Synthesis of N-Acyl Triazolyl-Pyrazolines via Acylation Initiated by the Hydrazone Moiety with Carboxylic Acids

Article abstract of DOI:10.1080/00397911.2015.1104357

An efficient synthesis of N-acyl/N-substituted acyl pyrazolines and their triazole hybrids have been accomplished via acylation of pyrazolines and pyrazoline-triazole hybrids with carboxylic acids and/or substituted carboxylic acids in the absence of activating agents/catalysts. In the present study, a mechanism envisaging the in situ generation of a new transient acylating intermediate has been proposed to explain the acylation.

Full text of DOI:10.1080/00397911.2015.1104357

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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Synthesis of N-Acyl Triazolyl-Pyrazolines via.
Acylation Initiated by the Hydrazone Moiety with
Carboxylic Acids
Archana Sivasubramaniyan, Dinesh Murugan, Ranganathan Raja,
Sathishkumar Murugan, Shanmugavelan Poovan & Ponnuswamy
Alagusundaram
To cite this article: Archana Sivasubramaniyan, Dinesh Murugan, Ranganathan Raja,
Sathishkumar Murugan, Shanmugavelan Poovan & Ponnuswamy Alagusundaram (2015):
Synthesis of N-Acyl Triazolyl-Pyrazolines via. Acylation Initiated by the Hydrazone Moiety with
Carboxylic Acids, Synthetic Communications, DOI: 10.1080/00397911.2015.1104357
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1104357
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Date: 23 October 2015, At: 22:08

Synthesis of N-Acyl Triazolyl-Pyrazolines via. Acylation Initiated by the Hydrazone
Moiety with Carboxylic Acids
Archana Sivasubramaniyan1, Dinesh Murugan1, Ranganathan Raja1, Sathishkumar
Murugan1, Shanmugavelan Poovan2, Ponnuswamy Alagusundaram1
1Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University,
Madurai, Tamilnadu, India, 2Department of Chemistry, Tamilnadu Open University,
Chennai, Tamilnadu, India
Corresponding author, Ponnuswamy Alagusundaram, E-mail: ramradkrish@yahoo.co.in
Abstract
An efficient synthesis of N-acyl/N-substituted acyl pyrazolines and their triazole hybrids
have been accomplished via acylation of pyrazolines and pyrazoline-triazole hybrids with
carboxylic acids and/or substituted carboxylic acids in the absence of activating
agents/catalysts. In the present study, a mechanism envisaging the insitu generation of a
new transient acylating intermediate has been proposed to explain the acylation.
KEYWORDS: acylation; pyrazolines; triazole; hybrids; hydrazones
INTRODUCTION
Amides and heterocyclic moieties are present in many bioactive natural products and
commercial drugs exhibiting themselves as synthetic targets. Pyrazolines and their amide
1

derivatives viz N-acyl, N-sulfonamide and N-thiomide pyrazolines show interesting
pharmacological profile such as anti-bacterial1, anti-inflammatory and analgesic2, anti-
fungal3, anti-tubercular4, anti-cancer5, anti-microbial6 and anti-convulsant7 activities, anti-
inflammatory – antimicrobial agents8 and MAO-inhibitors9.
Bioactivities of various pyrazoline derivatives vide supra indicate that by varying the acyl
side chain, a diversified bioactivity has been noted (Figure 1). Herein, it is pertinent to
mention that a little emphasis has been focused on the synthesis of N-acyl pyrazoline with
substituent in the acyl part. To the best of our knowledge, except N-acetyl-, N-propionyl-
and N-α-chloroacetyl pyrazolines10-16, no other substituted N-acyl pyrazolines have been
reported.
The N-(substituted acyl) pyrazolines with varying substituents such as chloro- or
hydroxy- or mercapto- group in the acyl moiety have been chosen for synthesis in the
present investigation. The significance of choosing these substituents is to use them as
potential synthons for the synthesis of hitherto unknown hybrid heterocyclic compounds
via substitution and further modification.
On the other hand, venture into the synthesis of hybrid heterocycles as potential bioactive
compounds is of recent interest. In this regard, we have reported17 the synthesis and
bioactivities of hybrid heterocycles viz. 1,2,3-triazolyl pyrazoline hybrids, 1,2,3-triazolyl-
2-aminopyrimidine hybrids, 1,2,3-triazolyl dihydropyrimidine-2-thione hybrids and
1,2,3-triazolyl indole hybrids.
2

In view of the importance of N-acyl pyrazoline and hybrid heterocycles, we were
prompted to synthesize acylated-pyrazolines and their triazole hybrids in the present
research.
The acylation of alcohols, phenols and amines is an important transformation in organic
synthesis. Acylation of such functional groups are often necessary during the course of
various transformations in a synthetic sequence, especially in the construction of
polyfunctional molecules such as nucleosides, carbohydrates, steroids and natural
products. Generally, acylation is carried out using acid chlorides or acid anhydrides with
the usage of various catalysts such as CoCl2,18 Bu3P,19 Triflates,20-24 TaCl5,25 zeolite,26
clays,27ionic liquids,28 ZrOCl2.8H2O,29 alumina,30 ZnO31 and titanocene bis
(perfluorooctanesulfonate).32 However, in recent studies33-38 acylating agents viz. acetyl
chloride and acyl anhydride are used rarely due to their labile and hazardous nature.
Moreover, some of the pyrazolines have been reported39-41 as decomposable.
Interestingly and surprisingly, acylation of pyrazolines occurs with just carboxylic acid
without any catalyst which seems to be noteworthy. Furthermore, so far no emphasis has
been given for probing into the same and the acylating agent (formed if any) involved
during the reaction. Hence, we were provoked to investigate on the same. This was
because understanding (by tracing) the acylating intermediate involved, it would help to
establish a new catalyst/activating agent-free acylating protocol with less hazardous and
readily available carboxylic acids rather than the highly labile/reactive and hazardous
3

conventional reagents and catalysts. In this regard, recently we have reported17a
a
probable mechanism for the same envisaging a transient acylating intermediate that might
have been generated insitu. A deeper look on the same and its applicability has been
focused and explored in the present study.
At the outset, a mixture of pyrazoline and acetic acid under refluxing temperature afford
the N-acetyl pyrazoline in 95% yield in 1 h (Scheme 1). For further optimization, the
reaction was carried out by varying the reaction temperature and time (Table 1, entries 1–
5). The optimized temperature and time identified were 110 °C and 1 hour in acetic acid
wherein excellent yield of N-acetyl product (95 %) was noted. Interestingly, the
acetylation is noted to proceed even at room temperature.
RESULTS AND DISCUSSION
Encouraged by the optimization, it was planned to explore the acylation of pyrazoline
using various carboxylic acids as the acylating agent without any catalyst. The optimized
condition was followed for the acylation of the pyrazoline with various carboxylic acids
to synthesize the N-acylated pyrazolines (Table 2) and N-acylated pyrazoline-triazole
hybrids (Table 3) in excellent yields.
Pyrazoline/pyrazoline-triazole hybrids were heated at 110 °C with liquid carboxylic acids
such as acetic, propionic, butyric, thioglycolic and thiopropionic acids for an hour to
afford corresponding N-acyl pyrazolines . Additionally, solid aliphatic acids such as
phenyl-, phenoxy-, chloro- acetic acids and glycolic acid were used for acylation. In
4

case of solid aliphatic acid the acylation was achieved in molten states. Further, the
acylation was performed under aqueous condition, the results of which are presented in
table 4. It is noteworthy that acetic acid/water ratio had an impact on the efficiency of
acylation of pyrazoline. i.e. upto acetic acid/water ratio (50/50) (Table 4, entry 2 & 3), the
yield of the product was good. Further by increasing the quantity of water in the ratio
(Table 4, entry 4 & 5), no acylation occurred. Apparently, the poor solubility of
pyrazoline in highly aqueous media would have hindered the reaction progress.
A plausible mechanism for N-acylation of pyrazolines (Scheme 2) using carboxylic acids
is sketched below in which the product formation may be expected via three possible
routes viz. route A, B & C. A transient acylating intermediate may be expected by the
protonation of the imino nitrogen of the pyrazoline followed by the attack of the
carboxylic acid at the imino carbon. In route A, an intermolecular attack of a lone pair on
nitrogen atom on the carbonyl carbon of the intermediate may lead to the product III. On
the other hand, route B deals with an intramolecular attack of a lone pair of the nitrogen
atom on the carbonyl carbon of the intermediate may afford the same product. In route
C, insitu formation of an anhydride may be expected to take place by the reaction of the
intermediate with carboxylic acid, which may acylate the pyrazoline.
Having proposed the above possible routes for the acylation of pyrazolines with
carboxylic acid, it was further attempted to investigate the most probable route. In this
regard, external amine viz. benzyl amine was added into the reaction mixture (pyrazoline
and acetic acid) and refluxed under the optimized reaction condition. The attempt
5

resulted in the acylation of pyrazoline alone even though benzyl amine was present in the
medium. This indicated that the reaction proceeds via the intramolecular pathway (route
B) rather than the intermolecular mechanism. Had it been the intermolecular route, it
should have afforded the N-acetyl pyrazoline and N-acetyl benzylamine. This was
further confirmed unambiguously by treating a mixture of pyrazoline and benzylamine
with acetic anhydride under refluxing condition identical to the above wherein N-
acetylation of both occurred. Thus, the mechanism involved in the acylation of
pyrazoline with carboxylic acid was unequivocally confirmed to be intramolecular.
It is pertinent to mention here that the above mechanism involving the initial protonation
of the imino nitrogen of the hydrazone moiety of the pyrazoline followed by the attack of
the carboxylic acid as nucleophile at the electrophilic imino carbon is supported by
similar mechanism reported in the acylation of amines and alcohols using carbodimide42.
Having investigated the mechanism and its applicability, we were interested to
investigate the acylation of partial skeletons of pyrazolines to develop further insight into
the mechanism so that its applicability can be expanded and generalized towards a
common acylation reaction using carboxylic acid.
In this regard, the partial skeletons (A & B) (figure 2) of pyrazoline were refluxed with
acetic acid and the product identified. With regard to the partial skeleton, hydrazones of
benzaldehyde and acetophenone were individually treated with acetic acid under
optimized condition. It was notable that at the outset the reaction was not smooth
6

affording a viscous unidentifiable product. Literature data related to this was noted in a
patent43. wherein hydrazones get acylated with a slight modified reaction condition viz.
one pot synthesis of acylation of hydrazone. However, the work was restricted only to
acylation with acetic acid. So we planned to apply this protocol to generalize the same
and hence landed successfully in the acylation of hydrazones with different carboxylic
acids in very excellent yields (Table 5).
In conclusion, the present study discloses that the N-acylation of pyrazoline readily
occurs using carboxylic acids as the acylating agent without any catalyst /activating
agent. The investigation proposes an interesting mechanism via the insitu generation of
transient acylating intermediate as an acyl group contributor. The novel synthetic
protocol has been applied for the synthesis of a variety of N-acyl pyrazolines and their
triazole hybrids. Further studies in this regard is under progress which may pave way for
the development of a general novel new acylating protocol in organic synthesis using
carboxylic acids without catalyst/activating agents.
EXPERIMENTAL
General
All chemicals, reagents, and solvents were of commercially high purity grade purchased
from Avra Synthesis Pvt. Ltd. and Merck Ltd. India. Silica gel (60–120 mesh) was used
for column chromatographic isolation and purification of the compounds synthesized.
1
Melting points were obtained on electro-thermal apparatus and are uncorrected. H NMR
(300 MHz) and 13C NMR (75 MHz) spectra were recorded in CDCl3 on Bruker Avance
7

(300 MHz) spectrometer and the chemical shifts are reported as values in parts per
million (ppm) relative to tetramethylsilane, with coupling constant (J) values in Hertz
General Procedure for The Synthesis of Pyrazolines44
Equimolar quantities of 3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (1 mmol) and
hydrazine hydrate (1 mmol) in ethanol (10 mL) was refluxed for 3 hours. The resulting
mixture was poured onto crushed ice. The solid obtained was filtered as the pure
product.
General Procedure for Acylation of 5-(4-Methoxyphenyl)-3-Phenyl-4,5-Dihydro-
1H-Pyrazole
5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole 1 (1 mmol), was dissolved in
carboxylic acids (2 mL) 2 and heated at 110 °C for an hour. After the completion of the
reaction (monitored by TLC), the mixture was treated with aqueous sodium bicarbonate
to neutralize the excess acid. Then the reaction mixture was extracted with
dichloromethane to separate the organic layer and dried over anhydrous sodium sulfate
and concentrated under reduced pressure. The residue was purified by column
chromatography using pet ether: ethyl acetate (93:7) as the eluent to afford the pure
products (3a-3i) in excellent yields (91-95 %). While compounds 3a10, 3b11, 3f12are
known, others are hitherto unknown compounds.
1-(5-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)butan-1-one (3c). Yield:
94%. White solid. M.p. 105-107 °C. FTIR (KBr) ʋ /cm-1 1658, 1599. 1H NMR (300
8

MHz, CDCl3): δ 7.74 (d, J = 6.7 Hz, 2H); 7.47 – 7.37 (m, 3H); 7.15 (d, J = 8.7 Hz, 2H);
6.82 (d, J = 8.7 Hz, 2H); 5.52 (dd, J = 11.8, 4.6 Hz, 1H); 3.74 (s, 3H); 3.71 – 3.61 (m,
1H); 3.11 (dd, J = 17.7, 4.6 Hz, 1H); 2.77 (ddd, J = 15.0, 9.0 Hz, 2H); 1.79 – 1.66 (m,
2H); 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 171.0; 158.6; 153.1; 134.0;
131.3; 129.9; 128.4; 126.6; 126.2; 125.1; 113.9; 59.2; 54.8; 41.7; 35.8; 18.1; 13.7. Anal.
Calcld. for (%) C20H22N2O2: C 74.51, H 6.88, N 8.69; Found : C 74.57, H 6.93, N, 8.74.
General Procedure for the Synthesis of Triazole-Pyrazoline Hybrids
Equimolar quantities of 1-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-4-(4-
methoxyphenyl) but-3-en-1-one (1 mmol) and hydrazine hydrate (1 mmol) in Ethanol (10
mL) was refluxed for 3 hours. The resulting mixture was poured onto crushed ice. The
solid obtained was filtered as a pure product.
General Procedure for the Acylation of 1-Benzyl-4-(5-(4-Methoxybenzyl)-4,5-
Dihydro-1H-Pyrazol-3-Yl)-5-Methyl-1H-1,2,3-Triazole
1-Benzyl-4-(5-(4-methoxybenzyl)-4,5-dihydro-1H-pyrazol-3-yl)-5-methyl-1H-1,2,3-
triazole 1 (1 mmol) in carboxylic acids (2 mL) 2 was heated at 110 °C for 1 hour. After
the completion of the reaction (as monitored by TLC), the mixture was treated with
aqueous sodium bicarbonate to wash the excess acid. Then the reaction mixture was
extracted with dichloromethane to separate the organic layer and dried over anhydrous
sodium sulfate and concentrated under reduced pressure. The residue was purified by
column chromatography using pet ether: ethyl acetate (90:10) as the eluent to afford the
9

pure products (3j-r) in excellent yields (89-94 %). While compounds (3j& 3k)17 are
known, other compounds are hitherto unknown.
1-(3-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-
pyrazol-1-yl)butan-1-one (3l). Yield: 94%. Gummy matter. FTIR (KBr) ʋ /cm-1 1626,
1568. 1H NMR (300 MHz, CDCl3): δ 7.35 (s, 3H); 7.23 – 7.11 (m, 2H); 6.94 (d, J = 7.4
Hz, 2H); 6.83 (d, J = 8.0 Hz, 2H); 5.55 (s, 2H); 5.49 (dd, J = 12.0, 4.4 Hz, 1H); 3.83 –
3.72 (m,1H); 3.77 (s, 3H); 3.43 (dd, J = 18.3, 4.4 Hz, 1H); 2.65 (dd, J = 14.0, 7.0 Hz,
2H); 2.52 (s, 3H); 1.83 – 1.54 (m, 2H); 0.93 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 170.8; 158.5; 149.0; 137.8; 133.9; 133.6; 132.7; 128.7; 128.1; 126.9; 126.6;
113.8; 58.0; 54.8; 51.5; 42.7; 35.8; 18.0; 13.7; 9.1. Anal. Calcld. for (%) C24H27N5O2 : C
69.04, H 6.52, N 16.77; Found: C 69.08, H 6.50, N 16.81.
General Procedure for the Synthesis of N-Acyl Hyrazones (8a-I)
Acetophenone/benzaldehyde or 1-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)ethanone 5
(1 mmol), was dissolved in carboxylic acids (2 mL) 2 to which hydrazine hydrate 6 (1
mmol), was added slowly while the mixture was maintained in ice cold condition with
stirring for 30 min. Then the mixture was allowed to reach the room temperature and then
heated to reflux for 6 hours. Then it was treated with aqueous NaHCO3 solution followed
by the extraction with dichloromethane. Then, the organic layer was separated and dried
over anhydrous Na2SO4. It was then separated by column chromatography using
petroleum ether: ethyl acetate (93:7) as the eluent to afford the product (8a-i) in excellent
yields (90-94 %). While compound 8a43is known, others are hitherto unknown.
10

N'-(1-Phenylethylidene)propionohydrazide (8b). Yield: 93%. White solid. M.p. 137-139
1
°C. FTIR (KBr) ʋ /cm-1 1676, 1560. H NMR (300 MHz, CDCl3): δ 8.62 (s, 1H); 8.00 –
7.61 (m, 2H); 7.71 – 7.41 (m, 3H); 2.82 (q, J = 7.5 Hz, 2H); 2.22 (s, 3H); 1.24 (t, J = 7.5
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 177.6; 147.1; 138.1; 128.7; 128.1; 125.8; 26.0;
12.8; 8.6. Anal. Calcld. for (%) C11H14N2O : C 69.45; H 7.42, N 14.73; Found: C 69.48,
H 7.47, N 14.70.
FUNDING
The authors thank IRHPA, DST for providing 300 MHz NMR instrument for recording
the NMR spectra for the compounds synthesized and UGC-BSR for giving financial
support.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher’s website
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Table 1. Optimization of temperature/time in the synthesis of N-AcetylPyrazolines 3a
Entry
Temp [°C]
RT
Time [h]
Yield [%]a
1
8
1
2
3
1
45
60
70
85
95
2
70-80
70-80
70-80
110
3
4
5
aIsolated yield
16

Table 2. Synthesis of N-acylated pyrazolines 3a-i
Substrate
Yield
[%]a
Entry
1
Acids
Product
1
1
acetic acid
95
92
94
3a
3b
3c
2
3
1
1
propionic acid
butyric acid
4
1
phenyl acetic acid
91
3d
3e
phenoxy acetic
acid
5
6
1
1
93
94
chloro acetic acid
3f
17

7
8
9
1
1
1
glycolic acid
thioglycolic acid
thiopropionic acid
91
90
92
3g
3h
3i
aIsolated yield
18

Table 3. Synthesis of N-acylated pyrazoline-triazole hybrids 3j-r
Substrate
Yield
[%]a
Entry
1
Acids
Product
1a
1a
acetic acid
92
3j
2
3
4
1a
1a
1a
propionic acid
butyric acid
90
3k
94
91
3l
phenyl acetic
acid
3m
phenoxy acetic
acid
5
1a
89
3n
3o
chloro acetic
acid
6
7
1a
1a
91
93
glycolic acid
3p
19

thioglycolic
acid
8
9
1a
1a
92
94
3q
3r
thiopropionic
acid
aIsolated yield
20

Table 4. Screening of AcOH / Water ratio in the synthesis of N-acetyl pyrazoline 3a
Entry
AcOH /Water Ratio
Yield[%]a
95
1
100/0
70/30
50/50
30/70
10/90
2
89
3
83
4
No reaction
No reaction
5
aIsolated yield
21

Table 5. Synthesis of N-acylated hydrazones 8a-i
Entry
Substrate
Acids
Product
Yield [%]a
1
acetic acid
91
5
8a
propionic
acid
2
3
4
5
93
92
93
90
5
5
8b
butyric acid
8c
acetic acid
5a
5a
8d
propionic
acid
8e
22

6
butyric acid
94
5a
8f
7
acetic acid
93
5b
8g
propionic
acid
8
91
5b
8h
9
butyric acid
90
5b
8i
aIsolated yield.
23

Scheme 1. Synthesis of N-acylated pyrazolines/ N-acylated pyrazoline-triazole hybrids
24

Scheme 2. Plausible mechanism for N-acylation
25

Scheme 3. Synthesis of N-acyl hydrazones
26

Figure 1. Some biologically potent pyrazolines and N-acyl pyrazolines
27

Figure 2. Partial skeletons of pyrazoline.
28