Synthesis of 5-substituted 1H-tetrazoles catalyzed by ceric ammonium nitrate supported HY-zeolite

Article abstract of DOI:10.1016/j.tetlet.2014.08.066

In this Letter we wish to report a simple and efficient synthetic protocol for the synthesis of 5-substituted 1H-tetrazole derivatives through the [2+3] cycloaddition of nitriles with sodium azide using ceric ammonium nitrate supported HY-zeolite as a novel catalyst. Excellent yields of the corresponding tetrazoles were obtained through this cost-effective protocol under aerobic conditions with shorter reaction time under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2014.08.066

Accepted Manuscript
Synthesis of 5-substituted 1H-tetrazoles catalyzed by ceric ammonium nitrate
supported HY-zeolite
Paramasivam Sivaguru, Kaliyan Bhuvaneswari, Rangasamy Ramkumar,
Appaswami Lalitha
PII:
S0040-4039(14)01409-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.066
TETL 45033
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 July 2014
12 August 2014
14 August 2014
Please cite this article as: Sivaguru, P., Bhuvaneswari, K., Ramkumar, R., Lalitha, A., Synthesis of 5-substituted
1H-tetrazoles catalyzed by ceric ammonium nitrate supported HY-zeolite, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.08.066
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Graphical Abstract
Synthesis of 5-substituted 1H-tetrazoles
catalyzed by ceric ammonium nitrate
supported HY-zeolite
Leave this area blank for abstract info.
Paramasivam Sivaguru, Kaliyan Bhuvaneswari, Rangasamy Ramkumar, Appaswami Lalitha*

1
Tetrahedron Letters
journal hom epage: www.elsevier.com
Synthesis of 5-substituted 1H-tetrazoles catalyzed by ceric ammonium nitrate
supported HY-zeolite
Paramasivam Sivaguru, Kaliyan Bhuvaneswari, Rangasamy Ramkumar, Appaswami Lalitha*
Department of Chemistry, Periyar University, Periyar Palkalai Nagar, Salem 636011, Tamil Nadu, India
ARTICLE INFO
ABSTRACT
Article history:
Received
In this letter we wish to report a simple and efficient synthetic protocol for the synthesis of 5-
substituted 1H-tetrazole derivatives through the [2+3] cycloaddition of nitriles with sodium
azide using ceric ammonium nitrate supported HY-zeolite as a novel catalyst. Excellent yields of
the corresponding tetrazoles were obtained through this cost-effective protocol under aerobic
conditions with shorter reaction time under mild reaction conditions.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
5-Substituted 1H-tetrazoles
Ceric ammonium nitrate supported HY-zeolite
[2+3] cycloaddition
Nitriles
Sodium azide
Tetrazoles are one of the most stable nitrogen rich
heterocyclic compounds among other heterocyclic systems. Due
to their higher nitrogen content they show the exciting acidity,
basicity and complex formation constants. Tetrazole containing
molecules have several applications in the field of organic
synthesis, coordination chemistry, material science and medicinal
chemistry.1,2 Recently, the tetrazole ring, particularly, the 5-
substituted-1H-tetrazole that is commonly referred to as tetrazolic
acid, has been widely employed in medicinal chemistry as a
bioisostere for carboxylic acid group.3 Compounds with this
tetrazole building blocks have been shown to possess strong
biological activities, especially as sedatives,4 antihypertensive,4
antiallergic,4 antimicrobial,5 antibacterial,6 antifungal,7 anti-
inflammatory,8 hormonal,9 diuretics10 and herbicides.11 Tetrazoles
have also been considered as cis-peptide bond mimics,12 as
lipophilic spacers,13 and as ion and peptide chelating agents.14
These important rings have also been used in explosives,15
information recording systems,16 as anti-foggants in
photography,17 and in high-density energy materials.18 Tetrazoles
also serve as valuable synthetic intermediates in making
thiazoles, oxazolidones, and triazoles.19,20 As these tetrazole
moieties are not found in nature,21 researchers are very much
interested in the development of their synthetic methods and the
studies of their molecular structure, physicochemical properties
and applications.22-26
reagents/solvents, long reaction times, low yield of products,
water sensitivity, etc. In addition, there was a formation of highly
volatile and toxic hydrazoic acid as by-product in some
methods.29 Moreover, synthesis of tetrazoles from sterically
hindered aromatic or alkyl nitriles requires high temperatures and
moisture-free reaction conditions.30
The homogeneous catalysts such as a stoichiometric amounts
of inorganic salts, metal complexes, trimethylsilyl azide and
tetrabutylammonium fluoride (TBAF) have been used for the
synthesis of tetrazoles during earlier days.31 As, these
homogeneous catalytic processes suffered from the serious
problems of the catalyst separation and recovering, the
heterogeneous alternatives are highly desirable and have already
attracted much attention. Recently, Zn/Al hydrotalcite, Cu2O,
Cu/Zn alloy, Sb2O3, FeCl3/SiO2, CuFe2O4, BaWO4, ZnS, natural
natrolite and CoY zeolite have been reported to show good
catalytic performance for the synthesis of the tetrazole moieties.32
In continuation of our research on the synthesis of
heterocyclic compounds using metal nitrates supported HY-
zeolite as catalysts,33 herein we report the use of ceric ammonium
nitrate supported HY-zeolite as a greener heterogeneous catalyst
for the construction of tetrazole derivatives (Scheme 1). To the
best of our knowledge there are no methods reported in the
literature for the synthesis of 5-substituted 1H-tetrazoles from
nitriles using ceric ammonium nitrate supported HY-zeolite as a
catalyst.
As reported by Hantzsch and Vagt, the most common
synthetic method for the 5-substituted tetrazoles involves the
[2+3] cycloaddition of an azide with a nitrile.27 There are
numerous other reports available in the literature for this
cycloaddition reaction.28 However all the reported methods have
some disadvantages like vigorous reaction conditions with
tedious work-up procedures, use of expensive or unavailable
Scheme 1. Synthesis of 5-substituted tetrazoles

2
Tetrahedron Letters
In order to find out the suitability of the solvents as reaction
solvents screened (Table 1, Entry 4). Polar solvents like ethanol
and methanol produced only 25 and 33% yields even after 24h
(Table 1, Entries 1 & 2). This cycloaddition did not proceed well
while using chloro solvents such as chloroform or
dichloromethane as medium (Table 1, Entries 7 & 8). When,
toluene has been used as the reaction medium, the cycloaddition
product was obtained in 65% yield in 24h (Table 1, Entries 3 &
5). We have also tried the reaction in water, but the yield of the
desired product was very low (Table 1, Entry 9).
medium for this cycloaddition reaction, a model reaction with
benzonitrile and sodium azide has been carried out with a number
of solvents using 30 mol% of CAN supported HY-zeolite as
catalyst and the results are summarized in Table 1.
Table 1. Effect of reaction medium for the cycloaddition
reactiona
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
Ethanol
24
24
4
25
33
93
65
82
-
In order to optimize the suitable metal nitrate supported HY-
zeolite catalyst, we have carried out the cycloaddition reaction of
benzonitrile and sodium azide with different metal nitrates
supported HY-zeolite and simple HY-zeolite as catalysts and the
results are presented in Table 2. It is evident from Table 2 that,
when the model cycloaddition reaction has been carried out under
catalyst-free condition at 110 °C in DMF, the desired product
was not formed even after 24 h (Table 2, Entry 1). About 65% of
yield was observed in the reaction performed with 0.5g of HY-
zeolite as a catalyst under similar conditions. The yield of the
product increased when metal nitrate supported on HY-zeolite
(Table 2, Entries 3-21) has been used as a catalyst. Among the
different metal nitrates supported HY-zeolite catalysts studied,
the ceric ammonium nitrate supported HY-zeolite provided good
yield (Table 2, Entry 8).
Methanol
DMF
Toluene
48
6
DMSO
Chloroform
Dichloromethane
Water
24
24
24
-
10
aReaction of benzonitrile (1 equiv) with sodium azide (3 equiv) in the
presence of 30 mol% of CAN supported HY-zeolite as a catalyst at 110 °C in
different solvents.
bIsolated Yield.
The results revealed that, DMF was found to be a superior one
in terms of reaction time and the product yield among the
Table 2. Optimization of reaction conditionsa
Entry
Catalyst
mol% of metal nitrate
Temperature (°C)
Time (h)
24
24
24
24
24
12
7
Yield (%)b
1
-
-
110
110
110
110
110
110
110
110
110
RT
-
2
HY-Zeolite
-
45
53
61
65
73
82
93
85
-
3
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
CAN/HY-Zeolite
Cu(NO3)2/HY-Zeolite
Ni(NO3)2/HY-Zeolite
Fe(NO3)3/HY-Zeolite
Bi(NO3)2/HY-Zeolite
Co(NO3)2/HY-Zeolite
Cd(NO3)2/HY-Zeolite
Zn(NO3)2/HY-zeolite
CAN
1
4
2
5
5
6
10
20
30
60
30
30
30
30
30
30
30
30
30
30
30
30
30
7
8
4
9
4
10
11
12
13
14
15
16
17
18
19
20
21
22
24
15
12
6
60
49
63
79
86
75
66
78
73
62
59
72
35
80
100
140
110
110
110
110
110
110
110
110
4
10.5
24
20
24
19
24
15
24
aCycloaddition reaction of benzonitrile and sodium azide with different catalysts in DMF as a reaction medium.
bIsolated Yield.
In order to optimize the suitable mol% of ceric ammonium
nitrate (with respect to benzonitrile), we have conducted the
cycloaddition reaction with 1, 2, 5, 10, 20, 30, 60 mol% of CAN
supported HY-zeolite and observed that 30 mol% of CAN
supported HY-zeolite yielded 93% of conversion. Increase in the
mol% of CAN beyond 30 mol% didn’t produce any notable
change in the reaction time and the yield of the product. When
the same reaction was carried out with only 30 mol% of CAN as
a catalyst without zeolite the corresponding product was obtained
in very poor yield (35%) even after longer reaction time (Table 2,
Entry 22). From these observations, we concluded that the
reaction is feasible in the presence of CAN supported on HY-
zeolite.

3
Next, we have tried to optimize the suitable temperature for
this cycloaddition reaction. In connection to this, initially the
model cycloaddition reaction has been conducted at room
temperature where, there was no product formation (Table 2,
Entry 10). So, we tried the synthesis of the title compound at
different temperatures for different time periods (Table 2, Entry
11, 12, 13) and observed that the reaction was successfully
completed at 110 °C, in 4h with 93% of yield (Table 2, Entry 8).
If the temperature was increased above 110 °C, there was no
change in the product yield and reaction rate (Table 2, Entry 14)
and so, 110 °C was fixed as the most suitable temperature and
further reactions were carried out at this temperature.
may be due the lack of close proximity of the reactant
molecules on the catalyst (Table 3, Entry 4).
Table 3. Effect of amount of the catalyst supporta
Entry
Support (g)
Time (h)
Yield (%)b
1
2
3
4
0.1
0.2
0.5
1
16
11
4
53
65
93
85
6
aReaction of benzonitrile (1 equiv) with sodium azide (3 equiv) in the
presence of 30 mol% of CAN as a catalyst and DMF as a medium at 110 °C
under different concentration of HY-zeolite.
Amount of HY-zeolite also played a vital role in this
cycloaddition reaction. We have performed the model
cycloaddition reaction of benzonitrile and sodium azide with
different amounts 30 mol% CAN supported HY-zeolite (0.1, 0.2,
0.5, 1g) and observed that 0.5g of HY-zeolite was optimum for
this cycloaddition reaction (Table 3, Entry 3). Whereas, while
increasing the catalyst amount to 1g, the time required for the
completion of the reaction was increased with lesser yield. This
bIsolated Yield.
Using this optimized reaction conditions, we have studied the
effect of substituents on the aromatic nitriles and the results are
presented in Table 4. Aromatic nitriles having both electron
donating and electron withdrawing groups at any position
resulted in the corresponding products in good to excellent yield.
Table 4. CAN supported HY-zeolite catalyzed synthesis of 5-substituted tetrazoles
Producta
Entry
Substrate
Reaction time (h)
Yield (%)b
1
4
93
2
3
6
87
95
2.5
4
5
6
2.5
94
73
69
7
8
7
8
8
6
75
78
N
N
N
N
H
Br

4
Tetrahedron Letters
9
9
73
N
N
N
10
11
4
75c
N
H
O2N
3.5
67c
12
13
14
5
5
6
63
85
83
15
5
88
aReaction of different substituted nitriles (1 equiv) with sodium azide (3 equiv) in the presence of 30 mol% of CAN supported HY-zeolite as a catalyst and DMF
as a medium at 110 °C.
bIsolated Yield.
cNovel Compounds.
3. (a) Butler, R. N. Adv. Heterocycl. Chem. 1977, 21, 323. (b) Malik,
M. A.; Wani, M. Y.; Al-Thabaiti, S. A.; Shiekh, R. A. J. Incl.
Any of the substituent at the ortho position led to slightly
lower yield with longer reaction time (Table 4, Entries 2, 8 & 9)
Phenom. Macrocycl. Chem. 2014, 78, 15.
which may be attributed to the steric effect. Benzylic nitriles also
smoothly reacted in this protocol providing the corresponding
4. Ellis, E. P.; West, G. B.; Progress in Medicinal Chemistry;
Biomedical Press, 1980, vol. 17, pp 151.
tetrazoles in good yields (Table 4, Entries 14 & 15). This
cycloaddition reaction works well with disubstituted aromatic
nitriles, but the yields were relatively lower (Table 4, Entries 10-
12).
5. Narender Rao, S.; Ravisankar, T.; Latha, J.; Sudhakar Babu, K.
Der Pharma Chem. 2012, 4, 1093.
6. Narasaiah, T.; Subba, D.; Rasheed, S.; Madhava, G.; Srinivasulu,
D.; Brahma Naidu, P.; Naga Raju, C. Der Pharm Lett. 2012, 4,
854.
7. Ahmad Malik, M.; Al-Thabaiti, S. A.; Malik, M. A. Int. J. Mol.
Sci. 2012, 13, 10880.
In conclusion, we have demonstrated a simple, novel and
practical method for the synthesis of 5-substituted-1H-tetrazoles
via the [2+3] cycloaddition of nitriles and sodium azide using 30
mol% of CAN supported HY-zeolite as a green catalyst. Salient
features of this protocol are excellent yields, shorter reaction
times, mild conditions, easy availability of catalyst, elimination
of toxic hydrazoic acid and simple work-up procedure.
8. Bepary, S.; Das, B. K.; Bachar, S. C.; Kundu, J. K.; Shamsur rouf,
A. S.; Datta, B. K. Pak. J. Pharm. Sci. 2008, 21, 295.
9. Li, J.; Chen, S. Y.; Tino, J. A. Bioorg. Med. Chem. Lett. 2008, 18,
5.
10. Nachman, R. J.; Coast, G. M.; Kaczmarek, K.; Williams, H. J.;
Zabrocki, J. Acta Biochim. Pol. 2004, 51, 121.
11. Camilleri, P.; Kerr, M. W.; Newton, T. W.; Bowyer, J. R. J. Agric.
Food Chem. 1989, 37, 196.
Acknowledgments
12. Beusen, D. D.; Zabrocki, J.; Slomczynska, U.; Head, R. D.; Kao,
J. L. F.; Marshall, G. R. Biopolymers 1995, 36, 181.
13. Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B. J. Am.
Chem. Soc. 2003, 125, 9983.
14. Lodyga-Chruscinska, E.; Sanna, D.; Micera, G.; Chruscinski, L.;
Olejnik, J.; Nachman, R. J.; Zabrocki, J. Acta Biochim. Pol. 2006,
53, 65.
The authors would like to acknowledge the financial support
received from Council of Scientific and Industrial Research (No.
02(0025)/11/EMR-II), New Delhi, India.
15. Hiskey, M.; Chavez, D. E.; Naud, D. L.; Son, S. F.; Berghout, H.
L.; Bome, C. A. Proc. Int. Pyrotech. Semin. 2000, 27, 3.
16. Koldobskii, G. I.; Ostrovskii, V. A. Usp. Khim. 1994, 63, 847.
17. Tuites, R. C.; Whiteley, T. E.; Minsk, L. M. US Patent 1, 245, 614
1917.
References and notes
1. Butler, R. N. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon:
Oxford, U.K., 1996; Vol. 4.
18. Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993, 58, 4139.
19. Moderhack, D. J. Prakt. Chem. 1988, 340, 687.
20. Huisgen, R.; Sauer, J.; Sturm, H. J.; Markgraf, J. H. Chem. Ber.
1960, 93, 2106.
2. (a) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379; (b) Myznikov,
L. V.; Hrabalek, A.; Koldobskii, G. I. Chem. Heterocycl. Compd.
2007, 43, 1; (c) Roh, J.; Vavrova, K.; Hrabalek, A. Eur. J. Org.
Chem. 2012, 6101; (d) Koldobskii, G. I. Russ. J. Org. Chem. 2006,
42, 487.

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21. Patil Umakant. B.; Kumthekar Kedar. R.; Nagarkar Jayashree. M.
Tetrahedron Lett. 2012, 53, 3706.
31. (a) Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, K. B. J.
Am. Chem. Soc. 2003, 125, 9983. (b) Bonnamour, J.; Bolm, C.
Chem. Eur. J. 2009, 15, 4543. (c) Bosch, L.; Vilarrasa, J. Angew.
Chem. Int. Ed. 2007, 46, 3926.
22. Li, J. Y.; Zhou, X. Q.; Zhou, Y.; Fang, Y.; Yao, C. Spectrochim.
Acta A Mol. Biomol. Spectrosc. 2013, 102, 66.
23. Pagacz-Kostrzewa, M.; Mucha, M.; Weselski, M.; Wierzejewska,
M. J. Photochem. Photobiol. A Chem. 2013, 251, 118.
24. Shao, Y.; Zhu, W.; Xiao, H. J. Mol. Graph. Model. 2013, 40, 54.
25. Bhaskar, V. H.; Mohite, P. B. J. Optoelectron. Biomed. Mater.
2010, 2, 249.
32. (a) Kantam, M. L.; ShivaKumar, K. B.; Sridhar. C. Adv. Synth.
Catal. 2005, 347, 1212. (b) Kantam, M. L.; ShivaKumar, K. B.;
Raja, K. P. J. Mol. Catal:A 2006, 247, 186. (c) Aridoss, G.; Laali, K.
K. Eur. J. Org. Chem. 2011, 31, 6343. (d) Venkateshwarlu, D. G.;
Rajanna. K. C.; Saiprakash, P. K. Synth. Commun. 2009, 39, 426. (e)
Rama. V.; Kanagaraj, K.; Pitchumani, K. J. Org. Chem. 2011, 76,
9090. (f) He, J. H.; Li, B. J.; Chen, F. S.; Xu, Z.; Yin, G. J. Mol.
Catal:A 2009, 304, 135. (g) Lang, L. M.; Li, B. J.; Liu, W.; Jiang,
L.; Xu. Z.; Yin, G. Chem. Commun. 2010, 46, 448.
26. Chatzopoulou, M.; Bonovolias, I. D.; Nicolaou, I.; Demopoulos,
V. J.; Vizirianakis, I. S.; Tsiftsoglou, A. S. Eur. J. Med. Chem.
2012, 50, 75.
27. Hantzsch, A.; Vagt, A. Justus Liebigs Ann. Chem. 1901, 314, 339.
28. (a) Meshram, G. A.; Deshpande, S. S.; Wagh, P. A.; Vala, V. A.
Tetrahedron Lett. 2014, http://dx.doi.org/10.1016/j.tetlet.2014.
04.101; (b) Coca, A.; Turek, E. Tetrahedron Lett. 2014,
http://dx.doi.org/10.1016/j.tetlet.2014.03.049; (c) Mani, P.; Singh,
A. K.; Awasthi, S. K. Tetrahedron Lett. 2014, 55, 1879; (d) Kuhn,
B. L.; Fortes, M. P.; Kaufman, T. S.; Silveira, C. C. Tetrahedron
Lett. 2014, 55, 1648; (e) Lang, L.; Zhou, H.; Xue, M.; Wang, X.;
Xu, Z. Mater. Lett. 2013, 106, 443; (f) Yao, Y. W.; Zhou, Y.; Lin,
B. P.; Yao, C. Tetrahedron Lett. 2013, 54, 6779.
33. Sivaguru, P.; Lalitha, A. Chin. Chem. Lett. 2014, 25, 321.
Supplementary Material
Experimental procedure, spectral data of all the compounds
and copy of 1H NMR, 13C NMR & LC-MS spectra for unknown
compounds are presented as supplementary material.
29. (a) Curran, D. P.; Hadida, S.; Kim, S. Y. Tetrahedron 1999, 55,
8997; (b) Shelkar, R.; Singh, A.; Nagarkar, J. Tetrahedron Lett.
2013, 54,106.
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30. (a) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945.
(b) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro,
L. J. Org. Chem. 2004, 69, 2896. (c) Wittenberger, S. J.; Donner,
B. G. J. Org. Chem. 1993, 58, 4139.

Highlights
ꢀ Highly efficient, easy to prepare, cost effective greener catalyst.
ꢀ Operational simplicity and activity under mild reaction conditions.
ꢀ Excellent product yields with greater substrate scope.
ꢀ Devoid of waste by-products and hence eco-friendly.