A simple, advantageous synthesis of 5-substituted 1 h -tetrazoles

Article abstract of DOI:10.1055/s-0029-1219150

An advantageous synthesis of 5-substituted 1H-tetrazoles has been developed by treatment of organic nitriles with NaN₃ in the presence of iodine or the heterogeneous catalyst, silica-supported sodium hydrogen sulfate (NaHSO₄SiO₂). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219150

LETTER
391
A Simple, Advantageous Synthesis of 5-Substituted 1H-Tetrazoles1
S
ynthesis of 5-Su
i
bstitute
s
d 1
H
-Tet
w
razoles anath Das,* Cheruku Ravindra Reddy, Duddukuri Nandan Kumar, Martha Krishnaiah, Ravirala Narender
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193198; E-mail: biswanathdas@yahoo.com
Received 16 October 2009
for aliphatic nitriles, 2-butanone9 was used at 75 °C; in all
cases, the conversion was complete within 2–18 h. Ali-
phatic and heteroaromatic nitriles generally required
shorter reaction times. Aromatic nitriles containing both
electron-donating and electron-withdrawing groups un-
derwent the conversion smoothly. The structures of the
Abstract: An advantageous synthesis of 5-substituted 1H-tetra-
zoles has been developed by treatment of organic nitriles with NaN3
in the presence of iodine or the heterogeneous catalyst, silica-
supported sodium hydrogen sulfate (NaHSO4·SiO2).
Key words: 5-substitued 1H-tetrazole, organic nitrile, NaN3,
NaHSO4·SiO2, [3+2] cycloaddition, heterogeneous conditions
1
products were confirmed by their spectroscopic (IR, H
and 13C NMR and MS) and analytical data.
The conversion proceeded well with sterically hindered
ortho-substituted aromatic and heteroaromatic nitriles
(Table 1, entries i and k), which is in contrast to reports
that such nitriles are difficult to convert into the corre-
sponding 5-substituted 1H-tetrazoles and that high tem-
peratures and long reaction times are required.5a The
biphenyl tetrazole 2i (entry i), which can conveniently be
prepared by following the present method, is frequently
found in angiotensin II antagonists such as losartan and
related compounds.10 An organic nitrile containing a ster-
ically bulky aryl group, such as 2-cyanonaphalene, also
afforded the tetrazole derivative in high yield (entry j). 2-
Chloronicotinonitrile, which is a very reactive substrate,
underwent the present conversion within 4.5 h to furnish
the product in 86% yield (entry k).
Tetrazoles have found important applications in pharma-
ceuticals as lipophilic spacers and carboxylic acid surro-
gates, in material sciences as specialty explosives and
information recording systems, and in coordination chem-
istry as ligands.2 They are also precursors of different
nitrogen-containing heterocycles.3 5-Substituted 1H-tet-
razoles are usually prepared through [3+2] cycloaddition
of organic nitriles and azides.4 However, earlier methods
have some drawbacks such as the use of toxic metals and
strong Lewis acids, drastic reaction conditions, and the in
situ formation of hydrazoic acid, which is toxic and explo-
sive. Sharpless and co-workers reported an improved pro-
cedure for the synthesis of 5-substituted 1H-tetrazoles
from the corresponding nitriles and NaN3 in the presence
of either a stoichiometric amount or 50 mol% of Zn(II)
salts in water.5 Subsequently, other improved methods for
the preparation of these compounds have been reported.6
In a continuation of our work7 on the development of
useful synthetic methodologies, we have observed that
organic nitriles, when treated with NaN3 in the pre-
sence of silica-supported sodium hydrogen sulfate
(NaHSO4.SiO2)8 or iodine, in DMF or 2-butanone under
reflux, afforded the corresponding 5-substituted 1H-tetra-
zoles in high yields (Scheme 1).
Methods for the preparation of haloalkyl tetrazoles are
limited,11 but the present procedure can be conveniently
utilized for the preparation of such compounds. Trichlo-
romethyl nitrile, being a bulky substrate, underwent con-
version at 75 °C in 3 h to afford the desired product in
75% yield (entry m). It has been reported that when car-
bonyl groups are present in the substrate in addition to the
nitrile, is often difficult to keep the former intact during
the conversion into tertazoles.7a,12 However, by using the
present method, 4-formyl benzonitrile produced only the
expected 5-substituted 1H-tetrazole, with the carbonyl
group remaining unaffected (entry g).
The catalyst, NaHSO4·SiO2 can easily be prepared8 from
readily available starting materials, and can be easily re-
moved from the reaction mixture by filtration. In the ab-
sence of catalyst, or only in the presence of silica gel, the
reaction did not proceed, although the products were ob-
tained in low yields with NaHSO4. The yields of the prod-
ucts using either catalyst are comparable.13 Although
NaHSO4·SiO2 acts as a week Brønsted acid and I2 is a
Lewis acid, both catalysts can polarize the C≡N bond of
organic nitriles, thus facilitating their [3+2] cycloaddition
with sodium azide to form the tetrazole derivatives.
Using this methodology, a series of 5-substituted 1H-
tetrazoles was prepared from various organic nitriles (ar-
omatic, heteroaromatic and aliphatic; see Table 1). For ar-
omatic and heteroaromatic nitriles, DMF was used as
solvent and the reaction was conducted at 120 °C, while
NaHSO4⋅SiO2 or I2
DMF or 2-butanone
N
HN
NaN3
+
CN
R
N
120 °C or 75 °C
2–18 h
N
R
1
2
79–92%
Scheme 1
SYNLETT 2010, No. 3, pp 0391–0394
1
2.
0
2.
2
0
1
0
Advanced online publication: 22.12.2010
DOI: 10.1055/s-0029-1219150; Art ID: D29509ST
© Georg Thieme Verlag Stuttgart · New York

392
B. Das et al.
LETTER
Table 1 Synthesis of 5-Substituted 1H-Tetrazolesa
Entry
Substrate (1)
Product (2)
Conditionsb
Time (h)
Yield (%)c
N
HN
CN
A
B
10
10
91
89
N
a
N
N
HN
CN
N
A
B
10
10
88
85
b
c
N
Me
Me
N
HN
CN
N
A
B
10
10
89
88
N
Me
H2N
Cl
Me
N
HN
CN
N
A
B
10
10
79
80
d
e
f
N
H2N
N
HN
CN
A
B
10
10
82
81
N
N
Cl
N
HN
CN
N
A
B
10
10
91
87
N
O2N
OHC
O2N
N
HN
CN
N
A
B
10
10
83
85
g
N
OHC
MeO
N
HN
CN
N
A
B
10
10
92
91
N
h
MeO
O
O
Me
Me
A
B
12
12.5
91
90
i
N
HN
N
CN
N
N
N
HN
CN
A
B
10
9
81
83
N
j
N
HN
CN
N
A
B
4.5
6
86
84
k
l
N
N
Cl
N
Cl
H
A
B
18
18
79
74
N
CN
N
N
N
Synlett 2010, No. 3, 391–394 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Substituted 1H-Tetrazoles
393
Table 1 Synthesis of 5-Substituted 1H-Tetrazolesa (continued)
Entry
Substrate (1)
Product (2)
Conditionsb
Time (h)
Yield (%)c
H
Cl
C
D
3
4.5
75
77
Cl
Cl
Cl
N
m
N
N
CN
O
Cl
Cl
N
O
H
C
D
2
3.5
82
81
n
N
O
N
O
CN
N
N
a The structures of the products were confirmed from their spectroscopic (IR, 1H and 13C NMR and MS) and analytical data.
b Conditions A: Nitrile, NaN3 (1.5 equiv), NaHSO4·SiO2 (45 g per mol of nitrile), DMF, 120 °C. Conditions B: Nitrile, NaN3 (1.5 equiv), I2 (15
g per mol of nitrile), DMF, 120 °C. Conditions C: Nitrile, NaN3 (1.5 equiv), NaHSO4·SiO2 (45 g per mol of nitrile), 2-butanone, 75 °C. Condi-
tions D: Nitrile, NaN3 (1.5 equiv), I2 (15 g per mol of nitrile), 2-butanone, 75 °C.
c Isolated yield after purification.
(7) (a) Das, B.; Satyalakshmi, G.; Suneel, K. Tetrahedron Lett.
2009, 50, 2770. (b) Das, B.; Balasubramanyam, P.;
Krishnaiah, M.; Veeranjaneyulu, B.; Reddy, G. C. J. Org.
Chem. 2009, 74, 4393. (c) Das, B.; Damodar, K.; Bhunia, N.
J. Org. Chem. 2009, 74, 5607.
In conclusion, we have developed a convenient and highly
advantageous synthesis of 5-substituted 1H-tetrazoles.
The valuable features of this method include the avoid-
ance of toxic metal derivatives and explosive hydrazoic
acid, and its general applicability; the approach can be
used to convert aryl, heteroaryl and alkyl nitriles, sterical-
ly hindered ortho-substituted aryl nitriles, organic nitriles
containing bulky aryl groups, chloroalkyl nitriles and or-
ganic nitriles containing a carbonyl group.
(8) Breton, G. W. J. Org. Chem. 1997, 62, 8952.
(9) (a) Ahn, S.; Reddy, J. P.; Kariuki, B. M.; Chatarjee, S.;
Ranganathan, A.; Pedireddy, V. R.; Rao, C. N. R.; Harris,
K. D. M. Chem. Eur. J. 2005, 11, 2433. (b) Devender, T.;
Bharathi, D. V.; Manikyamba, P. Indian J. Chem., Sect. A
2008, 47, 863.
(10) La Bourdonnec, B.; Meulon, E.; Yous, S.; Goossens, J.-F.;
Houssin, R.; Henichart, J.-P. J. Med. Chem. 2000, 43, 2685.
(11) Matthews, D. P.; Green, J. E.; Shuker, A. J. J. Comb. Chem.
2000, 2, 19.
Acknowledgment
The authors thank CSIR and UGC, New Delhi for financial assi-
stance.
(12) Nishiyama, K.; Yamaguchi, T. Synthesis 1988, 106.
(13) Typical experimental procedure using NaHSO4·SiO2: To
a mixture of benzonitrile (2.0 mmol) and NaN3 (3.0 mmol)
in DMF (5 mL), NaHSO4·SiO2 (0.09 g) was added. The
mixture was stirred at 120 °C for 10 h until the reaction was
complete (reaction monitored by TLC). The catalyst was
removed by filtration and washed with EtOAc (2 × 5 mL).
The filtrate was treated with EtOAc (30 mL) and 4 M HCl
(20 mL) and stirred vigorously. The organic layer was
separated and the aqueous layer was extracted with EtOAc
(2 × 10 mL). The combined organic extracts were washed
with H2O (2 × 10 mL) and concentrated. The crude product
was subjected to column chromatography (silica gel;
hexane–EtOAc) to obtain pure 5-phenyl tetrazole (91%).
Typical experimental procedure using I2: To a mixture of
benzonitrile (2.0 mmol) and NaN3 (3.0 mmol) in DMF
(5 mL), I2 (0.03 g) was added and the mixture was stirred at
120 °C. After completion of the reaction (10 h), the mixture
was treated with EtOAc (30 mL) and 4 M HCl (20 mL) and
stirred vigorously. The organic layer was separated and the
aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic portion was washed with saturated
sodium thiosulfate solution (2 × 10 mL) and H2O
References and Notes
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7945. (b) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4,
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(2 × 10 mL) and subsequently concentrated. The residue
was purified by column chromatography (silica gel; hexane–
EtOAc) to afford pure 5-phenyl tetrazole (89%).
Spectroscopic data of representative novel compounds: 2c:
IR: 3442, 1598, 1563,1484, 1411 cm–1; 1H NMR (200 MHz,
DMSO-d6): d = 7.91 (1 H, br s), 7.84 (1 H, d, J = 8.0 Hz),
7.40 (1 H, t, J = 8.0 Hz), 7.30 (1 H, d, J = 8.0 Hz), 2.45 (3 H,
s); 13C NMR (50 MHz, DMSO-d6): d = 155.7, 138.6, 131.1,
128.2, 127.4, 123.8, 20.2; MS (ESI): m/z = 161 [M + H]+;
HRMS (ESI): m/z [M + H]+ calcd for C8H9N4: 161.0827;
found: 161.0830. 2d: IR: 3477, 1663, 1603, 1515, 1317 cm–1;
Synlett 2010, No. 3, 391–394 © Thieme Stuttgart · New York

394
B. Das et al.
LETTER
1H NMR (200 MHz, DMSO-d6): d = 7.30 (2 H, d, J = 8.0
Hz), 6.62 (2 H, d, J = 8.0 Hz), 5.43 (2 H, br s); 13C NMR (50
MHz, DMSO-d6): d = 157.6, 151.2, 132.1, 119.0, 112.2; MS
(ESI): m/z = 162 [M + H]+; Anal. Calcd for C7H7N5: C,
52.17; H, 4.35; N, 3.11. Found: C, 52.28; H, 4.29; N, 3.17.
2h: IR: 3507, 1709, 1564, 1431, 1286 cm–1; 1H NMR (200
MHz, DMSO-d6): d = 8.20 (2 H, d, J = 8.0 Hz), 8.11 (2 H, d,
J = 8.0 Hz), 3.91 (3 H, s); 13C NMR (50 MHz, DMSO-d6):
d = 155.8, 132.2, 131.2, 130.0, 129.1, 126.3, 51.4; MS (ESI):
m/z = 205 [M + H]+; HRMS (ESI): m/z [M + H]+ calcd for
C9H9N4O2: 205.0725; found: 205.0735. 2k: IR: 3453, 1628,
1527, 1482 cm–1; 1H NMR (200 MHz, DMSO-d6): d = 9.42
(1 H, d, J = 8.0 Hz), 8.41 (1 H, d, J = 8.0 Hz), 7.56 (1 H, t,
J = 8.0 Hz); 13C NMR (50 MHz, DMSO-d6): d = 155.8,
147.1, 140.6, 131.0, 128.2, 127.1; MS (ESI): m/z = 182, 183
[M + H]+; Anal. Calcd for C6H4ClN5: C, 39.67; H, 2.20; N,
38.57. Found: C, 39.78; H, 2.14; N, 38.63. 2n: IR: 3426,
1648, 1237 cm–1; 1H NMR (200 MHz, DMSO-d6): d = 10.46
(1 H, br s), 4.50 (2 H, q, J = 7.0 Hz), 1.42 (3 H, t, J = 7.0
Hz); 13C NMR (50 MHz, DMSO-d6): d = 157.1, 151.6, 54.6,
14.8; MS (ESI): m/z = 143 [M + H]+; Anal. Calcd for
C4H6N4O2: C, 33.80; H, 4.23; N, 39.44. Found: C, 33.91; H,
4.28; N, 39.37.
Synlett 2010, No. 3, 391–394 © Thieme Stuttgart · New York

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