[Cu(phen)(PPh3)2]NO3-catalyzed microwave-assisted green synthesis of 5-substituted 1H-tetrazoles

Article abstract of DOI:10.1007/s11164-017-3080-7

Abstract: An efficient synthetic methodology for construction of 5-substituted 1H-tetrazoles under microwave irradiation in green medium is described. With [Cu(phen)(PPh₃)₂]NO₃ as catalyst and H₂O-isopropyl alcohol (IPA) as reaction medium, various substituted nitriles underwent (3?+?2) cycloaddition reaction with NaN₃ under microwave irradiation to provide corresponding 5-substituted 1H-tetrazoles in high yield. This method is not only efficient and general but also benefits from high functional group tolerance. This environmentally friendly synthetic methodology is visualized as an alternative to existing procedures, providing a simple route to privileged scaffolds.

Full text of DOI:10.1007/s11164-017-3080-7

Res Chem Intermed
DOI 10.1007/s11164-017-3080-7
[Cu(phen)(PPh ) ]NO -catalyzed microwave-assisted
3 2 3
green synthesis of 5-substituted 1H-tetrazoles
1
1
1
1
R. D. Padmaja
•
D. R. Meena
•
Barnali Maiti
•
Kaushik Chanda
Received: 20 April 2017 / Accepted: 12 July 2017
Ó Springer Science+Business Media B.V. 2017
Abstract An efficient synthetic methodology for construction of 5-substituted 1H-te-
trazoles under microwave irradiation in green medium is described. With
[Cu(phen)(PPh ) ]NO as catalyst and H O-isopropyl alcohol (IPA) as reaction medium,
various substituted nitriles underwent (3 ? 2) cycloaddition reaction with NaN under
3 2 3 2
3
microwave irradiation to provide corresponding 5-substituted 1H-tetrazoles in high
yield. This method is not only efficient and general but also benefits from high functional
group tolerance. This environmentally friendly synthetic methodology is visualized as an
alternative to existing procedures, providing a simple route to privileged scaffolds.
Graphical Abstract
Electronic supplementary material The online version of this article (doi:10.1007/s11164-017-3080-7)
contains supplementary material, which is available to authorized users.
&
&
1
Barnali Maiti
barnalimaiti.m@gmail.com
Kaushik Chanda
chandakaushik1@gmail.com
Department of Chemistry, School of Advanced Sciences, VIT University, Vellore 632014, India
123

R. D. Padmaja et al.
Keywords (3 ? 2) Cycloaddition Á Tetrazoles Á Green media Á Microwave
irradiation
Introduction
Considerable research effort has been directed toward synthesis of functionalized
heterocyclic small molecules using combinatorial chemistry strategies for use in
drug discovery research. Tetrazoles, a ubiquitous pharmacophore, is present in
natural products and pharmaceutical molecules [1–4]. Tetrazole moiety can be
regarded as a bioisosteric substituent of carboxylic acid in developing bioactive
substances [5, 6]. Due to its excellent metabolic stability, electronic distribution,
hydrogen bonding, and lipophilic character, tetrazole moiety facilitates interactions
between ligands and receptors, enhancing cell membrane passage [7–10]. As
depicted in Fig. 1, functionalized tetrazole derivatives are generally encountered in
natural products (A) and many commercial drugs such as losartan (B) with
antihypertensive activity, tomelukast (C) with antileukotriene antiasthmatic prop-
erty, as well as selective antagonists of a-amino-3-hydroxy-5-methyl-4-isoxa-
zolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors (D, E) for
treatment of schizophrenia and cerebral ischemia [11–13]. In cell proliferation
assay, the important tetrazole compound dimethylthiazolyldiphenyl tetrazolium
bromide (MTT) is used [14, 15].
Moreover, this privileged scaffold also plays important roles in coordination
chemistry, in the photographic industry, or as components of special explosives
[
15, 16].
In view of the enormous biological importance of tetrazole derivatives, much
effort has been devoted to their efficient synthesis. The commonest method for
synthesis of tetrazoles involves reaction of NaN with organic nitriles. In 2001,
3
Sharpless and coworkers demonstrated synthesis of 5-substituted 1H-tetrazoles by
reacting NaN with organic nitriles using ZnCl as catalyst [17, 18]. Since then, a
3
2
plethora of homogeneous and heterogeneous catalysts have been reported for
synthesis of tetrazole derivatives, such as AlCl [19], Pd(PPh ) [20], tetrabuty-
3
3 4
lammonium fluoride (TBAF) [21], ZnO [22], Yb(OTf)3 [23], ZnBr2 under
microwave irradiation [24], FeCl -SiO [25], I or silica-supported NaHSO [26],
3
2
2
4
CoY zeolite [27], Cu(OAC) [28], Et NÁHCl [29], mesoporous ZnS [30], chitosan-
2
3
derived magnetic ionic liquid [31], AgNO [32], CAN-HYzeolite [33], activated
3
Fuller’s earth [34], and ONO pincer-type Pd(II) complex [35]. In 2012, Bhosale
et al. demonstrated catalyst-free synthesis of 5-substituted 1H-tetrazoles using
glycerol as solvent [36]. Nevertheless, most of these synthetic methodologies suffer
from some drawbacks, such as high cost of synthesis, high catalyst loading, longer
reaction time, harsher reaction conditions with use of explosive hydrazoic acid, use
of toxic high-boiling organic solvents, and lower product yields. To overcome these
limitations, it is always imperative to develop atom-efficient, economical, green,
and one-pot synthetic methodologies with wide substrate scope. Recently,
significant interest has been directed at development of organic reactions in water
1
23

3 2 3
[Cu(phen)(PPh ) ]NO -catalyzed microwave-assisted green…
Fig. 1 Biologically active tetrazole derivatives
under microwave irradiation due to its nontoxic, nonflammable, and nonhazardous
properties [37–42]. Along with water, isopropyl alcohol can be chosen as a
cosolvent to reduce the polarity of the reaction mixture by enhancing the solubility
of organic substrates, being biodegradable via the acetone pathway. Furthermore,
advancement of microwave-assisted library synthesis provides faster access to
targeted compounds, as discovery of novel compounds with potential bioproperties
is time-consuming and expensive. Using H O-IPA as reaction medium along with
2
microwave irradiation, we therefore wished to develop a convenient, microwave-
assisted Cu(I)-catalyzed methodology for synthesis of 5-substituted 1H-tetrazoles in
green medium. In comparison with reported synthetic protocols described above,
the present methodology for synthesis of 5-substituted 1H-tetrazoles offers several
advantages, such as use of microwave irradiation to reduce the reaction time to
minutes for fast synthesis of target compounds, H O-IPA as green and ecofriendly
2
solvent, excellent yields with high purity, and wide functional group tolerance.
In our quest for diversity-oriented synthesis of bioactive heterocycles [43–45],
we envisaged a concise route to 5-substituted 1H-tetrazole derivatives from readily
available organic nitriles and NaN3 in H O-IPA as reaction medium under
2
microwave irradiation. The synthetic strategy involves (3 ? 2) dipolar cycloaddi-
tion of organic nitriles with NaN to obtain 5-substituted 1H-tetrazole derivatives in
excellent yield.
3
Results and discussion
Our main target is to determine the suitability of [Cu(phen)(PPh ) ]NO as catalyst
3
2
3
under different reaction conditions to obtain 5-substituted 1H-tetrazole derivatives
in good yield. The initial investigations of this (3 ? 2) cycloaddition reaction
commenced with benzonitrile (1a) and sodium azide as model substrates in presence
123

R. D. Padmaja et al.
of [Cu(phen)(PPh ) ]NO as catalyst under N2 atmosphere; the results are
3
2
3
summarized in Table 1. Initial attempts to react benzonitrile (1a) with sodium
azide in presence of 5 mol % [Cu(phen)(PPh ) ]NO as catalyst under solvent-free
3
2
3
condition at 130 °C for 6 h did not yield any product 5-phenyl-1H-tetrazole (2a)
Table 1, entry 1). Moreover, in acetonitrile and tetrahydrofuran (THF) as solvents,
(
the reaction did not yielding any 5-phenyl-1H-tetrazole 2a (Table 1, entries 2, 3).
Further analysis of the reaction mixtures indicated presence of starting materials
only. Next, we turned our attention to polar aprotic solvents such as dimethyl
sulfoxide (DMSO), which was proven to be ineffective for this reaction with
multiple spots (Table 1, entry 4). Apart from DMSO, when the same reaction was
carried out in dimethylformamide (DMF) solvent for 12 h at 130 °C, 5-phenyl-1H-
tetrazole 2a was formed in 75 % yield (Table 1, entry 5). The solvent plays an
important role in obtaining higher yield of the tetrazole derivatives. Changing the
solvent polarity from polar aprotic to polar protic, e.g., EtOH, at refluxing
temperature for 12 h yielded the 5-phenyl-1H-tetrazole 2a in 50 % yield (Table 1,
entry 6). With a view to enrich the synthetic efficiency, the same set of reactions
was performed under microwave irradiation for 15 min using H O-IPA as solvent at
2
6
5 °C, obtaining the 5-phenyl-1H-tetrazole 2a in 82 % yield (Table 1, entry 7).
Table 1 Optimization of reaction condition for synthesis of 5-phenyl-1H-tetrazole
b
Entry
Cu(I) catalyst
Solvent
Temperature
Time
Yield (%)
1
2
3
4
5
6
7
8
9
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
5 mol%
10 mol%
10 mol%
10 mol%
No catalyst
No solvent
130 °C
Reflux
Reflux
130 °C
130 °C
Reflux
6 h
0
CH
3
CN
6 h
0
THF
6 h
0
DMSO
DMF
EtOH
12 h
Trace
75
50
82
80
85
50
30
0
12 h
12 h
a
H
H
H
2
2
2
O-IPA
O-IPA
O-IPA
MW , 65 °C
Reflux
15 min
10 h
a
MW , 65 °C
15 min
15 min
15 min
15 min
a
1
1
1
0
1
2
Glycerol
MW , 65 °C
a
Ethylene glycol
MW , 65 °C
a
H
2
O-IPA
MW , 65 °C
3
Reaction performed using 1a (1 mmol), NaN (1.5 mmol)
a
Microwave reactions carried out in microwave model no. CATA R (Catalyst Systems, Pune) at power
of 245 W
b
Yield of isolated product
1
23

3 2 3
[Cu(phen)(PPh ) ]NO -catalyzed microwave-assisted green…
Furthermore, the same set of reactions was finished in 10 h under refluxing
condition (Table 1, entry 8).
It is interesting to note that, on increasing the catalyst loading up to 10 mol%, the
yield of the reaction did not increase significantly under microwave irradiation for
1
5 min (Table 1, entry 8). So, catalyst loading of 10 mol% was found to be
adequate to obtain the maximum yield of 85 % for 5-phenyl-1H-tetrazole 2a
Table 1, entry 9). However, when changing the solvent system from H O-IPA to
(
2
glycerol or ethylene glycol, we did not observe any significant increase in the yield
of 5-phenyl-1H-tetrazole 2a (Table 1, entry 10, 11). Subsequently, we performed
the same set of reactions under metal-free condition, which did not yield any
5-phenyl-1H-tetrazole 2a product (Table 1, entry 12). Finally, we obtained the
optimized reaction condition for this (3 ? 2) cycloaddition reaction as 10 mol%
Cu(I) catalyst in H O-IPA solvent under microwave irradiation. Use of H O-IPA as
2
2
solvent and microwave irradiation in this synthetic methodology dramatically
reduced the reaction time from several hours to minutes with excellent yield.
Scheme 1 demonstrates the Cu(I)-catalyzed synthesis of 5-substituted 1H-tetrazole
derivatives via (3 ? 2) cycloaddition reaction using microwave irradiation in green
medium. Upon reaction completion followed by acidic treatment, substituted 1H-
tetrazole derivatives were obtained in excellent yield.
Encouraged by the synthetic efficiency of the reaction protocol described above,
we further investigated the scope of this reaction with substituted nitriles. The
results are summarized in Table 2.
The overall time for completion of the reaction was typically 15–25 min. The
corresponding 5-substituted 1H-tetrazole derivatives were obtained in excellent
yield after simple work-up involving filtration of the catalyst, acidic treatment, and
solvent evaporation. Finally, the crude products were purified by column
1
13
chromatography followed by spectroscopic characterization using H and
C
nuclear magnetic resonance (NMR) and mass spectroscopy (MS). Due to the
electrophilic nature of the nitrile moiety attached to the aromatic rings, both the
yield and reaction time varied with the substituents present on the aromatic rings.
Aromatic nitriles containing either unsubstituted or electron-withdrawing groups
reacted efficiently to obtain corresponding 1H-tetrazole derivatives in excellent
yield as compared with electron-donating substituents with lower yield. The
benzylic nitrile also reacted nicely with sodium azide to obtain the corresponding
1
H-tetrazole in high yield, whereas use of aliphatic nitriles did not succeed in the
present reaction condition. To enrich the synthetic versatility, we tried to use
organic azides, but failed to obtain corresponding tetrazoles. Regarding the
mechanism of the reaction, we believe that the mild Lewis acid character of the
Scheme 1 Cu(I)-catalyzed microwave-assisted green synthesis of substituted 1H-tetrazoles
123

R. D. Padmaja et al.
Table 2 Cu(I)-catalyzed microwave-assisted synthesis of substituted 1H-tetrazoles
Reaction conditions 1 (1 mmol), NaN
Yield of isolated product 2
3
(1.5 mmol)
Cu(I) catalyst activates the nitriles towards [3 ? 2] cycloaddition with sodium azide
via coordination bond with the lone pair of electrons present on the nitrogen atom of
nitriles. The corresponding 5-substituted 1H-tetrazole derivatives were obtained by
acidic treatment with dil. HCl (see Supporting Information).
1
23

3 2 3
[Cu(phen)(PPh ) ]NO -catalyzed microwave-assisted green…
Conclusions
We have developed an efficient ecofriendly approach for synthesis of biologically
interesting 5-substituted 1H-tetrazole derivatives. The synergistic effects of
microwave irradiation and use of H O-IPA as green solvent effectively accelerated
2
formation of 5-substituted 1H-tetrazoles in short reaction time. To the best of the
authors’ knowledge, this is the first report of Cu(I)-catalyzed synthesis of
5
-substituted 1H-tetrazoles in green medium. Work is currently underway in our
laboratory towards Cu(I)-catalyzed synthesis of bioactive heterocycles for potential
biological applications.
Experimental
General procedures
Unless otherwise indicated, all common reagents and solvents were used as obtained
1
from commercial suppliers without further purification. H NMR (400 MHz) and
1
3
C NMR (100 MHz) were recorded on a Bruker DRX400 spectrometer. Chemical
shifts are reported in ppm relative to the internal solvent peak. Coupling constants,
J, are given in Hz. Multiplicities of peaks are given as: d (doublet), m (multiplet), s
(
singlet), and t (triplet). Mass spectra were recorded on a PerkinElmer Calrus600
GC–MS spectrometer. IR spectra were recorded on a Bomen DA8 3FTS
spectrometer. Microwave-assisted reactions were carried out in a Catalyst Scientific
microwave oven system (model no. CATA R; Catalyst System, Pune) operating at
2
450 MHz equipped with glass vial extension and a condenser for performing the
reaction. The microwave was equipped with a temperature control system (external
probe).
General procedure for synthesis of 5-substituted 1H-tetrazoles (2)
In a round-bottomed flask, a mixture of organic nitrile 1 (1.0 equiv) and NaN (1.5
3
equiv) was added to 5 ml solution of H O-IPA (1:1) containing 10 mol%
2
[
Cu(phen)(PPh ) ]NO as catalyst under N2 atmosphere. The reaction mixture
3 2 3
was irradiated under microwave heating at 245 W for 15–25 min at 65 °C. Reaction
progress was monitored by thin-layer chromatography (TLC). After reaction
completion, the mixture was filtered to remove the catalyst. The filtrate was
acidified with 5 N HCl (20 ml) to neutralize the product, extracted with ethyl
acetate (2 9 10 ml). The combined organic layer was dried over anhydrous MgSO4.
The combined filtrate was subjected to evaporation to obtain the crude compound,
which was purified over silica gel column (60–120 mesh) using 50 % ethyl acetate
in hexane as eluent to obtain corresponding 5-substituted 1H-tetrazoles 2 as product.
1
5
8
1
-Phenyl-1H-tetrazole (2a) Pale-white solid. H NMR (400 MHz, DMSO-d ) d
6
1
3
.04–8.03 (m, 2H), 7.59 (m, 3H), 4.06 (brs, NH); C NMR (100 MHz, DMSO-d ) d
6
-
31.2, 129.4, 126.9, 124.2; IR (KBr, cm ): 3431, 2980, 2835, 2684, 2600, 2337,
1
123

R. D. Padmaja et al.
-
1
1
z 146.0592; found 146.0583 (M?).
739, 1606 cm ; MS (EI) m/z: 146 (M?); HRMS (EI, m/z) calcd. for C H N : m/
7 6 4
1
5
-(p-Tolyl)-1H-tetrazole (2b) White solid. H NMR (400 MHz, DMSO-d ) d 7.92
6
13
d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 2.38 (s, 3H); C NMR (100 MHz,
(
-
1
DMSO-d ) d 155.2, 141.1, 129.9, 126.9, 121.4, 21.0; IR (KBr, cm ): 3431, 2916,
6
-
845, 2690, 2447, 1878, 1732 cm ; MS (EI) m/z: 160 (M?); HRMS (EI, m/z)
1
2
calcd. for C H N : m/z 160.0749; found 160.05 (M?).
8
8 4
1
-(4-Methoxyphenyl)-1H-tetrazole (2c) Pale-white solid. H NMR (400 MHz,
5
1
3
DMSO-d ) d 7.99 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H);
C
6
NMR (100 MHz, DMSO-d ) d 161.4, 154.8, 128.6, 116.3, 114.8, 55.4; IR (KBr,
6
-
1
-1
cm ): 3075, 2931, 2742, 1610, 1502 cm ; MS (EI) m/z: 176 (M?); HRMS (EI,
m/z) calcd. for C H N O: m/z 176.0698; found 176.0666 (M?).
8
8 4
1
5
-(3-Nitrophenyl)-1H-tetrazole (2d) White solid. H NMR (400 MHz, CDCl ) d
3
8
.55 (s, 1H), 8.06 (d, J = 7.6 Hz, 1H), 8.37–8.35 (m, 1H), 8.17 (s, 1H), 7.74 (d,
13
J = 7.6 Hz, 1H); C NMR (100 MHz, DMSO-d ) d 162.3, 148.3, 133.1, 131.2,
1
6
-
1
-1
26.1, 125.6, 121.5; IR (KBr, cm ): 3094, 2970, 1643, 1525 cm ; MS (EI) m/z:
91 (M?); HRMS (EI, m/z) calcd. for C H N O : m/z 191.0443; found 191.0554
1
7
5 5 2
(
M?).
1
-(3-Chlorophenyl)-1H-tetrazole (2e) Yellow solid. H NMR (400 MHz, DMSO-
5
1
3
d6) d 7.84 (s, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.42 (d, J = 6.8 Hz, 2H); C NMR
100 MHz, DMSO-d ) d 162.3, 133.9, 131.4, 130.9, 126.5, 126.4, 125.6; IR (KBr,
(
6
-
1
-1
cm ): 3431, 3331, 2972, 2827, 2465, 1654, 1556 cm ; MS (EI) m/z: 180 (M?);
HRMS (EI, m/z) calcd. for C H ClN : m/z 180.0203; found 180.0200 (M?).
7
5
4
1
5
-(m-Tolyl)-1H-tetrazole (2f) White solid. H NMR (400 MHz, DMSO-d ) d 7.84
6
(
d, J = 7.6 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H), 7.72 (m, 1H), 7.44–7.39 (m, 2H);
3
1
C NMR (100 MHz, DMSO-d ) d 138.8, 131.9, 129.3, 127.4, 124.1, 123.9, 20.9;
6
-
1
-1
IR (KBr, cm ): 3061, 2918, 2696, 2605, 1562 cm ; MS (EI) m/z: 160 (M?);
HRMS (EI, m/z) calcd. for C H N : m/z 160.0749; found 160.05 (M?).
8
8 4
1
-(4-Bromophenyl)-1H-tetrazole (2g) Yellow solid. H NMR (400 MHz, DMSO-
5
1
3
d6) d 7.99 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H); C NMR (100 MHz,
-
1
DMSO-d ) d 155.0, 132.5, 128.9, 124.7, 123.6; IR (KBr, cm ): 2995, 2899, 2723,
6
-
617, 1734, 1600 cm ; MS (EI) m/z: 223 (M?); HRMS (EI, m/z) calcd. for
1
2
C H BrN : m/z 223.9698; found 223.9790 (M?).
7
5
4
1
-(4-Chlorophenyl)-1H-tetrazole (2h) Yellow solid. H NMR (400 MHz, DMSO-
5
1
3
d6) d 8.04 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H); C NMR (100 MHz,
-
1
DMSO-d ) d 154.9, 135.9, 129.5, 128.7, 123.2; IR (KBr, cm ): 2997, 2762, 2632,
1
m/z 180.0203; found 180.0273 (M?).
6
-
1
691, 1606 cm ; MS (EI) m/z: 180 (M?); HRMS (EI, m/z) calcd. for C H ClN :
7 5 4
1
3
-(1H-Tetrazol-5-yl)aniline (2i) Brown solid. H NMR (400 MHz, DMSO-d ) d
6
13
7
.18 (t, J = 8.4 Hz, 1H) d 6.86 (d, J = 6.8 Hz, 3H), 5.59 (S, 2H); C NMR
1
23

3 2 3
[Cu(phen)(PPh ) ]NO -catalyzed microwave-assisted green…
(
cm ): 3433, 3352, 3223, 2225, 1625 cm ; MS (EI) m/z: 161 (M?).
100 MHz, DMSO-d ) d 149.9, 130.5, 119.9, 119.2, 118.9, 116.2, 111.9; IR (KBr,
-1 -1
6
1
5
-Benzyl-1H-tetrazole (2j) Pale-white solid. H NMR (400 MHz, DMSO-d ) d
6
1
3
.36–7.32 (m, 2H) 7.28–7.26 (m, 3H), 4.29 (s, 2H); C NMR (100 MHz, DMSO-
7
-
1
d ) d 136.4, 129.2, 129.1, 127.5, 29.3; IR (KBr, cm ): 3101, 2949, 2854,
529 cm ; MS (EI) m/z: 160 (M?); HRMS (EI, m/z) calcd. for C H N : m/
8 8 4
6
-
1
1
z 160.0749; found 160.0649 (M?).
1
5
-(o-Tolyl)-1H-tetrazole (2k) White solid. H NMR (400 MHz, DMSO-d ) d
6
13
.69–7.51 (m, 1H), 7.49–7.38 (m, 3H), 2.48 (s, 3H); C NMR (100 MHz, DMSO-
7
-
1
d ) d 137.6, 131.8, 131.2, 129.9, 126.8, 124.3, 20.9; IR (KBr, cm ): 2966, 2713,
6
-
1
737 cm ; MS (EI) m/z: 160 (M?).
1
1
5
7
1
1
-(o-Bromophenyl)-1H-tetrazole (2l) Yellow solid. H NMR (400 MHz, CDCl ) d
3
1
3
.71–7.65 (m, 2H), 7.48–7.44 (m, 2H); C NMR (100 MHz, CdCl ) d 143.4,
3
-
1
34.35, 133.2, 127.7, 125.3, 125.0, 118.8; IR (KBr, cm ): 3088, 2916, 2223, 1732,
-
538 cm ; MS (EI) m/z: 223 (M?).
1
1
-(1H-Tetrazol-5-yl)benzaldehyde (2m) White solid. H NMR (400 MHz, DMSO-
4
d ) d 10.09 (s, 1H), 8.26 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H), 3.38 (brs,
6
1
3
NH); C NMR (100 MHz, DMSO-d ) d 192.7, 165.1, 137.5, 130.4, 127.6; IR (KBr,
6
-1
-
1
cm ): 3406, 2864, 1666, 1575 cm ; MS (EI) m/z: 174 (M?); HRMS (EI, m/z)
calcd. for C H N O: m/z 174.0542; found 174.0513 (M?).
8
6 4
1
Methyl 4-(1H-tetrazol-5-yl)benzoate (2n) White solid. H NMR (400 MHz,
1
3
DMSO-d ) d 8.19–8.14 (m, 4H), 3.89 (s, 3H); C NMR (100 MHz, DMSO-d ) d
6
6
1
66.0, 155.9, 132.1, 130.6, 129.2, 127.7, 52.9;, 165.1, 137.5, 130.4, 127.6; IR (KBr,
-
1
-1
cm ): 3097, 3010, 2954, 1710 cm ; MS (EI) m/z: 204 (M?); HRMS (EI, m/z)
calcd. for C H N O : m/z 204.0647; found 204.1623 (M?).
9
8 4 2
Supporting Information
The Supporting Information is available free of charge on the Publications website.
1 13
Experimental section along with H and C NMR spectra of compounds 2a–n.
Acknowledgements The authors thank the Chancellor and Vice Chancellor of VIT University for
providing the opportunity to carry out this study. Further the authors wish to thank the management of this
university for providing seed money as research grant. Barnali Maiti thanks DST-Govt of India for
funding through DST-SERB-YSS/2015/00450. Kaushik Chanda thanks CSIR-Govt of India for funding
through grant no. 01(2913)/17/EMR-II. The authors thank the reviewers for giving constructing
comments for the overall improvement of the manuscript.
References
1
. M.B. Hossain, D. van der Helm, R. Sanduja, M. Alam, Acta Crystallogr. C 41, 1199–1202 (1985)
. S. Berghmans, J. Hunt, A. Roach, P. Goldsmith, Epilepsy Res. 75, 18–28 (2007)
2
123

R. D. Padmaja et al.
3
. J.H. Toney, P.M. Fitzgerald, N. Grover-Sharma, S.H. Olson, W.J. May, J.G. Sundelof, D.E. Van-
derwall, K.A. Cleary, S.K. Grant, J.K. Wu, J.W. Kozarich, D.L. Pompliano, G.G. Hammond, Chem.
Biol. 5, 185–196 (1998)
4
. Y. Tamura, F. Watanabe, T. Nakatani, K. Yasui, M. Fuji, T. Komurasaki, H. Tsuzuki, R. Maekawa,
T. Yoshioka, K. Kawada, K. Sugita, M. Ohtani, J. Med. Chem. 41, 640–649 (1998)
. R.J. Herr, Bioorg. Med. Chem. 10, 3379–3393 (2002)
5
6
7
8
. L. Myznikov, A. Hrabalek, G. Koldobskii, Chem. Heterocycl. Compd. 43, 1–9 (2007)
. R.G. Franz, AAPS PharmSci. 3, 1–13 (2001)
. F.H. Allen, C.R. Groom, J.W. Liebeschuetz, D.A. Bardwell, T.S.G. Olsson, P.A. Wood, J. Chem. Inf.
Model. 52, 857–866 (2012)
9. C. Hansch, A. Leo, Exploring QSAR: Fundamentals and Applications in Chemistry and Biology
(American Chemical Society, Washington, 1995)
1
1
0. P.W.J. Kenny, Chem. Inf. Mod. 49, 1234–1244 (2009)
1. D.J. Carini, J.V. Duncia, P.E. Aldrich, A.T. Chiu, A.L. Johnson, M.E. Pierce, W.A. Price, J.B.
Santella, G.J. Wells, R.R. Wexler, P.C. Wong, S.E. Yoo, P.B.M.W. Timmermans, J. Med. Chem. 34,
2525–2547 (1991)
1
1
2. W.S. Marshall, T. Goodson, G.J. Cullinan, D. Swansonbean, K.D. Haisch, L.E. Rinkema, J.H.
Fleisch, J. Med. Chem. 30, 682–689 (1987)
3. P.L. Ornstein, M.B. Arnold, N.K. Allen, T. Bleisch, P.S. Borromeo, C.W. Lugar, J.D. Leander, D.
Lodge, D.D. Schoepp, J. Med. Chem. 39, 2219–2231 (1996)
1
1
1
4. M.V. Berridge, P.M. Herst, A.S. Tan, Biotechnol. Annu. Rev. 11, 127–152 (2005)
5. G.I. Koldobskii, V.A. Ostrovskii, Usp. Khim. 63, 847–865 (1994)
6. V.A. Ostrovskii, M.S. Pevzner, T.P. Kofman, M.B. Shcherbinin, I.V. Tselinskii, Targets Heterocycl.
Syst. 3, 467–526 (1999)
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
7. Z.P. Demko, K.B. Sharpless, J. Org. Chem. 66, 7945–7950 (2001)
8. Z.P. Demko, K.B. Sharpless, Org. Lett. 4, 2525–2527 (2002)
9. D.P. Matthews, J.E. Green, A.J. Shuker, J. Comb. Chem. 2, 19–23 (2000)
0. Y.S. Gyoung, J. Shim, Y. Yamamoto, Tetrahedron Lett. 41, 4193–4196 (2000)
1. D. Amantini, R. Beleggia, F. Fringuelli, F. Pizzo, L. Vaccaro, J. Org. Chem. 69, 2896–2898 (2004)
2. M. Lakshmi Kantam, K. Kumar, C. Sridhar, Adv. Syn. Catal. 347, 1212–1214 (2005)
3. W.K. Su, Z. Hong, W.G. Shan, X.X. Zhang, Eur. J. Org. Chem. 2723–2726 (2006)
4. J.J. Shie, J.M. Fang, J. Org. Chem. 72, 3141–3144 (2007)
5. M. Nasrollahzadeh, Y. Bayat, D. Habibi, S. Moshaee, Tetrahedron Lett. 50, 4435–4438 (2009)
6. B. Das, C.R. Reddy, D.N. Kumar, M. Krishnaiah, R. Narender, Synlett 391–394 (2010)
7. V. Rama, K. Kanagaraj, K. Pitchumani, J. Org. Chem. 76, 9090–9095 (2011)
8. M.M. Heravi, A. Fazeli, H.A. Oskooie, Y.S. Beheshtiha, H. Valizadeh, Synlett 23, 2927–2930 (2012)
9. H. Yoneyama, Y. Usami, S. Komeda, S. Harusawa, Synthesis 45, 1051–1059 (2013)
0. L. Lang, H. Zhou, M. Xue, X. Wang, Z. Xu, Mater. Lett. 106, 443–446 (2013)
1. A. Khalafi-Nezhad, S. Mohammadi, RSC Adv. 3, 4362–4371 (2013)
2. P. Mani, A.K. Singh, S.K. Awasthi, Tetrahedron Lett. 55, 1879–1882 (2014)
3. P. Sivaguru, K. Bhuvaneswari, R. Ramkumar, A. Lalitha, Tetrahedron Lett. 55, 5683–5686 (2014)
4. D.R. Rekunge, K.S. Indalkar, G.U. Chaturbhuj, Tetrahedron Lett. 57, 5815–5819 (2016)
5. A. Vignesh, N.S.P. Bhuvanesh, N. Dharmaraj, J. Org. Chem. 82, 887–892 (2017)
6. K.P. Nandre, J.K. Salunke, J.P. Nandre, V.S. Patil, A.U. Borse, S.V. Bhosale, Chin. Chem. Lett. 23,
161–164 (2012)
3
3
3
4
4
4
4
4
4
7. K. Manabe, S. Limura, X.M. Sun, S. Kobyashi, J. Am. Chem. Soc. 124, 11971–11978 (2002)
8. C. Capello, U. Fischer, K. Hungerb u¨ hler, Green Chem. 9, 927–934 (2007)
9. R.A. Sheldon, Green Chem. 7, 267–268 (2005)
0. A. Chanda, V.V. Fokin, Chem. Rev. 109, 725–748 (2009)
1. B. Maiti, K. Chanda, C.M. Sun, Org. Lett. 9, 4826–4829 (2009)
´
2. J. Garc ´ı a-Alvarez, J. D ´ı ez, C. Vidal, C. Vicen, Inorg. Chem. 52, 6533–6542 (2013)
3. B. Maiti, K. Chanda, RSC Adv. 6, 50384–50413 (2016)
4. S. Rajasekhar, B. Maiti, K. Chanda, Synlett 28, 521–541 (2017)
5. R.N. Rao, B. Maiti, K. Chanda, ACS Comb. Sci. 19, 199–288 (2017)
1
23