A modified and practical synthetic route to indazoles and pyrazoles using tungstate sulfuric acid

Article abstract of DOI:10.1002/jccs.201400251

Tungstate sulfuric acid-catalyzed Knorr reaction have been used as a simple, rapid, atom economic and green method for the synthesis of indazole and pyrazole derivatives based on the condensation of hydrazine derivatives and ss-dicarbonyl compounds under solvent-free conditions. It was found that the catalyst could be recovered and reused without significant loss of its activity. The use of this method provides a novel and improved modification of Knorr synthesis in terms of clean reaction profile, use of a safe catalyst and solvent-free conditions. A green method for the synthesis of indazole and pyrazole derivatives from the condensation of hydrazine derivatives with dicarbonyl compounds has been described. Tungstate sulfuric acid (TSA) catalyzed efficiently the reactions to give good yields.

Full text of DOI:10.1002/jccs.201400251

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Communication
A Modified and Practical Synthetic Route to Indazoles and Pyrazoles Using Tungstate
Sulfuric Acid
S. Setareh Rahmatzadeh,a Bahador Karamia* and Saeed Khodabakhshib
aDepartment of Chemistry, Yasouj University, Yasouj, Zip Code: 75918-74831 P.O.Box 353, Iran
bNanotechnology Research Center, Research Institute of Petroleum Industry, Tehran, Iran
(Received: May 21, 2014; Accepted: Sept. 22, 2014; Published Online: ??; DOI: 10.1002/jccs.201400251)
Tungstate sulfuric acid-catalyzed Knorr reaction have been used as a simple, rapid, atom economic and
green method for the synthesis of indazole and pyrazole derivatives based on the condensation of
hydrazine derivatives and b-dicarbonyl compounds under solvent-free conditions. It was found that the
catalyst could be recovered and reused without significant loss of its activity. The use of this method pro-
vides a novel and improved modification of Knorr synthesis in terms of clean reaction profile, use of a safe
catalyst and solvent-free conditions.
Keywords: Tungstate sulfuric acid; Hydrazine; Knorr; Indazole; Pyrazole.
INTRODUCTION
Among the organic compounds, aza-heterocycles
Scheme 1 Preparation of tungstate sulfuric acid (1)
such as pyrazole and indazole derivatives, which present
considerable biological importance,1,2 are embedded in a
wide range of natural products and medicinal synthetic
compounds exerting anti-aggregatory,3 anti-arrhythmic,4
muscle relaxing,5 and anti-diabetic activities.6 For exam-
ple, Celecoxib is a pyrazole derivative used as an analge-
sic.7 The term “pyrazole” was given to this class of com-
pounds by Ludwig Knorr in 1883.8 Although there are
many ways to prepare pyrazole ring, the condensation of
the 1,3-dicarbonyls with hydrazine derivatives remains the
most common and facile method to assemble this ring sys-
tem. Many of the reported methods for the Knorr synthesis
of pyrazoles suffer from drawbacks, such as the use of or-
ganic solvent and unrecoverable catalyst,9 harsh reaction
conditions,10 and long reaction times.11
strategy for the synthesis of pyrazole derivatives 9-13 and
indazoles 14 from the reaction of hydrazine derivatives 2
with b-dicarbonyls 3-8 using tungstate sulfuric acid (TSA)
(Scheme 2). TSA has proved as a powerful, safe, and recy-
clable catalyst under solvent-free conditions. Solid phase
reactions are considered “green” because they eliminate a
huge amount of waste (the spent solvent) and require less
energy to isolate the product (solvent removal is obviously
not an issue).17
Interests in the environmental control of chemical
processes have increased remarkably during the last three
decades as a response to public concern about the use of
hazardous chemicals. Therefore, to improve the effective-
ness of this method in preventing chemical waste, it is im-
portant to investigate optimal reaction conditions. To deter-
mine the suitable reaction conditions, the reaction of hy-
drazine (2a) with acetylacetone (3) was taken as a model
reaction. At first, we found that in the absence of TSA1, the
reaction did not complete in long reaction times (240 min)
even at a high temperature (Table 1). After examination of
the various amounts of 1 at 80 °C, we found that the reac-
tion can be efficiently carried out by adding 10 mol% of the
RESULTS AND DISCUSSION
The challenge in chemistry is to develop practical
methods with convenient conditions and reagents, and the
concept of “green chemistry” is becoming ever important
in the scientific community. We found that anhydrous so-
dium tungstate reacts with chlorosulfonic acid (1:2 mole
ratio) to give tungstate sulfuric acid (TSA 1). The reaction
is easy and clean and no gas is generated during the reac-
tion (Scheme 1).12
In connection with our studies on the catalyzed or-
ganic reactions,13-16 herein, we describe a new and green
* Corresponding author. Email: karami@mail.yu.ac.ir,karamivk@yahoo.com
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201400251
J. Chin. Chem. Soc. 2014, 61, 000-000
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1

Communication
Rahmatzadeh et al.
Preparation of pyrazoles and indazoles us-
Table 1. Optimization of the reaction conditions
Catalyst [mol%]/
Scheme 2
ing tungstate sulfuric acid (1)
Entry
Time [min]
Yield [%]
Temperature [oC]
1
-/25
-/80
240
240
240
240
25
trace
10
25
50
85
70
70
95
85
85
2
3
-/120
5/25
4
5
5/80
6
5/120
10/25
10/80
10/120
20/80
20
7
240
5
8
9
5
10
15
Table 2. Synthesis of indazoles and pyrazoles using TSA (1) at
80 °C under solvent-free conditions
Entry Producta
Time [min] Yield [%]
M.p. [°C]
1
9a
5
5
95
90
85
90
90
80
87
85
85
85
87
83
82
80
80
85
80
109-111 [22]
Oil [23]
2
9b
3
9c
40
10
10
100
10
10
40
30
25
100
30
20
20
35
20
121-123 [23]
79-81 [24]
Oil [24]
4
10a
10b
10c
11a
11b
11c
12a
12b
12c
13b
13c
14a
14b
14c
5
6
94-96 [24]
127-128 [25]
Oil [23]
7
8
9
128 [26]
10
11
12
13
14
15
16
17
200-202 [25]
140-142 [27]
152-154 [28]
Oil [-]
catalyst under solvent-free conditions in a short time span
of 5 min. The use of excess amounts of the catalyst did not
have a marked influence on the product yield or reaction
rate. The probable reason for this is the coordination of
excessive catalyst to the hydrazine.
165-167 [-]
150-152 [29]
Oil [30]
175-177 [-]
According to Table 2, under optimized reaction con-
ditions, various b-dicarbonls were allowed to undergo re-
action with hydrazine derivatives in a molar ratio of 1:1
with catalyst affording product 9-14 in good to excellent
yields.
The 1H NMR (DMSO-d6, 400 MHz) spectrum of 11c
exhibited a singlet of the methyl group protons (d = 2.36), a
singlet of the pyrazole ring methyne group proton (d =
6.42). Four doublet signals (7.23, 7.44, 7.68 and 8.34) and
multiplet signal (d = 7.38-7.33) corresponding to the aro-
matic protons. The proton decoupled 13C NMR spectrum of
11c also showed 14 distinct resonances in agreement with
the proposed structure.
a Yield of Isolated products.
ble and the reaction proceeded under solvent-free condi-
tions. In this process, the recycled catalyst was used for
four cycles during which a little appreciable loss was ob-
served in the catalytic activities (Fig. 1).
A plausible mechanism for the synthesis of 9-14 and
recyclability of TSA was proposed in Scheme 3.
EXPERIMENTAL
General: Chemicals were purchased from Merck and
Aldrich. The TSA was prepared according to our previously pub-
lished works.18-21 The progress of the reactions was monitored by
TLC (silica gel 60 F254, n-hexane/AcOEt). IR spectra (KBr disc)
were recorded on a FT-IR Shimadzu-470 spectrometer and the 1H
NMR spectra were recorded on a Bruker-Instrument DPX-400
Not only the ecological profile (through helping to
decrease hazardous industrial waste), but also the eco-
nomic profile (through the elimination of expensive or-
ganic solvent) is further improved if the catalyst is recycla-
2
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JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Synthetic Route to Indazoles and Pyrazoles
3 H). 13C-NMR (100 MHz, DMSO-d6): 149.47, 143.73, 140.21,
130.79, 128.9, 128.68, 128.47, 127.14, 127.07, 125.17, 107.86,
13.67. 1-(2,4-Dinitrophenyl)-5-methyl-3-phenyl-1H-pyrazole
(11c): IR: 3120, 2990, 1650, 1610, 1510vs, 1390. 1H-NMR (400
MHz, DMSO-d6): 9.68 (d, J = 2, 1 H); 8.33 (d, J = 8.4, 1 H); 7.43
(d, J = 8.4, 1 H); 7.35-7.22 (m, 5 H); 6.42 (s, 1 H); 2.36 (s, 3 H).
13C-NMR (100 MHz, DMSO-d6): 152.69. 145.73, 145.29,
145.00, 139.2, 129.69, 129.56, 129.23, 127.00, 120.85, 109.43.
3,5-Diphenyl-1H-pyrazole (12a): IR (KBr): 3300, 3100, 2920,
1490. 1H-NMR (400 MHz, DMSO-d6): 7.20 (s, 1 H); 7.51-7.31
(m, 5 H); 7.90, 7.83 (two d, J = 7.2, 5 H,); 13.41 (s, 1 H).
13C-NMR (100 MHz, DMSO-d6): 152.30, 146.03, 145.37,
137.18, 136.28, 128.77, 128.29, 121.52, 117.08. 3-Methyl-1-
phenyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (13b): IR
(KBr): 3114, 2987, 1649, 1598, 1463, 1221. 1H-NMR (400 MHz,
DMSO-d6): 7.14-7.61 (m, 5 H); 2.98 (m, 2 H); 2.56 (s, 4 H); 2.15
(s, 3 H). 13C-NMR (100 MHz, DMSO-d6): 148.98, 143.44,
140.46, 129.34, 128.35, 122.37, 118.37, 30.97, 26.70, 22.19,
13.01. 1-(2,4-Dinitrophenyl)-3-methyl-1,4,5,6-tetrahydrocy-
clopenta [c]pyrazole (13c): IR (KBr): 3055, 2990, 1610, 1510,
1370. 1H-NMR (400 MHz, DMSO-d6): 8.95 (s, J = 2.4, 1 H); 8.66
(dd, J = 8.2, 2.4, 1 H); 7.75 (d, J = 8.4, 1 H); 2.80 (m, 2 H); 2.62 (s,
4 H); 2.21 (s, 3 H). 13C-NMR (100 MHz, DMSO-d6): 152.30,
146.03, 145.37, 137.28, 126.28, 128.77, 128.28, 121.52, 117.08,
32.15, 23.19, 20.34, 12.40. 1-(2,4-Dinitrophenyl)-3-methyl-
4,5,6,7-tetrahydro-1H-indazole (14c): IR (KBr): 3060, 2980,
1600, 1510, 1380. 1H-NMR (400 MHz, DMSO-d6): 8.84 (d, J =
2.4, 1 H); 8.57 (dd, J = 8.8, 2.4, 1 H); 7.99 (d, J = 8.8, 1 H); 2.48 (s,
3 H); 2.25 (s, 3 H); 1.72 (d, J = 4.4, 5 H). 13C-NMR (100 MHz,
DMSO-d6): 152.30, 146.03, 145.37, 137.28, 126.28, 128.77,
128.28, 121.52, 117.08, 33.35, 23.16, 23.09, 20.29, 10.41.
Proposed mechanism for the hedrazines
Scheme 3
condensation with b-dicaronyl compounds
using TSA (1)
Avance 2 model. Known products were characterized by compar-
ison of their spectra and physical data with those reported in the
literature.22-30
Preparation of Pyrazoles and Indazoles Using TSA (1):
A mixture of hydrazine 2 (1 mmol), b-dicarbonyl 3-8 (1 mmol)
and TSA(0.1 mmol) was stirred and heated at 80 °C in a preheated
oil bath for an appropriate time. After completion of the reaction
as indicated by TLC (AcOEt/n-hexane, 1:4), the reaction mixture
was dissolved in hot EtOH and catalyst was separated by filtra-
tion. The solvent was evaporated and the products 9-14 were puri-
fied by recrystallization in EtOH. The separated catalyst was
washed with diethyl ether, dried at 70 °C for 45 min, and reused in
another reaction.
Selected Spectral Data: 5-Methyl-1,3-diphenyl-1H-pyr-
azole (11b): IR (KBr): 3095, 2950, 1650, 1500, 1390. 1H-NMR
(400 MHz, DMSO-d6): 7.33-7.24 (m, 10 H); 6.35 (s, 1 H); 2.43 (s,
CONCLUSIONS
In summary, a new catalytic application of TSA as a
highly efficient and green solid acid catalyst to synthesize
indazoles and pyrazoles was presented. Simple experimen-
tal procedure, utilization of a clean and recyclable catalyst,
the use of readily available starting materials, short period
of reactions and good to excellent yields make this method
a valid contribution to the existing methodologies.
ACKNOWLEDGEMENTS
The authors are thankful to Yasouj University Re-
search Council for the partial financial support.
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