C
S. D. Guggilapu et al.
Letter
Synlett
methyl-1-phenyl-1H-pyrazole 4-oxime did not proceed
(entry 17), possibly due to the steric effects of the methyl
substituents in the ortho-positions of the substrate.
The synthesis of nitriles from oximes by using InCl3 has
been previously reported.21 However in this conversion, we
propose that nitrile formation does not occur as an initial
step. Instead, nucleophilic attack by the azide on the elec-
tron-deficient carbon atom occurs, followed by cycloaddi-
tion and elimination to afford the tetrazole. In this process,
the InCl3 serves as a Lewis acid, activating the C=N bond by
coordinating to the oxygen atom of the oxime. This might
facilitate the cycloaddition of NaN3 across the C=N bond
(Scheme 2).
present protocol include compatibility with many function-
al groups, use of a mild and an inexpensive catalyst, a sim-
ple experimental procedure, a low catalyst loading, and
high yields.
Acknowledgment
The authors thank the Department of Pharmaceuticals, Ministry of
Chemicals and Fertilizers (Government of India) for providing funds.
References and Notes
(1) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R. K.
Prog. Med. Chem. 1980, 17, 151.
(2) Butler, R. N. Comprehensive Heterocyclic Chemistry; Katritzky, A.
R.; Rees, C., Eds.; Pergamon: Oxford, 1996.
InCl3
OH
N
N
N
HO
N
H
N
N
O
InCl3
InCl3
(3) (a) Hallinan, E. A.; Tsymbalov, S.; Dorn, C. R.; Pitzele, B. S.;
Hansen, D. W. Jr. J. Med. Chem. 2002, 45, 1686. (b) Ford, R. E.;
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1986, 29, 538. (c) Vieira, E.; Huwyler, S.; Jolidon, S.; Knoflach, F.;
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Hrabálek, A.; Koldobskii, G. I. Chem. Heterocycl. Compd. (Engl.
Transl.) 2007, 43, 1.
H
N
N
N
Na
Na
H2O
H/H2O
N
N
N
InCl3
N
H
Scheme 2 Plausible mechanism for the InCl3-catalyzed synthesis of 5-
substituted 1H-tetrazoles
(5) (a) Kumar, C. N. S. S. P.; Parida, D. K.; Santhoshi, A.; Kota, A. K.;
Sridhar, B.; Rao, V. J. Med. Chem. Commun. 2011, 2, 486.
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K.; Itoh, K.; Kubo, K.; Kohara, Y.; Naka, T. J. Pharmacol. Exp. Ther.
1994, 268, 1540.
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M.; Keykha, H.; Nasrollahzadeh, M.; Bijanzadeh, H.-R.;
Kleinpeter, E. J. Mol. Struct. 2007, 841, 61.
We also compared the efficiency of InCl3 with other
Lewis acids such as SnCl4, FeCl3, ZnCl2, B(C6F5)3, and BF3·OEt2
for the synthesis of 5-phenyl-1H-tetrazole (Table 3). We
found that InCl3 was superior to other Lewis acids in terms
of the yield and reaction time.
Table 3 Comparative Study of Various Lewis Acids in the Synthesis of
5-Phenyl-1H-tetrazolea
(8) (a) Sarvary, A.; Maleki, A. Mol. Diversity 2015, 19, 189. (b) Roh,
J.; Vávrová, K.; Hrabálek, A. Eur. J. Org. Chem. 2012, 6101.
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J. Bioorg. Med. Chem. 2002, 10, 3379.
Entry
Lewis acid
Yieldb (%)
Time (h)
(9) (a) Wittenberger, S. J. Org. Prep. Proced. Int. 1994, 26, 499.
(b) Sarvary, A.; Maleki, A. RSC Adv. 2015, 5, 60938.
1
2
3
4
5
6
InCl3
90
32
25
45
–
15
24
24
24
24
24
SnCl4
(10) (a) Bosch, L.; Vilarrasa, J. Angew. Chem. Int. Ed. 2007, 46, 3926.
(b) Venkateshwarlu, G.; Premalatha, A.; Rajanna, K. C.;
Saiprakash, P. K. Synth. Commun. 2009, 39, 4479.
(c) Bonnamour, J.; Bolm, C. Chem. Eur. J. 2009, 15, 4543.
(11) (a) Vorona, S.; Artamonova, T.; Zevatskii, Y.; Myznikov, L. Syn-
thesis 2014, 46, 781. (b) Demko, Z. P.; Sharpless, K. B. J. Org.
Chem. 2001, 66, 7945. (c) Lakshmi, K.; Kumar, K. B. S.; Sridhar, C.
Adv. Synth. Catal. 2005, 347, 1212. (d) Bakunova, S. M.; Bakunov,
S. A.; Patrick, D. A.; Suresh Kumar, E. V. K.; Ohemeng, K. A.;
Bridges, A. S.; Wenzler, T.; Barszcz, T.; Kilgore Jones, S.;
Werbovetz, K. A.; Brun, R.; Tidwell, R. R. J. Med. Chem. 2009, 52,
2016.
FeCl3
ZnCl2
B(C6F5)3
BF3·OEt2
–
a Reaction conditions: benzaldoxime (1a; 1 mmol), NaN3 (1.5 mmol), Lewis
acid (3 mol%), DMF (5 mL), 120 °C.
b Isolated yield.
In summary, we have established a simple and efficient
protocol for the synthesis of 5-substituted 1H-tetrazoles by
using a range of aromatic oximes and NaN3 in the presence
of InCl3 as a Lewis acid catalyst.22 The advantages of the
(12) (a) Matthews, D. P.; Green, J. E.; Shuker, A. J. J. Comb. Chem.
2000, 2, 19. (b) Kumar, A.; Narayanan, R.; Shechter, H. J. Org.
Chem. 1996, 61, 4462.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D