Tetrazoles: LIV. Alkylation of 5-aryltetrazoles under microwave activation

Article abstract of DOI:10.1134/S1070428009050133

The application of microwave activation (MWA) to alkylation of 5-aryltetrazoles with dimethyl sulfate in organic solvents did not considerably affect the selectivity of the process compared to nonactivated procedure. A significant enhancement of the selec

Full text of DOI:10.1134/S1070428009050133

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 5, pp. 725−727. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © Yu.A. Efimova, T.V. Artamonova, G.I. Koldobskii, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 5,
pp. 740−742.
Tetrazoles: LIV.* Alkylation of 5-Aryltetrazoles
under Microwave Activation
Yu.A. Efimova, T.V.Artamonova, and G. I. Koldobskii
St. Petersburg State Technological Institute, St. Petersburg,190013 Russia
e-mail: koldobsk@lti-gti.spb.ru
Received September 24, 2008
Abstract—The application of microwave activation (MWA) to alkylation of 5-aryltetrazoles with dimethyl sulfate
in organic solvents did not considerably affect the selectivity of the process compared to nonactivated procedure.
A significant enhancement of the selectivity to the formation of N2-methyl-isomer occurred only in the alkylation
in the dimethyl sulfate solution.
DOI: 10.1134/S1070428009050133
One of the main procedures for preparation of 1- and
2-substituted tetrazoles consists in the alkylation of the
tetrazole and 5-substituted derivatives [2, 3]. In spite of
certain drawbacks inherent to this method, mainly the
low selectivity of the reaction, this preparation procedure
for 1- and 2-substituted tetrazoles still attracts the attention
of many researchers by the simplicity of the reaction
conditions and also by the opportunity of the employment
of functionally substituted alkylating agents.
validity of this assumption was also supported by the
recent data on the alkylation of 1,2,4-triazole [8, 9] and
acylation of 5-aryl(hetaryl)-tetrazoles with carboxylic
acids anhydrides under microwave irradiation [1].
Based on the above line of reasoning we investigated
the alkylation of a series of 5-aryltetrazoles with dimethyl
sulfate in chloroform under the microwave activation, and
we found that in all events in this process formed isomeric
1- and 2-methyl-5-aryltetrazoles.
The thorough analysis of the large experimental
material on the application of the microwave activation
in the organic synthesis [4–7] suggested that the alkylation
of the 5-substituted tetrazoles under the microwave
activation might affect the selectivity of the reaction. The
The ratio of isomeric tetrazoles was established from
the 1H NMR spectra. Inasmuch as the chemical shifts of
the methyl group protons in the spectra of 1- and 2-methyl-
5-aryltetrazoles are considerably different we calculated
the composition of the two-component mixtures without
the isolation of individual isomers.
Scheme 1.
These results were compared with the data obtained
by the alkylation of 5-aryltetrazole Ia–Ic under thermal
heating with respect to the isomers ratio F = N1/N2, where
N1 and N2 were the concentrations of 1- and 2-methyl-5-
aryltetrazoles respectively, and it was concluded that the
microwave irradiation insignificantly affected the
selectivity of the alkylation (Table 1).
RC6H4
NH
+
MeOSO3Me
N
N
N
Ia_Ic
RC6H4
Me
RC6H4
MBA
N
N
At the same time the effect of the nature of substituent
in the position 5 of the heterocycle on the isomers ratio is
clearly seen both in reactions under thermal heating and
microvwave activation. For instance, in the alkylation of
5-(4-methoxyphenyl)tetrazole under the microwave
activation the fraction of N2-isomer in the reaction product
+
Et3N, CHCl3
N
N
N
N
Me
N
N
R = 4-MeO (a), H (b), 4-Br (c).
* For communication LIII, see [1].
725

EFIMOVA et al.
726
It is presumable that these nontrivial results obtained
in this study for the alkylation of 5-aryltetrazoles under
the microwave activation are due mainly to the features
of this reaction mechanism. Thus it was shown formerly
[11] that the alkylation of 5-substituted tetrazoles proceed-
ed along a two-stage mechanism involving the formation
as a result of the electrophilic attack on a tetrazolide of
an unstable intermediate which subsequently decomposed
unimolecularly by two parallel routes giving isomeric 1-
and 2-methyltetrazoles.
increased, whereas for tetrazoles Ib and Ic the opposite
trend was observed.
In continuation of the study of this reaction we
investigated the alkylation of 5-phenyltetrazole with
dimethyl sulfate in such solvents as dibutyl ether, dioxane,
benzene, and toluene, and also when it was dissolved in
the alkylating agent since it was assumed [10] that the
microvwave irradiation was the most efficient when the
chemical reactions proceeded in nonpolar solvents or
without solvent.
At the same time it is obvious that the alkylation of
5-phenyltetrazole in a large excess of the alkylating agent
and in the absence of a base should proceed by another
mechanism. This circumstance was revealed in a sig-
nificant change of the isomers ratio in going from the
nonactivated to the activated process (Table 2).
It proved however that notwithstanding the nature of
the solvent in going from the nonactivated process to the
reaction under microwave activation the ratio of the
formed isomeric 1- and 2-methyl-5-phenyl-tetrazoles was
materially unchanged (Table 2).
At the same time in the alkylation of 5-phenyltetrazole
dissolved in the alkylating agent without addition of base
independent of the way of heating the reaction product
was significantly enriched with 1-methyl-5-phenyl-
tetrazole: therewith in going from the nonactivated process
to the reaction under microwave activation the isomers
ratio changed in favor of 2-methyl-5-phenyltetrazole
(Table 2).
EXPERIMENTAL
IR spectra were taken on a spectrophotometer
1
Shimadzu FTIR-8400S from KBr pellets, H NMR
spectra were registered on a spectrometer Bruker WM-
400 (400 MHz) from solutions in acetone-d6. The reactions
under the microwave activations were performed in
a reactor Milestone P/N 44072.
Finally the alkylation of 5-phenyltetrazole with dimethyl
sulfate in the presence of treiethylamine in a highly polar
solvent like acetonitrile resulted in the same ratio of
formed isomeric 1- and 2-methyl-5-phenyltetrazoles both
in the nonactivated and activated process (F 0.33).
The ratio of isomeric 1- and 2-methyl-5-aryltetrazoles
was measured by integration of the signals in the NMR
spectrum from protons of the methyl groups in the
Table 1. Alkylation of 5-aryltetrazoles Ia–Ic with dimethyl sulfate in chloroform, 4 h, 40°C
Thermal heating
Compound no.
MWA
Overall yield, %
Isomers ratio F
Overall yield, %
Isomers ratio F
Ia
Ib
Ic
71
65
62
0.4
72
70
59
0.37
0.44
0.23
0.35
0.21
Table 2. Alkylation of 5-phenyltetrazole with dimethyl sulfate in various media, 4 h, 40°C
Thermal heating
Solvent
MWA
Overall yield, %
Isomers ratio F
Overall yield, %
Isomers ratio F
Dibutyl ether
Dioxane
80
81
84
88
70
0.38
0.31
0.34
0.38
1.03
79
81
82
87
75
0.34
0.32
0.33
0.36
0.77
Benzene
Toluene
Dimethyl sulfatea
a 0.5 h, 40°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009

TETRAZOLES: LIV.
727
and dried in air. We isolated 0.25 g of 5-phenyltetrazole
(conversion 75%).
positions 1 and 2 of the ring. The value of the ratio was
taken as an average of three measurements.
5-Aryltetrazoles were obtained by known procedures
[12, 13]. The purity and homogeneity of 1- and 2-methyl-
5-aryltetrazoles was checked by TLC on Silufol UV-254
plates, eluent ethyl acetate–tetrachloromethane, 2:3, and
also by IR spectra and elemental analysis. Characteristics
of all compounds were consistent with the published data
[13].
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The alkylation was carried out by the same procedure
both at the thermal heating and under the microwave
activation.
a. Alkylation of 5-phenyltetrazole in chloroform.
A mixture of 6.8 mmol of 5-phenyltetrazole, 8.1 mmol of
dimethyl sulfate, and 8.1 mmol of triethylamine in 30 ml
of chloroform was vigorously stirred for 4 h at 40°C under
the microwave activation. The reactor was cooled to
20°C, chloroform was removed at a reduced pressure.
The solid residue was washed in succession with 10%
solution of NaOH (15 ml), with water (2 × 20 ml), dried
in air, and analyzed.
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b. Alkylation of 5-phenyltetrazole in dimethyl sulfate.
A mixture of 6.8 mmol of 5-phenyltetrazole and 105 mmol
of dimethyl sulfate was vigorously stirred for 0.5 h at
40°C under the microwave activation. The solution
obtained was cooled to 20°C, samples for analysis were
taken, 30 ml of H2O was added, and the stirring was
continued for 2 h at 50°C. The unreacted 5-phenyl-
tetrazole was filtered off, washed with water (2 × 20 ml),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 5 2009