Synthesis of arylaminotetrazoles by ZnCl2/AlCl 3/silica as an efficient heterogeneous catalyst

Article abstract of DOI:10.1007/s00706-011-0670-8

Arylaminotetrazoles were efficiently synthesized from secondary arylcyanamides by application of ZnCl₂/AlCl₃/silica as a reusable heterogeneous Lewis acid catalyst. 5-Arylamino-1H-tetrazoles can be obtained from arylcyanamides carryi

Full text of DOI:10.1007/s00706-011-0670-8

Monatsh Chem (2012) 143:925–930
DOI 10.1007/s00706-011-0670-8
ORIGINAL PAPER
Synthesis of arylaminotetrazoles by ZnCl2/AlCl3/silica
as an efficient heterogeneous catalyst
•
Davood Habibi Mahmoud Nasrollahzadeh
Received: 3 May 2011 / Accepted: 4 October 2011 / Published online: 17 November 2011
Ó Springer-Verlag 2011
Abstract Arylaminotetrazoles were efficiently synthe-
sized from secondary arylcyanamides by application of
ZnCl2/AlCl3/silica as a reusable heterogeneous Lewis acid
catalyst. 5-Arylamino-1H-tetrazoles can be obtained from
arylcyanamides carrying electron-withdrawing substituents
on the aryl ring, while with electron-releasing groups
1-aryl-5-amino-1H-tetrazoles will be produced. The former
isomer is also produced within longer reaction times
(*20 h) even with electron-releasing groups.
Nevertheless, the utility of these compounds is limited due
to their insufficient synthetic availability.
Aminotetrazoles are conventionally synthesized by
diazotation of aminoguanidine derivatives [6] or azidation
of cyanamides [7, 8], carbodiimides [9], thioureas [10, 11],
aminoiminomethanesulfonic acids [12], and benzotriazol-
1-ylcarboximidamides [13]. 5-Amino groups can also be
introduced into the tetrazole ring by nucleophilic substi-
tution of the tetrazoles containing leaving groups in
5-position with the appropriate amines [14]. In addition,
5-(monosubstituted amino)-1H-tetrazoles were synthe-
sized by thermal isomerization of 1-substituted 5-amino-
1H-tetrazoles in boiling ethylene glycol or melt state
(180–200 °C) [5, 8, 15].
Keywords Arylaminotetrazole ꢀ
Electron-releasing substituent ꢀ
Electron-withdrawing substituent ꢀ
Secondary arylcyanamide ꢀ Heterogeneous catalyst
These methods have disadvantages such as production
of a mixture of isomers, i.e., 5-arylamino-1H-tetrazoles 3
and 1-aryl-5-amino-1H-tetrazoles 4 [7], application of
hydrazoic acid, low yield, long reaction times, harsh
reaction conditions, difficulty of work-up due to the
application of homogeneous catalyst, use of expensive and
toxic reagents, and in situ generation of hydrazoic acid.
In recent years great efforts have been devoted to the
introduction and application of effective and safe hetero-
geneous acid catalysts [16, 17]. The high catalytic activity,
low toxicity, recyclability, and particularly low price make
the use of solid-supported reagents attractive alternatives to
the conventional methods. It is strongly needed to develop
a method without the application of a homogeneous system
as well as avoiding the in situ generation of hydrazoic acid.
In the course of our researches on the synthesis of
different heterocycles [18, 19] and applications of hetero-
geneous reagents [20], we report herein the synthesis of
arylaminotetrazoles (3a–3e and 4f–4m) from a wide vari-
ety of arylcyanamides 1a–1m and sodium azide (2) in the
presence of the ZnCl2/AlCl3/silica (ZAS) catalyst at
Introduction
The chemistry of tetrazoles has gained increasing attention
since the early 1980s [1]. Tetrazoles have a wide range of
applications as lipophilic spacers and carboxylic acid sur-
rogates in pharmaceuticals, as specialty explosives and
information recording systems in materials, as ligands in
coordination chemistry, and as precursors to a variety of
nitrogen-containing compounds [2]. Furthermore, a range
of aminotetrazoles have been reported as biologically
active compounds [3, 4] and anticorrosive additives [5].
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0670-8) contains supplementary
material, which is available to authorized users.
D. Habibi (&) ꢀ M. Nasrollahzadeh
Faculty of Chemistry, Bu-Ali Sina University,
6517838683 Hamedan, Iran
e-mail: davood.habibi@gmail.com
123

926
D. Habibi, M. Nasrollahzadeh
Scheme 1
Ar
NH2
NH
N
N
N
ZnCl 2 /AlCl3 /silica (ZAS)
DMF, 120 °C
H
N
or
Ar
C
N + NaN3
N
Ar
N
N
H
N
N
3a-3e
4f -4m
1a-1m
2
Table 1 Synthesis of arylaminotetrazoles
Ar
NH2
N
N
NH
N
H
or
Ar
N
C
N
NaN3
+
Ar
N
N
N
H
N
N
1a-1m
2
3a-3e
4f-4m
Entry
Ar
Product
Time/min
Yield/%a
M.p./°C (lit. m.p./°C) [Ref]
1
4-NO2–C6H4–
2-Cl–C6H4–
3a
3b
3c
3d
3e
4f
125
110
100
100
80
73
218–220 (218–220) [25]
228–230 (228–230) [25]
272–274 (272–274) [25]
249–250 (249–250) [25]
215–217 (215–217) [25]
217–219 (215–217) [8]
178–179 (175.5–177) [8]
199–201 (199–201) [25]
191–192 (191–192) [25]
220–221 (220–221) [25]
264–266
2
78
3
2,5-Cl2–C6H3–
4-Br–C6H4–
72
77, 73b
4
5
C6H5–
70
6
4-Cl–C6H4–
110
70
78
7
4-CH3–C6H4–
2,4-(CH3)2–C6H3–
2-CH3–C6H4–
1-Naphthyl
4g
4h
4i
60
8
65
70
9
70
74
10
11
12
13
a
4j
70
75
1,4-Phenylenebis
4-CH3O–C6H4–
2,4-(CH3O)2–C6H4–
4k
4l
35
77
70
73
211–213 (211–213) [25]
183–185 (183–185) [25]
4m
70
76
Isolated yield
b
Yield after the third cycle
120 °C in DMF after appropriate times (Scheme 1;
Table 1).
120 °C after 65–70 min, while the species bearing the
electron-withdrawing groups NO2 or Cl (entries 1–3)
require higher reaction times. The products were com-
pletely regiospecific. This observation is in contrast with
those reports that the other reagents will often produce a
mixture of isomers (Scheme 2) [7, 19].
Results and discussion
To evaluate the efficiency of various reagents in the
cycloaddition reaction, the activity of different catalytic
systems was investigated in a model reaction between 2,5-
dichlorophenylcyanamide (two equivalents) and sodium
azide (three equivalents) at 120 °C. It was found that the
ZAS catalyst was superior since the products are regio-
specific, while a mixture of isomers was produced with the
other reagents (Table 2).
The influences of various substituents in different ortho,
meta, or para positions on the type of products were
examined. The formation of isomers 3 or 4 is strongly
influenced by the substituents in arylcyanamides 1
(Table 1). Generally, when the substituent on the aryl ring
of 1 is electron-releasing, formation of 1-aryl-5-amino-1H-
tetrazoles 4 is favored via the guanidine azide intermediate
B (Table 1, entries 7–9, 12, and 13), while with electron-
withdrawing substituents the product is shifted toward the
formation of 5-arylamino-1H-tetrazoles 3 via the guanidine
azide intermediate A (Table 1, entries 1–4). In the research
carried out before, the nature of the substituent did not have
any effect [2–5, 7, 8, 15, 21, 22]. No clear explanation was
given by the previous workers about the isolation or
Also, to optimize the yields, different amounts of ZAS
were used for the synthesis of 3d from the reaction of 1d
with 2, the best result being obtained with 0.09 g ZAS
(Table 2, entry 8).
As shown in Table 1, cyanamides having methyl as an
electron-releasing group (entries 7–9) were completed at
123

Synthesis of arylaminotetrazoles by ZnCl2/AlCl3/silica
927
Table 2 Comparison of ZAS activity with other reagents in the
synthesis of arylaminotetrazoles
H
H
N N
H
Solvent Time/min Product Yield/%a
N
Entry Catalyst
N
N
H
N
N
N
1
PPh3
DMF
DMF
120
100
25
3 ? 4
75
70
85
86
90
87
77
77
76
73
70
65
Cl
R
2
LiCl
3 ? 4
N
3b
b
–
N
3b'
3
SiO2-HClO4
Al2O3-SO3H
Fe(HSO4)3
Glacial HOAcc
3 ? 4
b
–
4
30
3 ? 4
Scheme 4
b
–
5
30
3 ? 4
6
30 hd
100
100
100
100
100
100
3 ? 4
aminotetrazoles from cyanamides, only 1-aryl-5-amino-
1H-tetrazole 4 or a mixture of isomers 3 ? 4 was obtained
[7, 19].
7
ZAS (0.14 g) DMF
ZAS (0.09 g) DMF
ZAS (0.09 g) DMSO
ZAS (0.08 g) DMF
ZAS (0.07 g) DMF
ZAS (0.06 g) DMF
3
3
3
3
3
3
8
9
Due to presence of the two CN groups, 1k (Table 1,
entry 11) interestingly afforded the double-addition product.
4-Nitrophenylcyanamide (Table 1, entry 1) interestingly
gave 5-(4-nitrophenylamino)-1H-tetrazole (3a), while with
the methods reported before, 1-(4-nitrophenyl)-5-amino-1H-
tetrazole (4a) or a mixture of isomers was obtained
(Scheme 3).
10
11
12
a
Isolated yield
b
c
d
Solvent-free
Glacial acetic acid as both solvent and proton source
Room temperature
According to Table 1, even though entry 6 has an
electron-withdrawing group, the product (4f) is not the
same as the products in entries 1–4 (3a–3d). This is in
concordance with the report which was published before
for the synthesis of aminotetrazoles using ZnCl2 in water
[18]. Formation of the 5-arylamino-1H-tetrazole isomer
(3b and 3c in Table 1) is probably favored through the
intramolecular hydrogen bonding (Scheme 4) in 3b (chlo-
rine atom at ortho position) and 3c (chlorine atom at ortho
and meta positions).
detection of other isomers, although Stolle and Heintz [11]
reported the isolation of 5-anilinotetrazole in low yield
from the reaction of phenylthiourea with lead oxide and
sodium azide. In other words, in the synthesis of
FeCl3 -SiO2
3
4
+
DMF, 110 °C
The tendency towards formation of 5-arylamino-1H-
tetrazoles 3 relative to 1-aryl-5-amino-1H-tetrazoles 4
increases as the reaction time is increased (Table 3). The
isomer 3 is favored with longer reaction times (*20 h)
even with electron-releasing groups (Scheme 5).
Substitution on the R group of monosubstituted guanyl
azides will change the distribution of charge in the inter-
mediate by induction or resonance effect. Electronegative
Ar-NH-CN
+
Glacial HOAc
rt
3
3
4
4
+
+
NaN3
HN 3
Ethanol, xylene, reflux
Scheme 2
Scheme 3
O2N
N NH
N
N
ZnCl2 /AlCl3 /silica (ZAS)
DMF, 120 °C
3a
NH
3a 4a 3a 4a
FeCl3 -SiO2
DMF, 110 °C
+
(
/
= 1.8)
O2N
NH C N
+
Glacial HOAc
rt
NaN3
3a 4a 4a 3a
+
(
/
= 4.6)
O2N
HN3
NH2
N
N
Ethanol, xylene, reflux
4a
N
N
123

928
D. Habibi, M. Nasrollahzadeh
direct measurement of the distribution of the tautomeric
guanyl azides A and B at equilibrium.
Table 3 Synthesis of arylaminotetrazoles at longer reaction times
(*20 h)
2-Methylphenylcyanamide (Table 1, entry 9) interest-
ingly gave 1-(2-methylphenyl)-5-amino-1H-tetrazole (4i),
while with HOAc and FeCl3–SiO2, 5-(2-methylphenyla-
mino)-1H-tetrazole (3i) and a mixture of isomers were
obtained, respectively (Scheme 6) [23].
N
NH
N
H
Ar
N
C
N
NaN3
+
Ar
N
N
H
1a 1m
-
2
3a 3e 3f 3i 3l
- , - ,
The isomers 3 and 4 have different chemical properties.
5-Arylamino-1H-tetrazoles 3 are acidic substances, while
1-aryl-5-amino-1H-tetrazoles 4 have basic properties due
to their NH2 functional group.
Entry Ar
Product Yield/ M.p./°C (lit. m.p./°C)
a
%
[Ref]
1
2
3
4
5
6
7
8
4-NO2-C6H4-
2-Cl-C6H4-
3a
3b
73
76
71
75
73
74
75
70
218–220 (218–220) [25]
228–230 (228–230) [25]
272–274 (272–274) [25]
249–250 (249–250) [25]
215–217 (215–217) [25]
226–228
The mechanism of the catalysis may originate from the
nitrile group coordinating with the surface of the solid acid.
The solid acid is supposed to activate the nitriles and
enhance their reactivity with sodium azide (Scheme 7).
However, further experiments are necessary to gain a
clearer insight into these reactions.
2,5-Cl2-C6H3- 3c
4-Br-C6H4-
C6H5-
3d
3e
3f
4-Cl-C6H4-
4-CH3-C6H4-
3g
3h
201–203 (200.5–201) [8]
192–193
2,4-(CH3)2-
C6H3-
Conclusions
9
2-CH3-C6H4-
3i
65
76
201–203
10
4-CH3O-C6H4- 3l
200–202 (200–202) [8]
We developed an effective cyclization reaction of various
cyanamides with sodium azide under thermal conditions in
the presence of ZnCl2/AlCl3/silica (ZAS) as an effective
heterogeneous catalyst. The significant advantages of this
methodology are high yields, regiospecific products, short
reaction times, elimination of dangerous and harmful
hydrazoic acid, easy and simple work-up procedure, low
cost, and easy preparation and handling of the catalyst.
ZAS is an ecofriendly catalyst because it produces little
waste and can be recovered by simple filtration and suc-
cessively reused without significant loss of activity.
a
Isolated yield
substitution will decrease the electron density around the
nitrogen to which R is bonded, increasing the percentage of
A and thus increase the amount of 5-arylamino-1H-tetra-
zoles 3. Electropositive substitution exerts the opposite
effect, increasing the percentage of B and so increasing the
amount of 1-aryl-5-amino-1H-tetrazoles 4. In other words,
the distribution of isomeric tetrazoles 3 and 4 is probably a
Scheme 5
R
NH2
NH
C
N
NH
N
N
NH2
N
R
R
R
C
N
N
N3
N
N
N
H
N3
H
N
B
A
4
3
Scheme 6
NH2
ZnCl2 /AlCl3 /silica (ZAS)
DMF, 120 °C
H3C
N
4i
3i
CH3
NH
N
N
C
N
N
N
FeCl3 -SiO2
3i + 4i
CH3
+
DMF, 110 °C
NaN3
NH
Glacial HOAc
rt
N
NH
N
123

Synthesis of arylaminotetrazoles by ZnCl2/AlCl3/silica
929
Scheme 7
ZAS
N
C
N
N
N
N
N NH
N
N
ZnCl 2 /AlCl 3 /silica (ZAS)
N
H
H
+
C
Ar
Ar
Ar
N
3a-3e
N
N
H
N
NH
H
Ar
1a-1m
2
N
N
NH2
N
N
4f-4m
Ar
C
ZAS
N
N
N
N
N
H
Experimental
heated up to 120 °C for the appropriate time (Table 1) and
stirred. After completion of the reaction (monitored by
TLC), the reaction mixture was cooled to 25 °C and the
catalyst was filtered and washed with water and ethanol.
The solution was treated with 35 cm3 ethyl acetate and
20 cm3 4 N HCl and stirred vigorously. The resultant
organic layer was separated, and the aqueous layer was
again extracted with 25 cm3 ethyl acetate. The combined
organic layers were washed with water, concentrated, and
washed with ethanol to give different arylaminotetrazoles.
The physical data (m.p., IR, NMR) of known compounds
were found to be identical to those reported in the literature
[8, 18, 25].
All reagents were purchased from Merck and Aldrich chem-
ical companies and used without further purification. Products
were characterized by infrared (IR), Fourier-transform (FT)-
IR, 1H and 13C nuclear magnetic resonance (NMR), elemental
1
analysis (CHN), and melting points. H NMR spectra were
recorded on Bruker Avance DRX 300- and 500-MHz instru-
ments. NMR spectra were recorded in DMSO-d6 and acetone-
d6. Chemical shifts (d) are reported in ppm relative to tetra-
methylsilane (TMS) as internal standard. J values are given in
Hz. 13C NMR spectra were recorded at 125 and 75 MHz. IR
(KBr) and FT-IR (KBr) spectra were recorded on Shimadzu
470 and PerkinElmer 781 spectrophotometers, respectively.
Melting points were taken in open capillary tubes with a
N-(4-Chlorophenyl)-1H-tetrazol-5-amine
(3f, C7H6ClN5)
¨
BUCHI 510 melting point apparatus. The elemental analysis
M.p.: 226–228 °C; FT-IR (KBr):v = 3,269, 3,210, 3,130,
3,071, 1,625, 1,579, 1,546, 1,493, 1,246, 1,093, 1,057, 835,
was performed using a Heraeus CHN-O-Rapid analyzer.
Thin-layer chromatography (TLC) was performed on silica
gel polygram SIL G/UV 254 plates. The cyanamides 1a–1m
were prepared according to the literature [24].
782, 728, 503 cm-1 1H NMR (300 MHz, DMSO-d6):
;
d = 7.35 (d, J = 8.9 Hz, 2H), 7.56 (d, J = 8.9 Hz, 2H),
9.97 (s, 1H), 15.40 (s, br, 1H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 156.1, 139.8, 129.3, 125.1, 118.7 ppm.
Caution! All reactions of azides and tetrazole com-
pounds must be treated as potentially explosive and
conducted behind a rigid safety screen.
N-(2,4-Dimethylphenyl)-1H-tetrazol-5-amine
(3h, C9H11N5)
General procedure for the preparation of ZnCl2/AlCl3/
silica (ZAS)
M.p.: 192–193 °C; FT-IR (KBr): v = 3,255, 3,130, 2,920,
1,629, 1,605, 1,580, 1,542, 1,495, 1,268, 1,216, 1,158,
1
1,116, 1,067, 991, 869, 827, 781, 726, 600, 559 cm-1; H
Anhydrous AlCl3 (1.27 g, 9.5 mmol) and 1.27 g ZnCl2
(9.3 mmol) were added to 5.1 g silica gel (grade 60,
230–400, washed with 1 M HCl, and dried under vacuum
at 80 °C for 72 h) in 50 cm3 carbon tetrachloride. The
mixture was stirred and refluxed for 2 days in the absence
of light under N2 atmosphere, filtered, washed with dry
CCl4, and then dried under vacuum at 70 °C for 5 h.
NMR (300 MHz, aceton-d6): d = 2.29 (s, 6H), 7.04 (d,
J = 7.9 Hz, 2H), 7.66 (d, J = 7.9 Hz, 1H), 8.30 (s, br, 1H)
ppm; 13C NMR (75 MHz, aceton-d6): d = 156.6, 136.3,
134.1, 132.2, 129.9, 128.1, 121.8, 20.7, 17.9 ppm.
N-(2-Methylphenyl)-1H-tetrazol-5-amine (3i, C8H9N5)
M.p.: 201–203 °C; FT-IR (KBr): v = 3,435, 3,315, 2,910,
1,646, 1,606, 1,577, 1,542, 1,457, 1,352, 742, 593 cm-1
;
1H NMR (300 MHz, DMSO-d6): d = 2.17 (s, 3H), 5.99 (s,
1H), 6.86 (t, J = 7.0 Hz, 1H), 7.04–7.11 (m, 2H), 7.66 (s,
1H), 7.77 (d, J = 8.0 Hz, 1H) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 156.2, 138.2, 130.0, 126.9, 125.9, 121.9,
120.8, 17.9 ppm.
General procedure for the synthesis
of arylaminotetrazoles using ZnCl2/AlCl3/silica
A mixture of arylcyanamide 1a–1m (2 mmol), 0.2 g NaN3
(2, 3 mmol), and 0.09 g ZAS in 7 cm3 distilled DMF was
123

930
D. Habibi, M. Nasrollahzadeh
1,10-(1,4-Phenylene)bis(1H-tetrazol-5-amine)
(4k, C8H8N10)
3. Wittenberger SJ (1994) Org Prep Proced Int 26:499
4. Herr RJ (2002) Bioorg Med Chem 10:3379
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M.p.: 264–266 °C; FT-IR (KBr):v = 3,357, 3,139, 1,652,
1,588, 1,519, 1,426, 1,293, 1,141, 1,070, 843 cm-1; H
1
NMR (500 MHz, DMSO-d6): d = 7.03 (s, 4H), 7.83 (s,
4H) ppm; 13C NMR (125 MHz, DMSO-d6): d = 155.9,
134.6, 126.3 ppm.
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Longbottom DA, Nesi M, Scott JS, Storer RI, Taylor SJ (2000) J
Chem Soc Perkin Trans 1:3815
Catalyst reuse and stability
The reusability of the catalyst was tested in the synthesis of
5-(4-bromophenylamino)-1H-tetrazole. In a typical exper-
iment, after completion of the reaction, ZAS was isolated
from the reaction mixture by simple filtration and washed
with water and ethanol, followed by drying in an oven at
100 °C for 50 min. The recovered catalyst (98%) was
reused three times without any loss of activity (Table 1,
entry 4). This reusability demonstrates the high stability of
the catalyst under the operating conditions.
17. Gorte RJ (1999) Catal Lett 62:1
18. Habibi D, Nasrollahzadeh M, Faraji AR, Bayat Y (2010) Tetra-
hedron 66:3866
19. Habibi D, Nasrollahzadeh M (2010) Synth Commun 40:3159
20. Modarresi-Alam AR, Nasrollahzadeh M, Khamooshi F (2007)
Arkivoc (xvi):238
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Acknowledgments The authors gratefully acknowledge the finan-
cial support from the Bu-Ali Sina University, Hamedan 6517838683,
Iran.
22. Garbrecht WL, Herbst RM (1953) J Org Chem 18:1003
23. Modarresi-Alam AR, Nasrollahzadeh M (2009) Turk J Chem
33:267
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