(NH4)2Ce(NO3)6 as an inexpensive, eco-friendly, efficient catalyst for the synthesis of 5-substituted 1-H tetrazoles from nitriles

Article abstract of DOI:10.1016/j.tetlet.2014.09.010

Ceric ammonium nitrate (CAN) is found to be a suitable, inexpensive, and effective non-toxic catalyst for a smooth (3+2) cycloaddition of organic nitriles with NaN₃ to afford 5-substituted 1H-tetrazoles in excellent yields. Shorter reaction times, easy work-up, and substantial and pure product formation are the key advantages of the present method.

Full text of DOI:10.1016/j.tetlet.2014.09.010

Tetrahedron Letters 55 (2014) 6034–6038
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
(NH4)2Ce(NO3)6 as an inexpensive, eco-friendly, efficient catalyst
for the synthesis of 5-substituted 1-H tetrazoles from nitriles
⇑
Satyanand Kumar, Shristy Dubey, Nisha Saxena, Satish Kumar Awasthi
Chemical Biology Laboratory, Department of Chemistry, University of Delhi, 110007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2014
Revised 2 September 2014
Accepted 3 September 2014
Available online 16 September 2014
Ceric ammonium nitrate (CAN) is found to be a suitable, inexpensive, and effective non-toxic catalyst for
a smooth (3+2) cycloaddition of organic nitriles with NaN3 to afford 5-substituted 1H-tetrazoles in excel-
lent yields. Shorter reaction times, easy work-up, and substantial and pure product formation are the key
advantages of the present method.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Ceric ammonium nitrate (CAN)
5-Substituted 1H-tetrazole
[3+2] cycloaddition
Heterogeneous conditions
X-ray analysis
Tetrazoles are nitrogen containing heterocyclic compounds,
which are generally not found in nature. Over the last two decades,
applications of tetrazole-based pharmacophore have increased
rapidly, and are currently under thorough review owing to their
wide range of applications.1 The 5-substituted-1H-tetrazole
fragment has been used in a number of clinical drugs, such as anti-
hypertensive sartan family drugs (Valsartan I, Losartan II, Fig. 1).2
In addition to this, they are also used for different applications such
as coordination chemistry as ligands,3 agriculture,4 photography,5
information recording systems in materials,6 explosives7 among
others. Further, due to their similarity in acidity and planarity, they
can function as lipophilic spacers and carboxylic acid substitutes8
in pharmaceuticals. Finnegan’s invention for the synthesis of
tetrazoles came long time back and since then a number of reports
followed with the combination of myriad of the new catalysts. The
conventional method of synthesizing tetrazoles is based on the
addition of azide ions to organic nitriles in suitable solvent in
the presence of catalyst. Majority of these catalysts are based on
metals such as cadmium9 (CdCl2), copper10 (CuI, Cu2O, CuFe2O4
nano particles, CuSO4Á5H2O, CuO, copper triflates), iron11 (FeCl3–
SiO2, Fe(OAc)2, Fe3O4/ZnS Hollow Nanospheres) palladium12
(Pd(PPh3)4), aluminum13 (AlCl3, Al(HSO4)3, (Me)3Al), zinc14
(mesoporous ZnS nanospheres, ZnBr2, ZnCl2), zinc copper alloy,15
Zn/Al hydrotalcite,16 silver17 (silver benzoate), titanium18 (TiO2),
O
N
COOH
Me
OH
N
Me
HN
N
N
N
N
Me
Cl
N
N
HN
N
II-Lasartan
I - Valsartan
Figure 1. 5-Substituted-1H-tetrazole fragment in clinical drugs.
tungstates19 (MWO4 M = Ba, Ca, Zn, Cd, Cu, Na, H) as well as
recently used lanthanides as triflates20 (Yb(OTf)3ÁxH2O) among
others. In addition to this, some other heterogeneous catalysts,
such as COY zeolites21 and acid catalysts22 (silica sulfuric acid,
NaHSO4ÁSiO2) are also applied for the synthesis of tetrazole via
cycloaddition. Sharpless23 used Zn(II) salt in water for tetrazole
synthesis in a widely accepted approach. However, it is found that
sterically hindered aromatic nitrile requires high temperatures
(140–170 °C) and in the case of the aliphatic nitriles low yield of
conversion is also mentioned.
Similarly, many of the aforementioned procedures are found
inefficient for the synthesis of aliphatic tetrazoles or excluded from
the study. Currently, a number of above mentioned methods of tet-
razole synthesis are in use but some of these known methods have
potential limitations such as low yields, drastic reaction conditions,
use of expensive water sensitive reagents, toxic metal catalysts,
⇑
Corresponding author. Tel.: +91 1127666646x121, 134.
E-mail addresses: skawasthi@chemsitry.du.ac.in, satishpna@gmail.com (S.K.
Awasthi).
http://dx.doi.org/10.1016/j.tetlet.2014.09.010
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

S. Kumar et al. / Tetrahedron Letters 55 (2014) 6034–6038
6035
Table 1
tedious work-up, complex isolation, and recovery procedures,
which emphasize the need of new methods devoid of aforemen-
tioned limitations. Therefore, researchers in this area are exploring
the potential of other catalysts for the synthesis of substituted 1-H
tetrazole for combating the issues related to the tetrazole
synthesis.
Ceric ammonium nitrate (CAN) is a commercially available,
non-toxic, eco-friendly,24 and extensively used catalyst, and due
to these advantages, it is found safer and suitable for both labora-
tory as well as industry. CAN has been widely used as wonderful
catalyst in numerous reactions such as nitration,25 oxidation,26
opening of epoxies,27 cycloaddition,28 esterification,29 regioselec-
tive iodination,30 1,4-additon,31 epoxide to b-nitro alcohol,32 syn-
thesis of 3,4-dihydropyrimidin-2(1H)-one,33 unsymmetrical bis
(indolyl)alkanes,34 in aza-Michael reaction,35 thiocyanation of
alkenes,36 2-phenylquinazolines,37 CAC bond formation,38 depro-
tection of triisopropylsilyl group,39 and many more.
Our research group is focused on the design and synthesis of
antimicrobial agents.40–42 Recently, we reported new catalysts for
the synthesis of tetrazoles43 using Ag (nanoparticles) and AgNO3.
In continuation to search new and efficient economically viable
catalyst, we selected ceric ammonium nitrate for its efficacy in
the synthesis of tetrazoles via (3+2) cycloaddition.
Choice of appropriate reaction medium, efficient eco-friendly
catalyst, and optimum reaction temperature plays a key role in
obtaining higher yield of title compounds. On investigating the lit-
erature, it is observed that currently many rare earth metal based
compounds are exploited for their catalytic profile. Lewis acidity of
Ce(IV) in CAN supports its use in the (3+2) cycloaddition reaction.
Effect of (NH4)2Ce(NO3)6 as catalyst, solvents, temperature, and time on the synthesis
of tetrazole 1b from nitrile 1a
Entry Catalyst (NH4)2Ce(NO3)6
(mmol %)
Solvent
Temp
(°C)
Time
(h)
Yield 1b
(%)
1
2
5
5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
110
110
110
110
110
110
110
110
20.0
80.0
90.0
110
110
110
110
81
8.0
24
70
75
50
97
97
0.0
98
98
00
50
70
66
60
60
58
0
3
10
10
10
0.0
15
20
10
10
10
10
10
15
10
10
10
10
10
10
2.0
6.0
8.0
6.0
6.0
6.0
12.0
12.0
12.0
8.0
10
15
8.0
22
12
24
4⁄
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
NMP
Toluene
CH3CN
EtOH
CHCl3
DCM
78
60
38
100
5
0
0
0
24
24
1,4-
Dioxane
Acetone
Water
21
22
10
10
56
80
24
24
0
0
⁄optimized protocol.
dichloromethane, 1,4-dioxane, acetone, and H2O, were also tested
for their efficiency as solvent in the synthesis, they were found
not suitable for the synthesis due to either low yield or no reaction.
This limits the choice to DMF, DMSO, toluene, and NMP. The DMF
was selected over DMSO as a reaction solvent due to some advan-
tages over others like the ease of removal in vacuum and conve-
nient work-up procedure. Further, we investigated the effect of
catalyst (CAN) loading and temperature over the formation and
yield of substituted 1-H tetrazoles by performing various reactions
(Table 1, entries 1–11). It is evident that the small loading of cata-
lyst (5 mmol %) would require longer reaction time to perform
cyclization, with poor yield of final compound (Table 1, entries 1
and 2). Interestingly, higher ratio of catalyst (15 mmol % and
20 mmol %) neither reduces the reaction time nor significantly
improves the yield of tetrazoles (Table 1, entries 7 and 8). Keeping
these results in mind, we set up the optimized reaction conditions
for cyclization between benzonitriles, sodium azide in DMF, and
CAN as catalyst, at 110 °C. The optimized reaction conditions are
represented by Scheme 1 (Table 1 entry 4). This optimized protocol
(1 mmol nitrile, 1.5 mmol NaN3, and 10 mmol % of CAN in DMF at
110 °C)44 yielded persistently considerable amount of products in
all cases (Table 2).
In the present case, the coordination capacity of Ce(IV) with
p elec-
trons of the nitrile group ease cycloaddition via activation of the
nitrile entity which approves the addition of the dipolar azide
group. This leads the reaction to get an added selectivity and even-
tually leads to the formation of a particular product only.
In this Letter, we report the synthesis of 5-substituted 1-H
tetrazoles via (3+2) cycloaddition using different organic nitriles
(1a–14a) with sodium azide and CAN as catalyst (Schemes 1 and
2). In an effort to develop a better catalytic system, the protocol
was standardized by carrying out reaction between benzonitrile
and sodium azide as the model and the results are summarized
in Table 1. Further, the solvent for reaction medium was optimized
(Table 1, entries 10–16). DMF was found to be the most suitable
solvent giving a maximum yield of 97%, whereas DMSO, NMP,
and toluene prove to be other good solvents and gave 66%, 60%,
and 58% yields, respectively (Table 1, entries 12, 13 and 15).
Although, other solvents such as acetonitrile, EtOH, CHCl3,
N
N
N
N
N
C
In addition to this, reaction was also performed in standardized
conditions without CAN but no product formation was observed
(Table 1, entry 6).
H
10 mmol % (NH4)2Ce(NO3)6, NaN3 (1.5 mmol)
R
°
DMF, 110 C, 6h
R
This process is found significantly useful for various tetrazole
syntheses such as aromatic and aliphatic nitrile transformations.
We achieved >95% yield in all aromatic tetrazole syntheses irre-
spective of the groups (Table 2, entries 1–9). One of the most
attractive conversions in this series is the ditetrazole synthesis
from their respective dicyano derivatives (Table 2, entry 6). In
addition to this, aliphatic nitriles gave slightly lower yields
(82–94%) irrespective of the functional group (Table 2, entries
10–16). It is interesting to note that, benzyl alcohol (Table 2, entry
9b), thioether, ester (Table 2, entry 10b), and ether (Table 2, entry
8b) functional groups are compatible with the CAN catalyst in the
tetrazole synthesis.
1a-8a
1b-8b
Scheme 1. Reaction of benzonitrile (aromatic nitrile) with sodium azide in DMF.
N
HN
N
NC
R
N
10 mmol % (NH4)2Ce(NO3)6, NaN3 (1.5 mmol)
DMF, 110 C, 6h
°
R
9a-14a
9b-14b
The comparative overviews of present approach along with a
few previously known methods are summarized in Table 3.
Scheme 2. Reaction of benzylnitrile (aliphatic nitrile) with sodium azide in DMF.

6036
S. Kumar et al. / Tetrahedron Letters 55 (2014) 6034–6038
Table 2
(NH4)Ce(NO3)6 catalyzed synthesis of aromatic/aliphatic 5-substituted 1H-tetrazoles (1b–16b)
S. No.
Nitriles[a]
CN
Tetrazoles[b]
Compound
Time (h)
6.0
Yieldsb (%)
97
H
N
N
N
1a
1b
N
H
N
Cl
CN
N
N
2
3
2b
3b
6.0
6.0
99
98
Cl
N
H
N
Br
CN
N
N
Br
N
N
H
H3C
CN
N
N
4
5
4b
5b
6.0
6.0
95
98
H3C
N
N
H
N
N
N
CN
N
N
N
Cl
Cl
CN
CN
N
HN
N
N
N
O2N
6c
6b
7b
6.0
6.0
97
96
O2N
HO
N
HN
N
H
N
HO
CN
N
7
N
N
Br
Br
H
N
N
H3CO
CN
N
N
H3CO
8
9
8b
9b
6.0
6.0
96
97
Br
Br
H
CN
N
N
N
N
HO
HO
O
C
S
O
H
C2H5O
C2H5O C
N
N
N
N
CN
CH3
C
10
11
10b
11b
6.0
6.0
94
87
S
C
S
C
H3C
S
H3C
H3C
CN
N
N
HN
N
N
HN
N
12
13
14
15
16
12b
13b
14b
15b
16b
6.0
6.0
6.0
6.0
6.0
82
86
86
89
90
N
H3C
CN
CH3
N
HN
N
CN
N
H3C
H3C
CN
N
N
N
HN
H3C
H3C
N
HN
N
CN
CN
N
Cl
Cl
N
N
N
HN
Cl
Cl
a
b
c
Reaction of nitriles 1 with NaN3 (1.5 mmol) was conducted in DMF in the presence of 10 mmol % (NH4)2Ce(NO3)6 at 110 °C as shown in Table 2.
Experimental yield.
Reaction of nitrile 6a with NaN3 (3.0 mmol) was conducted in DMF in the presence of 20 mmol % of (NH4)2Ce(NO3)6 at 110 °C as shown in Table 2.

S. Kumar et al. / Tetrahedron Letters 55 (2014) 6034–6038
6037
Table 3
remain intact. The CAN catalyst already has considerable impor-
tance in industry sector for various applications. Use of CAN in tet-
razole synthesis is another new additional application. The other
noteworthy advantages of this methodology comprise simple
work-up procedure, easy handling of the catalyst, elimination of
hazardous and unsafe hydrazoic acid formation, and no require-
ment of column chromatography at the end.
Comparative overview of the present method with few previously known methods
S. No. Tetrazoles[b] Catalyst
Temp (°C) Time (h) % Yields
1
4b
Cu2O10
120
12
77.0
(79.0)
95
55.0 (56)
79.0
(82.0)
66.0
(76.0)
97
66.0
(66.0)
0.0
74.0
(74.0)
87
2
3
4
4b
1b
1b
(NH4)2Ce(NO3)6 110
6.0
24
14
11
Fe(OAc)2
80
120
18
TiO2
23
5
1b
ZnCl2
Reflux
24
Acknowledgments
6
7
1b
11b
(NH4)2Ce(NO3)6 110
6.0
24
S.K. acknowledges to the University Grant Commission, New
Delhi, India for providing Junior Research Fellowship. S.K.A. is
thankful to the UGC New Delhi, Delhi, India (Scheme No. FN
37.410/2009) and in part, the University of Delhi, Delhi, India for
the financial assistance and the USIC, University of Delhi, for
spectral studies.
Cu2O10
120
8
9
11b
11b
Fe(OAc)2
80
120
28
24
18
TiO2
10
11b
(NH4)2Ce(NO3)6 110
6.0
Entries 1–10 represent aromatic and aliphatic tetrazole synthesis, respectively.
Parentheses show reported yield.
Supplementary data
11
The spectroscopic data of all compounds are found as supple-
mentary, and crystallographic data for the compound 13b have
been deposited with the Cambridge Crystallographic Data Centre
(995816). Data can be obtained free of charge, on application to
the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44
(0)1223 336033 or e-mail: deposit@ccdc.-cam.ac.Uk).
Aliphatic nitrile fails to give tetrazole on use of catalyst, Fe(OAc)2
(Table 3, entry 8) while CAN gave 87% tetrazoles with aliphatic
substrate. (Table 3, entry 10). Further, ZnCl2 is used as a catalyst
for the aliphatic tetrazole synthesis but requires drastic conditions
(170 °C, 24–48 h).23 Hence, CAN is a better catalyst for both ali-
phatic and aromatic tetrazole synthesis.
This study reveals that the above (3+2) cycloaddition reaction
bears an ample range of substituents, irrespective of their electronic
behavior, position, and independent of the type of aromatic/hetero-
aromatic/aliphatic ring involved in transformation.
Supplementary data associated with this article can be found, in
theonline version, at http://dx.doi.org/10.1016/j.tetlet.2014.09.010.
References and notes
A plausible mechanism is presented through Scheme 3. It is
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44. Experimental condition for 5-substituted 1-H tetrazoles (1b–16b): The
representative tetrazole 1b was synthesized via following procedure: sodium
azide (1.5 mmol) was added to a magnetically stirred solution of nitrile 1a
(1 mmol) in anhydrous DMF and the CAN (10 mmol %) was added. The reaction
mixture was constantly stirred for another 6 h at 110 °C under nitrogen
atmosphere. After the completion of reaction as seen by TLC, the reaction
mixture was brought to room temperature and the solvent was evaporated
under vacuum. The crude thus obtained, was dissolved in ethyl acetate (20 mL)
and solution was washed with acidified water (4 M HCl, 15 mL) twice.
Separated organic layer was washed with brine solution dried over
anhydrous Na2SO4, and solvent was removed under high vacuum to obtain
tetrazole 1b as a white crystalline solid in 97% yield.
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