An efficient protocol for facile synthesis of new 5-substituted-1H-tetrazole derivatives using copper-doped silica cuprous sulfate (CDSCS) as heterogeneous nano-catalyst

Article abstract of DOI:10.5935/0103-5053.20160138

A facile and highly efficient protocol for synthesis of new 5-substituted-1H-tetrazoles derivatives using copper-doped silica cuprous sulfate (CDSCS) is described. In this method, the cycloaddition reaction of sodium azide with structurally diverse nitriles involving bioactive N-heterocyclic cores exploiting CDSCS in refluxing H₂O/i-PrOH (1:1, v/v) furnishes the corresponding 5-substituted-1H-tetrazoles in good to excellent yields (up to 93percent). The influence of parameters effective in progress of reaction including solvent type, temperature and catalyst was studied and discussed. In this protocol, CDSCS was proved to be an efficient heterogeneous nano-catalyst to easily achieve the new tetrazole derivatives. The advantages of CDSCS in current protocol known are its cheapness, thermal and chemical stability, ease of recyclability and reusability for several consecutive runs without significant decline in its reactivity.

Full text of DOI:10.5935/0103-5053.20160138

http://dx.doi.org/10.5935/0103-5053.20160138
J. Braz. Chem. Soc., Vol. 28, No. 1, 11-20, 2017.
Printed in Brazil - ©2017 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Article
An Efficient Protocol for Facile Synthesis of New 5-Substituted-1H-Tetrazole
Derivatives Using Copper-Doped Silica Cuprous Sulfate (CDSCS) as Heterogeneous
Nano-Catalyst
Mohammad Navid Soltani Rad*
Medicinal Chemistry Research Laboratory, Department of Chemistry, Shiraz University of
Technology, 71555-313 Shiraz, Iran
A facile and highly efficient protocol for synthesis of new 5-substituted-1H-tetrazoles derivatives
using copper-doped silica cuprous sulfate (CDSCS) is described. In this method, the cycloaddition
reaction of sodium azide with structurally diverse nitriles involving bioactive N-heterocyclic cores
exploiting CDSCS in refluxing H2O/i-PrOH (1:1, v/v) furnishes the corresponding 5-substituted-
1H-tetrazoles in good to excellent yields (up to 93%). The influence of parameters effective in
progress of reaction including solvent type, temperature and catalyst was studied and discussed. In
this protocol, CDSCS was proved to be an efficient heterogeneous nano-catalyst to easily achieve the
new tetrazole derivatives. The advantages of CDSCS in current protocol known are its cheapness,
thermal and chemical stability, ease of recyclability and reusability for several consecutive runs
without significant decline in its reactivity.
Keywords: azide, CDSCS, cycloaddition, nitrile, 1H-tetrazole
Introduction
anticancer,30 antineoplastic,31 antiallergic,32-34 and antiviral35
especially anti-HIV36 activities.
Tetrazole and its derivatives are an important class
of N-heterocyclic compounds exhibiting widespread
applications.1,2 Tetrazoles are extensively applied in
different industries as instance: stabilizers in photography
and photo imaging,3,4 explosives in rocket propellants,5-7
chelating agents in coordination chemistry,8,9 plant growth
regulators, herbicides, fungicides in agriculture,3,10 and
anti-wears and frictions in lubricants.11 Additionally,
tetrazoles can be served as bioisosteres for the carboxylic
acids.12-14 Replacing a carboxyl group with tetrazolyl moiety
extensively improves the metabolic stability, bioavailability
and cell permeability of a drug molecule.15,16 When increase
in the lipophilicity factor (log P) for a drug molecule
involving carboxylic moiety is desired, one can replace
the carboxylic moiety with tetrazole as a more lipophilic
bioisostere. Consequently, tetrazoles are widely applied
in synthesis of many well-known drugs like losartan,17-19
candesartan,18,19 zolarsartan18,19 and valsartan.17 In addition,
tetrazoles exhibit varied biological activities such as
antihypertensive,17-21 antibacterial,22,23 antifungal,24,25
anticonvulsant,26 anti-inflammatory,27,28 antitubercular,29
The synthesis of tetrazole and its derivatives has
attracted considerable attention since the broad utilities
found for tetrazoles. In this context, the different
preparative methods have been emerged so far.37,38 Among
them, the [3 + 2]-cycloaddition reaction of nitriles with
azides is a well-known and most extensively studied and
used procedure for synthesis of diverse 5-substituted-
1H-tetrazoles.39,40 In this regard, several homogeneous
reagents or catalysts have been developed to synthesize
5-substituted-1H-tetrazoles.41,42 Although these methods
exhibit some advantages to access 1H-tetrazoles, their scale
up synthesis are restricted by one or more disadvantages
such as harsh reaction conditions, low yields, long reaction
times, the use of strong Lewis acids, the in situ generation
of HN3 as a highly dangerous volatile material with a
great risk of eruption and toxicity, production of the stable
metal-tetrazole complexes, the use of expensive and toxic
metals or solvents, tedious work-up procedure and failure
to undertake the recovery or reusability of the catalyst.
Nowadays, heterogeneous catalysts have gained
considerable attention due to both economic and
environmental standpoints. The successful applications of
heterogeneous systems in various organic transformations
*e-mail: soltani@sutech.ac.ir

12
An Efficient Protocol for Facile Synthesis of New 5-Substituted-1H-Tetrazole Derivatives
J. Braz. Chem. Soc.
are well documented. Employing the heterogeneous
catalysts often leads to the simple experimental procedures,
mild reaction conditions, recovery and reusability of the
catalyst, the minimization of undesirable chemical wastes,
and the production of large quantities of products by using a
small amount of catalyst. Thus, the exploit of heterogeneous
catalysis has an exact superiority over homogeneous
catalyst. In recent decade, some heterogeneous catalytic
systems were developed to promote the synthesis of
5-substituted-1H-tetrazoles;43-55 nevertheless, drawbacks
are usually accompanied with these heterogeneous
catalysts comprising: (i) the strong acidic nature of some
catalysts that largely aggravates the release of dangerous
HN3; (ii) the use of weakly bonded or none-bonded metal
salts supported on mineral supports which normally lead
to desorption of active metal species during the reaction
progress or work-up procedure; (iii) the formation of stable
metal-tetrazole complexes that makes the tedious work-up
procedure and (iv) the thermal or chemical instability. Thus,
the employment of a heterogeneous catalyst that obviates
the above drawbacks is of particular interest.
Silica-based catalysts offer several advantages like
cheapness, mild reaction conditions, high yields and
selectivity, non-corrosive properties, ease of handling and
preparation. In addition, they could be easily removed
from the reaction mixture, recovered, and reused by a
simple flash filtration. Recently, we have reported the
synthesis, characterization, and application of copper-doped
silica cuprous sulfate (CDSCS) as a novel and efficient
heterogeneous nano-catalyst for the CuI-catalyzed ‘Click’
synthesis of 1,4-disubstituted 1,2,3-triazoles56 and also
3,5-disubstituted isoxazoles.57 In light of the unique biological
activities of tetrazoles and also in continuation of our ongoing
research in utilizing CDSCS in organic synthesis,56-58
we herein report a practical and environmentally benign
catalytic protocol for efficient synthesis of 5-substituted-
1H-tetrazole derivatives using CDSCS (Scheme 1). In this
synthesis, the desired nitriles 1 were primarily achieved by
the reaction of diverse nucleophiles with 2-chloroacetonitrile
or 3-chloropropanenitrile in the presence of an equimolar
mixture of triethylamine (TEA)-K2CO3 and catalytic amount
of tetrabutylammonium iodide (TBAI) in MeCN at reflux
condition. Then, to access tetrazoles 2, the cycloaddition
reaction of nitriles 1 with sodium azide was carried out
utilizing CDSCS in H2O/i-PrOH at reflux condition.
Results and Discussion
The first step of this synthetic approach was initiated
by the preparation of the essential nitriles 1. In this context,
various nucleophiles comprising azole derivatives, purine
and pyrimidine nucleobases and phenols underwent the
N- or O-alkylation reaction with 2-chloroacetonitrile or
3-chloropropanenitrile through the SN2-type reaction.
The reaction of the selected nucleophiles with above
chloronitriles was carried out using TEA-K2CO3 (1:1) in
the presence of TBAI (cat.) in refluxing MeCN (anhyd.) to
gain 1.Afterward, to assess the optimized reaction condition
for [3 + 2]-cycloaddition of 1 with NaN3, the influence of
various parameters including temperature, solvent, and
catalyst was studied. In this regard, the cycloaddition
reaction of 2-(1H-benzo[d]imidazol-1-yl)acetonitrile (1a)
with NaN3 was selected as a sample reaction.
To progress the reaction efficiently, the choice of an
appropriate solvent is crucial. Among tested solvents, the
use of water has attracted enormous interest in organic
transformations, since water is a cheap, clean, and universal
solvent exhibiting extraordinary physical properties and
enviro-economic benefits.59 In this regard, the model
reaction was carried out in an aquatic media at room
temperature. However, the corresponding tetrazole 2a was
obtained only in 19% yield (Table 1, entry 1). To increase
the reaction yield, the model reaction was investigated at
varied temperatures (Table 1). As indicated in Table 1, the
use of pure water at different temperatures failed to afford
the satisfactory results even at reflux condition. This can be
attributed to the lack of solubility of nitrile 1a in pure water.
Consequently, the influence of several 1:1 (v/v) solutions
N N
CDSCS, NaN3
K2CO3-TEA/ TBAI (cat.)
Nu
Nu
CN
+ Cl
CN
n
Nu H
N
MeCN, reflux
N
H
H2O, i-PrOH, reflux
n
n
1
2
n = 1, 2
CDSCS:
SiO2
OSO3Cu
O
N
H
N
Me
N
:
H
Nu
,
,
,
, ...
OH
MeO
OH
Et
N
N
H
O
N
Me
Scheme 1. CDSCS catalyzed synthesis of 5-substituted 1H-tetrazoles.

Vol. 28, No. 1, 2017
Soltani Rad
13
Table 1. Effect of solvent and temperature on the model reactiona
N
N
N
CDSCS
Solvent,
NaN3
N
N
N
CN
N
HN
1a
2a
entry
1
Solvent
H2O
T / °C
r.t.
time / h
Yieldb / %
19
24
10
7
2
H2O
50
28
3
H2O
60
39
4
H2O
70
7
42
5
H2O
80
5
50
6
H2O
reflux
r.t.
4
58
7
H2O/i-PrOHc
H2O/i-PrOHc
H2O/Me2COc
H2O/DMFc
H2O/DMSOc
H2O/NMPc
H2O/HMPAc
H2O/THFc
THF
18
4
62
8
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
93
9
6
40
10
11
12
13
14
15
16
7
46
7
49
6
53
7
50
8
81
12
46
i-PrOH
5
60
aReaction conditions: nitrile (0.01 mol), NaN3 (0.015 mol), CDSCS (0.05 mol%), solvent (50 mL); bisolated yield; c1:1 (v/v).
of H2O with some water miscible organic solvents were
examined (Table 1).
CDSCS (Table 2). To this end, we examined the potency of
several heterogeneous or homogeneous catalysts including
Lewis and proton acids, solid supports, and ammonium salts
which are often applied in synthesis of tetrazole derivatives.
As the results in Table 2 indicate, higher yield of 2a in
shorter reaction time were observed utilizing CDSCS in
comparison with other tested catalysts. The use of other
catalysts yielded 2a in moderate to reasonable amounts in
variable times.
As indicated in Table 1, a solution of H2O/i-PrOH
(1:1, v/v) was found to be the most appropriate solvent for
synthesis of tetrazole derivatives in the presence of CDSCS
(Table 1, entry 8). Therefore, this solvent was used for all
subsequent reactions. Employing H2O/tetrahydrofuran
(THF) (1:1, v/v) solution afforded the corresponding
tetrazole in 81% yield after 8 h (Table 1, entry 14).
Moreover, the combination of water with other miscible
solvents like acetone, dimethylformamide (DMF), dimethyl
sulfoxide (DMSO), N-methylpyrrolidone (NMP), and
hexamethylphosphoramide (HMPA) yielded the moderate
amount of product (Table 1, entries 9-13). In addition, when
THF and/or i-PrOH were used separately as a solvent, 2a
was obtained in 46 and 60% yields, respectively (Table 1,
entries 15, 16).Also, in an attempt to carry out the reaction
in H2O/i-PrOH (1:1, v/v) solution at r.t. 2a was produced
in 62% yield after 18 h (Table 1, entry 7).
It is well understood that cycloaddition reaction
between nitrile and azide is very slowly achieved in the
absence of a suitable catalyst and thus it is unsuitable for
large scale synthesis. In this connection, the choice of an
efficient catalyst is critically essential for progress of the
reaction. To investigate the catalytic potency of CDSCS, the
effect of different catalysts was studied and compared with
The optimized stoichiometric ratio of nitrile/sodium
azide to access 2a using CDSCS (0.05 mol%) was
determined to be 1:1.5.
The generality and versatility of current protocol
was screened by applying the optimized condition to
various structurally diverse nitriles 1a-1o (Table 3).
Due to Table 3, CDSCS proved to be a convenient and
efficient heterogeneous nano-catalyst for cycloaddition
reaction of sodium azide with different nitriles tethered
to bioactive cores. As shown in Table 3, nitriles bearing
azole derivatives (Table 3, entries 1-4, 10, 11), xanthine
(Table 3, entry 9), purine and pyrimidine nucleobases
(Table 3, entries 5 and 6) were employed to produce their
corresponding 5-substituted-1H-tetrazole derivatives in
good to excellent yields. Moreover, nitriles involving
amine (Table 3, entry 12), cyclic amides (Table 3, entries 7
and 8), and phenols (Table 3, entries 13-15) underwent

14
An Efficient Protocol for Facile Synthesis of New 5-Substituted-1H-Tetrazole Derivatives
J. Braz. Chem. Soc.
Table 2. Comparing the influence of different catalysts with CDSCS in synthesis of 2aa
N
N
N
N
Catalyst
NaN3
H2O/i-PrOH, reflux
N
N
CN
N
HN
1a
2a
entry
1
Catalyst
time / h
24
24
12
24
4
Yieldb / %
TBAFc
NH4Clc
Et3N.HClc
FeCl3–SiO2c
CDSCSd
40
59
75
54
93
30
48
79
67
70
52
67
53
72
41
50
2
3
4
5
6
amberlyst-15c
HClc
silica sulfuric acidc
Cu2Oc
24
24
12
10
12
24
5
7
8
9
10
11
12
13
14
15
16
CuFe2O4c
Zeolited
ZnBr2c
ZnOc
AlCl3c
15
10
12
8
TMSClc
e
H3PW12O40
aReaction conditions: nitrile (0.01 mol), NaN3 (0.015 mol), catalyst, H2O/i-PrOH (50 mL); bisolated yield; can equimolar amount was used; d0.05 mol%;
e1 mol%.
cycloaddition reaction with azide to obtain the desired
tetrazole derivatives. The structures of all synthesized
compounds were confirmed by 1H and 13C NMR, elemental
analysis, mass and infrared (IR) spectroscopy techniques.
The applicability of the present protocol in preparative
scale was also examined. In this context, the cycloaddition
reaction of nitrile 1a with NaN3 was performed on a
100-mmol scale. Interestingly, 2a was obtained in an
excellent yield (89%) after 4 h which is comparable to
smaller scale synthesis (Table 3, entry 1).
The recoverability and reusability of the catalyst is an
important issue from different aspects like commercial
applications and environmental concerns. In this connection,
the reusability of CDSCS was investigated for sample
reaction (Table 4).
The separation of the catalyst from the reaction media
was conducted using a sintered glass funnel. The catalyst
was then washed with ethyl acetate (2 × 15 mL) and dried
in a vacuum oven at 90 ºC for 20 min. The catalyst was
sequentially applied for 5 runs without the addition of the
fresh catalyst to the reaction media.As shown in Table 4, the
catalyst can be reused for many consecutive times without
considerable decline in its catalytic activity. To determine
the amount of leached Cu from CDSCS, the copper content
of catalyst was determined using inductively coupled
plasma (ICP) analysis for both fresh and reused catalyst
(after 5 runs). Based on the ICP results, the leached Cu was
found to be 0.014%, which is negligible.
Conclusions
In conclusion, we have described a convenient protocol
for facile and high yield synthesis of the new structurally
diverse 5-substituted-1H-tetrazoles utilizing CDSCS as a
highly efficient heterogeneous nano-catalyst. CDSCS was
proved to be a useful catalyst for cycloaddition reaction
of sodium azide with different nitriles involving bioactive
cores in H2O/i-PrOH (1:1, v/v) at reflux condition, which
affords the corresponding tetrazole derivatives in good
to excellent yields. The use of ecofriendly solvent, the
reusability of the catalyst, the simplicity of the process,
cheapness, and applicability in preparative scale are benefits
that can be mentioned for current synthetic protocol.
Experimental
General
All chemicals were purchased from either Fluka
or Merck. Reactions were followed by TLC using

Vol. 28, No. 1, 2017
Soltani Rad
15
Table 3. Synthesis of 5-substituted-1H-tetrazole derivatives using CDSCSa
entry
Nitrile
Productb
time / h
Yieldc / %
N
N
N
1
4
93
N
N
N
CN
1a
2a
N
HN
N
N
N
CH3
N
CH3
CN
2
3
4
5
89
85
N
N
1b
2b
N
HN
N
N
N
CH3
O2N
NH
CN
N
N
N
N
O2N
CH3
1c
2c
N
N
HN
CN
N
N
4
6
87
N
N
N
1d
Ph
2d
Ph
O
O
HN
HN
5
3.5
83
O
N
H
N
O
N
N
1e
CN
2e
N
N
NH2
N
NH2
N
N
N
N
6
5.5
82
N
N
N
N
N
N
2f
1f
CN
HN
N
O
N
N
O HN
CN
N
7
8
3
87
91
N
S
S
O
O
O
1g
O
2g
H
N
O
O
N
N
CN
N
3.5
N
N
1h
O
2h
O

16
An Efficient Protocol for Facile Synthesis of New 5-Substituted-1H-Tetrazole Derivatives
J. Braz. Chem. Soc.
Table 3. Synthesis of 5-substituted-1H-tetrazole derivatives using CDSCSa (cont.)
N
N
CN
N
NH
O
O
H3C
N
N
9
4
90
H3C
O
N
N
N
N
O
N
N
CH3
1i
H3C
2i
N
N
N
N
N
N
10
11
7
4
86
89
CN
N
N
H
Ph
Ph
2j
1j
N
N
N
N
HN
N
N
CN
N
2k
1k
H
N
CN
N
N
N
N
12
13
5.5
92
91
N
N
N
1l
2l
H
N
CN
N
Et
O
6
N
N
Et
O
1m
2m
H
N
CN
N
N
Me
O
14
15
6
89
N
Me
O
1n
Cl
2n
Cl
H
N
CN
N
N
Cl
O
6
90
N
Cl
O
1o
2o
aReaction conditions: nitrile (0.01 mol), NaN3 (0.015 mol), CDSCS (0.05 mol%), H2O/i-PrOH (50 mL); ball products were characterized by 1H and 13C NMR,
IR, CHN, and MS analysis; cisolated yield.
SILG/UV 254 silica-gel plates. The fresh CDSCS was
prepared according to our previous reported procedure.56,58
Column chromatography was performed on silica gel 60
(0.063-0.200 mm, 70-230 mesh; ASTM). Melting points
were measured using Electrothermal IA 9000 melting point
apparatus in open capillary tubes and are uncorrected.
IR spectra were obtained using a Shimadzu FTIR-8300
spectrophotometer. 1H and 13C NMR spectrum was recorded
on Brüker Avance-DPX-250/400 spectrometer operating
at 250/62.5 and/or 400/100 MHz, respectively. Chemical
shifts are given in d relative to tetramethylsilane (TMS) as
an internal standard, coupling constants J are given in Hz.
1
Abbreviations used for H NMR signals are: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet,
br = broad and etc. GC-MS was performed on a Shimadzu
GCMS-QP1000-EX apparatus (m/z; rel. %). Elemental
analyses were performed on a PerkinElmer 240-B micro-
analyzer.

Vol. 28, No. 1, 2017
Soltani Rad
17
Table 4. The reusability of CDSCS in successive trails for synthesis of 2aa
N
N
N
CDSCS
NaN3
N
H2O/i-PrOH, reflux
N
N
CN
N
HN
1a
2a
entryb
time / h
Yieldc / %
1
2
3
4
5
4
4
93
93
91
90
87
4.5
4.5
5
aReaction conditions: nitrile (0.01 mol), NaN3 (0.015 mol), recovered CDSCS, H2O/i-PrOH (50 mL); bthe entry number corresponds to the trial number;
cisolated yield.
General procedure for synthesis of alkyl nitriles 1a-1o
1-((1H-Tetrazol-5-yl)methyl)-1H-benzo[d]imidazole (2a)
Recrystallization (EtOAc) afforded a yellow solid;
yield: 1.86 g (93%); mp 235-240 °C (dec.); IR (KBr)
n / cm-1 3385, 3100, 2968, 2800, 1616, 1462, 1410;
1H NMR (250 MHz, DMSO-d6) d 8.28 (s, 1H, C(2)-H,
benzimidazole), 7.64-7.61 (m, 2H, aryl), 7.22-7.13 (m,
2H, aryl), 5.55 (s, 2H, NCH2), 2.51 (s, 1H, exchangeable
with D2O, NH, tetrazole); 13C NMR (250 MHz, DMSO-d6)
d 51.7, 116.6, 117.8, 122.2, 123.2, 133.6, 137.5, 145.6,
155.6; MS (EI): m/z (%) = 200 (14.5) [M+]; anal. calcd.
for C9H8N6: C, 53.99; H, 4.03; N, 41.98; found: C, 54.06;
H, 4.15; N, 41.92.
In a double-necked round bottom flask (100 mL)
equipped with a condenser, it was added a mixture,
consisting of nucleophile (including: N-heterocyclic
compounds or phenolic derivatives) (0.01 mol),
2-chloroacetonitrile or 3-chloropropanenitrile (0.013 mol),
Et3N (0.01 mol), K2CO3 (0.01 mol), and a catalytic amount
of TBAI (0.1 g) in anhydrous MeCN (40 mL). The
mixture was refluxed until TLC monitoring indicates no
further improvement in the reaction. The solvent was
evaporated in vacuo and the remaining foam was dissolved
in CHCl3 (100 mL) and subsequently washed with water
(2 × 100 mL). The organic layer was dried (Na2SO4) and
evaporated. The crude product was purified by column
chromatography on silica gel.
1-((1H-Tetrazol-5-yl)methyl)-2-methyl-1H-benzo[d]imidazole
(2b)
Recrystallization (EtOAc) afforded a creamy solid;
yield: 1.90 g (89%); mp > 300 °C (dec.); IR (KBr) n / cm-1
3384, 3100, 2982, 1619, 1580, 1480; 1H NMR (250 MHz,
DMSO-d6) d 7.57-7.46 (m, 2H, aryl), 7.16-7.08 (m, 2H,
aryl), 5.46 (s, 2H, NCH2), 4.55 (s, 1H, exchangeable
with D2O, NH, tetrazole), 2.67 (s, 3H, CH3); 13C NMR
(250 MHz, DMSO-d6) d 17.9, 49.1, 115.5, 116.6, 121.5,
123.0, 134.7, 140.3, 151.2, 158.4; MS (EI): m/z (%) = 214
(11.4) [M+]; anal. calcd. for C10H10N6: C, 56.07; H, 4.71;
N, 39.23; found: C, 56.19; H, 4.62; N, 39.35.
General procedure for synthesis of 5-substituted-1H-
tetrazole 2a-2o
In a double-necked round bottom flask (100 mL)
equipped with a condenser, it was added a mixture,
consisting of alkyl nitrile (0.01 mol), NaN3 (0.015 mol),
and CDSCS (0.3 g, 0.05 mol%) in H2O/i-PrOH (1:1 v/v,
50 mL). The mixture was heated at reflux until TLC
monitoring indicates no further improvement in the
conversion (Table 3). The reaction mixture was then cooled
to room temperature, vacuum-filtered using a sintered-
glass funnel and the residue was washed with ethyl acetate
(2 × 20 mL). The filtrate was treated with 5 N HCl to
reach pH = 3 and it was allowed to stir for 30 minutes.
Subsequently, the organic layer was separated, dried over
anhydrous Na2SO4 and evaporated. The crude product was
purified by recrystallization and/or column chromatography
on silica gel eluted with proper solvents.
5-((2-Methyl-4-nitro-1H-imidazol-1-yl)methyl)-1H-tetrazole
(2c)
Column chromatography (silica gel, EtOAc–MeOH,
1:1) afforded a brown solid; yield: 1.77 g (85%); mp 208-
212 °C (dec.); IR (KBr) n / cm-1 3350, 3128, 2900, 1645,
1500, 1456, 1300; 1H NMR (250 MHz, DMSO-d6) d 8.30
(s, 1H, C(5)-H, imidazole), 5.40 (s, 2H, NCH2), 4.40 (s,
1H, exchangeable with D2O, NH, tetrazole), 2.43 (s, 3H,
CH3); 13C NMR (250 MHz, DMSO-d6) d 15.7, 48.2, 121.1,

18
An Efficient Protocol for Facile Synthesis of New 5-Substituted-1H-Tetrazole Derivatives
J. Braz. Chem. Soc.
147.8, 153.0, 160.9; MS (EI): m/z (%) = 209 (8.1) [M+];
anal. calcd. for C6H7N7O2: C, 34.45; H, 3.37; N, 46.88;
found: C, 34.38; H, 3.42; N, 46.94.
169.1; MS (EI): m/z (%) = 265 (19.7) [M+]; anal. calcd. for
C10H8N4O3S: C, 45.45; H, 3.05; N, 21.20; S, 12.13; found:
C, 45.56; H, 3.11; N, 21.14; S, 12.25.
5-((2-Phenyl-1H-imidazol-1-yl)methyl)-1H-tetrazole (2d)
Recrystallization (EtOAc) afforded a bright brown
solid; yield: 1.96 g (87%); mp 216-220 °C (dec.); IR
(KBr) n / cm-1 3280, 3150, 2937, 2850, 1653, 1476;
1H NMR (250 MHz, DMSO-d6) d 7.94-7.91 (m, 2H, aryl),
7.58-7.46 (m, 3H, aryl), 7.20 (s, 1H, C(4)-H, imidazole),
6.95 (s, 1H, C(5)-H, imidazole), 5.28 (s, 2H, NCH2), 2.50
(s, 1H, exchangeable with D2O, NH, tetrazole); 13C NMR
(250 MHz, DMSO-d6) d 49.0, 121.0, 125.5, 127.0, 127.4,
129.6, 131.0, 152.1, 160.1; MS (EI): m/z (%) = 226 (17.3)
[M+]; anal. calcd. for C11H10N6: C, 58.40; H, 4.46; N, 37.15;
found: C, 58.31; H, 4.58; N, 37.02.
2-(2-(1H-Tetrazol-5-yl)ethyl)isoindoline-1,3-dione (2h)
Recrystallization (EtOAc) afforded a creamy solid;
yield: 2.21 g (91%); mp > 300 °C (dec.); IR (KBr) n / cm-1
1
3374, 3063, 2950, 1772, 1620, 1510, 1458; H NMR
(250 MHz, DMSO-d6) d 7.28-7.09 (m, 4H, aryl), 4.34
(t, 2H, J 7.2 Hz, NCH2), 3.46 (s, 1H, exchangeable with
D2O, NH, tetrazole), 3.08 (t, 2H, J 7.2 Hz, NCH2CH2);
13C NMR (250 MHz, DMSO-d6) d 27.6, 42.6, 126.3, 131.6,
134.2, 159.4, 167.0; MS (EI): m/z (%) = 243 (13.9) [M+];
anal. calcd. for C11H9N5O2: C, 54.32; H, 3.73; N, 28.79;
found: C, 54.43; H, 3.82; N, 28.86.
7-(2-(1H-Tetrazol-5-yl)ethyl)-1,3-dimethyl-1H-purine-
2,6(3H,7H)-dione (2i)
1-((1H-Tetrazol-5-yl)methyl)pyrimidine-2,4(1H,3H)-dione
(2e)
Column chromatography (silica gel, MeOH) afforded a
brown foam; yield: 2.48 g (90%); IR (KBr) n / cm-1 3300,
2985, 1716, 1702, 1693, 1658, 1379;1H NMR(250 MHz,
DMSO-d6) d 7.86 (s, 1H, C(8)-H, theophylline), 4.55
(t, 2H, J 5.7 Hz, NCH2), 3.41 (t, 2H, J 5.7 Hz, NCH2CH2),
3.27 (s, 3H, N(1)-CH3), 3.09 (s, 3H, N(3)-CH3), 2.54 (s,
1H, exchangeable with D2O, NH, tetrazole); 13C NMR
(250 MHz, DMSO-d6) d 20.1, 31.0, 32.3, 34.5, 106.3,
136.8, 145.9, 147.7, 154.5, 159.8; MS (EI): m/z (%) = 276
(20.7) [M+]; anal. calcd. for C10H12N8O2: C, 43.48; H, 4.38;
N, 40.56; found: C, 43.59; H, 4.27; N, 40.61.
Recrystallization (EtOAc) afforded a creamy solid; yield:
1.61 g (83%); mp 285-290 °C; IR (KBr) n / cm-1 3365,
3129, 2876, 1723, 1706, 1650, 1458; 1H NMR (250 MHz,
DMSO-d6) d 11.37 (s, 1H, exchangeable with D2O, NH,
uracil), 7.67 (d, 1H, J 7.5 Hz, C(6)-H, uracil), 5.70 (d, 1H,
J 7.5 Hz, C(5)-H, uracil), 5.07 (s, 2H, NCH2), 4.07 (s, 1H,
exchangeable with D2O, NH, tetrazole); 13C NMR (250 MHz,
DMSO-d6) d 47.3, 103.4, 142.1, 151.5, 156.4, 161.7; MS
(EI): m/z (%) = 194 (10.8) [M+]; anal. calcd. for C6H6N6O2: C,
37.12; H, 3.11; N, 43.29; found: C, 37.24; H, 3.26; N, 43.24.
9-((1H-Tetrazol-5-yl)methyl)-9H-purin-6-amine (2f)
5-(2-(2-Phenyl-1H-imidazol-1-yl)ethyl)-1H-tetrazole (2j)
Recrystallization (EtOAc) afforded a creamy solid;
yield: 2.06 g (86%); mp 250-255 °C (dec.); IR (KBr)
n / cm-1 3300, 3050, 2960, 1650, 1485; 1H NMR (250 MHz,
DMSO-d6) d 7.58-7.44 (m, 5H, aryl), 7.32 (s, 1H, C(4)-H),
6.95 (s, 1H, C(5)-H), 4.29 (t, 2H, J 7.5 Hz, NCH2), 3.07
(t, 2H, J 7.5 Hz, NCH2CH2), 1.98 (s, 1H, exchangeable
with D2O, NH, tetrazole); 13C NMR (250 MHz, DMSO-d6)
d 30.0, 54.5, 120.8, 125.8, 126.3, 127.0, 127.2, 130.2,
149.7, 155.1; MS (EI): m/z (%) = 240 (15.8) [M+]; anal.
calcd. for C12H12N6: C, 59.99; H, 5.03; N, 34.98; found:
C, 60.07; H, 5.16; N, 34.87.
Recrystallization (EtOAc) afforded a creamy solid;
yield: 1.78 g (82%); mp > 300 °C (dec.); IR (KBr) n / cm-1
3328, 3100, 2853, 1676, 1520, 1471; 1H NMR (250 MHz,
DMSO-d6) d 8.12 (s, 1H, C(8)-H, adenine), 8.05 (s, 1H,
C(2)-H, adenine), 7.17 (s, 2H, exchangeable with D2O,
NH2), 5.42 (s, 2H, NCH2), 4.80 (s, 1H, exchangeable with
D2O, NH, tetrazole); 13C NMR (250 MHz, DMSO-d6)
d 54.3, 118.4, 139.9, 147.7, 151.5, 155.6, 162.8; MS (EI):
m/z (%) = 217 (9.5) [M+]; anal. calcd. for C7H7N9: C, 38.71;
H, 3.25; N, 58.04; found: C, 38.63; H, 3.18; N, 58.12.
2-((1H-Tetrazol-5-yl)methyl)benzo[d]isothiazol-3(2H)-one
1,1-dioxide (2g)
1-(2-(1H-Tetrazol-5-yl)ethyl)-1H-benzo[d]imidazole (2k)
Recrystallization (EtOAc) afforded a brown solid; yield:
1.90 g (89%); mp 300-304 °C (dec.); IR (KBr) n / cm-1
3326, 3100, 2926, 1653, 1501, 1470; 1H NMR (250 MHz,
DMSO-d6) d 8.10 (s, 1H, C(2)-H, benzimidazole),
7.62-7.55 (m, 2H, aryl), 7.24-7.14 (m, 2H, aryl), 4.55 (t, 2H,
J 6.5 Hz, NCH2), 3.17 (t, 2H, J 6.5 Hz, NCH2CH2), 2.51
(s, 1H, exchangeable with D2O, NH, tetrazole); 13C NMR
Recrystallization (EtOAc) afforded a pale-yellow
solid; yield: 2.30 g (87%); mp 225-229 °C (dec.); IR
(KBr) n / cm-1 3324, 3050, 2976, 1715, 1600, 1460, 1321,
761; 1H NMR (250 MHz, DMSO-d6) d 7.84-7.45 (m, 4H,
aryl), 4.44 (s, 2H, NCH2), 2.51 (s, 1H, exchangeable with
D2O, NH, tetrazole); 13C NMR (250 MHz, DMSO-d6)
d 39.5, 126.3, 126.8, 127.3, 131.6, 132.0, 139.3, 156.6,

Vol. 28, No. 1, 2017
Soltani Rad
19
(250 MHz, DMSO-d6) d 31.1, 60.5, 116.1, 117.3, 124.1,
125.2, 134.6, 138.7, 149.3, 161.7; MS (EI): m/z (%) = 214
(12.7) [M+]; anal. calcd. for C10H10N6: C, 55.94; H, 4.63;
N, 39.14; found: C, 55.83; H, 4.75; N, 39.28.
(250 MHz, DMSO-d6) d 71.2, 116.3, 127.4, 129.7, 154.7,
159.0; MS (EI): m/z (%) = 210 (18.1) [M+]; anal. calcd. for
C8H7ClN4O: C, 45.62; H, 3.35; Cl, 16.83; N, 26.60; found:
C, 45.69; H, 3.43; Cl, 16.80; N, 26.67.
1-(2-(1H-Tetrazol-5-yl)ethyl)-4-phenylpiperazine (2l)
Column chromatography (silica gel, EtOAc-n-hexane,
1:1) afforded a bright brown solid; yield: 2.37 g (92%);
mp > 300 °C (dec.); IR (KBr) n / cm-1 3340, 3100, 2992,
Supplementary Information
1H and 13C NMR spectra of synthesized tetrazoles are
available free of charge at http://jbcs.sbq.org.br as PDF file.
1
1659, 1653, 1476; H NMR (250 MHz, DMSO-d6)
d 7.26-7.20 (m, 2H, aryl), 6.91-6.81 (m, 3H, aryl), 4.96 (s,
1H, exchangeable with D2O, NH, tetrazole), 3.83 (t, 2H,
J 6.5 Hz, CH2), 3.09 (t, 2H, J 7.2 Hz, CH2), 2.72-2.65 (m,
8H, 4 CH2); 13C NMR (250 MHz, DMSO-d6) d 28.2, 49.1,
52.2, 56.1, 114.3, 119.5, 130.5, 150.0, 160.2; MS (EI): m/z
(%) = 258 (19.7) [M+]; anal. calcd. for C13H18N6: C, 60.44;
H, 7.02; N, 32.53; found: C, 60.31; H, 7.08; N, 32.61.
Acknowledgments
The author is grateful to Shiraz University ofTechnology
Research Councils for partial support of this work.
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Published online: May 5, 2016