Facile one-pot synthesis of new [1,2,4]triazolo[1,5-a]pyridine derivatives by ultrasonic irradiation

Article abstract of DOI:10.1080/00397911.2017.1357078

Herein, we report an ultrasonic promoted facile and convenient “one-pot” procedure for the synthesis of new [1,2,4]triazolo[1,5-a]pyridine derivatives 3, 4 and 5, using Amberlite IRA-400, in short reaction times and high yields and its comparison with classical reaction conditions. The structures of new compounds were assigned with the help of analytical ¹H, ¹³C NMR, and mass spectral studies.

Full text of DOI:10.1080/00397911.2017.1357078

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Facile one-pot synthesis of new [1,2,4]triazolo[1,5-
a]pyridine derivatives by ultrasonic irradiation
Lazhar Zribi, Fathi Zribi, José Marco-Contelles, Fakher Chabchoub &
Lhassane Ismaili
To cite this article: Lazhar Zribi, Fathi Zribi, José Marco-Contelles, Fakher Chabchoub &
Lhassane Ismaili (2017): Facile one-pot synthesis of new [1,2,4]triazolo[1,5-a]pyridine derivatives
by ultrasonic irradiation, Synthetic Communications, DOI: 10.1080/00397911.2017.1357078
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1357078
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Date: 05 October 2017, At: 08:37

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1357078
Facile one-pot synthesis of new [1,2,4]triazolo[1,5-a]pyridine
derivatives by ultrasonic irradiation
Lazhar Zribia, Fathi Zribia, José Marco-Contellesb, Fakher Chabchouba, and
Lhassane Ismailic
aLaboratory of Applied Chemistry, Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of
c
Sfax, Sfax, Tunisia; bLaboratory of Medicinal Chemistry, SEPCO (IQOG, CSIC), Madrid, Spain; Laboratoire de
Chimie Organique et Thérapeutique, Neurosciences Intégratives et Cliniques, University of Bourgogne
Franche-Comté, Besançon, France
ABSTRACT
ARTICLE HISTORY
Received 4 April 2017
Herein, we report an ultrasonic promoted facile and convenient “one-
pot” procedure for the synthesis of new [1,2,4]triazolo[1,5-a]pyridine
derivatives 3, 4 and 5, using Amberlite IRA-400, in short reaction times
and high yields and its comparison with classical reaction conditions.
The structures of new compounds were assigned with the help of
KEYWORDS
Amberlite IRA-400;
multicomponent reaction;
one-pot synthesis;
triazolopyridines; ultrasound
irradiation
1
analytical H, 13C NMR, and mass spectral studies.
GRAPHICAL ABSTRACT
Introduction
It is well known that triazoles and triazolopyridine derivatives display several biological
activities such as anti-inflammatory,[1] antibacterial,[2] antiproliferative,[3] and
antidepressant.[4] Furthermore, triazolopyridines have been described as inhibitors of the
cardiac channel,[5] p38 MAP kinase,[6] JmjC histone lysine demethylase KDM2A,[7], and
identified as p38 inhibitors.[8]
On the other hand, ultrasound-assisted organic synthesis is considered as an important
technique for green and sustainable synthetic processes[9] that require small amounts of
solvents, and consume less energy,[10] showing important advantages, such as improved
chemical yields, shorter reaction times, lower costs, easier manipulation[9,11] as well as
minimal secondary side reactions.[12]
Multicomponent reactions (MCRs) are “one-pot” processes in which at least three or
more different starting materials react, affording the target products.[13–15] MCRs are a
simple and convergent atom-economic synthetic approach that offers advantages over
conventional multistep reactions for the synthesis of versatile arrays of molecules without
CONTACT Fakher Chabchoub
fakher.chabchoub@yahoo.fr
Faculty of Sciences of Sfax, B. P 802, 3000 Sfax-Tunisia;
Lhassane ismaili lhassane.ismaili@univ-fcomte.fr
UFR SMP, 19 Rue Ambroise Paré, 25030 Besançon cedex France.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2017 Taylor & Francis

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L. ZRIBI ET AL.
isolation of intermediates, fulfilling thus some of the goals of “green and sustainable
chemistry”.[16–18]
Heterogeneous catalysts have attracted particular attention owing to their remarkable
economic and environmental benefits. Indeed, these catalysts can be easily removed from
the reaction mixture and reused, unlike to homogeneous catalysts that provide faster
reaction rates, certainly, but the separation and recovery of the catalyst from the reaction
mixture still remain a major issue.[19]
Thus, taking into account and by combining MCRs, ultrasound-assisted organic
synthesis, and heterogeneous catalysts, aiming at reducing the environmental and health
impacts of chemical synthesis, we report herein the transformation of 2-(5-phenyl-4H-
1,2,4-triazol-3-yl)acetonitrile into several new [1,2,4]triazolo[1,5-a]pyridine derivatives in
good yields, through an MCR, under ultrasonic irradiation, and its comparison with
classical reaction conditions.
Results and discussion
The synthesis of the target compounds 3, 4, and 5 has been performed using a short
synthetic procedure as follows: first, 2-(5-phenyl-4H-1,2,4-triazol-3-yl)acetonitrile (2)[20]
was prepared by a new and facile method using the “one-pot” MCR, by reacting hydrazine
monohydrate with ethyl cyanoacetate, at 0 °C, followed by treatment with imidate 1, at
reflux in absolute ethanol for 4 h (Scheme 1). Next, compound 2 was reacted with malo-
nonitrile and aromatic aldehydes under classical reaction conditions using catalytic
amounts of piperidine, or using Amberlite IRA-400 as basic catalyst under ultrasound
Scheme 1. Synthesis of 2-(5-phenyl-4H-1,2,4-triazol-3-yl)acetonitrile (2) and [1,2,4]triazolo [1,5-a]
pyridine derivatives 3 and 4.

SYNTHETIC COMMUNICATIONS®
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Scheme 2. Synthesis of [1,2,4]triazolo [1,5-a]pyridine derivatives 5.
irradiation reaction conditions (Schemes 1 and 2). Under the classical heating conditions,
the reaction was achieved in 90 min when we used malononitrile and 120 min with ethyl
cyanoacetate.
Regarding the Amberlite IRA-400-promoted procedure under ultrasound irradiation
reaction conditions, the catalyst type and the ultrasound power intensity were critical.
The results are shown in Table 1. When the catalyst was tested for a model reaction without
sonication at 80 °C for 2 h, no product was obtained (Table 1, entries 1, 2). Furthermore, it
was noted that reaction in the presence of Amberlite IRA400 and ultrasonic irradiation
power of 60 W gave the best result with the highest yield (95%) after only 6 min (Table 1,
entry 5).
We have generalized, this reaction using several aldehydes to obtain 5-amino-2,
7-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-6,8-dicarbonitriles 3a–h and ethyl 5-amino-
8-cyano-2,7-diphenyl-[1,2,4]triazolo[1,5-a]pyridine-6-carboxylates 4a–g using malono-
nitrile or ethyl cyanoacetate, respectively (Table 2). In the aim to extend the scope of
this method, heterocyclic aldehyde (thiophene-2-carbaldehyde) was used in the same
condition and conducted to 5-amino-2-phenyl-7-(thiophen-2-yl)-[1,2,4]triazolo[1,5-a]
pyridine-6,8-dicarbonitrile and ethyl 5-amino-8-cyano-2-phenyl-7-(thiophen-2-yl)-
[1,2,4]triazolo[1,5-a]pyridine-6-carboxylate 5a–c. All compounds were characterized
by the usual spectroscopic methods and elemental analyses. As shown in Table 2,
compounds 3, 4, and 5 were isolated in good yields ranging from 67 to 71% under
the classical reaction conditions, and from 79 to 95% yields under the ultrasonic
irradiation reaction conditions, thereby demonstrating that ultrasound method improves
not only the reaction time but also the yields. It can also be noted that the reaction
Table 1. Optimization of the effect of ultrasonic irradiation on the synthesis of 3aa.
Entry
Power (W)
Time (min)
Temperature (°C)
Yield (%)b
1
2
3
4
5
—
—
40
50
60
120
120
20
r.t
80
60
60
60
—
—
91
92
95
12
6
a2-(5-Phenyl-4H-1,2,4-triazol-3-yl)acetonitrile (1 mmol), benzaldehyde (1 mmol), malononitrile (1 mmol), Amberlite IRA-400,
6 min, 60 °C, EtOH (5 cm3) under ultrasound irradiation (60% of amplitude).
bIsolated yields.

4
L. ZRIBI ET AL.
Table 2. MCR synthesis of 3a–e and 4a–e under classical and under ultrasound irradiation conditions.
Classical conditiona
Yields (%)c
Time (min)
71 90
Ultrasonic irradiationb
Entry
Y
R
R1
Yields (%)c
Time (min)
Melting point (°C)
1
2
CN
CN
H
H
H
95
95
93
93
92
85
92
83
83
81
80
79
80
84
91
94
93
93
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
>260
>260
>260
>260
>260
>260
>260
>260
256
>260
240
250
230
4-CH3
4-OCH3
3-OCH3
2-OCH3
4-NO2
4-OCH3
4-NO2
H
70
68
67
67
61
65
59
71
71
69
69
67
57
66
67
66
64
90
90
3
CN
H
4
CN
H
90
5
CN
H
90
6
CN
H
110
110
110
120
120
120
120
120
140
120
90
7
CN
CH3
CH3
H
8
CN
9
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CN
10
11
12
13
14
15
16d
17d
18d
4-CH3
4-OCH3
3-OCH3
2-OCH3
4-NO2
4-OCH3
H
H
H
H
H
>260
254
>260
>260
>260
CH3
H
d
—
d
CN
CO2Et
—
CH3
H
90
120
d
—
aCompound 2 (1 mmol), aromatic aldehydes (1 mmol), malononitrile (1 mmol), piperidine, 90 min, 80 °C, EtOH (15 cm3).
bCompound 2 (1 mmol), aromatic aldehydes (1 mmol), malononitrile (1 mmol), Amberlite IRA-400, 6 min, 60 °C, EtOH (5 cm3)
under ultrasound irradiation (60% of amplitude).
cIsolated yields.
dReactions with heteroaromatic aldehyde (thiophene-2-carbaldehyde).
performed using the ultrasonic irradiation procedure gave better results with malononi-
trile than with ethyl cyanoacetate
The proposed mechanism of this reaction starts by the formation of arylidene inter-
mediate I; next, the carbanion II attacks intermediate I to obtain III. The intramolecular
cyclization and oxidation give the required compounds 3 or 4 (Scheme 3). Compounds 5
were probably obtained by the same mechanism.
Conclusion
In this work, we have reported the MCR of [1,2,4]triazolo[1,5-a]pyridine derivatives under
classical condition and under ultrasound irradiation reaction conditions. From these
results, we conclude that the ultrasound method is an efficient, green, fast, and convenient
procedure for the synthesis of these triazolopyridines, with significant advantages such as
reduced reaction time, mild reaction condition, productivity and higher yield, easier of
execution, and economic viability respect to the classical procedure.
Experimental
This includes general procedure for the synthesis of compounds 3a–h, 4a–g, and 5a–c.
Experimental procedures for the intermediate and spectral data of all derivatives are
presented in Supporting Information.
Materials and methods
Melting points were determined on a Kofler apparatus (Wagner Munz) and are uncor-
rected. An ultrasonic model Bioblock Scientific 750 W probe was used to generate

SYNTHETIC COMMUNICATIONS®
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Scheme 3. Proposed mechanism of [1,2,4]triazolo[1,5-a]pyridine derivatives.
ultrasonic irradiation and homogenize the reaction mixture. The reactions were monitored
with TLC using aluminum sheets with silica gel 60 F254 from Merck. IR spectra were
1
performed on a Perkin–Elmer PARAGON FT-IR spectrometer. H and 13C NMR spectra
were recorded on a Bruker spectrometer using DMSO-d6 as a solvent. The chemical shifts
are reported in parts per million, using tetramethylsilane as an internal reference. The
multiplicities of the signals are indicated as follows: br, broad; s, singlet; d, doublet; t,
triplet; q, quadruplet; and m, multiplet, the coupling constants are expressed in Hz.
Elemental analysis was performed on Thermofinnigan Flash EA 1112. High-resolution
mass spectra were obtained at Centre Commun de Spectrométrie de Masse (Lyon, France)
on a Bruker micrOTOF-Q II spectrometer (Bruker Daltonics) in positive electrospray
ionization-time of flight.
General procedure for the synthesis of [1,2,4]triazolo[1,5-a]pyridine (3),
(4) and (5)
Method 1
A solution of 2-(5-phenyl-4H-1,2,4-triazol-3-yl)acetonitrile (2) (1 mmol), malononitrile or
ethyl cyanoacetate (1 mmol) and aromatic aldehydes (1 mmol) in absolute ethanol (5 cm3),
in the presence of IRA-400 (0.3 g), was placed in flask equipped with an ultrasonic probe.
The reaction was heated in an oil bath at 60 °C and sonicated in the ultrasonic generator
(Bioblock Scientific 70 W) at low 20 kHz (amplitude of 60%) for 6 min. After the reaction
was completed, the mixture was filtered, washed with ethanol, and dried to give
compounds 3a–h, 4a–g, and 5a–c.

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L. ZRIBI ET AL.
Method 2
A solution of compound 2 (1 mmol), malononitrile or ethyl cyanoacetate (1 mmol) and
aromatic aldehydes (1 mmol) in absolute ethanol (15 cm3), in the presence of piperidine
(1 mmol), was heated at 80 °C for 90 min. After the completion of reaction, the mixture
was filtered, washed with ethanol, and dried to give compounds 3a–h, 4a–g, and 5a–c.
Funding
This work was supported by Regional Council of Franche-Comte [Grant Numbers 2016YC-04540,
04560].
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