Alkylation of 5-benzyltetrazole under microwave activation conditions

Full text of DOI:10.1007/s10593-008-0069-6

Chemistry of Heterocyclic Compounds, Vol. 44, No. 4, 2008
LETTERS TO THE EDITOR
ALKYLATION OF 5-BENZYL-
TETRAZOLE UNDER MICROWAVE
ACTIVATION CONDITIONS
J. A. Efimova, E. A. Mashkova, T. V. Artamonova, and G. I. Koldobskii
Keywords: 5-benzyltetrazole, 4-bromobenzyl bromide, microwave activation.
The alkylation of 5-substituted tetrazoles is a common method for obtaining 1,5- and 2,5-disubstituted
tetrazoles [1]. An important feature of this reaction is that the alkylation leads most often to a mixture of
isomeric disubstituted tetrazoles, whose separation is quite difficult.
In a continuation of a study of the methods for the preparation of functionally-substituted tetrazoles, we
studied the alkylation of 5-benzyltetrazole 1 using 4-bromobenzyl bromide 2 in acetonitrile and chloroform
under thermal and microwave activation conditions, assuming that the use of microwave activation would give
different regioselectivity for this reaction [2].
Br
MeCN
Br
H
N
N
+
Et3N
N
2
1
N
Br
+
N
N
N
N
N
N
N
Br
N
4
3
However, regardless of the nature of the solvent and reaction conditions, the ratio of the isomeric
tetrazole products 3 and 4 remained 1:1. On the other hand, the total yield of the isomeric tetrazoles and reaction
rate under microwave activation conditions proved much higher than upon thermal heating.
Upon thermal heating, the reaction requires 3 h at 75°C in acetonitrile to give a yield of 50% and 3 h at
60°C in chloroform to give a yield of 59%. Under microwave activation conditions, the reaction requires only
1 h at 75°C in acetonitrile with 74% yield and 1 h at 60°C in chloroform with 96% yield.
__________________________________________________________________________________________
St. Petersburg State Technological Institute (Technical University), St. Petersburg 190013, Russia;
e-mail: koldobsk@tu.spb.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 632-633,
April, 2008.
498
0009-3122/08/4404-0498©2008 Springer Science+Business Media, Inc.

Br
MeCN
Et3N
Br
H
N
+
N
N
2
1
N
Br
+
N
N
N
N
N
N
N
Br
N
4
3
The ratio of isomeric tetrazoles 3 and 4 was determined by 1H NMR spectroscopy by analyzing aliquots
taken from the reaction solution at the end of the alkylation. The ratios of the isomeric tetrazoles were obtained
as the arithmetic mean of three parallel measurements. The IR spectra were taken on a Shimadzu FTIR-8400S
1
spectrometer for KBr pellets. The H NMR spectra were taken on a Bruker WM-400 spectrometer at 400 MHz
in acetone-d6. The signal of the residual protons of the deuterated solvent at δ 2.00 ppm served as the internal
standard. The elemental analysis was carried out on a LECO CHNS(O)-932 analyzer. The reactions under
microwave activation conditions were carried out in a Milestone P/N 44072 reactor. The purity of the products
obtained was monitored by thin-layer chromatography on Silufol UV-254 plates using 2:3 ethyl
acetate−carbon tetrachloride as the eluent.
5-Benzyl-1-(4-bromobenzyl)tetrazole (3) and 5-benzyl-2-(4-bromobenzyl)tetrazole (4). 4-Bromo-
benzyl bromide (0.78 g, 3.1 mmol) and triethylamine (0.49 g, 4.1 mmol) were added to a solution
of 5-benzyltetrazole (0.5 g, 3.1 mmol) in acetonitrile (20 ml). The reaction mixture was stirred for 1 h at 75°C
under microwave activation conditions (90 W) and cooled to 10-15°C. Then, 50 ml water was added. The
crystalline precipitate was filtered off, washed with water, and dried in the air. The total yield of isomeric
tetrazoles 3 and 4 was 0.76 g (74%). The mixture of isomers was separated by fractional crystallization from
carbon tetrachloride.
5-Benzyl-1-(4-bromobenzyl)tetrazole (3). Mp 90°C (carbon tetrachloride). IR spectrum, ν, cm-1: 807,
1
852, 1013, 1071, 1120, 1197, 1229, 1277, 1411, 1454, 1503, 1593, 2851, 2924, 3034, 3064, 3090. H NMR
spectrum, δ, ppm (J, Hz): 4.35 (2H, s, C–CH2); 5.60 (2H, s, N–CH2); 7.06 (2H, d, J = 8.8, ArH); 7.16-7.27 (5H,
m, ArH); 7.45 (2H, d, J = 9.2, ArH). Found, %: C 54.72; H 3.99; N 17.06. C15H13BrN4. Calculated, %: C 54.71;
H 3.95; N 17.02.
5-benzyl-2-(4-bromobenzyl)tetrazole (4). mp 49°C (1:3 water−ethanol). IR spectrum, ν, cm-1: 799,
1
825, 1014, 1069, 1137, 1197, 1260, 1345, 1427, 1457, 1488, 1593, 2925, 2958, 2998, 3033, 3086. H NMR
spectrum, δ, ppm (J, Hz): 4.19 (2H, s, C–CH2); 5.83 (2H, s, N–CH2); 7.21-7.28 (5H, m, ArH); 7.31 (2H, d,
J = 7.6, ArH); 7.56 (2H, d, J = 9.2, ArH). Found, %: C 54.88; H 3.99; N, 17.00. C15H13BrN4. Calculated, %:
C 54.71; H, 3.95; N 17.02.
In the alkylation in chloroform, the solvent was removed in vacuum prior to separation of the products.
The alkylation of 5-benzyltetrazole 1 under thermal heating conditions was carried out analogously.
This work was carried out with the financial support of the Russian Fundamental Research Fund
(Grant 08-03-00342a).
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2.
G. I. Koldobskii, Zh. Org. Khim., 42, 487 (2006).
D. V. Kuznetsov, V. A. Raev, G. L. Kuranov, O. V. Arapov, and R. R. Kostikov, Zh. Org. Khim., 41,
1757 (2005).
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