Glycerol mediated synthesis of 5-substituted 1H-tetrazole under catalyst free conditions

Article abstract of DOI:10.1016/j.cclet.2011.11.019

We have developed simple, cost effective and environmentally benign protocol for the synthesis of 5-substituted 1H-tetrazoles via [2,3] cycloaddition reaction from organic nitriles and sodium azide in glycerol under catalyst free condition. The corresponding 5-substituted 1H-tetrazoles were obtained with good to excellent yields (68-95%).

Full text of DOI:10.1016/j.cclet.2011.11.019

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 161–164
www.elsevier.com/locate/cclet
Glycerol mediated synthesis of 5-substituted 1H-tetrazole under
catalyst free conditions
Kamalakar P. Nandre a, Jagdish K. Salunke a, Jitendra P. Nandre a, Vijay S. Patil a,
Amul U. Borse b, Sidhanath V. Bhosale a,
*
a Department of Organic Chemistry, North Maharashtra University, Jalgaon 425001, India
b School of Chemical Sciences, North Maharashtra University, Jalgaon 425001, India
Received 24 August 2011
Available online 23 December 2011
Abstract
We have developed simple, cost effective and environmentally benign protocol for the synthesis of 5-substituted 1H-tetrazoles
via [2,3] cycloaddition reaction from organic nitriles and sodium azide in glycerol under catalyst free condition. The corresponding
5-substituted 1H-tetrazoles were obtained with good to excellent yields (68–95%).
# 2011 Sidhanath V. Bhosale. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 5-Substituted 1H-tetrazole; [3+2] Cycloaddition; Nitriles; Glycerol; Catalyst free
Today’s stringent environmental and legislative concerns demand for the greener methods that reduce the use of
toxic and corrosive reagents and stop the stoichiometric formation of inorganic waste [1]. However, it has been also
observed that the catalysts employed are not always ecofriendly and because this serious environmental pollution
often results. Therefore, in the area of green synthesis, design of catalyst free reactions is an important goal for
chemists [2]. In this regard, the use of glycerol in portfolio of available green solvents as a reaction solvent has
attracted great attention in the recent past and has become an active area of research in green chemistry [3].
In medicinal chemistry, tetrazoles a metabolically stable surrogate are often encountered as a bioisosteres [4] of
carboxylic acids in biologically active molecules [5]. Literature survey reveals that tetrazoles have valuable properties
as precursors of a variety of nitrogen-containing heterocycles [6]. They also have been used in wide range of
applications in material sciences [7], pharmaceuticals [8], and synthesis of non-covalent complexes [9]. A tetrazole
moiety has greater synthetic interest, prepared via [3+2] cycloaddition reaction starting from nitrile and sodium azide.
Various synthetic approaches have been disclosed for this transformation [10–13]. In last decade, Sharpless introduced
the term ‘‘click chemistry’’ for synthesis of tetrazoles in water requiring stoichiometric amount of Zn(II) salts [14]. But
in this case aromatic nitriles usually require mixed solvent system due to less solubility in water. Thus, there is great
need to develop the environmental friendly process.
Herein, we report for the first time glycerol as a greener promising medium for preparation of 5-substituted 1H-
tetrazoles in good to excellent yields (68–95%, Table 2) under catalyst free conditions. In typical experiment
* Corresponding author.
E-mail address: sidhanath2003@yahoo.co.in (S.V. Bhosale).
1001-8417/$ – see front matter # 2011 Sidhanath V. Bhosale. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.11.019

162
K.P. Nandre et al. / Chinese Chemical Letters 23 (2012) 161–164
CN
N
N
N
NaN3
Conditions
N
H
1a
2a
Scheme 1.
N
NaN ,
CN
Glycerol
o
3
n
HN
n
N
N
110 C
R
R
n= 0, 1
R= H, Me, OMe, NO , halides
2
Scheme 2.
benzonitrile (1a) reacts with sodium azide in the presence of glycerol giving corresponding tetrazole (2a) in 94% yield
(Scheme 1).
1. Experimental
1
All reagents were purchased from commercial suppliers and used without further purification. H NMR spectra
were recorded on 400 MHz spectrometer and were expressed in ppm downfield from TMS as internal standard, MS
analysis was carried out under ESI mode or LCMS spectrometer and IR spectra were recorded on Shimadzu model FT-
IR spectrometer (KBr pellets). Melting points were determined by open-end capillary tubes method and are
uncorrected. The products were purified by recrystallization using ethanol or hexane/ethyl acetate mixture.
2. Results and discussion
To improve the ecocompatibility of organic processes, among the several solvents were examined at variable
temperature listed in Table 1 under catalyst free synthesis of tetrazole. Without any solvent, this reaction yielded to a
lesser extent (Table 1, entry 1). A small rate of cycloaddition reaction goes on increase on changing the solvent from
PEG-400 (Table 1, entry 5) to water (Table 1, entry 6) after a prolonged reaction time. With 50% aqueous glycerol
(Table 1, entry 7) and 50% DMF:glycerol (Table 1, entry 8), the reaction was still slow but yielded the single product.
This supports the importance of glycerol, which was significantly accelerated in commercial glycerol alone (Table 1,
Table 1
Screening of solvents at variable temperature.a
Entry
Solvent
Temp. (8C)
Time (h)
Yieldb (%)
1
2
No solvent
DMF
90
120
120
120
90
24
24
24
20
48
48
24
10
02
04
18
18
18
<20
<20
Tracec
Tracec
27d
32d
68
3
DMSO
4
Dioxane
5
PEG-400
6
Water
100
100
120
110
160
90
7
Water:glycerol (1:1)
DMF:glycerol (1:1)
Glycerol
8
78
9
94
10
11
12
13
Glycerol
62
Water:methanol (1:1)
Isopropanol
Acetic acid
NR
NR
NR
85
90
a
Benzonitrile (1 mmol), NaN3 (1.2 mmol), solvent, catalyst free.
b
c
d
Yields of isolated pure product obtained by recrystallization in ethanol.
Product could not be isolated.
Incomplete conversion even after 48 h.

K.P. Nandre et al. / Chinese Chemical Letters 23 (2012) 161–164
163
entry 9). Thus, glycerol was identified as most efficient solvent for this transformation due to good solubility of both
organic nitriles as well as sodium azide at 110 8C. Most of the reactions completed in short reaction time with good to
excellent yield at 110 8C. Other aprotic solvents such as DMF, DMSO and dioxane lead to lower yields (Table 1,
entries 2–4), while protic solvents such as aq. methanol, isopropanol and acetic acid does not lead to expected product
(Table 1, entries 10–13).
These results prompted us to check the generality of this system to various nitriles (Scheme 2). As shown in Table 2,
substituted benzonitriles with electron-withdrawing (entries 2b, 2c) and electron-donating groups (entries 2d–2k)
were selectively converted into their corresponding tetrazoles in excellent yields. Benzyl nitriles were also cleanly
converted in to the corresponding tetrazoles in high yields (entries 2l–2n). But, the aliphatic nitriles do not proceed
in glycerol (entries 2o, 2p). Sterically hindered and Bulky nitrile also smoothly converted into their 5-substituted
Table 2
Synthesis of 5-substituted 1H-tetrazole in glycerol under catalyst free conditions.a
Entry
Substrate
Time (h)
2.0
Product
Yieldb (%)
94
CN
H
N
2a
N
N
N
CN
H
N
2b
2c
2d
1.0
1.0
1.5
95
N
N
O2N
NO2
O2N
CN
N
90c
89
H
N
N
N
N
NO2
CN
H
N
N
N
Br
Br
N
H
N
CN
CN
2e
2f
1.5
1.3
84
92
N
N
Cl
Cl
Cl
Cl
N
H
N
N
N
N
CN
H
N
2g
2h
2.0
3.5
78
91
N
N
F
F
N
CN
H
N
N
N
N
H3C
H3C
H3C
H3C
CN
2i
2j
3.0
4.6
92
H
N
N
N
N
78c
CN
H
N
N
N
H3C
MeO
H3C
NO2
N
NO2
H
CN
2k
2l
3.8
1.5
85
N
N
N
MeO
N
94c
H
N
N
N
CN
N
73c
68c
H
N
2m
2n
3.0
3.5
CN
N
N
N
H
CN
N
N
MeO
N
N
MeO
N
2o
2p
24
24
NR
NR
CN
HN
N
N
N
CN
HN
N
N
a
Benzonitrile (1 mmol), NaN3 (1.2 mmol), glycerol (20 mL), catalyst free, 110 8C.
Isolated yield.
b
c
Extractive workup.

164
K.P. Nandre et al. / Chinese Chemical Letters 23 (2012) 161–164
N
O
H
O
H
O
H
O
H
O
H
OH
δ
N
N
NaN3
1a
N
N
N
N
N
N
H
δ
N
HO
OH
2a
OH
Imidoyl azide
intermediate
Glycerol
Scheme 3.
1H-tetrazole (entry 2j). All sterically hindered and benzyl tetrazoles were obtained by extractive workup, while other
tetrazoles precipitated by aqueous HCl. In all cases products were isolated and characterized by IR, 1H NMR and MS.
Plausible mechanism for synthesis of 5-substituted 1H-tetrazole shown in Scheme 3. The intermediate imidoyl azide
[15] could be stabilized by several types of complexations and intramolecular hydrogen bonds of glycerol due to
presence of three oxygen basic centers which is responsible for enhancement of rate of the reaction.
3. Conclusion
To conclude, we have developed for the first time the use of glycerol in the synthesis of 5-substituted 1H-tetrazoles
under catalyst free condition. This method is applicable for aryl nitriles, benzyl nitriles and also for sterically hindered
nitriles. Short reaction time, good to excellent yields, safe process and simple workup make this method an attractive
and useful contribution to the present methodologies.
Acknowledgments
We are grateful for the financial support from Department of Atomic Energy – Board of Research in Nuclear
Sciences (DAE-BRNS) (No. 2009/37/39/BRNS/2268), Mumbai, India and North Maharashtra University, Jalgaon for
providing necessary facilities.
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