One-pot synthesis of 1,2,4-oxadiazoles from carboxylic acids using 4-(dimethylamino)pyridinium acetate as efficient, regenerable, and green catalyst with ionic liquid character

Article abstract of DOI:10.1007/s13738-014-0542-3

A recyclable bifunctional acid-base organocatalyst with ionic liquid character has been prepared and its catalytic activity for the preparation of oxadiazoles has been investigated.

Full text of DOI:10.1007/s13738-014-0542-3

J IRAN CHEM SOC
DOI 10.1007/s13738-014-0542-3
ORIGINAL PAPER
One-pot synthesis of 1,2,4-oxadiazoles from carboxylic acids using
4-(dimethylamino)pyridinium acetate as efficient, regenerable,
and green catalyst with ionic liquid character
Najmeh Nowrouzi · Dariush Khalili ·
Maryam Irajzadeh
Received: 31 May 2014 / Accepted: 29 September 2014
© Iranian Chemical Society 2014
Abstract A recyclable bifunctional acid–base organo-
catalyst with ionic liquid character has been prepared and
its catalytic activity for the preparation of oxadiazoles has
been investigated.
The 1,2,4-oxadiazole scaffold is a class of heterocycle
commonly found in biologically active molecules. This
motif is often used as an amide or ester bioisostere and is
found in several drugs and drug leads that may potentially
act as serotonergic (5-HT3) antagonists, tyrosine kinase
inhibitors, monoamine oxidase inhibitors, aldose reduc-
tase inhibitors, metabotropic glutamate subtype 5 (mGlu5)
receptor antagonists, muscarinic agonists, and S1P1 ago-
nists. Therefore, they have received considerable attention
in the drug discovery programs and development of clean,
safe, effective, economical, and high-yielding synthesis
routes is still desirable and is in demand [6–11]. Several
methods have been reported in the literature for the synthe-
sis of these useful heterocycles [12–16]. Most commonly,
1,2,4-oxadiazoles are synthesized from amidoximes and
carboxylic acid derivatives in two steps. During the first
step, the amidoxime prepared by the addition of hydroxy-
lamine to a nitrile compound is O-acylated by an activated
carboxylic acid derivative. The heterocycle is subsequently
formed by intramolecular cyclodehydration. Cyclization of
the O-acyl amidoxime is generally the most difficult and
time-consuming step and often requires multi-step pro-
cedures, exhaustive reflux conditions in DMF or pyridine
and the use of a strong base [17]. Activated carboxylic acid
derivatives used for the O-acylation step include ester [18],
orthoesters [15], acid chlorides [19], and anhydrides [20].
The use of carbodiimides such as EDC, CDI, and DCC for
the in situ activation of carboxylic acids has been also pre-
viously published [21, 22]. These methods, however, suf-
fer from several drawbacks. Toxicity, high reactivity of acid
chlorides, difficult storage and handling, as well as limited
commercial availability of acid chlorides are major disad-
vantages of using these chemicals for synthetic purposes.
In addition, carboxylic acids need a coupling reagent such
as DCC, EDC, CDI, TBTU, HOBt, or HBTU to react with
Keywords Oxadiazoles · Ionic liquid · Organocatalyst ·
Multi-component reaction · 4-(N,N-Dimethylamino)
pyridine
Introduction
Multi-component reactions (MCRs) have emerged as an
attractive and powerful strategy for organic synthesis com-
pared to multi-step reactions due to the creation of several
new bonds in a one-pot reaction, low number of reaction
and purification steps, selectivity, synthetic convergence,
high atom economy, simplicity, and synthetic efficiency.
Therefore, academic and industrial research groups have
increasingly focused on the use of MCRs to synthesize a
broad range of products. In fact, development of MCRs
can lead to new efficient synthetic methodologies to afford
many small organic compounds in the field of modern
organic, bioorganic, and medicinal chemistry [1–5].
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-014-0542-3) contains supplementary
material, which is available to authorized users.
N. Nowrouzi (*) · M. Irajzadeh
Department of Chemistry, Faculty of Sciences, Persian Gulf
University, Bushehr 75169, Iran
e-mail: nowrouzi@pgu.ac.ir
D. Khalili
Department of Chemistry, Shiraz University, Shiraz 71454, Iran
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J IRAN CHEM SOC
Table 1 Effect of catalyst loading and temperature on the three-com-
ponent condensation of benzonitrile, hydroxyl amine, and benzoic
acid in solvent-free conditions
amidoximes. In these cases, the reaction time is relatively
long. Application of toxic organic solvents during the main
process of synthesis and/or workup, relying on multi-step
conditions, tedious workup procedure, troublesome waste
discarding, high reaction time, and low yields are is another
deficiency of these methods from the green chemistry point
of view. Thus, obviation of these limitations is necessary to
develop a simple and green synthesis of oxadiazoles.
Ionic liquids, because of their low volatility, nonflam-
mability, capacity to dissolve various organic and inorganic
compounds, and potentially recyclable properties have
attracted considerable attention as environmentally friendly
reaction media and catalyst in the green organic synthesis
[23].
Nowadays, the design and synthesis of catalysts with
well-defined multiple active sites (acid, base, redox, etc.) is
an increasingly emerging field in chemistry [24–26]. The
different active sites may be used to promote sequential
transformations or to act synergistically to increase the rate
and selectivity of a given chemical reaction.
CN
CO2H
O
N
NH2OH
N
Cat.
Temperature
Entry
Temperature
Catalyst loading (mol %)
Yield (%)a
1
2
3
4
5
6
7
8
100
100
100
100
100
70
–
–
10
20
25
30
25
25
25
71
82
93
92
65
27
15
50
r. t.
Reaction conditions: 1.0 mmol of benzonitrile, 1.0 mmol of hydroxyl
amine, and 1.0 mmol of benzoic acid
a
Isolated yield
Bold values indicate the best reaction conditions
Results and discussion
yield within 6 h (Table 1, Entry 4). No oxadiazole forma-
tion was observed in the absence of the catalyst (Table 1,
Entry 1). To optimize the molar ratio of reactants, experi-
ments were performed to compare the effects of various
molar ratios on yield. We found that there was no benefit in
increasing the molar equivalents of hydroxylamine or car-
boxylic acid in relation to arylnitrile.
4-(N,N-Dimethylamino)pyridine (DMAP) is a very effective
nucleophilic base catalyst for organic transformations [27,
28]. However, these transformations suffered from hardly
recyclability of DMAP, which went against the promising
viewpoint of green chemistry in modern chemical research.
Several strategies have been developed to circumvent this
problem [29–32], but most have been accompanied by
activity loss [33–37] or recycling difficulty [38–41].
Considering both DMAP’s excellent catalytic properties
and advantages of ILs, here, we developed a new acidic–
basic task-specified ionic liquid, through the neutraliza-
tion reaction of DMAP and acetic acid. 4-(dimethylamino)
pyridinium acetate as a bifunctional acid–base catalyst,
having at the same time characteristics of ionic liquid, can
act as an efficient catalyst and media for the synthesis of
1,2,4-oxadiazoles in high yields via a one-pot reaction of
nitriles, hydroxyl amine, and carboxylic acids as reactants.
To study the effect of catalyst loading and temperature
on the three-component condensation reactions for the
synthesis of 1,2,4-oxadiazoles, the solvent-free reaction of
benzonitrile (1.0 mmol), hydroxyl amine (1.0 mmol) and
benzoic acid (1.0 mmol) in the presence of 4-(dimethyl-
amino)pyridinium acetate, as catalyst was selected as a
model. The reaction was carried out with different amounts
of catalyst (10, 20, 25, 30 mol %) and various temperature
(25, 50, 70 and 100 °C).
To assess the efficiency and the scope of this new
method in the preparation of 1,2,4-oxadiazoles, different
carboxylic acids were reacted with structurally and elec-
tronically diverse nitriles under the optimal reaction condi-
tions. The respective results are displayed in Table 2.
Among the various nitriles tested, ones with electron-
withdrawing substituents on the ring reacted more effi-
ciently than those with electron-releasing substituents
(Table 2, Entries 1 and 6 compared to Entry 9). Inverse,
the presence of electron-withdrawing groups on the aro-
matic acids resulted in the corresponding products in lower
yields; however, the presence of electron-donating groups
afforded the corresponding products with higher yields
(Table 2, Entries 6–8). So, it seems that electronic effects
play a major role in this process. The reaction was also per-
formed with aliphatic nitrile (Table 2, Entry 11). Propionic
acid as an aliphatic carboxylic acid (Table 2, Entry 12) and
terephthalic acid as a dicarboxylic acid (Table 2, Entry 13)
appear to react without difficulty.
The reusability of a catalyst is of great importance from
economic and environmental points of view. Therefore,
we investigated the recycling of the catalyst using a model
reaction of benzonitrile, hydroxyl amine and benzoic acid.
As it was shown in Table 1, at 100 °C, 25mol % of the
catalyst was sufficient to catalyze the reaction efficiently; in
this case, the corresponding product was obtained in 93 %
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J IRAN CHEM SOC
NMe2
Table 2 Synthesis of
1,2,4-oxadiazoles via three-
component condensation of
nitriles, hydroxyl amine, and
carboxylic acids
O
N
N
CO2H
CN
CH3CO2
N
H
R'
NH2OH
100 oC
R'
R
R
Yield
(%)a
Entry
ArCN
ArCO2H
Product
O
N
CN
CO2H
1
93 %
N
O
N
N
CO2H
CN
CN
CN
CN
2
3
4
5
93 %
95 %
85 %
50 %
N
CH3
OCH3
Cl
H3C
O
CO2H
N
H3CO
Cl
O
N
CO2H
N
O
N
CO2H
N
NO2
O2N
O
CN
N
CO2H
N
6
87 %
H3C
H3C
CN
CN
O
N
CO2H
CO2H
N
7
8
92 %
OCH3
H3C
H3C
H3CO
H3C
O
N
N
46 %
NO2
O2N
H3C
O
CN
CN
N
CO2H
N
9
96 %
F3C
F3C
F3C
O
N
CO2H
N
OCH3
10
11
95 %
60 %
F3C
H3CO
O
CO2H
N
CN
All reactions were performed
with 1.0 mmol of nitrile,
1.0 mmol of hydroxyl amine,
1.0 mmol of carboxylic acid,
and 25 mol % IL at 100 °C for
6 h
N
O
N
CN
CN
12
89 %
91 %
CO2H
N
a
Isolated yield
CO2H
O
O
N
b
N
2.0 mmol of nitrile and
13b
2.0 mmol of hydroxyl amine
were used
N
N
Ph
Ph
HO2C
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J IRAN CHEM SOC
Table 3 Recyclability of 4-(dimethylamino)pyridinium acetate for
the preparation of 3,5-diphenyl-1,2,4-oxadiazole
After completion of the reaction, water was added and the
precipitated mixture was filtered off for separation of crude
products. After washing the solid products with water com-
pletely, the water-containing IL (IL is soluble in water) was
evaporated under reduced pressure and IL was recovered
and reused. As shown in Table 3, the recovered catalyst was
reused seven runs without any loss of its activity.
The synthetic route to 1,2,4-oxadiazole derivatives is
shown in Scheme 1. In the presence of the catalyst, esteri-
fication reaction occurred between amidoxime (prepared
from the reaction of nitrile and hydroxyl amine) and car-
boxylic acid. Because of the better nucleophilicity of the
oxygen atom compared to amidine nitrogen atom [42], the
oxygen atom attacks the carboxylic acid carbonyl group.
Finally, cyclization, followed by dehydration reaction pro-
duced the corresponding oxadiazole.
Run
Yield of product (%)a
Yield of recovered catalyst (%)
1
2
3
4
5
6
7
93
93
90
91
87
83
83
100
100
98
98
95
93
93
The reaction between benzonitrile (1.0 mmol), hydroxyl amine
(1.0 mmol), and benzoic acid (1.0 mmol) was performed in the pres-
ence of 4-(dimethylamino)pyridinium acetate (25 mol %) at 100 °C
for 6 h
a
Isolated yield
Scheme 1 Proposed mecha-
nism of oxadiazole formation
2
R1
C NH
NMe2
NMe2
NH2OH
R1
R1
C
N
-H
N
H
1
+H
N
C
NH
2
1
H
NH
OH
2
R1
C
NH
NH2
C
HN
OH
R1
N
OH
R1
O
C
NH2
R2
R2
C OH2
2
2
N
HO
O
C
R2
OH
O
1
R1
N
N
1
R1
R2
O
C
NH2
R2
N
O
2
O
R1
1
NH
N
R1
R2
O
C
NH2
R2
2
N
O
H2O
R1
H
OH
N
R1
N
OH2
R2
N
O
NH2
OH
R2
O
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J IRAN CHEM SOC
Conclusion
For recycling the catalyst, after washing solid products
with water completely, the water containing ionic liquid (IL
is soluble in water) was evaporated under reduced pressure
and the ionic liquid was recovered and reused.
In summary, the efficiency and versatility of a recyclable
bifunctional acid–base organocatalyst with ionic liquid
character for the preparation of 1,2,4-oxadiazole derivatives
were demonstrated by the wide range of substituted and
structurally diverse carboxylic acids and nitriles to synthe-
size the corresponding products in good to excellent yields.
The synthetic methodology described herein allows for
ease of purification, as the desired product precipitates out
as a solid and can thus be isolated using simple filtration
as opposed to lengthy column chromatographic purifica-
tion techniques. Furthermore, one of the problems associ-
ated with the use of organocatalysts, i.e., catalyst recovery,
is solved here. Therefore, the organocatalyst presented here
shows the advantages of the molecularly designed homoge-
neous catalysts with the recyclability of the heterogeneous.
Acknowledgments We gratefully acknowledge the support of this
study by Persian Gulf University Research Council.
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