An efficient and facile synthesis of novel 1,2,3-triazolyl-N-acylpyrazoline hybrids

Article abstract of DOI:10.1016/j.cclet.2013.10.015

An efficient and facile synthesis of a library of hitherto novel 1,2,3-triazolyl-N-acetyl/N-propionylpyrazoline hybrids (16 examples) in excellent yields (90%-96%) has been accomplished from easily accessible 1,2,3-triazolyl chalcone precursors.

Full text of DOI:10.1016/j.cclet.2013.10.015

Chinese Chemical Letters 25 (2014) 146–148
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
An efficient and facile synthesis of novel 1,2,3-triazolyl-N-
acylpyrazoline hybrids
Poovan Shanmugavelan, Murugan Sathishkumar, Sangaraiah Nagarajan,
*
Alagusundaram Ponnuswamy
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient and facile synthesis of a library of hitherto novel 1,2,3-triazolyl-N-acetyl/N-propionylpyr-
azoline hybrids (16 examples) in excellent yields (90%–96%) has been accomplished from easily
accessible 1,2,3-triazolyl chalcone precursors.
Received 9 June 2013
Received in revised form 22 August 2013
Accepted 22 September 2013
Available online 8 November 2013
ß 2013 Alagusundaram Ponnuswamy. Published by Elsevier B.V. on behalf of Chinese Chemical
Society. All rights reserved.
Keywords:
Facile
Efficient
1,2,3-Triazole
Pyrazolines
Hybrids
1,2,3-Triazolyl-N-acylpyrazolines
1. Introduction
Chalcones, belonging to the flavonoids family, are convenient
synthons for the synthesis of five [18], six [19] and seven
Recently, considerable attention has been focused on pyrazo-
lines and substituted pyrazolines due to their interesting biological
activities. They possess anti-microbial [1], anti-fungal [2], anti-
depressant [3], anti-convulsant [4], anti-inflammatory [5], etc.
properties. Moreover, N-acetyl pyrazoline derivatives exhibit
important pharmaceutical profiles [6–8]. Hence, the pyrazoline
framework represents an interesting template for combinatorial
[9] as well as medicinal chemistry [10,11]. On the other hand,
1,2,3-triazoles have received much attention due to their
interesting bioactivity profile such as anti-biotic, anti-fungal
[12], anti-cancer [13], anti-HIV [14], anti-microbial [15], etc.
properties. Also, they serve as potential chemotherapeutic agents
for various diseases [16].
In connection with the above and in continuation of our earlier
work on environmentally benign, green synthesis of 1,2,3-triazolyl
chalcone hybrids [17], we decided to attempt the synthesis of
molecules containing both of the two pharmacologically active
moieties mentioned above in a single frame. Thus, we disclose the
synthesis of 1,2,3-triazolyl-N-acylpyrazoline hybrids from easily
accessible 1,2,3-triazolyl chalcones, the details of which are
presented vide infra.
membered [20] heterocyclic compounds. With regard to pyrazo-
line derivatives, several methods have been employed for their
synthesis, including the condensation of chalcones with hydrazine,
hydrazine derivatives [21–24] and thiosemicarbazide [25] under
acidic [21,22] or basic [25] conditions, and the cycloaddition of
nitrilimines, generated in situ from the corresponding hydrazonoyl
halides by the action of a suitable base, to carbon-carbon double
bonds of a dipolarophile [26–29]. Hence, considerable interest has
been focused on the synthesis of pyrazolines from chalcones.
2. Experimental
Typical procedure: To a solution of (E)-1-(1-benzyl-5-methyl-
1H-1,2,3-triazol-4-yl)-3-(4-methylphenyl)prop-2-en-1-one [18]
(1e, 1.0 equiv.) and hydrazine hydrate (2.0 equiv.) in acetic acid
(5 mL) was refluxed for 3 h. Then, the reaction mixture was poured
onto ice-water to afford the 1,2,3-triazolyl-N-acetylpyrazoline
hybrid (2e) in 96% yield as a white solid, which was filtered and
recrystallized from ethanol.
1-(3-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-5-(4-methyl-
phenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone (2e): Mp: 150–
151 8C; 1H NMR (300 MHz, CDCl3):
d 7.11–7.37 (m, 9H, ArH),
5.54 (s, 2H, NCH2), 5.50 (dd, 1H, J = 4.8 & 12.0 Hz, CH), 3.87(dd, 1H,
J = 12.0 & 18.6 Hz, CH2), 3.44 (dd, 1H, J = 4.8 & 18.6 Hz, CH2), 2.51(s,
3H, COCH3), 2.32 (s, 3H, CH3), 2.29 (s, 3H, ArCH3); 13C NMR
*
Corresponding author.
E-mail address: ramradkrish@yahoo.co.in (A. Ponnuswamy).
1001-8417/$ – see front matter ß 2013 Alagusundaram Ponnuswamy. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.10.015

P. Shanmugavelan et al. / Chinese Chemical Letters 25 (2014) 146–148
147
H C
3
Table 1
CH
N
.
2
Optimization for the synthesis of 1,2,3-triazole-N-acetylpyrzoline hybrid (3a).
3
NH NH H O
CH
2
2
3
O
N
N
CH COOH
3
N
N
N
N
Chalcone
Reaction condition
reaction condition
N
O
Conventional heating
MW-irradiation
Time (min)
1a
2a
Time (h)
Yield (%)
Temp. (8C)
Yield (%)
1a
1a
1a
1a
1a
1
55
75
88
95
95
10
20
30
20
100
100
100
130
55
60
60
60
Scheme 1. Optimization for the synthesis of 1,2,3-triazole-N-acetylpyrzoline
hybrid (3a).
2
2.5
3
3.5
(75 MHz, CDCl3): d 168.46, 149.47, 138.68, 138.24, 137.19, 134.25,
132.80, 129.41, 129.08, 128.53, 127.25, 125.65, 58.69, 51.95, 43.25,
21.79, 21.00, 9.41; Mass (ES/MS): m/z 396.58 [M+Na]+; Anal. Calcd.
for C22H23N5O: C 70.76, H 6.21, N 18.75. Found: C 70.70, H 6.22, N
18.78.
For the purpose of optimization, synthesis of N-acetylpyrazo-
line (3a) was attempted (Scheme 1) under different conditions viz.
(i) reaction through conventional heating (ii) reaction under
microwave irradiation. The details are presented below.
3. Results and discussion
A mixture of 1,2,3-triazolyl chalcone (1a, 1.0 equiv.) and
hydrazine hydrate (2.0 equiv.) in acetic acid was conventionally
heated to reflux. It was noted that the yield of N-acetylpyrazoline
(2a) was increased and reached 95% in three hours. However, by
changing the source of heating to microwave irradiation, a
comparable yield of the product could not be obtained
Perusal of literature indicates a lack of reports on the synthesis
of N-acylpyrazolines linked with a 1,2,3-triazole core. In this
regard, we herein report synthesis of novel 1,2,3-triazolyl-N-
acylpyrazoline hybrids in a facile and efficient manner starting
from chalcones [17].
CHO
R1
CH
R1
CH
3
3
NH NH ·H O
2
2
2
O
R COOH
2
N
N
N
N
O
50% Aq. NaOH
grinding, 4-7 min
room temp.
N
N
reflux, 3-4 hrs
1
R1
R2
a= H
R2
-CH3
-CH2CH3
b= 4-OMe
c= 4-NO2
CH
3
O
N
d= 4-Br
N
N
N
e= 4-Me
f= 2-Me
N
g= 2,4-di-Cl
h= 2-furfuradehyde
i= Thiophen-3-aldehyde
R1
2
Scheme 2. Synthesis of 1,2,3-triazolyl-N-acetyl/N-propionylpyrzolines (2).
O
Ar
Ar'
H
H N
2
OH NH
N
+
H N
H
N
HO
Ar
2
H
NH
H O
O
NH
Ar'
OH
2
NH
NH
Ar'
2
+
H N
2
Ar
Ar'
Ar
Ar'
Ar
Ar
Ar'
OH
Ar'
Ar
Ar'
HN NH
Ar
H
N
NH
HN
Ar
Ar
HO
R
NH
Ar'
N
Ar'
H O
Ar'
2
H+
O
NH
Ar'
-H
HN
Ar
N
H
N
Ar
O
O
Ar
N
H
R
NH
R
O
-H
N
Ar'
NH
O
HN
NH
+
NH
HN
H
Ar'
Ar'
Ar'
Ar
N
R
Ar
Ar
Ar
OH
2
OH
Ar'
R=CH /CH CH
3
(2a-p)
3
2
Scheme 3. A feasible mechanism for N-acylatedpyrazolines.

148
P. Shanmugavelan et al. / Chinese Chemical Letters 25 (2014) 146–148
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Synthesis of 1,2,3-triazolyl-N-acetyl/N-propionylpyrazoline hybrids (2a–p).
Entry
Chalcones (1a-i)
R2
Timea (h)
Product
Yield (%)
1
1a
1b
1c
1d
1e
1f
CH3
3
2a
2b
2c
2d
2e
2f
95
96
94
95
96
93
93
94
95
92
92
92
93
90
91
90
2
CH3
3
3
CH3
3.5
3
4
CH3
5
CH3
3
6
CH3
4
7
1g
1h
1i
CH3
4
2g
2h
2i
8
CH3
3.5
3.5
4
9
CH3
10
11
12
13
14
15
16
1a
1c
1d
1e
1g
1h
1i
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
2j
4
2k
2l
3.5
4
2m
2n
2o
2p
4
3
3
a
Reaction times are reported based on TLC monitoring.
(Table 1). Thus, conventional heating was found to be the best
methodology for the target compounds.
Following optimization, the broad scope of the present protocol
was established via the synthesis of a library of novel 1,2,3-
triazolyl-N-acetyl/N-propionylpyrazoline hybrids (2a–p, Scheme
2) in excellent yields (90%–96%, Table 2), and it was noted that the
reaction involving acids with long alkyl chains such as butyric acid,
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Acknowledgment
The authors wish to thank IRHPA, DST for providing 300 MHz
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