Ultrasonic-accelerated rapid protocol for the improved synthesis of pyrazoles

Article abstract of DOI:10.1016/j.ultsonch.2015.06.005

A simple, catalyst-free, green synthetic protocol is described for the one-pot synthesis of pyrazoles via multicomponent reaction of aromatic aldehydes, hydrazine monohydrate and ethyl acetoacetate and malononitrile/ammonium acetate in water under ultraso

Full text of DOI:10.1016/j.ultsonch.2015.06.005

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Ultrasonic-accelerated rapid protocol for the improved synthesis of pyrazoles
Nhlanhla Shabalala, Ramakanth Pagadala, Sreekantha B. Jonnalagadda
PII:
S1350-4177(15)00177-7
DOI:
http://dx.doi.org/10.1016/j.ultsonch.2015.06.005
ULTSON 2907
Reference:
Ultrasonics Sonochemistry
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Please cite this article as: N. Shabalala, R. Pagadala, S.B. Jonnalagadda, Ultrasonic-accelerated rapid protocol for
the improved synthesis of pyrazoles, Ultrasonics Sonochemistry (2015), doi: http://dx.doi.org/10.1016/j.ultsonch.
2015.06.005
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Ultrasonic-accelerated rapid protocol for the improved synthesis of pyrazoles
Nhlanhla Shabalala, Ramakanth Pagadala and Sreekantha B. Jonnalagadda*
School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Chiltern
Hills, Durban-4000, South Africa
Corresponding author: Tel.: +27 31 260 7325/3090; fax: +27 31 260 3091
E-mail: jonnalagaddas@ukzn.ac.za
Abstract:
A simple, catalyst-free, green synthetic protocol is described for the one-pot synthesis of
pyrazoles via multicomponent reaction of aromatic aldehydes, hydrazine monohydrate and ethyl
acetoacetate and malononitrile/ammonium acetate in water under ultrasound irradiation. This
protocol avoids traditional chromatography and purification steps and it affords highly selective
conversion with no byproducts.
Keywords: Ultrasound, multicomponent reaction (MCR), one-pot synthesis, pyrazole derivatives,
water as solvent.
1. Introduction
Development of simple and eco-friendly procedures for synthesis of compounds with
biological interest is the driving force for the discovery and design of new bioactive compounds.
Multicomponent reactions (MCRs) are gaining importance and are in high demand in modern
organic synthesis. It is particularly true in case of heterocycles [1] as those reactions facilitate
formation of several bonds in one unit operation [2, 3]. In the recent years, ultrasound irradiation
has gained recognition as a clean and advantageous approach in organic synthesis [4]. The
sonochemical phenomenon is the result of the interaction of suitable field of acoustic waves with
potentially reacting chemical system. This phenomenon occurs through acoustic cavitation. The
phenomenon of cavitation in an irradiated solution may be expressed as a sequential process of
involving the bubble formation, its growth and breakdown. Cavitation phenomenon develops
high temperature and pressure in the micro environment which creates turbulence and facilitates
the mass transfer in the neighborhood. Compared to conventional heating which provides
1

thermal energy in the macro system, ultra sonification reduces reaction times, improves yields
and minimizes side product formation by providing the activation energy in micro environment
[5]. As this technology involves energy conservation and minimal waste generation, it is widely
accepted as a green chemistry approach [6]. Furthermore, this technique can be applied to a
variety of organic syntheses accomplishing better yields, under mild reaction conditions and
shorter reaction times [7].
Countless biologically and pharmacologically important compounds constitute pyrazoles
and their derivatives [8]. A number of pyrazole containing compounds such as Celebrex, Viagra
and Acomplia have been successfully commercialized [9]. Pyrazoles have also found
applications in the agrochemical industry as ultraviolet stabilizers and energetic materials and in
the field of photoprotectors [10]. Owing to the attractive pharmacological properties of
pyrazoles, new methodologies for the design of different pyrazoles have attracted the attention of
the researchers. Several methods are available in literature for one-pot synthesis of pyrazoles
derivatives in presence or absence of catalysts [11]. Certain protocols reported to use catalysts
such as triethyamine [12], hydrotalcite [13], L-proline in [bmim]BF4 [14] and using water as a
solvent in catalyst-free condition [15], to mention a few. While Dabiri et al. [16] have reported
the synthesis of tetrahydropyrazolopyridine derivatives using ethanol as solvent; Zhao et al. [17]
have synthesized tetrahydropyrazolopyridine derivatives using a pre-formed pyrazolone and
ethanol as solvent under refluxing conditions. Many of the reported methods suffer some
drawbacks, like high temperature requirements, prolonged reaction times, toxic solvents and/or
expensive reagents. Some of the protocols have limitations of low yields or undesired product
formation due to poor selectivity of the process. Hence, there is definite longing for less
expensive and catalyst free protocols. Thus, the greater demand for better and efficient protocols
materials has accentuated the need to develop novel, value-added, eco-compatible and green
routes motivated the present work.
2. Materials and methods
2.1. Apparatus and analysis
All chemicals used were reagent grade and were used as received without further
1
purification. H NMR and C NMR spectra were recorded at 25 C at 400 MHz and 100 MHz
13
o
2

(Bruker Avance) instrument respectively, using TMS as internal standard. Chemical shifts are
given in parts per million (ppm). The FT-IR spectroscopy of samples was carried out on a Perkin
Elmer Perkin Elmer Precisely 100 FT-IR spectrometer in the 400-4000 cm-1 region. The HRMS
were recorded on a waters micromass LCT premier mass spectrometer using electrospray
ionization in the positive or negative mode. The ultrasonic assisted reactions are carried out in a
‘‘Spectralab model UMC 20 Ultrsonic cleaner” with a frequency of 40 kHz and a nominal power
250 W. Melting points were recorded on a hot stage melting point apparatus Ernst Leitz Wetzlar,
Germany and were uncorrected. All the reactions and the purity of products were monitored
using thin layer chromatography (TLC) on aluminum-backed plates coated with Merck Kieselgel
60 F254 silica gel, visualizing the spots under ultraviolet light and iodine chamber.
2.2. General procedure for the synthesis tetrahydropyrazolopyridine under silent conditions
A mixture of hydrazine hydrate (2.0 mmol) and ethyl acetoacetate (2.0 mmol) in H2O (15
mL) was magnetically stirred for 30 min at room temperature (25°C) followed by addition of
aldehyde (1.0 mmol) and ammonium acetate (4.0 mmol). The reaction mixture was heated at
70oC for appropriate time as shown in Table 2. After the starting material was completely
consumed, the reaction mixture was cooled to room temperature and water (10 mL) was added
and the resulting mixture was stirred for 30 min. The precipitated product was filtered, washed
with water and acetone then dried under vacuum. In most cases no further purification was
necessary.
2.3. General procedure for the synthesis of tetrahydropyrazolopyridine under ultrasound
irradiation
A 50 mL conical flask was charged with a mixture of hydrazine hydrate (2.0 mmol) and
ethyl acetoacetate (2.0 mmol) in H2O (15 mL). The mixture was irradiated for 10 min at room
temperature followed by addition of aldehyde (1.0 mmol) and ammonium acetate (4.0 mmol).
The reaction mixture was irradiated under sonication at 50oC for appropriate time as shown in
Table 2. To maintain the ultrasonic bath temperature, cold/hot water was either added or
removed manually. After the starting material was completely consumed, the reaction mixture
was cooled to room temperature and water (10 mL) was added and the resulting mixture was
3

irradiated for 15 min. The precipitated product was filtered, washed with water and acetone then
dried under vacuum. In most cases no further purification was necessary.
3,5-Dimethyl-4-phenyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5a)
Off-white solid; 1H NMR (400 MHz, DMSO-d6) δ = 2.07 (6H, s), 4.80 (1H, s), 7.08-7.21 (5, m),
11.19 (3H, br, s); 13C NMR (100 MHz, DMSO-d6): δ 10.8, 33.5, 104.7, 125.8, 127.9, 128.1,
140.5, 143.9, 161.5; IR (KBr, cm-1): 3274 (NH); HRMS of [C15H15N5 + Na] (m/z): 288.0845
(100%); Calc. Mass: 288.0822.
4-(4-Methoxy-phenyl)-3,5-dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5b)
1
Pale yellow solid; H NMR (400 MHz, DMSO-d6) δ = 2.03 (6H, s), 3.82 (3H, s), 4.53 (1H, s),
7.03 (2H, d, J = 8.7 Hz), 7.79 (2H, d, J = 8.6 Hz), 8.99 (3H, br, s); 13C NMR (100 MHz, DMSO-
d6): δ 10.3, 31.9, 54.9, 104.4, 113.0, 128.3, 135.1, 139.6, 157.1, 161.0; IR (KBr, cm-1): 3266
(NH); HRMS of [C16H17N5O + 1] (m/z): 296.1975 (100%); Calc. Mass: 296.1909.
4-(4-Bromo-phenyl)-3,5-dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5c)
Pale yellow solid; 1H NMR (400 MHz, DMSO-d6) δ = 2.07 (6H, s), 4.78 (1H, s), 7.04 (2H, d, J =
13
8.3 Hz), 7.37 (2H, d, J = 8.4 Hz), 11.32 (3H, br, s); C NMR (100 MHz, DMSO-d6): δ 10.2,
32.2, 104.4, 118.4, 129.7, 130.4, 131.9, 142.7, 157.5; IR (KBr, cm-1): 3225 (NH); HRMS of
[C15H14BrN5 + 1] (m/z): 344.0255 (100%); Calc. Mass: 344.0260.
[4-(3,5-Dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridin-4-yl)-phenyl]-dimethyl-
amine (5d)
Off-white solid; 1H NMR (400 MHz, DMSO-d6) δ = 2.05 (6H, s), 2.8 (6H, s), 4.69 (1H, s), 6.56
(2H, d, J = 8.8 Hz), 6.92 (2H, d, J = 8.5 Hz), 10.91 (3H, br, s); 13C NMR (100 MHz, DMSO-d6):
δ 10.3, 31.7, 40.4, 104.7, 112.2, 127.8, 131.1, 148.5, 159.7, 161.0; IR (KBr, cm-1): 3170 (NH);
MS (ESI), m/z = 309 (M+1, 100%); Anal. Calcd (C17H20N6): C 66.21, H 6.54, N 27.25%. Found:
C 66.19, H 6.51, N 27.20%.
4-(3,5-Dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridin-4-yl)-phenol (5e)
Pale yellow solid; 1H NMR (400 MHz, DMSO-d6) δ = 2.06 (6H, s), 4.71 (1H, s), 6.59 (2H, d, J =
8.5 Hz), 6.90 (2H, d, J = 8.4 Hz), 9.28 (1H, br, s), 11.04 (1H, s); 13C NMR (100 MHz, DMSO-
d6): δ 10.3, 31.8, 104.6, 114.4, 128.2, 133.3, 139.7, 155.0, 161.0; IR (KBr, cm-1): 3267 (NH);
HRMS of [C15H14BrN5 + Na] (m/z): 304.1229 (100%); Calc. Mass: 304.1239.
4

4-(2-Bromo-phenyl)-3,5-dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5f)
1
Off-white solid; H NMR (400 MHz, DMSO-d6) δ = 1.92 (6H, s), 5.04 (1H, s), 7.05-7.53 (4H,
m), 10.79 (3H, br, s); 13C NMR (100 MHz, DMSO-d6): δ 10.5, 30.6, 102.3, 126.8, 127.7, 128.2,
130.8, 132.3, 138.4, 142.3, 160.6; IR (KBr, cm-1): 3174 (NH); MS (ESI), m/z = 366 (M+Na,
100%); Anal. Calcd (C15H14BrN5): C 52.34, H 4.10, N 20.35%. Found: C 52.26, H 4.03, N
20.28%.
4-(2-Methoxy-phenyl)-3,5-dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5g)
1
White solid; H NMR (400 MHz, DMSO-d6) δ = 2.04 (6H, s), 3.72 (3H, s), 5.05 (1H, s), 6.77-
7.52 (4H, m), 10.75 (3H, br, s); 13C NMR (100 MHz, DMSO-d6): δ 10.3, 30.6, 55.3, 103.8,
110.3, 119.6, 126.6, 128.9, 131.8, 138.3, 155.8, 160.3; IR (KBr, cm-1): 3077 (NH); HRMS of
[C16H17N5O + 1] (m/z): 296.1996 (100%); Calc. Mass: 296.1909.
4-(2-Chloro-phenyl)-3,5-dimethyl-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5h)
Pale yellow solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.94 (6H, s), 5.08 (1H, s), 7.13-7.55 (4H,
m), 10.85 (3H, br, s); 13C NMR (100 MHz, DMSO-d6): δ 10.3, 30.6, 102.3, 126.3, 127.4, 128.9,
130.5, 132.2, 138.7, 140.6, 160.6; IR (KBr, cm-1): 3199 (NH); HRMS of [C15H14ClN5 + Na]
(m/z): 322.1119 (100%); Calc. Mass: 322.1110.
3,5-Dimethyl-4-(2-nitro-phenyl)-1,4,7,8-tetrahydro-dipyrazolo[3,4-b;4',3'-e]pyridine (5i)
1
Off-white solid; H NMR (400 MHz, DMSO-d6) δ = 1.92 (6H, s), 5.44 (1H, s), 7.37-7.68 (4H,
m), 10.98 (3H, br, s); 13C NMR (100 MHz, DMSO-d6): δ 10.0, 28.9, 101.9, 123.8, 127.1, 130.2,
131.6, 136.2, 138.6, 149.5, 160.5; IR (KBr, cm-1): 3381 (NH); HRMS of [C15H14N6O2 + 1]
(m/z): 311.1052 (100%); Calc. Mass: 311.1062.
2.4. General procedure for the synthesis pyrazoles under silent conditions
To a solution of arylaldehyde (2.0 mmol), malanonitrile (2.0 mmol), hydrazine hydrate
(2.0 mmol) and ethyl acetoacetate (2 mmol) in water (15 mL). The reaction mixture was stirred
at 70oC for the period of time as indicated in Table 2. After the completion of the reaction (The
reaction was monitored by TLC), the reaction mixture cooled to room temperature, the residue
was filtered and was washed with ethanol to produce the desired solid.
2.5. General procedure for the synthesis of pyrazoles under ultrasound irradiation
5

A 50 mL conical flask was charged with freshly distilled benzaldehyde (2.0 mmol),
malanonitrile (2.0 mmol), hydrazine hydrate (2.0 mmol) and ethyl acetoacetate (2 mmol) in
water (15 mL). The reaction mixture was irradiated at 50oC for the period of time (The reaction
was monitored by TLC) as indicated in Table 2. After the completion of the reaction, the reaction
mixture cooled to room temperature, the residue was filtered and was washed with ethanol to
produce the desired solid.
6-Amino-3-methyl-4-phenyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (7a)
White solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.77 (3H, s), 4.58 (1H, s), 6.85 (2H, s, -NH2),
7.15-7.32 (5H, m), 12.09 (1H, s, -NH); 13C NMR (100 MHz, DMSO-d6): δ 9.6, 36.1, 57.1, 97.6,
120.7, 126.7, 127.4, 128.4, 135.6, 144.3, 154.7, 160.8; IR (KBr, cm-1): 2191 (CN), 3369 (NH2);
HRMS of [C14H12N4O - 1] (m/z): 251.0929 (100%); Calc. Mass: 251.0933.
6-Amino-4-(4-methoxy-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile
(7b)
1
White solid; H NMR (400 MHz, DMSO-d6) δ = 1.77 (3H, s), 3.71 (3H, s), 4.53 (1H, s), 6.85
(2H, s, -NH2), 6.85 (2H, d, J = 8.6 Hz), 7.06 (2H, d, J = 8.6 Hz ), 12.07 (1H, s, -NH); 13C NMR
(100 MHz, DMSO-d6): δ 9.6, 35.3, 54.9, 57.6, 97.8, 113.7, 120.8, 128.4, 135.5, 136.4, 157.9,
160.6; IR (KBr, cm-1): 2191 (CN), 3256 (NH2); HRMS of [C15H14N4O2 - 1] (m/z): 281.1039
(100%); Calc. Mass: 281.1039.
6-Amino-4-(4-bromo-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (7c)
1
White solid; H NMR (400 MHz, DMSO-d6) δ = 1.78 (3H, s), 4.61 (1H, s), 6.91(2H, s, -NH2),
13
7.12 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.3 Hz ), 12.14 (1H, s, -NH); C NMR (100 MHz,
DMSO-d6): δ 9.6, 35.6, 56.7, 97.0, 119.7, 120.6, 129.6, 131.3, 135.7, 143.8, 154.6, 160.8; IR
(KBr, cm-1): 2189 (CN), 3395 (NH2); HRMS of [C14H11BrN4O - 1] (m/z): 329.0049 (100%);
Calc. Mass: 329.0038.
6-Amino-4-(4-dimethylamino-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-
carbonitrile (7d)
Off-white solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.78 (3H, s), 2.84 (6H, s), 4.44 (1H, s), 6.63
(2H, d, J = 8.6 Hz), 6.73 (2H, s, -NH2), 6.94 (2H, d, J = 8.6 Hz), 12.03 (1H, s, -NH); 13C NMR
(100 MHz, DMSO-d6): δ 9.7, 35.3, 40.1, 57.9, 98.1, 112.2, 120.9, 127.9, 131.9, 135.4, 149.1,
6

154.7, 160.5; IR (KBr, cm-1): 2187 (CN), 3344 (NH2); HRMS of [C16H17N5O - 1] (m/z):
294.1366 (100%); Calc. Mass: 294.1355.
6-Amino-4-(4-hydroxy-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (7e)
White solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.77 (3H, s), 4.46 (1H, s), 6.67 (2H, d, J = 8.4
13
Hz), 6.76 (2H, s, -NH2), 6.93 (2H, d, J = 8.4 Hz), 9.29 (1H, s, -OH), 12.04 (1H, s, -NH); C
NMR (100 MHz, DMSO-d6): δ 9.6, 35.4, 57.7, 98.0, 115.0, 120.8, 128.3, 134.7, 135.5, 154.7,
155.9, 160.5; IR (KBr, cm-1): 2174 (CN), 3371 (NH2); HRMS of [C14H12N4O2 - 1] (m/z):
267.0878 (100%); Calc. Mass: 267.0882.
6-Amino-4-(2-methoxy-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile
(7f)
1
White solid; H NMR (400 MHz, DMSO-d6) δ = 1.78 (3H, s), 3.77 (3H, s), 4.97 (1H, s), 6.78
13
(2H, s, -NH2), 6.87-7.20 (4H, m), 12.01 (1H, s, -NH); C NMR (100 MHz, DMSO-d6): δ 9.4,
29.1, 55.5, 56.3, 97.7, 111.2, 120.7, 120.8, 127.8, 128.5, 132.0, 135.0, 155.0, 156.3, 161.4; IR
(KBr, cm-1): 2194 (CN), 3374 (NH2); HRMS of [C15H14N4O2 - 1] (m/z): 281.1028 (100%); Calc.
Mass: 281.1039.
6-Amino-4-(2-bromo-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (7g)
White solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.75 (3H, s), 5.06 (1H, s), 6.94 (2H, s, -NH2),
7.13-7.58 (4H, m), 12.14 (1H, s, -NH); 13C NMR (100 MHz, DMSO-d6): δ 9.6, 35.8, 55.9, 97.0,
120.2, 122.3, 128.3, 128.8, 130.9, 132.6, 135.4, 142.5, 154.8, 161.1; IR (KBr, cm-1): 2189 (CN),
3389 (NH2); HRMS of [C14H11BrN4O - 1] (m/z): 329.0033 (100%); Calc. Mass: 329.0038.
6-Amino-4-(2-chloro-phenyl)-3-methyl-1,4-dihydro-pyrano[2,3-c]pyrazole-5-carbonitrile (7h)
White solid; 1H NMR (400 MHz, DMSO-d6) δ = 1.75 (3H, s), 5.06 (1H, s), 6.93 (2H, s, -NH2),
7.16-7.41 (4H, m), 12.13 (1H, s, -NH); 13C NMR (100 MHz, DMSO-d6): δ 9.4, 33.4, 55.7, 96.8,
120.3, 127.7, 128.5, 129.4, 130.6, 131.9, 135.3, 140.8, 154.9, 161.2; IR (KBr, cm-1): 2189 (CN),
3389 (NH2); HRMS of [C14H11ClN4O - 1] (m/z): 285.0539 (100%); Calc. Mass: 285.0543.
3. Results and discussion
Recently, we have reported some multicomponent reactions that provide easy access to
develop eco-sustainable and clean synthetic routes for the synthesis of various heterocyclic
derivatives [18] and an ultrasonic-assisted method for synthesis of polysubstituted pyridines [2a].
7

With sustained interest in development of useful multicomponent reactions, in this
communication we report an expedient approach to prepare pyrazole derivatives under
ultrasound irradiation for the first time and using water as a solvent.
Literature survey shows that there are no reports either on the synthesis of
tetrahydropyrazolopyridines under ultrasound irradiation, with or without catalyst, under solvent-
free conditions or by using water as a solvent. Our intention was to develop an eco-friendly,
methodology for the synthesis of heterocyclics of biological significance under sonochemical
conditions. In that pursuit, we report our success in the one-pot synthesis of
tetrahydropyrazolopyridine derivatives (5a-i) and pyranopyrazoles (7a-h) via four-component
coupling reaction under ultrasound irradiation at 50oC in water media (Scheme 1&2).
Preliminary studies were carried out using hydrazine hydrate (2.0 mmol), ethyl
acetoacetate (2.0 mmol) and benzaldehyde 4a (1.0 mmol) under silent and ultrasound irradiation
at room temperature (rt) separately, with using EtOH and water as a solvent. We did not observe
any trace of the desired product under the silent conditions (Table 1, entries 1-3). The reaction
was also carried out under silent conditions at increased temperatures above 50oC, reaction
occurred, but with low yields. Preliminary experiments with appropriate reagents were
conducted using water under ultrasound irradiation at 25 (rt), 40 and 50oC and with conventional
heating at 70oC. The increase in the reaction temperature under ultrasonification improved the
yields and reduced the reaction times. Impressively, at 50oC, the ultrasonic method gave the
preferred product (5a) selectively with 95% yield, which could be possibly due the phenomenon
of cavitations produced by ultrasound. Cavitation induces very high local temperatures and
pressure inside the bubbles, leading to a turbulent flow in the liquid and enhanced mass transfer
in the area. Based on the results, taking 50oC as optimum condition, all the reactions were
conducted at that temperature, and obtained results are summarized in Table 1. This study
validates that sonochemical approach with water as media is ideal for one-pot, four-component
reactions to achieve excellent yields.
The versatility of the protocol is further demonstrated by repeating the procedure for
synthesizing an array of tetrahydropyrazolopyridine (5a-i) and pyranopyrazoles (7a-h)
derivatives (Table 2). In this protocol, in addition to aromatic aldehydes, spatially-hindered
8

aldehydes such as 2-methoxy, 2-bromo and 2-chloro were also found acceptable giving good
yields.
All the synthesized compounds could be purified without applying any chromatographic
method. Thus escaping the need of volatile organic solvents generally required for work-up and
purification in many existing procedures. To our belief, this new technique is an excellent
method for the synthesis of tetrahydropyrazolopyridine derivatives and pyranopyrazoles.
Moreover, it is worth noting that new C-C and C-heteroatom bonds were formed with
concomitant creation of a pyrazoles involving four-component in one-pot process. All the
reaction products were totally characterized by various spectroscopic technics including, FTIR,
1H NMR, 13C NMR and MS (Supplementary data).
The results of Table 2 confirm the advantage of ultrasound method over conventional
thermal method, in terms of (i) time required for the formation of new C-C and C-heteroatom
bonds under ultrasonic irradiation is shorter, (ii) cyclization takes place at low temperature
compare to conventional heating, (iii) the isolated products are higher yields, and additionally
(iv) the reaction and work-up is simple to execute.
4. Conclusions
In summary, we report a remarkable, eco-friendly and expedient one-pot technique for
rapid synthesis of pyrazole derivatives from easily accessible starting materials, within 0.5 - 2.5
h. Ultrasound has accelerated the multicomponent reaction in good to excellent chemical yields
are achieved. Furthermore, sterically hindered substrates were also well accepted resulting in
good yields. This method will be of choice for the preparation of a variety of pyrazole
derivatives some of which are difficult to make via silent approaches.
Acknowledgments
The authors are thankful to the School of Chemistry & Physics, College of Agriculture,
Engineering and Sciences and University of KwaZulu-Natal, for the financial support and
research facilities.
9

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14

Tables and Schemes Captions
Table 1. Optimization of reaction conditions of the four-component reactions
Entry Product Temperature
(oC)
Solvent
Conventional
Sonication
No.
Time
(h)
Yield
a(%)
b
b
b
64
52
62
50
59
Time
Yield
a(%)
b
b
38
c
95
c
85
92
(h)
4.0
4.0
4.0
c
2.0
c
1.5
1.0
1
2
3
4
5
7
8
9
25
25
25
70
50
70
50
50
EtOH
H2O/EtOH
H2O
7.0
8.0
8.0
7.0
8.0
6.0
8.0
8.0
5a
5a
5a
5a
5a
7a
7a
7a
H2O
H2O
EtOH
EtOH
H2O
a Isolated yields, b Products were not found, c Reaction was not performed.
Table 2. Four-component reaction for the synthesis of tetrahydropyrazolopyridine (5a-i) and
pyranopyrazoles (7a-h) under both ultrasonic irradiation and silent condition
Entry Product
No.
Product
Conventional
Sonication
MP/(oC)
Reported
Time Yield Time Yield Found
a(%)
(h)
(h)
a(%)
1
7.0
64.0
2.0
95.0 239-240 240-241 [17]
5a
N
N
N
H
N
H
N
H
N
HN
2
3
4
6.0
6.0
6.5
60.0
58.0
61.0
2.5
2.0
2.5
96.0 183-184 185-187 [17]
5b
5c
5d
HN
HN
O
N
N
HN
HN
HN
94.0 165-166
-
-
Br
N
N
HN
HN
HN
92.0 235-236
N
N
15

N
N
HN
HN
HN
5
6
6.0
6.0
63.0
55.0
2.5
2.0
90.0 267-268 268-270 [17]
5e
5f
OH
Br
92.0 160-161
-
-
N
N
N
H
N
H
N
H
O
7
5.5
60.0
1.5
91.0 171-172
5g
N
N
N
H
N
H
N
H
Cl
8
9
6.0
6.5
64.0
60.0
2.0
2.5
94.0 164-165
-
-
5h
5i
N
N
N
H
N
H
N
H
NO2
N
92.0 187-188
N
N
H
N
H
N
H
10
3.5
70.0
1.0
92.0 204-205
205-207 [4f]
7a
CN
N
N
H
O
NH2
N
N
N
HN
11
12
13
2.0
3.0
3.5
69.0
80.0
64.0
1.0
0.5
1.0
94.0 210-211
97.0 214-215
96.0 217-218
-
7b
7c
7d
O
O
Br
N
H2N
CN
HN
213-215 [4f]
O
H2N
HN
CN
CN
-
O
H2N
16

N
HN
O
14
15
3.5
3.0
73.0
67.0
1.5
1.0
90.0 217-218
219-221 [4f]
7e
7f
OH
H2N
CN
O
91.0 249-250
-
CN
N
N
H
O
NH2
Br
16
17
3.0
2.5
72.0
78.0
1.0
1.0
94.0 201-202
-
7g
7h
CN
N
N
H
O
NH2
Cl
96.0 220-221
224-226 [4f]
CN
N
N
H
O
NH2
a Isolated yields.
17

Schemes
Scheme 1. multicomponent synthesis of tetrahydropyrazolopyridine 5a-i
R
H2O
2 NH2NH2
O
H
2
O
O
H2O
2
O
N
N
)))))), 50oC
N
H
N
H
N
H
1
NH4OAc
R
5a-i
4a-i
3
Scheme 2. multicomponent synthesis of pyrazoles derivatives 7a-h
R
2
H2O
CN
4a-h
1
N
)))))), 50oC
N
H
O
NH2
CN
7a-h
CN
6
18

Catalyst-free sonochemical rapid protocol for the benign methodology and
improved synthesis of pyrazoles
Ramakanth Pagadala, Nhlanhla Shabalala, Sreekantha B. Jonnalagadda*
Graphical abstract
19

Catalyst-free sonochemical rapid protocol for the benign methodology and
improved synthesis of pyrazoles
Nhlanhla Shabalala, Ramakanth Pagadala and Sreekantha B. Jonnalagadda*
School of Chemistry and Physics, University of KwaZulu-Natal, Westville Campus, Chiltern
Hills, Durban-4000, South Africa
Corresponding author: Tel.: +27 31 260 7325/3090; fax: +27 31 260 3091
E-mail: jonnalagaddas@ukzn.ac.za
Highlights
ꢀ One-pot multicomponent synthesis with excellent yields and water as solvent.
ꢀ Simple, eco-friendly and cost-effective protocol for pyrazole derivatives.
ꢀ An efficient method using ultrasound irradiation
ꢀ Short reaction times at moderate conditions.
20