Green chemistry: ZrOCl2·8H2O catalyzed regioselective synthesis of 5-amino-1-aryl-1H-tetrazoles from secondary arylcyanamides in water

Article abstract of DOI:10.1007/s00706-013-1038-z

A green and efficient method for the synthesis of 5-amino-1-aryl-1H- tetrazoles with excellent yields and high purity from secondary arylcyanamides is described. This method is completely green because no organic solvents or protic acid catalyst is used t

Full text of DOI:10.1007/s00706-013-1038-z

Monatsh Chem
DOI 10.1007/s00706-013-1038-z
ORIGINAL PAPER
Green chemistry: ZrOCl2Á8H2O catalyzed regioselective synthesis
of 5-amino-1-aryl-1H-tetrazoles from secondary arylcyanamides
in water
•
Behzad Khalili Faramarz Sadeghzadeh Darabi
•
•
Bagher Eftekhari-Sis Mehdi Rimaz
Received: 17 September 2012 / Accepted: 10 June 2013
Ó Springer-Verlag Wien 2013
Abstract A green and efficient method for the synthesis
of 5-amino-1-aryl-1H-tetrazoles with excellent yields and
high purity from secondary arylcyanamides is described.
This method is completely green because no organic sol-
vents or protic acid catalyst is used that can generate
hydrazoic acid (HN3). In addition, it is a very clean method
for acquiring 5-amino-1-aryl-1H-tetrazoles without gener-
ating 5-arylamino-1H(2H)-tetrazoles in most cases.
anhydrous hydrazoic acid and hydrogen cyanide gas under
pressure for the first time [2–10]. They are used as lipo-
philic spacers in pharmaceuticals [11] and in photography
as stabilizing materials [12]. They provide a main skeleton
in plant growth regulators, herbicides, and fungicides that
are used in agriculture [12]. They are also used as a gas
generator in automobile airbags and rocket propellants [13]
because they produce non-toxic and high-temperature gas
reaction products. The high burn rate and relative stability
are other useful properties of tetrazoles [10]. Some tetra-
zoles with antihypertensive, anti-allergic, and antibiotic
activity have been reported in the literature [14]. They are
used in cancer and AIDS treatments [2, 15–18]. Further-
more, aminotetrazole derivatives have been patented for
their anti-arthritic, muscle relaxation, anti-inflammatory,
and analgesic properties [8]. 5-Substituted tetrazoles,
5-aryl/alkyloxytetrazoles, and 5-aryl/alkylaminotetrazoles
are commonly prepared by the reaction of azide anion with
nitriles, cyanates, and cyanamides, respectively [2–8, 19–
21]. In most cases, the reaction actually proceeds in
hydrazoic acid solutions. Hydrazoic acid is an unstable
component and generates nitrogen and hydrogen under
decomposition, which can produce an explosive gas mix-
ture in combination with air or nitrogen at concentrations
above 8–15 %. Therefore, care must be taken to monitor its
concentration in the reaction mixture [2–8, 12, 21]. A
mixture of sodium azide and ammonium chloride can be
used as a substitute for hydrazoic acid with dimethyl-
formamide as the solvent [2–8, 12, 21]; the reaction
requires a long time and high temperatures.
Keywords 5-Amino-1-aryl-1H-tetrazoles Á
Arylcyanamides Á ZrOCl2Á8H2O Á
Regioselective synthesis Á Green chemistry
Introduction
Tetrazoles are increasingly popular heterocycles [1] with
various applications that were prepared by the reaction of
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-1038-z) contains supplementary
material, which is available to authorized users.
B. Khalili (&)
Department of Chemistry, Faculty of Sciences,
University of Guilan, P.O. Box 41335-1914, Rasht, Iran
e-mail: b.khalili@guilan.ac.ir
F. S. Darabi
Young Researcher Club, Parsabad Moghan Branch,
Islamic Azad University, Parsabad, Iran
B. Eftekhari-Sis
Department of Chemistry, University of Maragheh,
P. O. Box 55181-83111, Maragheh, Iran
Solubility in both organic solvents and water is another
disadvantage of dimethylformamide that can cause many
problems in the reaction workup. To resolve these
problems, several solvents were employed at various tem-
peratures to enhance the reaction [21]. Using sodium azide
M. Rimaz
Department of Chemistry, Payame Noor University,
P.O. Box 19395-3697, Tehran, Iran
123

B. Khalili et al.
Scheme 1
H
N
N
N
H
N
N
N
N
ZrOCl2·8H2O
N
H2N
+
+
CN
NaN3
Ar
H
Water/reflux
24 h
N
Ar
N
Ar
1a-1j
2a-2j
3a-3j
0%
78-98%
in acetic acid at 50 °C for the synthesis of some amino-1H-
tetrazoles in low yield (4–59 %) from the treatment of
amino (imino) methanesulfonic acid derivatives was
recently reported by Miller et al. [22]. Von Braun degra-
dation of tertiary amines with carcinogen bromide is
another way to prepare 5-monoalkylaminotetrazoles.
Elimination of an alkyl group of 5-dialkylaminotetrazoles is
possible with this method. Moreover, 5-monosubstituted
amino-1H-tetrazoles can be synthesized by heating
5-amino-1-substituted-1H-tetrazoles in a thermal isomeri-
zation process [23]. Harsh reaction conditions, longer
reaction times, low yield, use of toxic and expensive
reagents, and in situ generation of hydrazoic acid, which is
highly toxic and explosive, are some disadvantages of the
above-mentioned methods.
Table 1 Reaction of 2-chlorophenylcyanamide with sodium azide
under different conditions
N
N
ZrOCl2·8H2O
0.2-0.5 mmol
Cl
H
N
Cl
N
N
N
N
+
CN
N
Water/reflux
24-48 h
NH2
Na
1c
1 mmol
3c
1-3 mmol
Entry NaN3/mmol ZrOCl2Á8H2O/mmol Conversion/% Time/h
1
2
3
4
5
6
7
8
1
2
3
3
3
3
1
2
0.2
0.3
0.4
0.5
0.2
0.3
0.5
0.5
20
60
48
24
24
24
24
24
48
24
85
100
50
65
Due to their availability and low toxicity, Zr (IV) salts
have recently attracted much attention, which is reflected in
their applications in several organic transformations such
as electrophilic amination of activated arenes [24], trans-
thioacetylization of acetals [25], deoxygenation of
heterocyclic N-oxides [26], reduction of nitro compounds
[27], conversion of carbonyl compounds to 1,3-oxathiol-
anes [28], synthesis of nitriles from O-arylaldoximes [29],
Michael reaction of 1,3-dicarbonyls and enones [30],
opening of epoxide rings by amines [31], reactions of
indole, 1-methylindole, and pyrrole with a,b-unsaturated
ketone [32], and other organic transformations [33–42].
There are only a few reports on metal oxysalt-based
organic reactions [43].
35
70
Table 2 Reaction of arylcyanamides with sodium azide (3 eq) cat-
alyzed by zirconium oxychloride (0.5 eq) (Scheme 1)
Entry Product Ar
Yield/% M.p./°C Lit. m.p./°C
1
2
3a
3b
3c
3d
3e
3f
4-NO2–C6H4
4-Cl–C6H4
78
96
98
91
95
92
95
94
90
186–188 185–187 [22]
214–216 215–217 [22]
186–189 185–190 [22]
238–240 239–240 [8]
174–176 175–177 [22]
260–263 260–262 [8]
190–192 191–192 [22]
174–177 174–175 [22]
210–212 209–210 [22]
197–199 199–201 [22]
3
2-Cl–C6H4
4
4-Br–C6H4
5
4-CH3–C6H4
2,5-Cl2–C6H3
2-CH3–C6H4
3-Cl–C6H4
6
In this work, we describe a simple and green route to the
regioselective synthesis of 5-amino-1-aryl-1H-tetrazoles
using arylcyanamides, sodium azide, and ZrOCl2 as cata-
lyst in good yields. This reaction does not produce any
hydrazoic acid, and no organic solvent is used (Scheme 1).
7
3g
3h
3i
8
9
4-CH3O–C6H4
10
3j
2,4-(CH3)2–C6H3 93
can dissolve sodium azide and simplify the separation of
products from other reactants. Different reaction conditions
were examined for synthesis of 5-amino-1-(2-chloro-
phenyl)-1H-tetrazole using 2-chlorophenyl cyanamide
(1 mmol) to acquire the best results, which are summarized
in Table 1. As shown in the data in Table 1, the procedure
in entry 4 was selected for other cyanamide derivatives.
The results are shown in Table 2.
Results and discussion
Different cyanamide derivatives [44, 45] 1a-1j were reac-
ted with sodium azide in the presence of zirconium
oxychloride as catalyst in water to afford corresponding
5-amino-1-aryl-1H-tetrazoles. Water was selected as a
green and environmentally friendly reaction medium that
123

Green chemistry: ZrOCl2Á8H2O catalyzed regioselective synthesis of 5-amino-1-aryl-1H-tetrazoles
Scheme 2
HO
Cl Zr
HO
Cl Zr
Cl
Cl
Ar
N
N
N
N
NaN3
NaN3
H
X
Y
H2N
N
HN C N Ar
N C N Ar
4b
ZrOCl2
H
4a
3a-3j
Ar N C N
H
N
N
H
HN C N Ar
Zr
N C N Ar
Zr
H
N
A
N
Cl
Cl
Cl
Cl
OH
OH
5a
2a-2j
5b
Scheme 3
HO
Cl Zr
Cl
N N N
N N
N
HN C
N
Ar
4c
HO
Cl Zr
Cl
N
N
N
N
HO
Cl Zr
HN
Cl
4d
Ar
4b
H2O
HN C N Ar
HO
OH2
Cl Zr
Cl
HO
Cl Zr
N C N Ar
N
Cl
N
4e
HN
N
H
N
4a
Ar
HO
Zr
Cl
N
N
OH
Cl
N
N
H
Ar N C N
H2N
+
+
ZrOCl2
Ar
1a-1j
3a-3j
4f
-H2O
All products are known compounds and were identified
1
The proposed mechanism involves an attack of azide
by comparison of their spectral data (IR, and H, and 13C
anion on compound 4b, which is made from complexion of
arylcyanamide molecule 1a-1j with zirconium oxychloride
followed by cyclization of intermediate 4c to give com-
pound 4d in water to release the target molecules 3a-3j.
Hydrated zirconium oxychloride 4f can start a new cycle
after elimination of one H2O molecule (Scheme 3).
NMR) and physical properties with those of authentic
samples [22, 23]. 13C-NMR spectra displayed a signal at
d = 155–157 ppm for C5 of the tetrazole ring [46–49].
Arylcyanamide molecules 1a-1j can be complexes with
zirconium oxychloride in two pathways (X and Y) and
produce two intermediates, 4a and 5a, each of which can
tautomerize to 4b and 5b, respectively. According to
In this work, we describe a new methodology to acquire
5-amino-1-aryl-1H-tetrazoles without generation of 5-aryl-
amino-1H(2H)-tetrazoles in most cases. This methodology has
important advantages over previous methods; for example,
these results, pathway
(Scheme 2).
X is the predominate one
123

B. Khalili et al.
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acid as catalyst prevents making any hydrazoic acid during
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General procedure for synthesis of 5-amino-1-aryl-1H-
tetrazoles
To a solution of sodium azide (3 mmol) in 10 cm3 water
was added cyanamide (1 mmol) and catalyst (0.5 mmol).
The reaction mixture was refluxed for 24 h with vigorous
stirring until all the cyanamide was consumed (monitored
by TLC). The reaction mixture was filtered and washed
with water three times (3 9 15 cm3) to remove excess
sodium azide and catalyst. The products were dried under
vacuum and characterized by IR and NMR spectra and
melting points (Tables 1 and 2). Isomer 3a was not soluble
in ethanol and was separated from isomer 2a via a simple
procedure. Isomer 3a was precipitated from ethanol and
was collected on filter paper. The remaining isomer 3a in
the stock solution was precipitated and removed by adding
EtOH/H2O (3:1). The filtrate solution contained only iso-
mer 2a. Removing the solvents gives pure isomer 2a.
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