Indium triflate-catalyzed one-pot synthesis of 1-substituted-1H-1,2,3,4-tetrazoles under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2009.03.131

A simple, efficient, and general method has been developed for the synthesis of 1-substituted-1H-1,2,3,4-tetrazoles via a three-component condensation of amine, trimethyl orthoformate, and sodium azide in presence of a catalytic amount of indium triflate

Full text of DOI:10.1016/j.tetlet.2009.03.131

Tetrahedron Letters 50 (2009) 2668–2670
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Indium triflate-catalyzed one-pot synthesis of 1-substituted-1H-1,2,3,4-
tetrazoles under solvent-free conditions
*
*
Dhiman Kundu, Adinath Majee , Alakananda Hajra
Department of Chemistry, Visva-Bharati University, Santiniketan, West Bengal, 731 235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple, efficient, and general method has been developed for the synthesis of 1-substituted-1H-1,2,3,4-
tetrazoles via a three-component condensation of amine, trimethyl orthoformate, and sodium azide in
presence of a catalytic amount of indium triflate under solvent-free conditions. The reaction proceeds
smoothly to generate the corresponding 1-substituted tetrazoles in moderate to excellent yields under
heating.
Received 21 December 2008
Revised 10 March 2009
Accepted 17 March 2009
Available online 21 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indium triflate
1-Substituted-1H-1,2,3,4-tetrazoles
Three components, solvent-free
Cyclization
One-pot catalytic conversion of organic reactions with readily
available, non-toxic, and inexpensive reagents has attracted signif-
icant research interest in recent years. Multicomponent reactions
with atom-economy and the identification of catalytic procedures
that can be run under solvent-free conditions are ideal protocols
for the development of environmental-friendly and cost-advanta-
geous chemical processes.1 Tetrazoles have attracted considerable
interest in recent times because of their wide utility.2 Among them,
1-substituted tetrazoles have received much attention and have
been used in variety of synthetic and medicinal chemistry applica-
tions as well as in material science including propellants and
explosives.3 They are also regarded as biologically equivalent to
carboxylic acid group.4 Thus, synthesis of this heterocyclic nucleus
is of much current importance. The well-known procedure for the
synthesis of this heterocyclic nucleus is acid-catalyzed [3+2] cyclo-
addition between hydrazoic acid and isocyanide derivatives.5
However, one serious drawback of this reaction is the direct addi-
tion of large excess amounts of dangerous and harmful hydrazoic
acid. The other routes include the cyclization reaction of amines
or its hydrochloride salt with an orthocarboxylic acid ester and a
hydrazoic acid metal salt in the presence of acetic acid .6 Other
recent reported methods are acid-catalyzed cycloaddition between
isocyanides and trimethylsilyl azide, ytterbium triflate and acidic
ionic liquid-catalyzed cyclizations involving an amine, trimethyl
orthoformate, and sodium azide.7 Each of these reported methods
have one or more disadvantages such as the use of high boiling
solvents that are difficult to recover, toxic and explosive reagents,
harsh conditions, tedious work-up using volatile solvents, and spe-
cial efforts to prepare the catalyst. In view of these, the search for
finding a cost-effective, mild and simple selective protocol for the
synthesis of 1-substituted tetrazoles is still relevant.
In recent years, indium(III) compounds have evolved as mild
and water-tolerant Lewis acids imparting high regio-, stereo-,
and chemoselectivity in various organic transformations.8 Com-
pared to conventional Lewis acids, indium(III) compounds have
advantages of water stability, recyclability, and operational sim-
plicity. Particularly, indium triflate is found to be a more effective
catalyst than conventional Lewis acids in promoting various trans-
formations.9 Our own work also found indium(III) compounds to
be very efficient catalysts for two- and three-component coupling
reactions.10 We wish to report here another remarkable catalytic
activity of indium triflate for the one-pot condensation of sodium
azide, amines, and trimethyl orthoformate to 1-substituted tetra-
zoles under solvent-free conditions (Scheme 1).
The experimental procedure is very simple.11 Preliminary
experiments were carried out in order to determine the best reac-
tion conditions. The reaction of aniline (2 mmol), trimethyl
orthoformate (2.4 mmol), and sodium azide (2 mmol) was carried
N
N
In(OTf)3 (5 mol%)
CH(OMe)
R
NH2
NaN
+
3
3
+
100 oC
N
N
1
R
* Corresponding authors. Tel.: +91 3463 261526; fax: +91 3463 262728 (A.H.).
E-mail addresses: adinath.majee@visva-bharati.ac.in (A. Majee), alakananda.haj-
ra@visva-bharati.ac.in, ahajra75@yahoo.com (A. Hajra).
2
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.131

D. Kundu et al. / Tetrahedron Letters 50 (2009) 2668–2670
2669
Table 1
Effect of catalysts and solvents on the formation of tetrazole 2aa
Table 2
Synthesis of 1-substituted-1H-1,2,3,4-tetrazoles
Entry
Catalyst
Solvent
Time (h)
Yield of 2ab (%)
Entry
R
Products
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
InCl3
Zn(OTf)2
Zn(ClO4)2
Mg(ClO4)2
CH3CN
1,2-Dichloroethane
2-Methoxyethanol
Neat
Neat
Neat
Neat
Neat
2
2
2
2
4
4
4
4
85
82
72
90
65
75
60
72
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
2
90
92
88
89
90
85
84
80
80
82
78
75
81
85
75
80
70
4-MeC6H4
2,3-Me2C6H3
2-MeO-C6H4
2-ClC6H4
1.5
1.5
1.5
2
4-FC6H4
2
2-Cl-3-FC6H3
4-CO2Et-C6H4
3-NO2-C6H4
4-Vinylaniline
2-C5H4N
2.5
2.5
2.5
2
3
2.5
3
3.5
3.5
3.5
3.5
a
Conditions: Benzaldehyde (2.0 mmol), trimethyl orthoformate (2.4 mmol), and
sodium azide (2.0 mmol) in presence of a catalytic amount of catalyst (5 mol %) at
100 °C.
Furfurylamine
(S)-1-Phenylethylamine
C6H5CH2
b
Isolated yield.
nBu
Cyclohexyl
out in various solvents as well as neat in presence of different
catalysts.
The results reported in Table 1 revealed that In(OTf)3 (5 mol %)
was better suited to afford the tetrazole in excellent yield under
neat conditions at 100 °C (Table 1, entry 4).
tBu
a
Yields refer to those of pure isolated products fully characterized by spectral
and analytical data.
The use of other organic solvents afforded the desired product
in lower yields. Low conversions (60–72%) were obtained when
other Lewis acid catalysts such as InCl3, Zn(OTf)2, Zn(ClO4)2, and
Mg(ClO4)2 were employed. This method does not require any addi-
tives or anhydrous conditions and no precautions need to be taken
to exclude moisture from the reaction media.
After optimizing the reaction conditions, we next examined the
generality of this condition using trimethyl orthoformate, sodium
azide, and several amines. The results are summarized in Table 2.
Amines carrying different functional groups were subjected to
the coupling reactions and in all cases the desired product was ob-
tained in high yields. It was observed that under similar conditions,
a wide range of anilines containing electron-withdrawing as well
as electron-donating groups such as fluoro, chloro, methoxy,
methyl, ester, and nitro underwent condensation in short reaction
times with excellent isolated yields. The catalytic system also
worked well with heterocyclic amine such as 2-amino pyridine
and furfurylamine to generate the corresponding products with
good yields of 75% and 83% (entries 11 and 12). Even for ethyl ami-
no carboxylate, a good yield of the desired product (80%) was ob-
tained without observing the formation of the other side
products (entry 8). Encouraged by the above results, we continued
our task to explore the reactivity of different aliphatic amines with
trimethyl orthoformate and sodium azide under similar reaction
conditions. The catalytic system worked well with aliphatic amines
such as n-butylamine, cyclohexylamine, and tert-butylamine to
generate the corresponding products of 75%, 80%, and 70% (entries
15–17).
The reusability of the catalyst is an important benefit especially
for commercial applications. Thus, the recovery and reusability of
In(III) triflate were investigated. After completion, the reaction
mixture was diluted with cold water (5 mL) and extracted with
ethyl acetate (10 mL Â 3) to obtain the desired product. The cata-
lyst was recovered almost quantitatively after removal of water
under reduced pressure. The catalyst was used in the reaction
and it showed the same activity as a fresh catalyst without any loss
of its activity. After five recycles, the catalyst still had a high activ-
ity and gave the desired product in fairly good yield (83%, entry 3,
Table 2).
OMe
OMe
OMe
OMe
NHR
OMe
R NH2
-H
H
H
OMe
H
- OMe
OMe
OMe
MeO
In(OTf)3
In(OTf)3
A
- OMe
NHR
N3
N3
NHR
N3
NHR
NHR
OMe
NaN3
NHR
OMe
H
H
H
- OMe
H
H
MeO
In(OTf)3
B
-H
H
R
N
N
N
N
C N
Heat
N
R
N
N
C
2
Scheme 2. Proposed mechanism for the formation of tetrazole 2.

2670
D. Kundu et al. / Tetrahedron Letters 50 (2009) 2668–2670
2. Butler, R. N.. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
A proposed mechanism for the 1-substituted tetrazole-forming
W., Scriven, E. F. V., Eds.; Pergamon: Oxford, UK, 1996; Vol. 4.
3. (a) Brown, M. U.S. Patent 3,338,915, 1967; Chem. Abstr. 1968, 87299.; (b)
Ostrovskii, V. A.; Pevzner, M. S.; Kofmna, T. P.; Shcherbinin, M. B.; Tselinskii, I.
V. Targets Heterocycl. Syst. 1999, 3, 467; (c) Hiskey, M.; Chavez, D. E.; Naud, D.
L.; Son, S. F.; Berghout, H. L.; Bome, C. A. Proc. Int. Pyrotech. Semin. 2000, 27, 3;
(d) Burger, A. Prog. Drug Res. 1991, 37, 287; (e) Schelenz, T.; Schafer, W. J. Fuel
Prakt. Chem. 2000, 342, 91; (f) Ruelke, H.; Friedel, A.; Martin, E.; Kottke, K.;
Graefe, I.; Kuehmstedt, H. Pharmazie 1991, 46.
4. Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R. K. Prog. Med. Chem.
1980, 17, 151.
5. (a) Zimmerman, D. M.; Olofson, R. A. Tetrahedron Lett. 1969, 58, 5081; (b)
Fallon, F. G.; Herbst, R. M. J. Org. Chem. 1957, 22, 933.
reaction is shown in Scheme 2. It is clear from the sequence of
steps that the role of indium triflate is limited to activate methoxy
groups and to cleave C–O bonds to generate carbenium ions that
are resonance stabilized by neighboring hetero atom O or N, facil-
itating sequential nucleophilic displacements by amine and azide
anions. This would explain the formation of intermediates A and
B. Indium triflate-assisted elimination of methanol from B leads
to the proposed intermediate12 C which, upon cyclization yields
the final heterocycle 2.
In comparison with the Yb(OTf)3-catalyzed reaction7b (20 mol %
catalyst, 2-methoxyethanol as solvent), In(OTf)3 has three clear
advantages—it uses only 5 mol % of catalyst in a solvent-free reac-
tion that requires less reaction time and provides improved yield.
In summary, indium triflate was found to be a novel and highly
efficient Lewis acid catalyst for the synthesis of 1-substituted-1H-
1,2,3,4-tetrazoles via the condensation of amines, trimethyl ortho-
formate, and sodium azide. The significant advantages offered by
this method are: (i) solvent-free reaction, (ii) high yields, (iii) no
waste production, (iv) non-toxic metal catalyst, and (v) simple
operation. Another advantage of this method is its efficiency for
the high yield synthesis of tetrazoles from aliphatic amines. Fur-
ther studies on the application of the present methodology to the
synthesis of biologically active compounds are under investigation.
6. (a) Kamiya, T.; Saito, Y. U.S. Patent 3,767,667, 1973; (b) Litkei, G.; Patonay, T.;
Patonay-Peli, E.; Khilya, V. P. Pharmazie 1989, 44, 791.
7. (a) Jin, T.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 9435; (b) Su, W.;
Hong, Z.; Shan, W.; Zhang, X. Eur. J. Org. Chem. 2006, 2723; (c) Potewar, T. M.;
Siddiqui, S. A.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron Lett. 2007, 48, 1721.
8. (a) Loh, T. P.; Chua, G. L. Chem. Commun. 2006, 2739; (b) Chauhan, K. K.; Frost, C.
G. J. Chem. Soc., Perkin Trans. 1 2000, 3015; (c) Cintas, P. Synlett 1995, 1087; (d)
Podlech, J.; Maier, T. C. Synthesis 2003, 633; (e) Nair, V.; Ros, S.; Jayan, C. N.;
Pillai, B. S. Tetrahedron 2004, 60, 1959; (f) Ranu, B. C. Eur. J. Org. Chem. 2000,
2347; (g) Auge, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739; (h) Hoppe,
H. A. F.; Lloyd-Jones, G. C.; Murray, M.; Peakman, T. M.; Walsh, K. E. Angew.
Chem., Int. Ed. 1998, 37, 1545.
9. (a) Nakamura, M.; Endo, K.; Nakamura, E. Org. Lett. 2005, 7, 3279; (b) Ghosh, R.;
Maiti, S. J. Mol. Catal. A: Chem. 2007, 264, 2007.
10. (a) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529; (b) Ranu, B. C.;
Samanta, S.; Hajra, A. Synlett 2002, 987; (c) Ranu, B. C.; Hajra, A. J. Chem. Soc.,
Perkin Trans. 1 2001, 355; (d) Ranu, B. C.; Hajra, A. J. Chem. Soc., Perkin Trans. 1
2001, 2262; (e) Ranu, B. C.; Samanta, S.; Hajra, A. J. Org. Chem. 2001, 66, 7519;
(f) Ranu, B. C.; Hajra, A.; Jana, U. Tetrahedron Lett. 2002, 41, 531; (g) Ranu, B. C.;
Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270; (h) Ranu, B. C.; Hajra, A.; Jana, U.
Org. Lett. 1999, 1, 1141; (i) Ranu, B. C.; Majee, A. J. Chem. Soc., Chem. Commun.
1997, 1225.
Acknowledgments
11. Typical procedure for the synthesis of 1-(2,3-dimethylphenyl)-1H-1,2,3,4-tetrazole
A.H. is pleased to acknowledge the financial support from DST
(Grant No. SR/FTP/CS-107/2006). We are thankful to DST-FIST
and UGC-SAP. D.K. thanks CSIR for his fellowship. We also express
our sincere thanks to Professor B. C. Ranu, Department of Chemis-
try, Indian Association for the Cultivation of Science, for his advice
and constant encouragement.
(2c):
A
mixture of 2,3-dimethylaniline (242 mg, 2 mmol), trimethyl
orthoformate (255 mg, 2.4 mmol), and sodium azide (130 mg, 2 mmol) was
stirred in presence of indium triflate (56 mg, 5 mol %) at 100 °C for 1.5 h (TLC).
After completion, the reaction mixture was diluted with cold water (5 mL) and
extracted with ethyl acetate (10 mL Â 3). The combined organic layers were
washed with brine and dried over anhydrous Na2SO4. The residue was
concentrated and recrystallized from EtOAc–hexane (9:1) to afford the pure
product as a white solid (285 mg, 88%), mp 140–141 °C. IR:
m
= 2918, 2856,
1670, 1579, 1465, 1303 cmÀ1
;
1H NMR (300 MHz, CDCl3): d 8.03 (s, 1H), 7.13–
7.08 (m, 1H), 6.98–6.91 (m, 2H), 2.34 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz,
CDCl3): d 148.5, 143.8, 137.5, 127.5, 125.9, 125.1, 116.0, 20.4, 13.4. Anal. Calcd
for C9H10N4: C, 62.05; H, 5.79; N, 32.16. Found: C, 61.86; H, 5.61; N, 32.04.
12. Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc. 1958, 80, 3908.
References and notes
1. (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025; (b) Hobbs, H. R.; Thomas, N.
R. Chem. Rev. 2007, 107, 2786.