Regio-selective synthesis of 5-substituted 1H-tetrazoles using ionic liquid [BMIM]N3 in solvent-free conditions: A click reaction

Article abstract of DOI:10.1007/s11164-015-2105-3

A multi-component, one pot and regio-selective synthesis of different 5-substituted 1H-tetrazoles was successfully accomplished via a click reaction. In this respect, we have performed the reaction of either isatins or various aromatic aldehydes with malo

Full text of DOI:10.1007/s11164-015-2105-3

Res Chem Intermed
DOI 10.1007/s11164-015-2105-3
Regio-selective synthesis of 5-substituted 1H-tetrazoles
using ionic liquid [BMIM]N3 in solvent-free conditions:
a click reaction
Soheila Khaghaninejad1 Majid M. Heravi1
•
•
Tayebeh Hosseinnejad1 Hossein A. Oskooie1
Mehdi Bakavoli2
•
•
Received: 3 April 2015 / Accepted: 16 May 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A multi-component, one pot and regio-selective synthesis of different
5-substituted 1H-tetrazoles was successfully accomplished via a click reaction. In this
respect, we have performed the reaction of either isatins or various aromatic aldehydes
with malononitrile and ionic liquid, 1-butyl-3-methylimidazolium azide ([BMIM]N3), as
a relatively green source of azide mediated by o-phthalimide-N-sulfonic acid (OPNSA).
The calculated thermodynamic results demonstrate a reliable agreement with our ex-
perimentally observed regio-selectivity. From the electronic viewpoint, we have also
assessed the nature of regio-selectivity via quantum theory of atoms in molecule
analysis.
&
Majid M. Heravi
mmh1331@yahoo.com
1
2
Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran
Department of Chemistry, School of Science, Ferdowsi University of Mashhad, Mashhad, Iran
123

S. Khaghaninejad et al.
Graphical Abstract
O
O
CN
N
N
N
N
H
8
N
HN
H
N
N
N
NC
N
NC
N
N
R1
H
O
N
H
R2
4Z (Major)
6E (Major)
N
N
N
N
HN
H
HN
N
CN
O
NC
N
R
R
N
H
CN
CN
4E (minor)
6Z (minor)
C
n-But
N3
Keywords Click reaction Á Ionic liquid: 1-butyl-3-methylimidazolium azide Á
5-Substituted 1H-tetrazoles Á Density functional theory Á Quantum theory of
atoms in molecule Á Regio-selectivity
List of symbols
T
t
Temperature (°C)
Time (t)
Values of electron density
qb
2
r qb Laplacian of qb
Gb
Vb
Hb
Electronic kinetic energy density
Electronic potential energy density
Total electronic energy density
DEe,r The reaction energy from the total electronic energies
DE0,r The reaction energy with zero-point energies
DHr Reaction enthalpy
DGr Free energy
DSr
Entropy change
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
Introduction
Tetrazoles are among important heterocyclic systems. They are distinguished for the
resemblance of their pKa values with those of carboxylic acids and are compared
with carboxylic acids from the biological point of view [1, 2]. Several tetrazole
derivatives illustrate various biological potencies, such as antibacterial, anti-
inflammatory, antifungal, antiviral, antitubercolous, cyclo-oxygenase inhibitors,
antinociceptive, hypoglycemic and anticancer activities [3].
Several derivatives of this heterocycle are also important in coordination
chemistry [4] and have found widespread applications in pharmaceutical and
material science [1]. A few of them are also reported as being explosives [5]. They
also are used as gas-generating agent for air bags [3], and photography and
recording systems [4–8]. Due to these applications, tetrazoles have always been
considered as important synthetic targets [9].
The earliest reported method for the preparation of tetrazoles in 1932 involves
the reaction of hydrazoic acid (HN3) with organic cyanides [10]. However,
nowadays, this route has no practical value considering the high toxicity, explosive
nature, and low boiling point 37 °C of HN3 as a starting material [10].
One of the most efficient and facile synthetic pathways to tetrazole is the
conventional [2 ? 3] cycloaddition of nitriles with azide anion [11–15]. The
Huisgen cycloaddition reaction, which is basically a 1,3-dipolar cycloaddition, is a
facile route to obtain tetrazoles [16–19].
In 2001, Demko and Sharpless used the Huisgen cycloaddition strategy to
achieve tetrazoles via cycloaddition reaction of nitriles with NaN3 in the presence of
ZnBr2 as a catalyst [20]. They found this type of reaction to be modular, versatile,
regio-selective, high yielding and forming only non-hazardous by products. Due to
these extraordinary observed advantages, Sharpless and his co-workers exemplified
it for the concept of click chemistry [21]. Based on click chemistry, recently several
interesting papers have been published [22].
A number of other methods have also been reported for the preparation of
tetrazoles [23–26]. Nowadays, several methodology are on hand for the synthesis of
5-substituted 1H-tetrazoles, based on click reactions using various catalysts and
different conditions, such as InCl3 DMF/microwave heating [27], TMSN3/
TBAFÁ3H2O, solventless/50–120 °C [28], TMSN3/Fe(OAc)2/DMF-H2O/80 °C
[13], R2AlN3/toluene/-40–120 °C [29], CoY/DMF/120 °C [30], MBA-ZnO/
DMSO/120–130 °C [31], Cu2O/DMF-MeOH/80 °C [9], CuFe2O4/DMF/120 °C
[32], NaN3/Cu–Zn alloy nanopowder/DMF/90–135 °C [33], NaN3/zeolite and
zirconia/DMF and H2O/reflux [34], ionic liquids (ILs)/100 °C [35], AcOH/NMP-
H2O/microwave [12], montmorilloniteK10/microwave [36], HOAc/ILs/microwave
heating [15], Et3NÁHCl/PhNO2/microwave [37], and montmorillonite K10-M
(M = Fe, Zn, Cu, Ni)/DMF/reflux [38]. These methods have their own merits
and drawbacks. Most notably, in all of these known methods, organic solvents and
in particular, dipolar aprotic solvents such as DMF, are required [4–8, 39, 40].
Recent advances include the report of Pizzo and co-workers presenting the reaction
of nitriles with TMSN3 using TBAF as the catalyst [28]. More recently, Lakshmi
123

S. Khaghaninejad et al.
Kantam et al. [41–43] reported the synthesis of tetrazoles via reaction of nitriles
with NaN3 using nano crystalline ZnO or zinc hydroxyapatite as the catalyst at
elevated temperature.
Design of the solventless systems [44] ILs [45] as the relatively green source in
organic synthesis and reactions, especially those based on imidazolium cations
[46, 47], has stirred up interest among organic chemists in recent years. Historically,
ILs were applied in organic reactions in the nineteenth century [48]. Since the
various applications of ILs at ambient conditions have been realized, abundant
experimental results are published every year [49, 50]. We have recently used (3) as
a suitable and relatively green alternative to sodium azide, in DMF to synthesize
various azoles [51–54]. We are interested in click reaction [55]. We also try our best
to comply with the disciplines of green chemistry and bring them to practice in our
N
N
N
NC
N
R1
Isomer 4(Z)
Major
H
O
N
H
O
R1
(4a-c)
O
N
N
NH
N
H
N
CN
O
(1a-c)
Route a
R1
1a: R1 = H, 1b: R1= Br, 1c: R1 = NO2
Isomer 4(E)
Minor
N
H
CN
CN
+
BMIM N3
(3)
+
O
O
CN
Route b
O
(2)
Cat., 100 C, Solvent-free
O
N
O
HN
N
O
N
N SO3H
Cat =
N
N
(7)
(8)
N
O
CN
N
H
O
Isomer 6(Z)
Minor
H
Route c
H
R2
R2
(5a-d)
5a: R2 = H, 5b: R2 = OH, 5c: R2 = Br, 5d: R2 = NO2
N
N
H
N
NC
N
H
Isomer 6(E)
Major
R2
(6a-d)
Fig. 1 Synthesis of 5-substituted-1H-tetrazoles. Route a synthesis of tetrazoles of (4a–c), starting from
isatins (1a–c). Route b synthesis of tetrazoles starting from ninhydrin (7). Route c synthesis of tetrazoles
of (6a–d), starting from aldehydes (5a–d)
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
laboratory by anticipating solvent-free conditions [56–61], and have experience
handling ILs [57, 62–64].
Armed with these experiences, in this paper we wish to report a relatively green
method for the regio-selective synthesis of 5-substituted 1H-tetrazoles using (3) as a
relatively safe azide source, in the presence of o-phthalimide-N-sulfonic acid
(OPNSA) [65] as a solid acid catalyst under solvent-free conditions. We also
confirmed the already claimed regio-selectivity of these reactions by computational
quantum chemistry approaches.
Results and discussion
In continuation of our efforts to improve the eco-compatibility of organic processes,
herein is the synthesis of 5-substituted 1H-tetrazoles.
To this purpose, we initially focused on a previously reported three-component
reaction, involving isatin, (1a), (2), and sodium azide, leading to 5-substituted 1H-
tetrazoles [6]. For the modification of this reaction, first we used (3) [54] instead of
NaN3 as an azide source in a one-pot, three-component reaction in solvent-free
conditions as amodel reaction. Thismodel reaction proceeded smoothly to completion
(monitored by TLC) to yield the corresponding tetrazole (Fig. 1, route a). To find the
optimal conditions, we used different solvents in our model reaction. To our delight,
the experimental results, which are summarized in Table 1, showed that solvent-free
conditions are the system of choice in comparison to using other solvents.
However, as shown in Table 1, the time of reactions is relatively long. Thus, the
use of an appropriate catalyst for decreasing the time of reaction was contemplated.
To find a suitable and efficient catalyst, we examined various catalysts in the model
reaction. The results are illustrated in Table 2, and show that among the accessible
catalysts used, (OPNSA) as an organocatalyst gives the best result in terms of
different parameters, especially in decreasing the reaction time profoundly.
The effects of the amounts of catalyst and (3), was also investigated. The optimal
amount was found to be 20 mol% of catalyst and 1.5 mmol of (3), respectively
(Table 3). Noticeably, this organocatalyst was recoverable and reusable in the same
reaction conditions.
Table 1 The synthesis of 5-substituted 1H-tetrazoles in different solventsa
Solvents
H2O
EtOH
Solventlessb
DMF
CH2Cl2
CH3CN
t/h
Yield (%)c
24
24
24
24
78
10
75
24
42
24
39
Trace
a
All reactions were successfully performed on a 1 mmol scale of substrates, 1.5 mmol IL in 3 cm3 of
solvent
b
The reaction in solvent-free conditions was conducted at 100 °C, and in other solvents at their reflux
temperatures
c
Yields refer to the isolated products
123

S. Khaghaninejad et al.
Table 2 Use of various catalysts for the synthesis of 4(Z) in solventless systems (20 mol%)a,b
Catalyst
Catalyst-free
(OPNSA)
HPA (H3PW12O40
)
DABCO
t/h
Yield (%)c
24
78
8
8
24
90
75
Trace
a
All reactions were performed on a 1 mmol scale, 1.5 mmol IL, 20 mol% of various catalysts in solvent-
free conditions
b
Reaction temperature is 100 °C
Yields are given for isolated products
c
Table 3 Effect of amounts of catalyst and (3) for the solvent-free synthesisa,b of (Z)-2-(2-oxoindolin-3-
ylidene)-2-(1H-tetrazole-5-yl) acetonitrile (4a)a,b
(OPNSA) (mol%)
[BMIM]N3 (mmol)
t (h)
Yield (%)c
5
1.5
1.5
1.5
1.5
1.5
1
14
11
9
75
80
82
90
90
70
85
91
10
15
20
25
20
20
20
a
8
9
8
1.2
2
8
9
All reactions were accomplished on a 1 mmolscale of isatin and (2)
b
c
Reaction temperature is 100 °C
Yields are given for isolated products
It should be noted that from this reaction, there is a possibility for the formation
of two regio-isomers as the products, as shown in Fig. 1. The proposed mechanism
for our development of the reaction using an organocatalyst and (3) as an azide
source is depicted in Fig. 4. The comparison of data obtained from our developed
strategy with those previously reported verifies the regio-selective formation of (Z)-
2-(2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl) acetonitrile, 4(Z) isomer. The sole
formation of Z-isomer had been already recognized via single crystal X-ray
crystallography [6]. Thus, by using (3), instead of sodium azide as an azide source
and conducting the reaction in solvent-free conditions, this click reaction can be
added as a new development to the numerous methods found in the literature. This
reaction is catalyzed by a readily accessible, easily recoverable and several times
reusable organocatalyst.
We have already studied the nature of regio-selectivity in the synthesis of
6-benzylthiazolo[3,2-b]1,2,4-triazoles during Sonogashira coupling [58], and have
reported the successful Pd-catalyzed regio-selective cyclization, unambiguously
confirmed by single crystal X-ray crystallography [58]. In order to determine the
relevance of computational methods to physical evidence, our group has previously
assessed [66] the origins of regio-selectivity in the regio-selective Sonogashira
synthesis of 1,2,4-triazoles via DFT computations [67], and found it satisfactory.
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
Thus, in the next step, we focused on computational investigations of the underlying
reasons for the experimentally observed regio-selectivity in this particular click
synthesis of 5-substituted 1H-tetrazoles, from the thermodynamic and electronic
points of view.
It is worthwhile to state that accurate information on the energetics of the full
catalytic pathway of this synthesis can be one of the most important aspects of
addressing the regio-selectivity challenge, which could be due to either thermody-
namic or kinetic effects. In this work, our theoretical look into the regio-selectivity
challenge for this synthesis iconcentrates only on the calculation of thermody-
namical properties of the reaction. Some quantum theory of atoms in molecule
N9
N4
N5
C8
H13
C12
C3
C2
N6
C1
N7
H14
C10
O11
Isomer 4(Z)
N5
N6
N4
H13
N7
C3
H14
C12
C2
C1
C8
N9
C10
O11
Isomer 4(E)
Fig. 2 Atomic numbering and energy-minimized structures obtained at the M06/6-31G* level of theory
for 4(Z) and 4(E)
123

S. Khaghaninejad et al.
(QTAIM) electronic analysis was also performed in order to confirm the observed
regio-selectivity proved already by X-ray data analysis.
In this context, we first concentrated on the quantum chemical modelling of the
changes in thermodynamic properties of this reaction, as illustrated in Fig. 1, route
a, based on DFT approaches. Thus, we determined the ground state structures of all
reactants and regio-isomeric products at the M06/6-31G* level of theory without
any symmetry restrictions in the geometry optimization procedure. We then utilized
harmonic frequency analysis to confirm that the found optimized geometries
corresponded to the true minima. We also employed the vibrational frequencies to
obtain enthalpies and Gibbs free energies and entropies. It should be mentioned that
M06 functional was recently introduced as a hybrid meta-GGA (generalized
gradient approximation) exchange–correlation functional that was parameterized
including both transition metals and non-metals, which is recommended for
application in organometallic and inorganometallic thermochemistry, kinetic studies
and non-covalent interactions [68]. All DFT computations were performed using the
GAMESS suite of programs [69]. In Fig. 2, we presented the theoretical optimized
structures of two possible regio-isomers, entitled as 4(Z) (as major product) and (E)-
2-(2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl) acetonitrile 4(E) (as by product),
obtained at the M06/6-31G* level of theory in the gas phase together with the
atomic numbering.
In Table 4, the calculated thermochemical data, including reaction electronic
energies (with and without zero-point energy corrections), enthalpies, Gibbs free
energies and entropies computed at M06/6-31G* level of theory for the production
of two regio-isomeric compounds, 4(Z) and 4(E) are reported. The following two
facts can be discussed from stringent analysis of the reported results in Table 4: (1)
the calculated values of reaction Gibbs free energy changes demonstrate that the
production of 4(Z) is more thermodynamically favourable than 4(E) in this
synthesis, which is in agreement with our structural elucidations; and (2) by a
comparative survey in the obtained results of Gibbs free energy and enthalpy, it can
be seen that Gibbs free energy changes of the reaction become more positive than
those obtained for enthalpy change values, with an increase of around 15 k-
cal mol-1, which could be assigned to the decrease in calculated entropy values
through the reaction, which is around -50 cal mol-1 K-1 at 298 K.
In the next step, we concentrated on topological study of electron density via
QTAIM [70, 71] to interpret the nature of regio-selectivity in this reaction from the
electronic point of view. In this respect, resulting M06/6-311?G** wave function
Table 4 Thermochemistry of the reaction calculated at the M06/6-31G* level of theory
Regio-isomers
DEe,r
DE0,r
DHr
DGr
DSr
4(Z)
4(E)
45.011
48.882
46.734
50.434
48.002
51.687
63.588
67.006
-52.275
-51.380
DEe,r is the reaction energy from the total electronic energies, DE0,r is the reaction energy with zero-point
energies included, DHr, DGr and DSr are the reaction enthalpy, free energy and entropy change, re-
spectively. Note that the conversion energy change values are in kcal mol-1 and the entropy change
Values are in cal mol-1 K-1
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
files for the optimized structures of 4(Z) and 4(E) were used as inputs to AIM2000
program [72]. Then, we focused on the calculation of some selected bond and ring
critical points (BCPs and RCPs, respectively) and their associated bond paths to
perform a comparative survey on the stability of 4(Z) and 4(E). In Table 5, we have
2
listed the calculated values of electron density, qb, its laplacian, r qb, electronic
kinetic energy density, Gb, electronic potential energy density, Vb, total electronic
energy density, Hb and |Vb|/Gb of some selected CPs for 4(Z) and 4(E). QTAIM
molecular graphs of 4(Z) and 4(E) are also presented in Fig. 3.
It should be stated that the aforementioned properties of electron density at BCPs
can be employed to determine the regions of concentration and depletion of the
electron charge density, and a basis for classifying the interatomic interactions [73].
For shared interactions (as covalent and polar bonds), the electronic charge is
concentrated in the internuclear region with qb [ 0.1 and corresponded negative
2
values of r qb and Hb. By contrast, for closed-shell interactions (as hydrogen
bonds, ionic bonds and van der Waals interactions), the electronic charge is depleted
in the interatomic surface with qb \ 0.1 accompanied by a relatively small and
2
positive value of r qb and also Hb [ 0 values. Moreover, it has been recently
studied that the |Vb|/Gb ratio is a good reliable indicator for classifying interatomic
interactions [74]. On the basis of this recently suggested indicator, closed-shell
interactions are associated with |Vb|/Gb B 1, intermediate interactions 1 \ |Vb|/
Gb \ 2 and shared interactions |Vb|/Gb [ 2.
As is clear from the reported results of Table 5, the following three facts can be
discussed: (1) comparative survey on the calculated electron density properties and
indicators on N4-N7 and C3-N7 BCPs in 4(Z) and 4(E) confirms the covalent
Table 5 Mathematical properties of some selected critical points (CPs) in 4(Z) and 4(E)
2
qb
r qb
Gb
Vb
Hb
|Vb|/Gb
4(Z)
BCP(N4-N5)
0.3878
0.3663
0.0367
0.0132
0.0082
0.0088
-0.6888
-1.0664
0.1387
0.0475
0.0450
0.0454
0.2149
0.2203
0.0335
0.0094
0.0089
0.0088
-0.5997
-0.6998
-0.0324
-0.0070
-0.0066
-0.0063
-0.3848
-0.4795
0.0011
0.0024
0.0023
0.0025
2.7906
3.1765
0.9671
0.7446
0.7415
0.7159
BCP(C3-N7)
BCP(O11-H14)
BCP(N9-H13)
RCP1
RCP2
4(E)
BCP(N4-N5)
BCP(C3-N7)
BCP(C8-O11)
BCP(N4-H13)
RCP1
0.3642
0.3392
0.0174
0.0213
0.0152
0.0060
-0.6468
-1.0284
0.0583
0.0754
0.0811
0.0302
0.2114
0.2284
0.0132
0.0161
0.0166
0.0059
-0.5895
-0.7190
-0.0118
-0.0134
-0.0130
-0.0042
-0.3781
-0.4906
0.0013
0.0027
0.0036
0.0016
2.7885
3.1479
0.8939
0.8322
0.7831
0.7118
RCP2
The properties have been obtained via QTAIM analysis on the M06/6-31G* calculated wave function of
electron density. Note that the numbering of atoms is in accordance with Fig. 2
123

S. Khaghaninejad et al.
N9
H13
C12
C8
N4
N7
N5
N6
RCP2
C2
C3
C1
RCP1
H14
C10
O11
Isomer 4(Z)
N5
N6
N4
N7
H14
H13
C3
C2
C12
RCP2
C8
N9
C1
RCP1
C10
O11
Isomer 4(E)
Fig. 3 Complete molecular graphs (MGs) of 4(Z) and 4(E) obtained by QTAIM analysis of M06/
6-311?G** electron density. Bond critical points: red circles; ring critical points: yellow circles; bond
paths: pink lines. (Color figure online)
character of these bonds and more importantly, shows that these bonds (formed via
a [2 ? 3] cycloaddition reaction of Knoevenagel intermediate with the IL to afford
4(Z) isomer) have been formed more strongly in comparison with that of 4(E); (2)
in 4(Z), the calculated values of electron density properties on O11-H14 BCP are
consistent with the electrostatic character of OÁÁÁH hydrogen bonding, while the less
positive values of electron density and its Laplacian on N9-H13 BCP indicate a
lesser electrostatic contribution for this interaction, which could not be correlated
with a NÁÁÁH hydrogen bonding; and (3) on C8-O11 and N4-H13 BCPs in 4(E), the
calculated electron density values, about 0.02, and the corresponding small positive
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
values of its Laplacian, about 0.06, demonstrate that both BCPs have a weak
electrostatic character with no covalent contribution and no hydrogen bonding
character for N4-H13 BCP, and can be considered as intramolecular van der Waals
interactions.
It is worthwhile to note that the presence of O11-H14, N9-H13 BCPs in 4(Z) and
C8-O11 and N4-H13 BCPs in 4(E) results in formation of additional multi-member
rings with the requisite ring critical points (denoted as RCP1 and RCP2) close to the
aforementioned BCPs. The corresponding values of electron density properties for
RCP1 and RCP2 in 4(Z) and 4(E) are reported in Table 5.
Finally, it can be concluded that all our obtained thermochemical results and
QTAIM analysis are in favour of 4(Z) as the major isomer and are in reasonable
agreement with the experimentally observed regio-selectivity, already confirmed by
X-ray crystallographic analysis [6]. Wepresent our method as being considered for
predication of the preference of formation of a certain regio-isomer, where regio-
selectivity is concerned.
Under the concluded optimized reaction conditions, in order to establish the
method, differently substituted isatins (1a–c) were reacted with (2) and (3), in the
presence of (OPNSA) as a catalyst of choice. All reactions were completed in the
indicated time (Table 6). The corresponding tetrazoles as the product were isolated
in excellent yields. All products were known and their physical data were compared
with those already reported and were found to be identical (Table 6).
A plausible mechanism for the synthesis of 5-substituted 1H-tetrazoles using
(OPNSA) as catalyst and (3) as a green azide source is represented in Fig. 4.
Mechanistically, the formation of tetrazoles can be rationalized by the initial un-
catalyzed formation of arylidene malononitrile via a Knoevenagel condensation of
(1a) and (2), followed by subjection of the intermediate to [2 ? 3] cycloaddition
reaction with the azide motif of (3) as a suitable and green 1,3-dipolar species to
afford 4(Z) isomer (Fig. 4).
Table 6 Synthesis of 5-substituted 1H-tetrazoles from isatins (1a–c)a,b
Entry
1
Product
Time (h)
8
Yield (%)c
mp (°C)
Lit. [6] mp (°C)
90
211–213
210–212
(4a)
2
3
8
71
84
215–217
226–230
218–220
225–227
(4b)
10
(4c)
a
All reactions were successfully performed using a 1 mmol scale of substituted isatins (1a–c), and (2),
1.5 mmol (3), and 20 mol% of (OPNSA) under optimized conditions
b
Reaction temperature is 100 °C
Yields are given for isolated products
c
123

S. Khaghaninejad et al.
H
O
O
OPNSA
NH
CN
N
O
O
H
HO
H
N
H2O
N
H
CN
H
OPNS
NH
O
O
N
(1)
N
H
H
N
H
H
C
H
C
H
C
C
H
H
C
NH
C
C
NC
C
N
N
(2)
NC
CN
O
Intermediate:
Knoevenogel
condensation
N
H2O
H
I. L.
(3)
OPNSA
HN
C
N
N
N
NC
NH
CN
O
C
N
N
N
O
N
H
N
H
OPNS
OPNS
IM
IM
HN
C
NC
NH
N
CN
O
N
N
C
N
O
N
N
N
H
N
H
H
NC
H
N
N
O
N
N
N
N
N
N
CN
O
IM
IM
N
H
N
N
N
N
N
N
N
H
NC
HN
CN
N
H
O
HCl (2N)
HCl (2N)
O
N
N
H
4(Z)
4(E)
H
Fig. 4 A possible mechanism for the formation of the 5-substituted 1H-tetrazoles 4(Z), 4(E) using
(OPNSA) as catalyst
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
In order to expand the utility of (3) as the 1,3-dipolar species in the click reaction,
various aldehydes (5a–d) were used instead of isatins (1a–c) under similar reaction
conditions (Fig. 1, route c). Contrary to the obtained products, and interestingly in
all cases, the corresponding (E)-(1H-tetrazole-5-yl) acrylonitriles (6a–d) were
obtained (Table 7). This regio-selectivity has also been reported previously, and
confirmed by characterization via X-ray crystallography, albeit that sodium azide
had been used as a source of azide being subjected to cycloadditions as 1,3-dipole
[6].
Although the above characterization seems reasonable and ultimate, it was
worthwhile to compare and discuss the dissimilarity between IR spectra of the
products of the reaction of isatins (1a–c) and those of various aldehydes (5a–d). IR
spectra of 4(Z) showed absorption bands in the region at 3261–3109 cm-1, which
belongs to the stretching vibration of N–H groups (Table 8). The strong and
intensive absorption bands for 4(Z) indicate a strong hydrogen bonding (NHÁÁÁO),
and the N–H groups are fixed and hydrogen exchange between N1, N2, N3 or N4 is
not likely to occur. For the (E)-(1H-tetrazole-5-yl) acrylonitrile, 6(E) compound, the
stretching vibration of N–H groups are broad, because of the lack of NHÁÁÁO bond
and rapid exchange of hydrogen from N1 to N2 or N3 or N4 [75, 76]. The N–H in-
plane bending for 4(Z) appears in 1585 and 1465 cm-1. The out-of-plane bending
appears at 497 and 626 cm-1 [77]. The group frequencies of N=N (azo compounds)
are well-known to organic chemists. The N=N band appears in the same region as
aromatic absorptions; however, it is weak, and is very difficult to identify [78].
Table 7 Synthesis of 5-substituted 1H-tetrazolesa,b (6a–d), starting from aldehydes (5a–d)a,b
Entry
1
Producta
Time (h)
10
Yield (%)c
mp (°C)
Lit. [6] mp (°C)
80
165–167
168–170
(6a)
2
3
4
8
9
75
64
85
162–164
160–162
169–171
159–161
165–167
166–168
(6b)
(6c)
10
(6d)
a
All reactions were performed on a 1 mmol scale of aldehyde and (2), 1.5 mmol IL and 20 mol% of
catalysts similar to previously given conditions
b
All products were known and identified by comparison of their physical data with those of previously
reported and found being identical
c
Yields are given for isolated products
123

S. Khaghaninejad et al.
Table 8 Spectral and physical data of prepared compounds
Compound Spectral data
(4a)
Powder (0.214 g, yield 90 %)
mp 211–213 °C (Lit. [6]: 210–212 °C)
FT-IR (KBr)/m (cm-1) 3261, 3109 (N–H), 2231 (C:N), 1730 (C=O), 1635, (C=C alkene),
1585, 1465 (N–H in-plane bending)
1HNMR: DMSO-d6): dH (ppm) 5.08 (broad, s, N–H, overlap with solvent), 6.89 (1H, d,
3
3
3JHH = 8 Hz, H-Ar.), 6.97 (1H, t, JHH = 7.8 Hz, H-Ar.), 7.43 (1H, t, JHH = 7.6 Hz,
3
H-Ar.), 8.212 (1H, d, JHH = 8 Hz, H-Ar.), 11.09 (1H, s, N–H)
(4b)
(4c)
(8)
Powder (0.225 g, yield 71 %)
mp 215–217 °C (Lit. [6]: 218–220 °C)
FT-IR (KBr)/m (cm-1) 3578, 3512 (N–H), 3153 (C–H Ar), 2234 (C:N), 1732 (C=O), 1595,
1463 (NH in-plane bending)
Powder (0.2 g, yield 84 %)
mp 221–224 °C (Lit. [6]: 225–227 °C)
FT-IR (KBr)/m (cm-1) 3526, 3437, 3350, 3267 (N–H), 3119 (C–H Ar.), 2214 (C:N), 1718
(C=O), 1527, 1479(N–H in-plane bending)
Powder (0.205 g, yield 82 %)
mp 160–164 °C (Lit. [6]: 156–158 °C)
FT-IR (KBr)/m (cm-1) 3522, 3447, 3304 (N–H), 3176 (C–H Ar.), 2220 (C:N), 1710
(C=O), 1641 (C=C Ar.), 1575, 1467 (N–H in-plane bending)
(6a)
(6b)
(6c)
(6d)
Powder (0.16 g, yield 80 %)
mp 165–167 °C (Lit. [6]: 168–170 °C)
FT-IR (KBr)/m (cm-1) 3431 (N–H), 3047 (C–H Ar.), 2204 (C:N), 1693 (C=C alkene),
1556, 1471(N–H in-plane bending)
Powder (0.16 g, yield 75 %)
mp 162–164 °C (Lit. [6]: 159–161 °C)
FT-IR (KBr)/m (cm-1) 3337 (broad N–H), 3121 (broad, O–H, C–H Ar.), 2231 (C:N), 1599
(C=C alkene), 1512, 1448(N–H in-plane bending)
Powder (0.18 g, yield 64 %)
mp 160–162 °C (Lit. [6]: 165–167 °C)
FT-IR (KBr)/m (cm-1) 3414 (broad N–H), 3080 (broad C–H Ar.), 2146 (C:N), 1682
(C=C), 1587, 1487 (N–H in-plane bending)
Powder (0.20 g, yield 85 %)
mp 169–171 °C (Lit. [6]: 166–168 °C)
FT-IR (KBr)/m (cm-1) 3342 (broad N–H), 3100 (C–H Ar.), 2197 (C:N), 1660 (C=C
alkene), 1524, 1471 (N–H in-plane bending), 1534–1349(N–O asy., sym.) [6]
Experimental
General
Melting points were measured, using a capillary tube method with a Barnstead
Electrothermal 9200 apparatus. Fourier transform infrared spectroscopy (FTIR)
1
spectra were recorded using KBr discs on a FTIR Bruker Tensor 27 instrument. H
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
nuclear magnetic resonance (NMR) spectra were recorded on a Bruker AQS-
AVANCE spectrometer at 400 and 125 MHz, using TMS as an internal standard. 1H
NMR spectra were obtained for solutions in DMSO-d6. The chemicals were
purchased from Aldrich and Merck with high-grade quality, and were used without
purification. All products were known and their physical data were compared with
those of already reported compounds and were found to be identical.
Synthesis of 5-substituted 1H-tetrazoles (4a–c) and (5a–d):
general procedure
A mixture of either isatin (1a–c), (1 mmol) or aldehyde, malononitrile (2),
(1 mmol = 0.07 g), 1-butyl-3-methylimidazolium azide[BMIM]N3 (3), (1.5 m-
mol = 0.28 g) and (OPNSA) (0.04 g) was stirred for 8 h at 100 °C under solvent-
free conditions. After completion of the reaction, as indicated by TLC, in order to
separate the catalyst, the viscose crude was treated with ethanol (20 ml). The
mixture was filtered under reduced pressure. The filtrate was analysed by thin layer
chromatography (TLC) and found to contain (OPNSA). The crude collected in the
funnel was washed with 2-methoxy-2-methylpropane (10 ml) to remove the
remaining catalyst. Evaporation of combined filtrates of ethanol and methoxy-2-
methylpropane was performed under reduced pressure to obtain the catalyst,
virtually quantitatively and without appreciable loss of catalytic activity. The crude
solid was poured into water (10 ml). The obtained suspension was acidified with
2 N HCl and subsequently extracted with ethyl acetate (2 9 15 ml). The organic
layer was separated, dried over anhydrous sodium sulphate, filtered, and the filtrate
was evaporated under reduced pressure to dryness to give the pure corresponding
5-substituted 1H-tetrazole (Tables 6, 7).
Synthesis of (OPNSA)
(OPNSA) was synthesized according to the previously reported method [65].
Synthesis of (3)
Compound (3) was synthesized in accordance with a previously reported procedure
[54].
Spectral and physical data for selected compounds
(Z)-2-(2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl) acetonitrile (4a): powder;
mp = 211–213 °C (Lit. [6]: 210–212 °C); FT-IR (KBr)/m (cm-1) 3261, 3109 (N–
H), 2231 (C:N), 1730 (C=O), 1635, (C=C alkene), 1585, 1465 (N–H in-plane
bending);1H NMR (DMSO-d6, 400 MHz): d (ppm): 5.08 (br, s, N–H, overlap with
3
3
solvent), 6.89 (d, 1H, JHH = 8 Hz, H-Ar.), 6.97 (t, 1H, JHH = 7.8 Hz, H-Ar.),
3
7.43 (t, 1H, JHH = 7.6 Hz, H-Ar.), 8.212 (d, 1H, JHH = 8 Hz, H-Ar.), 11.09 (s,
3
1H, N–H).
123

S. Khaghaninejad et al.
(Z)-2-(5-bromo-2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl) acetonitrile (4b):
powder; mp = 215–217 °C (Lit. [6]: 218–220 °C); FT-IR (KBr)/m (cm-1) 3578,
3512 (N–H), 3153 (C–H Ar.), 2234 (C:N), 1732 (C=O), 1595, 1463 (N–H in-plane
bending).
(Z)-2-(5-nitro-2-oxoindolin-3-ylidene)-2-(1H-tetrazole-5-yl) acetonitrile (4c):
powder, mp = 221–224 °C (Lit. [6]: 225–227 °C); FT-IR (KBr)/m (cm-1) 3526,
3437, 3350, 3267 (N–H), 3119 (C–H Ar.), 2214 (C:N), 1718 (C=O), 1527, 1479
(N–H in-plane bending).
(E)-3-phenyl-2-(1H-tetrazole-5-yl) acrylonitrile (6a): powder, mp = 165–167 °C
(Lit. [6]: 168–170 °C); FT-IR (KBr)/m (cm-1) 3431 (N–H), 3047 (C–H Ar.), 2204
(C:N), 1693 (C=C alkene), 1556, 1471 (NH in-plane bending).
(E)-3-(4-hydroxyphenyl)-2-(1H-tetrazole-5-yl) acrylonitrile (6b): powder,
mp = 162–164 °C (Lit. [6]: 159–161 °C); FT-IR (KBr)/m (cm-1) 3337 (broad N–
H), 3121 (broad, O–H, C–H), 2231 (C:N), 1599 (C=C alkene), 1512, 1448 (N–H
in-plane bending).
(E)-3-(4-bromophenyl)-2-(1H-tetrazole-5-yl)
acrylonitrile
(6c):
powder,
mp = 160–162 °C (Lit. [6]: 165–167 °C); FT-IR (KBr)/m (cm-1) 3414 (broad N–
H), 3080 (broad C–H Ar.), 2146 (C:N), 1682 (C=C), 1587, 1487 (N–H in-plane
bending).
(E)-3-(4-nitrophenyl)-2-(1H-tetrazole-5-yl)
acrylonitrile
(6d):
powder,
mp = 169–171 °C (Lit. [6]: 166–168 °C); FT-IR (KBr)/m (cm-1) 3342 (broad N–
H), 3100 (C–H Ar.), 2197 (C:N), 1660 (C=C alkene), 1524, 1471 (N–H in-plane
bending), 1534–1349 (N = Oasy., sym.).
2-(1,3-dioxo-1H-inden-2(3H)-ylidene)-2-(1H-tetrazole-5-yl) acetonitrile (8):
Powder, mp = 160–164 °C (Lit. [6]: 156–158 °C); FT-IR (KBr)/m (cm-1) 3522,
3447, 3304 (N–H), 3176 (C–H Ar), 2220 (C:N), 1710 (C=O), 1641 (C=C Ar.),
1575, 1467 (N–H in-plane bending).
Conclusion
In summary, we have designed a facile, relatively green and operational reaction to
develop the synthesis of 5-substituted 1H-tetrazole derivatives, starting from either
isatins (1a–c) or aromatic aldehydes (5a–d), to react with (2), using (3) as a
relatively green source of azide in the presence of 20 mol% of (OPNSA) as a solid
acid catalyst to conduct a click reaction in a relatively short reaction time, obtaining
the corresponding products in high yields. Noticeably, the readily accessible
organocatalyst used in this strategy can easily be recovered almost quantitatively,
and re-used several times. Finally, we have employed quantum chemistry
computational methods to confirm the experimentally observed regio-selectivity
from thermochemical and electronic viewpoints.
Acknowledgments M. M. Heravi is thankful to the Reaearch Council of Alzahra University for partial
financial assistance.
123

Regio-selective synthesis of 5-substituted 1H-tetrazoles using…
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