AgNO3 catalyzed synthesis of 5-substituted-1H-tetrazole via [3+2] cycloaddition of nitriles and sodium azide Dedicated to the memory of late Dr. Tarkeshwar Gupta

Article abstract of DOI:10.1016/j.tetlet.2014.01.117

An efficient one-pot, convenient catalysis for the synthesis of 5-substituted-1H-tetrazoles is reported. The [3+2] cycloaddition involves various nitriles, sodium azide in refluxing DMF and AgNO₃ as catalyst to give corresponding 5-substituted-

Full text of DOI:10.1016/j.tetlet.2014.01.117

Tetrahedron Letters 55 (2014) 1879–1882
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AgNO3 catalyzed synthesis of 5-substituted-1H-tetrazole via [3+2]
cycloaddition of nitriles and sodium azide
⇑
Pavnesh Mani, Ashawani Kumar Singh, Satish Kumar Awasthi
Chemical Biology Laboratory, Department of Chemistry, University of Delhi, New Delhi 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot, convenient catalysis for the synthesis of 5-substituted-1H-tetrazoles is reported. The
[3+2] cycloaddition involves various nitriles, sodium azide in refluxing DMF and AgNO3 as catalyst to give
corresponding 5-substituted-1H-tetrazoles in good to excellent yields. It is expected that the reaction
proceeds via in situ formation of a silver azide species, which participates in coordination of nitrile moi-
ety followed by cycloaddition of azide ion to give tetrazole.
Received 30 December 2013
Revised 24 January 2014
Accepted 25 January 2014
Available online 8 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Dedicated to the memory of late
Dr. Tarkeshwar Gupta
Keywords:
Cycloaddition
Nitriles
Tetrazole
AgNO3
Tetrazoles are heterocyclic compounds having a five membered
ring containing one carbon and four nitrogen atoms. Such hetero-
cyclic systems are not found in nature.1 The preparations of substi-
tuted tetrazoles have been the subject of intense investigation
especially from the nitrile functionality, which is widely recog-
nized as a useful intermediate in organic synthesis.2 Synthetic,
medicinal, and pharmaceutical applications of tetrazoles are well
explored and documented in the literature.3 Biphenyl tetrazoles
are also well known and used to synthesize sartan family drugs.4
The other class of its use includes propellants, explosives,5a and
in photography.5 In addition to the above it is found useful in agri-
culture as plant growth regulators6 and in crop protection, its
derivative plays a key role as herbicides, and fungicides.7
The synthesis of 5-substituted-1H-tetrazoles was found fasci-
nating and many new processes and revision of existing processes
since Finnegan’s invention have appeared.8 The principle of most of
them is almost common that is cycloaddition of nitrile with an
azide moiety, under the influence of several efficient catalysts
and different solvent conditions. Numbers of new catalysts have
also been investigated till date and among those which serve the
purpose are copper triflates,9 Fe(OAc)2,10 zinc(II) salts,11 Lewis
acids such as AlCl3,12 BF3–OEt2,13 FeCl3,14 TBAF,15 heterogeneous
catalysis COY zeolites,16 mesoporous ZnS nanospheres,17 Cu2O,18
and CuFe2O4 nano particles.19a Acid catalysts are also used for
the synthesis of tetrazole via cycloaddition19 Recently, many
chemists have reported the use of transition elements and their
salts as a catalyst. Sharpless and co-workers reported an innovative
procedure for the preparation of 5-substituted-1H-tetrazoles from
the corresponding nitriles and NaN3 in the presence of a stoichiom-
etric amount or 50 mol % of Zn(II) salts.20 Shortly, an efficient
method for the synthesis of tetrazoles was reported by the reaction
of nitriles with TMSN3 using 50 mol % of TBAF as catalyst.21
(Table 1) More recently, efficient synthesis of tetrazoles by reaction
of nitriles with NaN3 using nano crystalline ZnO or zinc hydroxyap-
atite as the catalyst is reported at 120–130 °C.22 These findings at-
tracted the attention toward the chemistry of transition metal
catalysis.
Table 1
Effect of catalyst and solvent on the formation of tetrazole 2a from 1a
Entry Catalyst
Solvent
AgNO3 (5 mmol %) DMF
AgNO3 (10 mmol %) DMF
Temp (°C) Time (h) Yield of 2a (%)
1
2
3
4
5
6
7
8
9
120
120
120
120
80
5
5
5
8
22
11
24
24
24
42
83
94
56
13
5
AgNO3 (20 mmol %) DMF
AgNO3 (10 mmol %) DMSO
AgNO3 (10 mmol %) CH3CN
AgNO3 (10 mmol %) EtOH
AgNO3 (10 mmol %) CHCl3
78
60
0
⇑
Corresponding author. Tel.: +91 11 27666646x121/134, mobile: +91 9582087608.
AgNO3 (10 mmol %) 1–4 Dioxane 100
AgNO3 (10 mmol %) Water 100
0
0
E-mail
addresses:
skawasthi@chemistry.du.ac.in,
satishpna@gmail.com
(S.K. Awasthi).
http://dx.doi.org/10.1016/j.tetlet.2014.01.117
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

1880
P. Mani et al. / Tetrahedron Letters 55 (2014) 1879–1882
Table 2
However, many of the above mentioned protocols have some
disadvantages like use of toxic metals, strong Lewis acid, expensive
reagents, low yield, harsh reaction conditions, water sensitivity,
and the usual separation and toxicity problems associated with
small alkyltin reagents. In addition to this in some cases formation
of highly volatile and toxic hydrazoic acid as by product warrant
the safety of the method.23 Despite extensive researches on
synthesis of tetrazoles, it is still an active research area which is
in need to develop, and demands new synthetic methodologies,
(Table 2) which simplifies the synthesis and minimizes the
drawbacks.
Effect of temperature on the formation of tetrazole 2a from 1a in DMF with
10 mmol % AgNO3
Entry
Temp (°C)
Time(h)
Catalyst
Yield (%)
1
2
3
4
25
50
100
120
12
12
12
5
AgNO3 (10 mmol %)
AgNO3 (10 mmol %)
AgNO3 (10 mmol %)
AgNO3 (10 mmol %)
0
28
49
83
The choice of a suitable catalyst for any reaction medium is of
key importance to get good results. Last few decades, transition
metal catalysis has drawn due attention of chemists due to their
wide spectrum of utilities in numerous chemical conversions.
The catalytic activities of such elements are mainly due to its abil-
ity of activation of a particular functionality via coordination to-
ward a certain type of reaction.24,25 This type of co-ordination/
activation approves the other reagents/substrates to react with
that functional group and thus the reaction attains an added
N
N
N
NH
N
10 mmol% AgNO3
DMF, 120 oC, 5h
NaN3
1a
2a
Scheme 1. Reaction of Benzonitrile with sodium azide in DMF.
Table 3
AgNO3-catalyzed synthesis of 5-substituted 1H-tetrazolesa
Sl. no
1
Substrate
CN
1
Time (h)
5
Product
2
Yieldb (%)
83
H
N
N
N
1a
2a
N
H
N
Br
Cl
CN
CN
N
N
2
3
1b
1c
5
5
2b
2c
78
80
Br
Cl
N
H
N
N
N
N
Br
H
N
N
N
N
MeO
Br
4
5
1d
1e
5
2d
2e
78
82
MeO
CN
Br
H
N
N
N
HO
Br
CN
5.5
HO
N
H
H2N
N
N
CN
N
N
6
7
1f
5.5
5
2f
81
81
H2N
O2N
H2N
O2N
H2N
H
N
N
N
1g
2g
CN
N
H
HN
CN
N
N
N
N
HN
O
O
8
1h
5
2h
76
O2N
HN
O2N
H
N
N
N
CN
HN
O
9
1i
1j
5
5
2i
79
87
N
O
O2N
O2N
H
N
N
N
10
2jc
HN
CN
CN
HN
O
N
O
O
H
N
HN
O
N
N
HN
O
O
N
11
1k
5
2k
84

P. Mani et al. / Tetrahedron Letters 55 (2014) 1879–1882
1881
Table 3 (continued)
Sl. no
Substrate
1
Time (h)
5
Product
2
Yieldb (%)
Cl
Cl
H
N
N
N
12
1l
2l
83
N
CN
N
N
N
NC
N
N
HN
HN
HN
N
N
13
1m
5
2m
83
O2N
NO2
a
The reaction of nitriles 1 with NaN3 (1.5 equiv) was conducted in DMF in the presence of 10 mmol % of AgNO3 at 120 °C for the time shown in Table 3.
Experimental yield.
Figure 2.
b
c
AgNO3
AgN3
NaN3
selectivity and produces specific products only. As an example, in
the present Letter, we wish to disclose our findings, which involve
the activation of nitrile functionality of cyanobenzene by AgNO3
catalyst which in situ gives AgN3 by the action of sodium azide
on it.26 This silver azide thus formed perhaps coordinates the
.
NaN3
NaNO3
N
1a
N
p-linkage of nitrile functionality of the substrate which results in
H
Ag
N
the activation of the azide anion, and this promotes it to react with
the nitrile functionality selectively, as a 1,3-dipole, to produce
benzenetetrazoles. This is an extension of diversification of
ongoing research work in our group.27 In quest of the above
approach we herein, report a simple and convenient, protocol for
the synthesis of 5-substituted 1H-tetrazole (2a) by cycloaddition
reaction between benzonitrile (1a) and sodium azide (NaN3
1.5 equiv) in the presence of 10 mmol % of AgNO3 in DMF as a
solvent (Scheme 1).28 The results of the [3+2] cycloaddition reac-
tion of various nitriles 1 with NaN3 are summarized in Table 3.
The reactions of the arylnitriles 1b and 1c, bearing an electron-
donating group at the para-position of the aromatic ring, with
sodium azide were carried out in DMF at 120 °C in the presence
of 10 mmol % AgNO3. The reactions were completed in 5 h
affording the corresponding tetrazoles 2b and 2c in 75% and 80%
yields, respectively (entries 2 and 3).
N
N
N
N
N
N
2a
A
AgCl
N
N
N
N
Ag
HCl
B
Figure 1. Proposed mechanism for the synthesis of tetrazole.
Introduction of the nitro group at meta position shows im-
proved yield (2g, 81%). The yield of tetrazoles further improved if
we use protected amines (2h and 2k in 76% and 84% respective
yields). Nitro derivatives were also prepared in excellent yields
(2i and 2j) in 79% & 87%, respectively In addition to this heterocy-
clic based tetrazoles can also be prepared efficiently using AgNO3
as a catalyst (Table 3, entry 12). The methodology was also found
applicable with benzimidazole transformation to bear additional
tetrazole moiety (Table 3, entry 12, yield 83%).
The above results specify that the tetrazole ring formation via
[3+2] cycloaddition reaction tolerates a wide range of substituents
irrespective of their electronic behavior, positions, and indepen-
dent of the type of aromatic ring involved in conversion.
Figure 2. ORTEP diagram of compound 2j.
A plausible mechanism is shown in Figure 1. Initially, AgNO3 re-
acts with NaN3 to produce the AgN3 catalytic species.26 The [3+2]
cycloaddition between the C–N bond of nitrile 1a and AgN3 takes
place readily to form the intermediate A; pre-coordination of the
nitrogen atom of the CN group of 1a with silver azide to form com-
plex B would accelerate this cyclization step. Figure 2 Protonolysis
of the intermediate B by 2 N HCl to maintain pH of solution in be-
tween 2 and 3, affords the 5-substituted 1H-tetrazole 2a and AgCl
as white solid was recovered at the end of the reaction through fil-
tration only.
The proposed mechanism is also supported by the experimental
facts. For this we carried out the reaction of 1a (1 equiv) with NaN3
(1.5 equiv) in DMF at 50 to 120 °C for 12 h but the reaction did not
proceed at all. This accounts for the absence of in situ generated
AgN3 catalyst required for the cycloaddition in tetrazole formation,
further the starting material 1a was recovered in 75% yield. These
results clearly indicate that, AgN3 is a key catalytic species which
enables the [3+2] cycloaddition with 1a to produce intermediate
A and B followed by the formation of tetrazole salt which on pro-
tonolysis affords desired 2a in good yield.

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P. Mani et al. / Tetrahedron Letters 55 (2014) 1879–1882
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Acknowledgments
S.K.A. is thankful to the University of Delhi, Delhi, India for
financial assistance and USIC, University of Delhi, for spectral
studies. P.M. and A.K.S. acknowledge the award of Senior Research
Fellowship and Junior Research Fellowship to UGC and CSIR, New
Delhi, India, respectively. We also acknowledge Dr. Nisha Saxena
for her kind suggestions.
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Supplementary data
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Supplementary data (crystallographic data (excluding structure
factors) for the structure in this Letter have been deposited with
the Cambridge Crystallographic Data Centre as supplementary
publication Nos. 977261. Copy of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK, (fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.-cam.
ac.Uk)) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.117.
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28. The representative tetrazole 2a was synthesized via following procedure: Sodium
azide (0.378 g, 0.046 mmol) was added to a solution of AgNO3 (5 mg, 10 mmol)
in DMF (5 ml) and reaction mixture was stirred for 5 min, to this stirred
solution benzonitrile 1a (0.4 ml, 0.033 mmol) was added dropwise over the
period of 1 min at room temperature and stirring continued for 10 min at the
same temperature and then heated at 120 °C for 5 h. After consumption of 1a,
the reaction mixture was cooled to room temperature and chilled by adding
crushed ice into the reaction mixture followed by addition of 2 N HCl till
reaction mixture reached the pH 2. The reaction mixture was then extracted
with ethyl acetate. The organic layer was dried with anhydrous Na2SO4, and
concentrated to obtain tetrazole 2a in 83% yield as an off white solid (268 mg),
mp = 215–217 °C. 1H NMR (400 MHz, DMSO-d6) d (ppm) 8.6 (1H, s), 8.0 (3H, d),
7.1(1H, s), 13C NMR (100 MHz, DMSO-d6 d (ppm); 147.77, 133.27, 129.97,
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124.73, 120.69 IR(KBr)/cmÀ1
: 2932, 1601, 1438, 1270, 744. Some of the
substituted tetrazole products 2 are known compounds and the spectral data
and melting points are identical to those reported in the literatures.
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