.55
2.25
1.45
2.00
2.10
2.35
1.40
1.55
2.05
2.40
81
90
88
85
78
88
86
83
75
84
83
80
73
2.05
1.10
1.35
1.40
2.20
1.30
1.45
1.55
2.25
1.20
1.40
1.30
2.30
82
87
87
85
80
83
85
83
79
86
80
78
78
1.50
0.50
1.05
1.15
2.05
1.05
1.35
1.35
1.55
0.55
1.40
1.30
2.15
90
97
95
94
88
95
90
90
89
90
89
89
84
CF3SO3
À 1d
4b
4c
4d
1.55
2.10
2.15
80
80
78
1.40
1.55
2.05
82
79
80
1.15
1.55
1.45
89
87
87
Table 2
One-pot preparation of DAGA with low concentration of m-xylene bridged dimeric pyrazolium salts 2(a–d).
Concentration of m-xylene linked dimeric pyrazolium salts
0.0000332 mmol
Time (h:m) Yield (%)
0.0000332 mmol
Time (h:m) Yield (%)
1.45 87
0.0000332 mmol
Time (h:m) Yield (%)
1.30 89
DAGA
derivative
S. no
1
Catalyst
Dimeric pyrazolium BrÀ 2a
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
1.55
1.05
1.25
1.45
2.10
1.20
1.40
2.00
2.05
1.15
1.35
1.55
2.20
1.30
1.55
2.05
81
88
79
81
79
85
75
80
73
81
73
75
73
80
71
73
cation with
0.55
1.15
1.25
2.00
1.10
1.25
1.45
1.55
1.05
1.20
1.35
1.45
1.20
1.35
1.55
92
85
87
85
90
86
86
83
89
84
84
81
87
83
83
0.40
0.55
1.05
1.45
0.55
1.10
1.15
1.40
0.45
1.00
1.10
1.55
1.05
1.20
1.25
95
95
91
89
96
80
89
87
93
89
88
85
90
90
88
2
3
4
PFÀ6 2b
BFÀ4 2c
CF3SOÀ3 2d
anion exchanged products of 1–3 (b–d) in 94–98% yield.
All our synthesized compounds are characterized using
spectral and analytical data.
We examined one-pot preparation of benzilic acid from
different aldehydes in the presence of alkaline condition
with very low concentration of our di/trimeric pyrazolium
salt 1–2 (a-d) at ambient reaction condition for about
25–75 min to give 80–97% yield (Table 3). The results
are summarized in Tables 1–3. Trimeric pyrazolium salts
3 (a–d) showed excellent catalytic behaviors than the
dimeric derivatives. We have used different counter
anions containing pyrazolium salts such as BrÀ/BF4À/PF6À/
CF3SOÀ3 containing trimeric pyrazolium salts and studied
the catalytic activities. Among these, bromide containing
trimeric pyrazolium derivatives showed excellent catalytic
behavior than the other. We concluded that the optimum
concentration of pyrazolium bromide is 0.000108 mmol
for the preparation of DAGA.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

T. Ramalingam and G. Kilivelu
Vol 000
Table 3
One-pot preparation of DAGA with different concentration of trimeric pyrazolium salts 3(a–d).
Concentration mesitylene linked substituted trimeric pyrazolium salts
0.0000231 mmol
Time (h:m) Yield (%)
0.0000463 mmol
Time (h:m) Yield (%)
1.05 72
0.0000694 mmol
Time (h:m) Yield (%)
1.05
DAGA
derivative
S. no
1
Catalyst
Trimeric pyrazolium
cation with
BrÀ 3a
PFÀ6 3b
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
4a
4b
4c
4d
1.30
0.50
1.05
1.15
1.50
1.00
1.15
1.30
1.45
0.55
1.10
1.30
2.00
1.15
1.25
1.45
72
87
84
79
70
85
80
76
69
83
79
75
68
81
78
71
85
97
93
92
83
95
92
90
81
94
91
88
80
93
89
87
0.35
0.55
1.00
1.25
0.50
1.05
1.15
1.15
0.45
1.00
1.10
1.45
1.00
1.15
1.25
90
89
87
70
89
85
86
69
88
84
82
68
85
83
81
0.25
0.45
0.50
1.25
0.40
0.55
1.00
1.15
0.35
0.50
1.05
1.45
0.50
1.00
1.10
2
3
4
BFÀ4 3c
CF3SOÀ3 3d
CONCLUSION
30–90 min to afford desired products of compound 1a/2a/
3a in quantitative yield.
We have prepared di/trimeric pyrazolium salts under
conventional/silica-supported muffle furnace condition.
The muffle furnace method is nearly 50 times faster than
the conventional method. Catalytic activity studies of our
synthesized di/trimeric pyrazolium salts are carried out
with different concentrations in DAGA preparation. We
observed that trimeric pyrazolium salt acted as an
excellent catalytic behavior than the dimeric salts due to
three active sites. So, even in very low concentration, it
showed potential catalytic activity. Among these, bromide
containing salt showed excellent activity than the others.
General procedure for anion exchange reaction.
Di/
trimeric substituted pyrazolium bromide 1a/2a/3a
(0.001407 mmol; 1.0 equiv.) is mixed with required
equivalent of different counter ions containing inorganic
salts such as NaBF4/K4PF6/LiCF3SO3 in the presence of
15 mL of water at ambient condition for 2 h followed by
Soxhlet extraction with dry THF for 2 h to give metal
bromide free anion exchanged product of di/trimeric
substituted pyrazolium cation with different counter
anions 1–3(b-d) in 89–94% yield.
General procedure for preparation of diaryl glycolic
acid. Simple/substituted aryl aldehyde (0.001323 mmol;
1.0 equiv.) is mixed with NaOH (0.001389 mmol; 1.0
equiv.), and optimized concentration of di/trimeric
pyrazolium salt (0.000108 mmol) is added in the presence
of 20 mL of dry CH3CN at room temperature with stirring
for about 25 min–1.15 h to afford DAGA in quantitative yield.
EXPERIMENTAL
General procedure for the preparation of pyrazolium
bromide.
Ethyl-5-amino-1-methylpyrazole-3-carboxylate
(0.01359 mmol; 2.05 equiv.) is treated with
1,5-dibromopentane/m-xylene dibromide (0.00568 mmol;
1.0 equiv.)/1,3,5-tris(bromomethyl)-2,4,6-trimethylbenzene
(0.005013 mmol; 3.03 equiv.) in the presence of 20 mL of
1:1 ratio of dry CH3CN:MeOH under refluxing condition for
19–23 h. to afford the desired compounds 1a/2a/3a in
82–88% yield.
Acknowledgments. R.T. thanks C. Manikandan and P.
Ganapathi, Senior research scholar, Department of Chemistry,
Presidency College, Chennai-5 for cooperation and moral support.
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