γ-Fe2O3: A magnetic separable catalyst for synthesis of 5-substituted 1H-tetrazoles from nitriles and sodium azide

Article abstract of DOI:10.1016/j.cclet.2010.05.003

An efficient route for the synthesis of 5-substituted 1H-tetrazole via [2+3] cycloaddition of nitriles and sodium azide is reported using γ-Fe₂O₃ nanoparticles as a magnetic separable catalyst. Under optimized conditions, the moderate to good yields (71-95%) can be obtained. The catalyst can be easily separated by a magnet and reused for several circles.

Full text of DOI:10.1016/j.cclet.2010.05.003

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 1029–1032
www.elsevier.com/locate/cclet
g-Fe2O3: A magnetic separable catalyst for synthesis
of 5-substituted 1H-tetrazoles from nitriles and sodium azide
*
Gang Qi , Yong Dai
Department of Chemistry and Biology, Yancheng Institute of Technology, Yancheng 224051, China
Received 15 December 2009
Abstract
An efficient route for the synthesis of 5-substituted 1H-tetrazole via [2+3] cycloaddition of nitriles and sodium azide is reported
using g-Fe2O3 nanoparticles as a magnetic separable catalyst. Under optimized conditions, the moderate to good yields (71–95%)
can be obtained. The catalyst can be easily separated by a magnet and reused for several circles.
# 2010 Gang Qi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: g-Fe2O3: Magnetic separable catalyst; Tetrazole; [2+3] Cycloaddition
Tetrazoles can be regarded as biologically equivalent to the carboxylic acid group and the research of tetrazoles is
currently under intensive focus mainly as a result of their wide range of applications [1] such as metabolically stable
surrogates for carboxylic acid [2] and isosteric replacements in drug design [3]. They can also function as ligands in
coordination chemistry [4] or information recording systems in material science [5]. The conventional methods of
synthesize tetrazoles has drawbacks including the use of Lewis acids or expensive and toxic metals [6]. The most
typical way for synthesis of tetrazoles is between nitriles and sodium azides [7]. This reaction can also be carried out
with TMS-N3 and TBAF instead of metal salts under the solvent-free condition [8], or in micellar media [9], and ionic
liquid [10]. Recently, Sharpless and co-workers reported a safe and convenient route for the synthesis of 5-substituted
1H-tetrazoles via [2+3] cycloaddition of sodium azide to the corresponding nitriles using stoichiometric amounts
Zn(II) salts [11]. After that, various homogeneous catalysts have been reported such as iron salts [12] and copper
complex [13] in organic solvent. Even though homogeneous catalyst exhibits excellent activity in the reaction, they
suffer from the disadvantage of incapable separation. As a result, several heterogeneous catalysts have been
developed, such as nanocrystalline ZnO [14], Zn/Al hydrotalcite [15], Zn hydroxyapatite [16] or Cu2O [17]. Our group
is also interesting in develop novel catalysts to prepare the tetrazoles with high yields in heterogeneous catalytic
system.
However, magnetic catalyst in preparation of tetrazoles has never been reported. Most of the catalysts in previous
work still have drawbacks such as uneasy separation of the reaction mixture, complicated synthesis methods, or
contain polluted metals as the catalytically active site. As a result, it is an challenging subject to find magnetic
* Corresponding author.
E-mail address: qigang@ycit.cn (G. Qi).
1001-8417/$ – see front matter # 2010 Gang Qi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.05.003

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G. Qi, Y. Dai / Chinese Chemical Letters 21 (2010) 1029–1032
Table 1
Screening of catalytic performance of g-Fe2O3 nanoparticlesa
[TD$INLE]
.
Entry
g-Fe2O3
Solvent
Yieldb (%)
TONc
1
2
0
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
H2O
0
0
0.1
0.2
0.5
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
62
2.48
1.62
0.68
1.28
1.66
1.50
Trace
1.60
0.98
1.60
1.12
3
81
4
85
5
64d
83e
75
6
7
8
Trace
9
NMP
DMF
DMF
DMF
80
10
11
12
49f
80h
56i
a
Reaction conditions: benzonitrile (2.5 mmol), g-Fe2O3 (0.2 g) and NaN3 (5.3 mmol) were stirred in 5 mL DMF for 36 h at 120 8C.
b
c
d
e
f
Isolated yield (average of two runs).
The formation of tetrazoles per unit catalyst.
Reacted for 24 h.
Reacted for 48 h.
Reacted at 100 8C.
Reaction at 130 8C.
Yield for the third use.
h
i
separable heterogeneous catalyst which is easy-prepared, environmentally friendly and of low cost for the synthesis of
5-substituted 1H-tetrazoles.
Herein, we reported that g-Fe2O3 nanoparticles can be an effective and magnetic separable catalyst of 5-substituted
1H-tetrazoles from nitriles and sodium azide in DMF.
The g-Fe2O3 nanoparticles were prepared according to the previous work with some modifications [18]. Briefly,
FeCl3Á6H2O and sodium acetate were dissolved in ethylene glycol containing PVP under magnetic stirring. The
obtained homogeneous yellow solution was transferred to a Teflon-lined stainless-steel autoclave and sealed to heat at
200 8C. The obtained black magnetite particles were washed with ethanol for four times and then calcined at 400 8C
for 2 h to prepare g-Fe2O3 nanoparticles. The XRD pattern is the same as the standard card of hematite.
Firstly, we optimized the amount of g-Fe2O3 catalyst, the solvent and the time required for the reaction and the
results including yields and turnover numbers (TON) were summarized in Table 1. Controlled experiment showed that
no reaction took place without g-Fe2O3 catalyst (Table 1, entry 1). 5-Phenyltetrazole can be produced with 81% yield
when 0.2 g g-Fe2O3 was added which is optimum amount (Table 1, entries 2–4). The increase amount of NaN3
improved the yield significantly (entries 2, 5, 6). The solvent has a profound influence on the yields (Table 1, entries 2,
7–9). DMF, DMSO and NMP are good solvent with 81, 75 and 80% yields respectively while DMF is more commonly
used as solvent under high temperatures. Water is not suitable for the reaction. The optimum reaction condition is 36 h
and 120 8C. Recyclability is important for industrial application of catalyst. The catalyst can be easily separated by a
magnet for further reuse and after reused for three times, the catalytic activity decreases to near 70% of the initial value
and exhibits good magnetism.
For comparison, different catalysts were investigated for synthesis of tetrazoles. a-Fe2O3 nanoparticles has
correspondingly the similar catalytic performance as g-Fe2O3 while it has no magnetic property which make it less
applicable in industrial production. Commercial a-Fe2O3 exhibits low activity according to its low BET surface area.
The synthesized Fe3O4 and Fe(OH)3 all gave lower yields than g-Fe2O3.
In order to get an insight into the effect of substrates on the yield of 5-substituted 1H-tetrazoles, various nitriles
were used as the starting materials and the results including yields, TON and turnover frequency (TOF) were listed in
Table 2. Among them, most of nitriles gave good yields over 80%. The 4-cyanopyridine as substrate gives the highest

G. Qi, Y. Dai / Chinese Chemical Letters 21 (2010) 1029–1032
1031
Table 2
Preparation of 5-substituted 1H-tetrazoles with various ironic catalystsa
[TD$INLE]
.
Entry
Catalystb
Yield (%)c
TONd
1
2
3
4
5
g-Fe2O3
a-Fe2O3
83
85
26
42
10
1.66
1.70
0.52
1.26
0.20
Commercial a-Fe2O3
Fe3O4
Fe(OH)3
a
Reaction conditions: benzonitrile (2.5 mmol), NaN3 (5.3 mmol), DMF (5 mL), reaction time 36 h, 120 8C.
Amount of Fe3+ used is equivalent to that of 0.2 g Fe2O3.
Isolated yields (average of two runs).
b
c
d
The formation of tetrazoles per unit catalyst.
yield 95%, while benzyl cyanide gives the lowest one 71% (Table 2, entries 8 and 10). In case of 2-chlorobenzonitrile,
75% yield was obtained which lower than 3-chloro and 4-chloro substituents (83 and 89%, respectively) because the
chloro group in the ortho-position hampered the tetrazole formation. Benzonitriles with different substituents in the
same para-position showed different reaction activity. The yields of the corresponding product were higher for
electron-donating groups than electron-withdrawing groups (entries 4, 5, 7) (Table 3).
Table 3
The synthesis of 5-substituted 1H-tetrazole with g-Fe2O3 under various substratesa
[TD$INLE]
.
Entry
Product
Yield (%)b
81
TONc
1.62
TOF (Â10À3 hÀ1 d
)
[TD$INLINE]
1
45.0
41.7
46.1
[TD$INLINE]
2
3
75
83
1.50
1.66
[TD$INLINE]
[TD$INLINE]
4
5
6
89
85
84
1.78
1.70
1.68
49.4
47.2
46.7
[TD$INLINE]
[TD$INLINE]
[TD$INLINE]
7
93
1.86
51.7

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G. Qi, Y. Dai / Chinese Chemical Letters 21 (2010) 1029–1032
Table 3 (Continued )
Entry
Product
Yield (%)b
71
TONc
1.42
TOF (Â10À3 hÀ1 d
)
[DT$INLE]
8
9
39.4
[DT$INLE]
92
95
1.84
1.90
51.1
[DT$INLE]
10
52.8
a
Reaction conditions: benzonitrile (2.5 mmol), NaN3 (5.3 mmol), g-Fe2O3 (0.2 g), DMF (5 mL), reaction time 36 h, 120 8C.
Isolated yields (average of two runs).
b
c
d
The formation of tetrazoles per unit catalyst.
Rate of the formation of tetrazoles per unit catalyst per unit time.
In conclusion, we have firstly reported that g-Fe2O3 nanoparticles can be an effective reusable heterogeneous
catalyst for the synthesis of 5-substituted 1H-tetrazole via [2+3] cycloaddition of nitriles and sodium azide with good
yields, TONs and TOFs. The catalyst shows good magnetic performance which can be easily separated from the
reaction mixture by a magnet. The catalyst is also easy-making, non-toxic and environmentally friendly which meet
the requirements of Green Chemistry that can be a promising alternative for widespread use in organic synthesis.
Acknowledgment
The authors thank the Jiangsu Province Foundation of Natural Science (No. BK2009678) for the financial support.
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