Tetrazoles: LI. Synthesis of 5-substituted tetrazoles under microwave activation

Article abstract of DOI:10.1134/S107042800705020X

Reaction of nitriles with sodium azide in the presence of ZnCl₂ under microwave activation (MWA) leads to the formation of 5-tetrazoles in high yields; therewith the process is 2-3 times shorter than the inactivated reaction. Nauka/Interperiodica 2007.

Full text of DOI:10.1134/S107042800705020X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 5, pp. 765−767. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © L.V. Myznikov, J.Roh, T.V. Artamonova, A.Hrabalek, G.I. Koldobskii, 2007, published in Zhurnal Organicheskoi
Khimii, 2007, Vol. 43, No. 5, pp. 767−769.
Dedicated to Professor V.A.Ostrovskii on occasion of his sixtieth birthday
Tetrazoles: LI.* Synthesis of 5-Substituted Tetrazoles under
Microwave Activation
L. V. Myznikova, J. Rohb, T. V. Artamonovaa, A. Hrabalekb, and G. I. Koldobskiia
aSt. Petersburg State Technological Institute, St. Petersburg, 190013 Russia
e-mail: koldobsk@tu.spb.ru
bCharles University in Prague, Faculty of Pharmacy
Received December 10, 2006
Abstract—Reaction of nitriles with sodium azide in the presence of ZnCl2 under microwave activation (MWA)
leads to the formation of 5-tetrazoles in high yields; therewith the process is 2-3 times shorter than the inactivated
reaction.
DOI: 10.1134/S107042800705020X
One of the most important goals of 5-substituted
tetrazoles chemistry is the search for new methods of
their preparation and the improvement of the known
procedures. This aim is first of all due to the application
of tetrazoles in the synthesis of pharmaceuticals widely
used in the treatment of cardiovascular diseases [2–4].
DMF considerably reduced the reaction time not
decreasing the yield of the final products [7–10]. The
synthesis of 5-substituted X tetrazoles in water in the
presence of ZnBr2 was also described, but the reaction
conditions were not mentioned [11, 12].
We found that nitriles of diverse structures reacted
with NaN3 in water in the presence of ZnCl2 under the
microwave irradiation to give in good yields 5-substituted
Till the middle of the previous century there were no
preferred methods among the numerous procedures
applied to the preparation of 5-substituted tetrazoles. The
situation changed in 1958 after Finnegan et al. publication
[5] on the synthesis in high yield of 5 substituted tetrazoles
at heating nitriles of diverse structure with sodium azide
in DMF in the presence of ammonium chloride. After-
wards the Finnegan method obtained universal recognition
and was widely applied to the preparation of versatile
5-substituted tetrazoles.
H
R
N
ZnCl2
RCN + NaN3
N
H2O, МВА
N
N
_
Iа If
I, R = PhCH2 (a), 4-MeOC6H4 (b), Ph (c), 4-BrC6H4 (d), 4-
NO2C6H4 (e), 2-pyridyl (f).
A considerable advancement in this direction was done
by Sharpless et al [6] who found that nitriles cleanly
reacted with sodium azide in water in the presence of
Lewis acids, ZnCl2 or ZnBr2. Under these conditions
the 5-substituted tetrazoles formed in high yield, and the
reaction in water was practically secure.
Reaction conditions and yields of 5-substituted tetrazoles
Ia–Ig
Microwave activation
Tetrazole
Yield, %
Temperature, °C
Time, h
Ia
Ib
Ic
Id
Ie
95
92
95
92
95
6
12
8
78
63
64
60
86
In this study we evaluated the opportunity of 5-sub-
stituted tetrazoles preparation in water under conditions
of microwave irradiation. It was formerly shown that
microwave activation in the synthesis of 5-substituted
tetrazoles in solvents like dimethoxyethane, dioxane, or
10
8
Ig
Ig
95
95
2
68
67
14
* For communication L, see [1].
765

MYZNIKOV et al.
766
tetrazoles (see the table). The essential fact is that the
reaction duration under microwave irradiation is 2-3 times
less than in the inactivated process.
in air. Yield 78%, mp 124°C (from water) [5]. 1H NMR
spectrum, δ, ppm: 4.20 s (2H CH2), 7.27–7.34 μ (5Harom).
Tetrazoles Ib–Ig were obtained in the same way.
Under similar conditions reacted aromatic dinitriles,
for instance, o-phthalodinitrile, and the corresponding
ditetrazole Ig formed in 67% yield (see the table).
5-(4-Methoxyphenyl)tetrazole (Ib), mp 228°C (from
2-propanol) [13]. 1H NMR spectrum, δ, ppm: 3.84 s
(3H, OCH3), 7.15 d (2Harom), 7.97 (2Harom).
The above should be supplemented with the informa-
tion that in some cases (tetrazoles Ia and Id) the reaction
was performed in a mixture H2O–1-BuOH, 40:1, in order
to increase the solubility of initial nitriles.
5-Phenyltetrazole (Ic), mp 215°C (from a mixture
ethanol–water, 1:2) [5]. 1H NMR spectrum, δ, ppm:
7.61–8.04 (5Harom).
5-(4-Bromophenyl)tetrazole (Id), mp 268–269°C
In continuation of the study on the methods of tetrazole
preparation we evaluated the opportunity of MWA
application to the synthesis of the 5-substituted tetrazoles
in the presence of ZnO. Recently this type catalyst was
used in an inactivated process by an example of nano-
crystalline ZnO [16].
1
(from 2-propanol) [13]. H NMR spectrum, δ, ppm: 7.78–
7.91 m (4Harom).
5-(4-Nitrophenyl)tetrazole (Ie), mp 219°C (from
1
ethanol) [14]. H NMR spectrum, δ, ppm: 8.27 d (2Harom),
8.42 d (2Harom).
5-(2-Pyridyl)tetrazole (If), a. mp 220–222°C (from
ethyl acetate) [15]. 1H NMR spectrum, δ, ppm: 7.59–
8.76 m (4Harom).
Our attempt to use as catalyst a commercially available
ZnO in reaction of 2-cyanopyridine with NaN3 in DMF
at the microwave irradiation was successful, and 5-(2-
pyridyl)tetrazole was obtained in 65% yield.
b. In 40 ml of DMF a mixture of 10 mmol of 2-cyano-
pyridine, 12 mmol of NaN3, and 10 mmol of ZnO was
stirred for 6 h at 120°C under conditions of microwave
activation. DMF was removed under a reduced pressure,
the residue was treated with H2O (30 ml), ZnO was filtered
off, the filtrate was acidified with concn. HCl to pH 6,
the separated precipitate was filtered off and dried in air.
Yield 65%, mp 220–222°C (from ethyl acetate).
Thus the application of MWAin the synthesis of 5-sub-
stituted tetrazoles permits successful application of widely
spread commercial ZnO instead of difficultly available
nanocrystalline substance.
In-depth analysis of the available experimental data
on application of the microwave activation in tetrazole
chemistry [17], including the findings of this study, permits
to make an important conclusion that the preparation of
5-substituted tetrazoles under the conditions of the
microwave irradiation is one of the most promising
procedures for the synthesis of these compounds.
1,2-Bis(5-tetrazolyl)benzene (Ig), mp 224–225°C
1
(from 2-propanol) [6]. H NMR spectrum, δ, ppm: 7.79–
8.08 m (4Harom).
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant
no. 06-03-032286a).
EXPERIMENTAL
REFERENCES
1H NMR spectra were registered on a spectrometer
Bruker WM-400 from solutions in DMSO-d6. Reactions
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P/N 44072. Commercial ZnO used corresponded to State
Russian Standard GOST 10262-73. The purity and
homogeneity of compounds obtained was checked by
TLC on Silufol plates, eluent ethyl acetate–CCl4, 2:3.
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