Solvent-free preparation of arylaminotetrazole derivatives using aluminum(III) hydrogensulfate as an effective catalyst

Article abstract of DOI:10.1016/j.cclet.2010.03.008

An efficient and simple method for the preparation of 5-arylamino-1H- tetrazole and 1-aryl-5-amino-1H-tetrazole derivatives is reported using aluminum(III) hydrogensulfate (Al(HSO₄)₃) as an effective heterogeneous catalyst from secon

Full text of DOI:10.1016/j.cclet.2010.03.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 892–896
www.elsevier.com/locate/cclet
Solvent-free preparation of arylaminotetrazole derivatives using
aluminum(III) hydrogensulfate as an effective catalyst
*
Ferydoon Khamooshi, Ali Reza Modarresi-Alam
Deparment of Chemistry, Faculty of Science, University of Sistan and Baluchestan, Zahedan, Iran
Received 24 November 2009
Abstract
An efficient and simple method for the preparation of 5-arylamino-1H-tetrazole and 1-aryl-5-amino-1H-tetrazole derivatives is
reported using aluminum(III) hydrogensulfate (Al(HSO4)3) as an effective heterogeneous catalyst from secondary arylcyanamides.
Generally, when the substitution in arylcyanamide is strongly electron-withdrawing the position of equilibrium would shift toward
the isomer of 1-aryl-5-amino-1H-tetrazole (B) and as the electron-donating of substituent increased, the position of equilibrium is
shifted toward the isomer of 5-arylamino-1H-tetrazole (A). The present methodology offers several advantages, such as excellent
yields, short reaction times, easy work-up and greener conditions.
# 2010 Ali Reza Modarresi-Alam. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 5-Arylamino-1H-tetrazole; 1-Aryl-5-amino-1H-tetrazole; Secondary arylcyanamide; Aluminum(III) hydrogensulfate (Al(HSO4)3);
Heterogeneous catalyst; Solvent-free; Solid acid
The number of patent claims and publications related to medicinal uses of tetrazoles continue to grow rapidly and
cover a wide range of applications [1,2]. They are currently used, for example, as a potential surrogate for cis-peptide
linkage and carboxylic acids, as anticonvulsants and in cancer and AIDS treatment [2–7]. Tetrazoles are also applied in
agriculture, as plant growth regulators, herbicides [1–8]. Tetrazoles also can play as explosives and rocket propellants
[8–11]. Another important application of tetrazoles is the preparation of imidoylazides [12,13]. Recently, several
synthesis of aryl and alkylaminotetrazoles have been reported using hydrazoic acid [14–16] and sodium azide under
solution [17–19], Scheme 1. Congreve has reported two-step synthesis of 1-aryl-5-amino-1H-tetrazoles B from the
corresponding 1-aryltetrazoles via cyanamide intermediate [20].
This reaction suffer from some drawbacks such as harsh reaction conditions, low temperatures (ꢀ70 8C), use of
large excess of sodium azide and organolithium reagents making it fairly complicated and potentially dangerous.
Vorobiov et al. published a three-step synthesis of 1-aryl-5-amino-1H-tetrazoles in low yields from the corresponding
aromatic amines via isolation of intermediate cyanamides [21]. Unfortunately, this approach is not well developed due
to insufficient stability of intermediate cyanamides. In most cases, N-arylureas and other by-products were mostly
formed and the intermediate cyanamides were not stable enough to be isolated. Moreover, the above mentioned
synthetic methods require the use of highly toxic and explosive hydrazoic acid. If hydrazoic acid is used, care must be
taken by monitoring the concentration of hydrazoic acid in the reaction mixture to avoid an explosion [14–16,18,22].
* Corresponding author.
E-mail address: modaresi@chem.usb.ac.ir (A.R. Modarresi-Alam).
1001-8417/$ – see front matter # 2010 Ali Reza Modarresi-Alam. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.008

F. Khamooshi, A.R. Modarresi-Alam / Chinese Chemical Letters 21 (2010) 892–896
893
Scheme 1.
Due to safety considerations, we required a method that did not use hydrazoic acid or an azide source that produce
hydrazoic acid in situ because of the associated hazards. Therefore, it is desirable to develop a more efficient and
convenient methods for the synthesis of arylaminotetrazoles. In recent years, organic reactions on aluminum(III)
hydrogensulfate (Al(HSO4)3) catalyst have received considerable attention in organic synthesis because of their ease
of handling, enhanced reaction rates, greater selectivity, simple work-up [23]. We have recently reported synthesis of
5-arylamino-1H-tetrazole and 1-aryl-5-amino-1H-tetrazole from arylcyanamides in glacial acetic acid [24]. In
continuation of our recent works on the application of heterogeneous reagents for the development of useful synthetic
methodologies [25–27], herein we wish to report a new protocol for the preparation of arylaminotetrazole 3–11
derivatives from secondary arylcyanamides 1 using a amount of Al(HSO4)3 as a solid acid catalyst (Scheme 2 and
Table 1). However, to the best of our knowledge there is not any report on synthesis of aminotetrazoles using of solid
acid catalysts in solvent-free.
1. Experimental
All reagents were purchased from Merck and Aldrich and used without further purification. 13C NMR and 1H NMR
spectra were recorded on Brucker using TMS as internal standard. Chemical shifts are reported in ppm, and coupling
Scheme 2.
Table 1
Synthesis of arylaminotetrazole derivatives 3–11 in the presence of Al(HSO4)3 by the reaction of sodium azide 2 and aromatic cyanamides 1 at
70 8C.
24
Entry Cyanamide Ar
Product
Reaction
Ratio of
Yield (%)a
M.p. (8C) of isomers
(tetrazole) time (min) isomers (B/A)b
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
4-NO2C6H4
2,5-Cl2C6H3
2-ClC6H4
3A, 3B
4A, 4B
5A, 5B
6A, 6B
7A, 7B
18
20
17
20
15
15
15
15
15
4.88
2.03
1.94
1.33
0.49
0.33
0.33
0.49
0.49
90 (17% A, 83% B) 3a: 218–220; 4a: 187–188
83 (33% A, 67% B) 4A: 272–274; 4B: 260–262
86 (36% A, 64% B) 5A: 227–229; 5B: 187–189
82 (43% A, 57% B) 3b: 245–247; 4b: 239–240
88 (67% A, 33% B) 7A: 200–202; 7B: 211–213
72 (75% A, 25% B) 8A: 190–192; 8B: 196–198
74 (75% A, 25% B) 9A: 245–247; 9B: 146–149
82 (67% A, 33% B) 10A: 202–204; 10B: 176–178
77 (67% A, 33% B) 11A: 201–203; 11B: 192–194
4-BrC6H4
4-CH3OC6H4
2,4-(CH3)2C6H3 8A, 8B
2,6-(CH3)2C6H3 9A, 9B
1g
1h
1i
4-CH3C6H4
2-CH3C6H4
10A, 10B
11A, 11B
a
Yields refer to the pure isolated products.
Determined by 1H NMR analysis.
b

894
F. Khamooshi, A.R. Modarresi-Alam / Chinese Chemical Letters 21 (2010) 892–896
constants are reported in Hz. IR spectra were recorded on a Shimadzu 470 spectrophotometer. TLC was performed on
Merck-precoated silica gel 60-F254 plates.
2. Caution
Although aminotetrazoles are kinetically stable and in most cases are insensitive to electrostatic discharge, friction,
and impact, they are nonetheless energetic materials and appropriate safety precautions should be taken, especially
when these compounds are prepared on a larger scale [9–11]. Hydrazoic acid is an unstable component which may
decompose violently, forming nitrogen and hydrogen. Depending on the literature source, an explosive gas mixture
can be formed with air or nitrogen above a concentration of more than 8–15% [22].
All of the products are known compounds and identified by comparison of some their spectral data (IR, 1H and 13
C
NMR) and physical properties with those of authentic samples [24,28]. All starting materials and solvents were
purified with the proper purification techniques before use, when necessary [29]. The cyanamides 1 were prepared
according to the literature [30].
2.1. General procedure for preparation of arylaminotetrazole derivatives 3–11 using Al(HSO4)3
A mixture of the cyanamide 1 (1 mmol), aluminum hydrogensulfate [23] (0.7 mmol) and sodium azide (1.5 mmol)
was heated at 70 8C under solid-state conditions. The reaction mixture was stirred for the appropriate time (Table 1).
The progress of the reaction was followed by TLC. After completion, the reaction mass was cooled to 25 8C, then
water was added and the mixture stirred for 5 min. The solid residue was filtered from the mixture. The desired pure
products was characterized by IR and NMR spectra [24]. As isomers 3–11B were not soluble in spirit alcohol, they
were separated from isomers 3–11A via a simple procedure [24]. Isomers 3–11B precipitated from spirit alcohol and
were easily collected on filter paper. The filtrates contained a small amount of isomers 3–11B and residue of isomers
3–11A. The remaining isomers 3–11B in the stock solution were precipitated and removed by adding EtOH/H2O (3:1).
The filtrate solution contained only isomers 3–11A. Removing the solvents gave pure isomers 3–11A.
3. Results and discussion
Aluminum(III) hydrogensulfate (Al(HSO4)3) as an effective heterogeneous catalyst was prepared from the reaction
of anhydrous aluminum chloride with sulfuric acid [23].
In order to improve yield and due to the biological importance of aminotetrazole derivatives, we started to study this
reaction by examining the different amounts of Al(HSO4)3 reagent to afford the product under thermal conditions
where best results was obtained with a 0.7 mmol of Al(HSO4)3 and the optimized results depicted for 4-Br-
phenylcyanamide in Table 2. Indeed, arylaminotetrazoles 3–11 were obtained from reaction of secondary
arylcyanamides 1 with sodium azide 2 in the presence of Al(HSO4)3 as a solid acid at 70 8C for appropriated time in
excellent yields, as summarized in Table 1. In order to include a reasonable range of electrical and steric effects the
arylsubstituted cyanamides studied included various groups in ortho, meta and para positions. The reaction of
arylsubstituted cyanamides resulted in mixture of isomers (A + B) (Table 1). Since isomers B were not soluble in spirit
alcohol they were separated from isomers A via a simple procedure as described elsewhere [24]. As shown in Table 1,
among the various cyanamides tested, electron-rich aromatic cyanamides reach completion at 70 8C after 15 min,
Table 2
Preparation of 4-Br drivative from the reaction of 4-Br-phenylcyanamide and sodium azide using variety amount of Al(HSO4)3 under solid-phase
condition at 70 8C.
Entry
Al(HSO4)3 (mmol%)
Time (min)
Yielda %
1
2
3
4
5
33
38
42
60
70
70
62
40
19
19
75
81
84
90
91
a
Isolated yield.

F. Khamooshi, A.R. Modarresi-Alam / Chinese Chemical Letters 21 (2010) 892–896
895
Table 3
Comparison effect of different catalysts in the synthesis of 5-(2-chlorophenyl)amino-1H-tetrazole (5A) and 5-amino-1-(2-chlorophenyl)-1H-
tetrazole (5B).
Entry
Catalyst
Solvent
Time (min)
Temperture (8C)
Yield%
1
2
PPh3
DMF
DMF
120
120
30
115
115
110
110
115
100
115
115
25
64
75
87
88
81
48
80
65
86
97
FeCl3–SiO2
SiO2–HClO4
Al2O3–SO3H
Zeolite
a
3
–
a
4
–
30
5
DMF
95
6
Zeolite
H2O
95
7
Zeolite
DMSO
DMF
95
8
LiCl
CH3COOHb
100
24 h
17
9
CH3COOH
a
–
10
Al(HSO4)3
70
a
Solvent-free.
b
Glacial acetic acid as both solvent and proton donor source.
whereas electron-poor aromatic species require little higher times (compare entries 1–4 with 5–8 in Table 1). In
addition, there is an excellent correlation between the effect of substitution on the benzene ring and the position of
equilibrium. In other words, isomers ratio in tetrazoles 3–11 are under effect of type of substituents in arylcyanamide
1. The detailed mechanism was described elsewhere so that tautomers A and B are formed via guanidine azide
intermediates A0 and B0, Scheme 1 [24].
Generally, when the substitution on aryl ring is strongly electron-donating the position of equilibrium would shift
toward the isomer of 5-arylamino-1H-tetrazole Avia guanidine azide intermediate A0 (Table 1 and entries 5–8) and as
the electronegativity of substituent increased, the position of equilibrium is shifted toward the isomer of 1-aryl-5-
amino-1H-tetrazoles B via guanidine azide intermediate B0 (Table 1 and entries 1–4). This is in contrast to the
substituent effect on aryl ring of mechanism that was presented by Henry and coworkers for thermal isomerization
[14]. All of the products are known compounds and identified by comparison of their spectral data (IR, H and 13
1
C
NMR) and physical properties with those of authentic samples [24,28]. Elimination of one strong and sharp absorption
band (CN stretching band), and appearance of two absorption bands in the range of 3140–3550 cmꢀ1 (NH stretching
bands) in IR spectrum, confirmed the formation of arylaminotetrazoles. 13C NMR spectra display signals for tetrazole
ring carbons of arylaminotetrazoles in the range of 154–157 ppm (depending on the nature of the substituents in the
amino functionality) [24,31]. To show the advantages of aluminum hydrogensulfate as a catalyst in comparison with
other reported results in the literatures [24,32], we compared the reaction of Al(HSO4)3 with PPh3, LiCl, SiO2–HClO4,
Al2O3–SO3H, zeolite, glacial acetic acid and FeCl3–SiO2 in the synthesis of 5-(2-chlorophenyl)amino-1H-tetrazole
(5A) and 5-amino-1-(2-chlorophenyl)-1H-tetrazole (5B) with comparison effect of these different catalysts have been
incorporated in Table 3. As shown in Table 3, aluminum hydrogensulfate is a better catalyst in the synthesis of
arylaminotetrazole.
4. Conclusions
In conclusion, we have developed a novel and highly efficient method for the synthesis of various
arylaminotetrazoles by the treatment of secondary arylcyanamides with sodium azide in the presence of Al(HSO4)3
as an effective catalyst. The significant advantages of this methodology are excellent yields, short reaction times,
solvent-free reaction conditions, elimination of dangerous and harmful hydrazoic acid, simple work-up procedure and
easy preparation and handling of the catalyst and no chromatographic separation is necessary to get the spectra-pure
compounds.
Acknowledgment
The authors are thankful to Sistan and Baluchestan University Research Council for support of this work.

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F. Khamooshi, A.R. Modarresi-Alam / Chinese Chemical Letters 21 (2010) 892–896
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