Efficient synthesis of 5-substituted 1H-tetrazoles catalysed by silver(I) bis(trifluoromethanesulfoyl)nimide

Article abstract of DOI:10.3184/174751915X14321416284581

An efficient method is developed for the synthesis of 5-substituted 1H-tetrazoles through the [3 + 2] cycloaddition reaction of nitriles with sodium azide using silver(I) bis(trifluoromethanesulfonyl)imide (AgNTf₂) as a catalyst. This procedure provides mild reaction conditions, short reaction times and high yields.

Full text of DOI:10.3184/174751915X14321416284581

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 JUNE, 321–323
RESEARCH PAPER 321
Efficient synthesis of 5-substituted 1H-tetrazoles catalysed by silver(I)
bis(trifluoromethanesulfoyl)nimide
Hongshe Wanga,b* and Weixing Zhaoa
aCollege of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, Shaanxi 721013, P. R. China
bState Key Laboratory of Explosion Science and Technology, Beijing Institute of Technology, Beijing 100081, P. R. China
An efficient method is developed for the synthesis of 5-substituted 1H-tetrazoles through the [3 + 2] cycloaddition reaction of nitriles with
sodium azide using silver(I) bis(trifluoromethanesulfonyl)imide (AgNTf2) as a catalyst. This procedure provides mild reaction conditions,
short reaction times and high yields.
Keywords: 5-substituted 1H-tetrazoles, silver bistrifluoromethanesulfonimide, nitriles, sodium azide
Tetrazoles are a class of heterocyclic compounds with a
wide range of applications in pharmaceuticals,1,2 energetic
materials,3,4 and coordination chemistry.5,6 Because of their
importance and usefulness, various synthetic methods have
been developed for the construction of tetrazole frameworks.
These include the reactions of nitriles with TMSN3,7,8
aldehydes with hydroxylamine and [bmim]N3,9 aldehydes with
acetohydroxamic acid and sodium azide10 and nitriles with
boron-azides.11 The [3+2] cycloaddition of nitriles with NaN3
is one of the most conventional pathways for the synthesis of
5-substituted 1H-tetrazoles. Sharpless and co-workers12 reported
an innovative procedure for the synthesis of tetrazoles by the
addition of nitriles to NaN3 using either a stoichiometric amount,
or 50 mol % of Zn(II) salts. Since then, many methods for the
synthesis of 5-substituted 1H-tetrazoles have been reported in
the presence of catalysts such as nanocrystalline ZnO,13 FeCl3–
SiO2,14 tungstates,15 Zn/Al hydrotalcite,16 NaHSO4·SiO2 or I2,17
ZnCl2,18 a terpyridine copper complex,19 AgNO3,20 TBAHS,21
4-(dimethylamino)pyridinium acetate,22 Ln(OTf)3-SiO2,23
B(C6F5)3,24 CAN/HY-zeolite25 and Yb(OTf)3·xH2O.26 Although
each of the above methods has its own merit, most of these are
associated with drawbacks such as long reaction times, high
reaction temperatures and the use of a large amount of catalysts.
In recent years, metal bis(trifluoromethanesulfonyl)imides
have been successfully used for the acetylation of phenols
and alcohols,27 [2+2] cycloadditions of siloxy alkynes with
carbonyl compounds,28 Friedel–Crafts acylation reactions,29
cycloisomerisation of 1,6-dienes30 and intermolecular
hydroamination of alkynes with anilines.31 However, many
metal bis(trifluoromethanesulfonyl)imides are not available
commercially and involve a high cost for their preparation and
therefore are not good contenders for general use. AgNTf2 is
commercially available and therefore better suited for catalytic
The reaction of benzonitrile with NaN3 was first examined
in the presence of various silver-based catalysts (Table 1). With
Ag2CO3, AgNO3 and AgOAc, compound 3a was produced in only
34, 25 and 30% yields, respectively. The reaction of benzonitrile
with NaN3 in DMF at 100oC in the presence of 10 mol% of AgNO3
was completed in 12 h affording the corresponding tetrazole 3a in
49% yield.20 With Ag2O and AgOTf, the desired product 3a was
isolated in 56 and 71% yields, respectively. Importantly, the best
yield (92%) was obtained in the presence of 5 mol% of AgNTf2.
The reaction was optimised for various reaction parameters
such as temperature, solvent, and catalyst loading. When the
reaction was carried out at room temperature, 3a was obtained in
only 8% yield (Table 2, entry 1). The effect of temperature on the
yield of product was monitored from 45 to 100oC (Table 2, entries
2–5). However, no further increase in the yield was obtained by
increasing the temperature from 85 to 100 C. Therefore, 85 C
was chosen as the optimum temperature for all further reactions.
The reaction afforded the corresponding product in a very
low yield in the absence of solvent (Table 3, entry 1). Among
the various solvents studied, toluene was found to be the most
effective solvent (Table 3, entries 2–5).
With respect to the catalyst loading, 5 mol % of AgNTf2 was
found to be optimal. The desired product 3a was isolated in lower
yield using a lower loading of AgNTf2 (Table 4, entries 1 and
2). However, no improvement was observed with 10 mol % of
AgNTf2 (Table 4, entry 4).
o
o
a
Table 1 Effect of catalysts on the reaction of benzonitrile with NaN3
Entry
Catalyst
Ag2CO3
AgNO3
AgOAc
Ag2O
Yield/%b
34
25
30
56
1
2
3
4
5
6
32
use. Previously, we have reported the use of Mg(NTf2)2 and
33
LiNTf2 as efficient catalysts for the organic reactions. In
AgOTf
AgNTf2
71
92
continuation of our work, we now report an efficient procedure
for the synthesis of 5-substituted 1H-tetrazoles from nitriles
with NaN3 in the presence of 5 mol% of AgNTf2 in toluene at
85 oC (Scheme 1).
o
a The reactions were performed in the presence of 5 mol% of catalyst in toluene at 85 C
for 3 h.
b Isolated yield.
a
Table 2 Effect of temperature on the reaction of benzonitrile with NaN3
H
R
N
Entry
Temperature/oC
Yield/%b
AgNTf2 (5 mol%)
Toluene, 85 oC
N
R-CN + NaN3
1
2
3
4
5
r.t.
45
60
85
100
8
N
N
33
61
92
92
1
2
3
Scheme 1 Synthesis of 5-substituted 1H-tetrazoles catalysed by AgNTf2.
* Correspondent. E-mail: hongshewang@126.com
a The reactions were performed in the presence of 5 mol% of AgNTf2 in toluene for 3 h.
b Isolated yield.

322 JOURNAL OF CHEMICAL RESEARCH 2015
a
Table 3 Effect of solvent on the reaction of benzonitrile with NaN3
Table 4 Effect of catalyst loading on the reaction of benzonitrile with
NaN3a
Entry
Solvent
None
CH3CN
DMF
DMSO
H2O
Toluene
Yield/%b
22
46
84
75
Entry
Catalyst/mol%
Yield/%b
20
41
92
92
1
2
3
4
5
6
1
2
3
4
1
3
5
10
26
92
a The reactions were performed in the presence of AgNTf2 in toluene at 85 oC for 3 h.
b Isolated yield.
a The reactions were performed in the presence of 5 mol% of AgNTf2 at 85 oC for 3 h.
b Isolated yield.
a
Table 5 Synthesis of 5-substituted 1H-tetrazoles catalysed by AgNTf2
M.p./oC
Entry
R
Product
Time/h
Yieldb/%
Found
Reported (lit.)
215–2167
258–26011
149–15019
234–2358
219–2217
231–2338
156–1577
248–2498
172–17421
151–15321
204–2057
239–2407
41–427
1
2
3
4
5
6
7
8
9
10
11
12
13
14
C6H5
4-ClC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3
3
3
92
93
84
90
96
87
88
90
81
78
96
92
86
84
214–216
256–258
149–151
234–236
218–220
231–233
157–159
248–250
173–174
152–154
202–204
236–238
42–44
3-BrC6H4
4-OHC6H4
4-NO2C6H4
4-MeOC6H4
3-MeOC6H4
4-MeC6H4
2-ClC6H4
2-MeC6H4
2-Furanyl
3-Pyridyl
CH3(CH2)3
Cyclopentyl
3
2.5
3.5
3
3
4
5
1
2
5
5
110–112
109–11121
15
3o
3p
3
4
94
257–259
190–192
256–25834
N
H
Cl
N
16
89
191–19335
OMe
a All reactions were conducted in the presence of 5 mol% of AgNTf2 in tolueneat 85 oC.
b Isolated yield.
To expand the efficiency and generality of this methodology,
additional reactions of NaN3 with a variety of nitriles (aromatic,
heteroaromatic, and aliphatic) were next attempted in the
presence of 5 mol% of AgNTf2 in toluene at 85 oC. The results
are summarised in Table 5. Treatment of NaN3 with aryl nitriles
including both electron-donating and electron-withdrawing
groups on the aromatic ring provided the corresponding products
in high yields. Interestingly, either an electron-donating or an
electron-withdrawing substituent at a para- or a meta-position
does not have a significant influence on the product yield (Table
5, entries 2–8). Introduction of either an electron-donating
or an electron-withdrawing group at position 2 gave good to
moderate yields, perhaps due to steric effects (Table 5, entries
9 and 10). The heterocyclic based tetrazoles were formed in
shorter reaction times with excellent yields (Table 5, entries 11
and 12). The reaction of NaN3 with aliphatic nitriles furnished
the desired tetrazoles in high yields, but longer reaction times
were needed (Table 5, entries 13 and 14). The reactions were
completed in 3 or 4 h affording the corresponding tetrazoles 3o
and 3p in 94% and 89% yields, respectively (Table 5, entries 15
and 16).
In conclusion, AgNTf2 was found to be a highly efficient
catalyst for the synthesis of 5-substituted 1H-tetrazoles from
nitriles with NaN3. The advantages of this protocol include high
yields, short reaction times, low reaction temperatures and the
use of a catalytic amount and commercially available catalyst.
Experimental
Melting points were determined on an XT4A electrothermal apparatus
equipped with a microscope and are uncorrected. NMR spectra
were recorded on a Bruker Avance 400 spectrometer for solutions
in DMSO-d6. IR spectra were recorded on a Nicolet FTIR-750
spectrometer. Elemental analyses were performed on a PerkinElmer
240-C instrument. All solvents were dried by standard procedures.
Synthesis of 7-chloro-1H-indole-3-carbonitrile
A mixture of 7-chloro-1H-indole-3-carboxaldehyde36 (3.6 g, 20 mmol),
hydroxylamine hydrochloride (1.40 g, 20 mmol), sodium acetate (1.60 g,
20 mmol), glacial acetic acid (63 g, 60 mL) and acetic anhydride (2.2 g,
2 mL) was placed in a round bottomed flask and heated under reflux for
4 h. Then the reaction mixture was cooled and poured into ice water.
The resulting precipitate was filtered, washed with water, dried and
recrystallised from methanol to give the pure product 7-chloro-1H-

JOURNAL OF CHEMICAL RESEARCH 2015 323
1
indole-3-carbonitrile (3.1 g, 88% yield): m.p. 180–182 oC. H NMR
This work was financially supported by the Project of State Key
Laboratory of Explosion Science and Technology (No. KFJJ12-
13M) and the Science Research Foundation of Baoji University
of Arts and Sciences (No. ZK14008).
(DMSO-d6, 400 MHz) δ 7.19–7.35 (m, 2H), 7.58–7.64 (m, 1H), 8.32 (d,
J = 5.0 Hz, 1H), 12.61 (s, 1H). 13C NMR (DMSO-d6, 100 MHz) δ 113.5,
115.7, 118.3, 119.6, 120.1, 122.2, 123.4, 127.9, 137.4. IR (KBr) nmax/cm-1
3272, 3124, 2240, 1583, 1441, 1352, 1300, 1211.
Received 16 March 2015; accepted 17 May 2015
Paper 1503251 doi: 10.3184/174751915X14321416284581
Published online: 4 June 2015
Synthesis of 1-(4-methoxyphenyl)pyrrole-2-carbonitrile
A mixture of 4-methoxyaniline (2.50 g, 20 mmol), 2,5-dimethoxy-
tetrahydrofuran (3.20 g, 24 mmol) and bismuth(III) nitrate
pentahydrate (0.6 g ) was placed in a three-necked flask in a microwave
oven equipped with a temperature sensor and a reflux condenser.
Then the mixture was irradiated for 10 min (300W) at 90 oC. After
completion of the reaction, the mixture was cooled and extracted with
diethyl ether (3 × 50 mL). The combined organic layers were dried
with anhydrous magnesium sulfate. The solvent was removed and the
crude product was purified by column chromatography on silica gel
using petroleum ether and acetone (10:1, v/v) as the eluent to give the
pure product 1-(4-methoxyphenyl)pyrrole (3.20 g, 93% yield): m.p.
108–112 oC (lit.37 104–108 oC).
Trimethylsilyl cyanide (4.50 g, 45 mmol) was added to a stirred
solution of phenyliodine bis(trifluoroacetate) (12.9 g, 30 mmol) and
BF3·Et2O (8.5 g, 60 mmol) in CH2Cl2 (15 mL) at room temperature.
After stirring for 30 min, 1-(4-methoxyphenyl)pyrrole (2.6 g,
15 mmol) was added in one portion, and the mixture was stirred for
additional 7 h under the same conditions whilst the reaction progress
was monitored by TLC. After the reaction was complete, saturated
aqueous sodium thiosulfate (80 mL) was added to the mixture. The
organic layer was separated, and the aqueous phase was extracted
with CH2Cl2. The combined extracts were dried with anhydrous
magnesium sulfate and evaporated to dryness. The crude product was
purified by column chromatography on silica gel using petroleum
ether and ethyl acetate (5:1, v/v) as the eluent to give the pure product
1-(4-methoxyphenyl)pyrrole-2-carbonitrile38 (1.1 g, 38% yield): m.p.
162–164 oC. 1H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 6.34 (t, J =3.0
Hz, 1H), 6.91–6.98 (m, 1H), 7.04 (d, J = 4.6 Hz, 1H), 7.18 (t, J = 3.9
Hz, 2H), 7.42–7.46 (m, 2H). 13C NMR (CDCl3, 100 MHz) δ 63.5, 104.4,
110.7, 113.6, 116.4, 116.8, 122.1, 126.0, 126.1, 127.2, 134.3, 160.4, 163.7.
IR (KBr) nmax/cm-1 3111, 2920, 2211, 1512.
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Synthesis of 5-substituted 1H-tetrazoles; general procedure
A mixture of the appropriate nitrile (1 mmol), NaN3 (1.5 mmol),
toluene (2 mL) and AgNTf2 (5 mol%) was placed in a round bottomed
flask and heated at 85 oC. The progress of the reaction was monitored
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