Amberlyst-15 catalyzed synthesis of 5-substituted 1-H-tetrazole via [3+2] cycloaddition of nitriles and sodium azide

Article abstract of DOI:10.1016/j.tetlet.2012.10.116

A mild and efficient method for the preparation of 5-substituted 1-H-tetrazole derivatives is reported using solid acidic resin Amberlyst-15 as an effective heterogeneous catalyst. This method is advantageous because of non-toxicity and stability of catalyst, high product yield, simple methodology, and easy work up. The catalyst was recovered by simple filtration and reused several times delivering moderate to good product yield.

Full text of DOI:10.1016/j.tetlet.2012.10.116

Tetrahedron Letters 54 (2013) 106–109
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Amberlyst-15 catalyzed synthesis of 5-substituted 1-H-tetrazole via [3+2]
cycloaddition of nitriles and sodium azide
⇑
Radheshyam Shelkar, Abhilash Singh, Jayashree Nagarkar
Department of Chemistry, Institute of Chemical Technology (Deemed), Nathalal Parekh Marg, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient method for the preparation of 5-substituted 1-H-tetrazole derivatives is reported
using solid acidic resin Amberlyst-15 as an effective heterogeneous catalyst. This method is advantageous
because of non-toxicity and stability of catalyst, high product yield, simple methodology, and easy work
up. The catalyst was recovered by simple filtration and reused several times delivering moderate to good
product yield.
Received 9 August 2012
Revised 25 October 2012
Accepted 27 October 2012
Available online 3 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amberlyst-15
Heterogeneous catalyst
Cycloaddition
Tetrazole
Tetrazoles have a wide range of applications in pharmaceutical
science. They possess antihypertensive, anti-allergic, antibiotic
activity1,2 and the amino substituted tetrazoles have anti-inflam-
matory,3 antineoplastic,4 antiviral, and receptor modulator5 activi-
ties. Tetrazoles are also used as plant growth regulators, herbicides,
and fungicides.6 Tetrazole derivatives have potential for drug
development for HIV or other immune diseases.7,8 Additionally
they have also application in photography9 and specialty explo-
sives.10 They are resistant to metabolic degradation as well as to
chemical oxidants.11 Tetrazoles show greater lipophilicity and
hence may serve as non-classical isosteres for the carboxylic acid
moiety in biologically active molecules.12,13 Example of a potential
anti-HIV drug candidate is shown in Figure 1. Tetrazoles play an
important role in organocatalysis, in coordination chemistry as a li-
gand with various coordination modes,14 and in preparation of
imidoylazides.15
advantages, new pathways have been developed, such as the cata-
lytic method using a stoichiometric amount of inorganic salts17
and transition metal complexes as catalysts.18 However, these
homogeneous catalytic processes suffer from serious problems
namely, the separation, recovery, and reusability of the catalyst.
Therefore, the heterogeneous alternatives are highly desirable
and have attracted much more attention. Several heterogeneous
catalytic systems were reported using various catalysts, such as,
nanocrystalline ZnO,19a Zn/Al hydrotalcite,19b Zn hydroxyapa-
tite,19c Cu2O,19d AlCl3,19e Pd (PPh3)4,19f and TBAF.19g These solid acid
catalysts play a prominent role in organic synthesis under hetero-
geneous conditions. Recently our group developed an efficient cat-
alytic system20 for the synthesis of tetrazole.
In continuation with this research work, we have tried to devel-
op an alternative heterogeneous and simple catalytic system for
the synthesis of tetrazole. Amberlyst-15 is non hazardous in nature
This broad utility has prompted significant effort toward the
tetrazole synthesis. The most convenient method for the prepara-
tion of 5-substituted 1-H-tetrazole is via [3+2] cycloaddition of
azide to corresponding nitriles. Earlier reported methods for the
synthesis of 5-substituted tetrazole suffer from some drawbacks
such as use of strong Lewis acid, expensive and toxic metals, use
of organic azide complexes such as tin or silicon organic azides
and the in situ generated hydrazoic acid which is highly toxic, vol-
atile and explosive.16 Synthesis of tetrazole from sterically hin-
dered aromatic or alkyl nitriles requires high temperatures and
moisture free reaction conditions. In order to overcome these dis-
R
NH
N
O
N
N
N
HN
N
O
O
OH
⇑
Corresponding author.
E-mail address: jayashreenagarkar@yahoo.co.in (J. Nagarkar).
Figure 1. Potential anti HIV drug candidate.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.116

R. Shelkar et al. / Tetrahedron Letters 54 (2013) 106–109
107
N
and easily separable from reaction mixture. Because of these
HN
features it is used in a variety of reactions.21 Amberlyst-15 is a
strongly acidic macro reticular polymeric resin based on cross
linked styrene divinyl benzene co-polymers. Herein we report a
new protocol for the preparation of 5-substituted 1-H-tetrazoles
from a wide variety of nitriles using Amberlyst-15 as solid acid
catalyst.
N
CN
N
AMBERLYST-15, NaN3
DMSO, 85° C, 12 Hrs.
Benzonitrile was selected as the starting material to synthesize
the corresponding tetrazoles. Various solid acid catalysts such as
Amberlyst-15, Amberlite-120, montmorilonite, aluminium oxide,
sulfated zirconia, and phosphated zirconia have been used for
model reaction. The results are summarized in Table 1. Amber-
lyst-15 exhibits high catalytic activity with 91% product yield
(Table 1, entry 1).
Scheme 1. Reaction of benzonitrile and sodium azide with Amberlyst-15 is used as
model reaction.
Table 2
Optimization of various reaction parameters for the preparation of 5-substituted 1-H-
tetrazolea
Entry Solvent Catalyst
Cat. concn (mol %) Temp (°C) Yieldb (%)
The most probable reason for its higher activity can be ex-
plained by its physical properties like high H+ exchange capacity
(4.2 meq/g) and surface area (42 m2/g) (Table 1, entry 1). The
Amberlite-120 gave a lower yield (Table 1, entry 2), even though
the H+ capacity and surface area are more or less similar to the
Amberlyst-15. This happens because, the moisture content of
Amberlyst-15 is 1.5–1.6% and that of Amberlite-120 is 53–58%.
Since the reaction is in organic medium, the excess moisture con-
tent of Amberlite-120 may affect the yield of the product. Hence
the Amberlyst-15 has superior catalytic activity. The data of H+
exchange capacity and surface area are provided by the supplier.
The effect of different parameters such as solvents, tempera-
tures, and catalyst concentrations was studied on model reaction
(Scheme 1) and the results are summarized in Table 2. In order
to get the optimal temperature we carried out the model reaction
at various temperatures (Table 2, entries 1–5) and at 85 °C we get
the maximum yield. The solvent has prominent influence on the
yield of product (Table 2, entries 6–11). DMSO, DMF, and NMP
are good solvents with 91%, 85%, and 80% yields, respectively,
whereas IPA, ethanol, and water are not suitable for the reaction.
23 mol %, w/w catalyst concentration was sufficient to give maxi-
mum yield of the required product (Table 2, entries 12–16). In
the absence of the catalyst at 85 °C, no reaction occurred even after
12 h (Table 2, entry 16).
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
Amberlyst-15 23
rt
30
39
84
87
79
91
85
80
35
30
<20
92
85
79
66
00c
60
80
90
100
85
85
85
85
85
85
85
85
85
85
85
NMP
IPA
9
10
11
12
13
14
15
16
Ethanol Amberlyst-15 23
Water
DMSO
DMSO
DMSO
DMSO
DMSO
Amberlyst-15 23
Amberlyst-15 28
Amberlyst-15 18
Amberlyst-15 14
Amberlyst-15 10
—
00
a
Reaction and conditions: benzonitrile (1 mmol), NaN3 (1.5 mmol), Amberlyst-15
(23 mol %, w/w), DMSO (3 mL), reaction time (12 h), and temperature (85 °C).
b
Isolated Yield.
c
In the absence of catalyst at 85 °C, no reaction occurred after 12 h.
stituent has a significant influence on the product yield. The exper-
imental results show that the electron-donating substituents at
4-position gave excellent yields. (Table 3, entries 2–6). Electron
donating group at 2-position might have given comparatively low-
er yield due to steric effect (Table 3, entry 7). Electron-withdrawing
effect is pronounced at 3-position than at 4-position which
explains the lower yield of 3-nitrobenzonitrile. (Table 3, entries 8
and 9).
The heteroaromatic nitriles such as 2-pyridinylnitrile gave the
corresponding tetrazole in moderate yield (Table 3, entry 10). Phen-
ylacetonitrile and 4-chlorophenylacetonitrile provided moderate to
good yield with same reaction time (Table 3, entries 11 and 12). We
also explore the reactions of aliphatic nitriles with sodium azide
under similar reaction conditions. The catalyst exhibited low activ-
ity for aliphatic nitriles in comparison with aromatic nitriles (Table
3, entries 13–14). The reaction was also scaled up by taking
10 mmol of starting material in which 79% yield of the product
Recyclability of the catalyst is important for the industrial appli-
cations. Therefore, the reusability of Amberlyst-15 was investi-
gated for three cycles. The catalyst was recovered from reaction
mixture by simple filtration, then washed with diethyl ether
(2 Â 10 mL) followed by treatment with 0.1 N HCl solution
and dried at 60 °C for an hour. The recovered catalyst can be reused
over three run cycles; only negligible loss of activity was observed
(ꢀ5% per cycle) (Table 3, entry 1).
To understand the scope and applicability of the catalyst to
cycloaddition reaction to form 5-substituted 1-H-tetrazole, differ-
ent functionalized benzonitriles have been screened and the
results are summarized in (Table 3).23 The aromatic nitriles gave
excellent yields (Table 3, entries 1–10). In case of aromatic nitriles,
an electron-donating or electron-withdrawing property of the sub-
Table 1
Characteristics of catalysts
Entry
Catalyst
H+ Capacity
Surface area (m2/g)
Particle size (mesh)
Yieldc (%)
1
2
3
4
5
6
Amberlyst-15a
4.2 meq/g
4.4 meq/g
3.4 meq/g
4.5 meq/g
—
42
45
220
200
85b
180b
20–50
16–50
<200
150–300
—
91
69
34
28
62
56
Amberlite-120a
Montmorilonitea
Aluminium oxidea
Sulfate zirconia
Phosphate zirconia
—
—
a
b
c
The H+ capacity, surface area (m2/g), and particle mesh size of the catalyst reported.22
The surface area of sulfated and phosphated zirconia is determined by using BET method.
Isolated yield.

108
R. Shelkar et al. / Tetrahedron Letters 54 (2013) 106–109
Table 3
Amberlyst-15 catalyzed synthesis of 5-substituted 1-H-tetrazolea
Entry
Substrate
Product
Yieldb (%)
CN
N
HN
N
1
91, 88c, 85d, 80e
N
CN
N
HN
HN
HN
N
N
2
3
93
94
Cl
Cl
CN
N
N
N
MeO
MeO
HO
Me
CN
CN
N
N
N
4
5
91
89
HO
Me
N
HN
N
N
CN
N
HN
N
N
6
7
8
9
87
82
84
75
Me2N
OH
Me2N
OH
N
HN
N
CN
N
CN
N
HN
N
N
O2N
O2N
O2N
O2N
CN
N
HN
N
N
CN
N
HN
N
10
11
64
74
N
N
N
N
HN
CN
N
N

R. Shelkar et al. / Tetrahedron Letters 54 (2013) 106–109
109
Table 3 (continued)
Entry
Substrate
Product
Yieldb (%)
N
HN
CN
N
12
13
N
46
Cl
Cl
H
N
CN
N
36
54
N
N
H3C
CN
H
N
N
14
H3C
N
N
a
Reaction and conditions: nitriles (1 mmol), NaN3 (1.5 mmol), Amberlyst-15 (23 mol %, w/w), DMSO (3 mL), reaction time (12 h), and temperature (85 °C).
Isolated yield.
Yield after first cycle.
Yield after second cycle.
Yield after third cycle.
b
c
d
e
13. Desarro, A.; Ammendola, D.; Zappala, M.; Grasso, S.; Desarro, G. B. Antimicrob.
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effectively as a catalyst for the large scale production of tetrazole.
15. Modarresi-Alam, A. R.; Khamooshi, F.; Rostamizadeh, M.; Keykha, H.;
Nasrollahzadeh, M.; Bijanzadeh, H. R.; Kleinpeter, E. J. Mol. Struct. 2007, 841, 61.
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17. Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945.
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19. (a) Kantam, M. L.; Shiva Kumar, K. B.; Sridhar, C. Adv. Synth. Catal. 2005, 347,
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2006, 247, 186; (c) Kantam, M. L.; Balasubrahmanyam, V.; Shiva Kumar, K. B.
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Conclusion
In conclusion, we report that Amberlyst-15 is an effective heter-
ogeneous catalyst for the [3+2] cycloaddition of sodium azide and a
wide variety of nitriles to form 5-substituted 1-H-tetrazoles with
excellent to good yields. The catalyst can be easily recovered and
reused.
Acknowledgment
20. Agawane, S. M.; Nagarkar, J. M. Catal. Sci. Technol. 2012. http://dx.doi.org/
10.1039/C2CY20094E.
The authors are thankful to the UGC-UPE Green Technology
Centre, New Delhi, India for awarding the fellowship.
21. (a) Das, B.; Damodar, K.; Chouwdhury, N.; Kumar, R. A. J. Mol. Catal. A: Chem.
2007, 274, 148–152; (b) Bhanushali, M. J.; Nandurkar, N. S.; Bhor, M. D.;
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23. General procedure for the synthesis of Tetrazole.
A mixture of benzonitrile
(103 mg, 1 mmol), sodium azide (97.5 mg, 1.5 mmol), and 3 mL DMSO solvent
was added in a 25 mL round bottomed flask. Further (50 mg, 23 mol %, w/w)
catalyst was added to the reaction mixture. The reaction mixture was heated to
85 °C for 12 h. After completion of the reaction (as monitored by TLC), the
catalyst was separated by simple filtration, washed with diethyl ether and the
filtrate was treated with ethyl acetate (30 mL) and 5 N HCl (20 mL) and stirred
vigorously. The resultant organic layer was separated and the aqueous layer
was again extracted with ethyl acetate (20 mL). The combined organic layers
were washed with water and dried over anhydrous sodium sulfate and were
evaporated under reduced pressure to give the product. The product was
purified by the column chromatography. The structure was confirmed by
spectral analysis (1H NMR, mass and elemental analysis).
Characterization of 5-phenyl 1-H-tetrazole. 1H NMR (300 MHz, CDCl3): d = 8.01–
8.04 (m, 2H), 7.57–7.61 (m, 3H), 3.42 (m, 1H) MS (70 eV): m/z (%) = 146 (M+,
16.2%), 118 (100.0%), 103 (12.4%), 90.95 (47.1%), 77 (31.7%), 62.9 (24.4%) and
51 (12.3%). CHNS = Anal. Calcd for C7H6N4: C, 57.53; H, 4.14; N, 38.34. Found C,
57.76; H, 4.74; N, 38.77.
11. Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Thieme: NewYork,
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12. Hansch, C.; Leo, L.; QASR Exploring Fundamentals and Applications in Chemistry
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