Tetrazoles: XLVI. Alkylation of 5-substituted tetrazoles with methyl chloromethyl ether and α-methylstyrene

Article abstract of DOI:10.1023/B:RUJO.0000036078.84508.e8

Alkylation of 5-aryl(hetaryl)tetrazoles with methyl chloromethyl ether under conditions of phase-transfer catalysis leads to formation of isomeric 1- and 2-methoxymethyltetrazoles at a ratio of ~1:2. The reaction of 5-substituted tetrazoles with α-methylstyrene in the presence of trichloroacetic acid gives the corresponding 2-(α,α-dimethylbenzyl)tetrazoles in high yield and with high regioselectivity.

Full text of DOI:10.1023/B:RUJO.0000036078.84508.e8

Russian Journal of Organic Chemistry, Vol. 40, No. 4, 2004, pp. 551–554. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 4, 2004,
pp. 580–583.
Original Russian Text Copyright © 2004 by Myznikov, Artamonova, Koldobskii, Hrabalek.
Tetrazoles: XLVI.* Alkylation of 5-Substituted Tetrazoles
with Methyl Chloromethyl Ether and α-Methylstyrene
L. V. Myznikov1, T. V. Artamonova1, G. I. Koldobskii1, and A. Hrabalek2
1 St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 198013 Russia
e-mail: koldobsk@tu.spb.ru
2 Faculty of Pharmacy, Charles University in Prague, Czechia
e-mail: hrabalek@faf.cuni.cz
Received November 10, 2003
Abstract—Alkylation of 5-aryl(hetaryl)tetrazoles with methyl chloromethyl ether under conditions of phase-
transfer catalysis leads to formation of isomeric 1- and 2-methoxymethyltetrazoles at a ratio of ~1:2. The
reaction of 5-substituted tetrazoles with α-methylstyrene in the presence of trichloroacetic acid gives the
corresponding 2-(α,α-dimethylbenzyl)tetrazoles in high yield and with high regioselectivity.
In continuation of our studies on the synthesis
of 1,5- and 2,5-disubstituted tetrazoles, we examined
alkylation of a series of 5-substituted tetrazoles with
methyl chloromethyl ether and α-methylstyrene. It was
shown previously that analogous reaction between
tetrazole and benzyl chloromethyl ether gives a mix-
ture of isomeric 1- and 2-benzyloxymethyltetrazoles
at a ratio of ~1:1 [2–4]. On the other hand, the alkyla-
tion of 5-(4-methoxyphenyl)tetrazoles and 5-(2,3-di-
methoxyphenyl)tetrazole with α-methylstyrene occurs
exclusively at the 2-position of the heteroring [5]. In
the present work we found that the use of methyl
chloromethyl ether as alkylating agent instead of
benzyl chloromethyl ether considerably increases the
selectivity of the process: according to the NMR data,
regardless of the substituent in the 5-position, isomeric
1- and 2-methoxymethyltetrazoles are formed at a ratio
of ~1 : 2. The reactions were carried out in the two-
phase system chloroform–10% aqueous NaOH in the
presence of tetrabutylammonium bromide at 20°C.
Under these conditions, the reaction occurred at a high
rate, and the overall yield of isomeric 1- and
2-methoxymethyltetrazoles was 79–93% (Scheme 1).
We also found that heating of 1-methoxymethyl-
tetrazoles in methyl chloromethyl ether for 8–10 h at
85–90°C results in their isomerization into the more
stable 2-substituted isomer. Obviously, the isomeriza-
tion follows a scheme proposed in [6] (Scheme 2).
This mechanism is supported by the fact that the
isomerization of 1-methoxymethyltetrazoles into
2-methoxymethyltetrazoles occurs only in the presence
of methyl chloromethyl ether.
The isomerization can also be effected in one step
without preliminary isolation of 1-substituted isomer.
For this purpose, a mixture of isomeric 1- and
2-methoxymethyltetrazoles obtained by alkylation of
the corresponding 5-substituted tetrazole under condi-
tions of phase-transfer catalysis, should be heated in
methyl chloromethyl ether for 10 h at 90°C. In all
Scheme 1.
R
R
CH2OMe
R
CHCl3–aq. NaOH
Bu4NBr
N
N
N
MeOCH2Cl
+
+
N
NH
N
N
N
N
CH2OMe
N
N
N
Ia–Id
IIa–IId
R = Ph (a), 4-MeOC6H4 (b), 4-ClC6H4 (c), 2-pyridyl (d).
* For communication XLV, see [1].
1070-4280/04/4004-0551 © 2004 MAIK “Nauka/Interperiodica”

MYZNIKOV et al.
552
Scheme 2.
CH2OMe
R
CH2OMe
N
+
N
+
N
R
R
CH2OMe
Cl–
Cl–
N
N
MeOCH2Cl
+
N
N
N
N
N
N
N
MeOCH2
MeOCH2
R
N
N
MeOCH2Cl
+
N
CH2OMe
N
of chloroform was added, and the mixture was stirred
for 1 h at 20°C. The organic phase was separated,
washed with 10% aqueous sodium hydroxide (5 ml)
and water (2×10 ml), and dried over magnesium
sulfate. The solvent was removed under reduced
pressure, and the residue was subjected to column
chromatography on silica gel using petroleum ether–
ethyl acetate (5:1) as eluent. The product was addi-
tionally purified by recrystallization from petroleum
ether–ethyl acetate (10:1).
cases, even on prolonged heating of isomeric
N-methoxymethyltetrazoles, an equilibrium establishes.
This follows from the presence of a small amount
(~10%) of the 1-isomer.
The alkylation of 5-substituted tetrazoles with
α-methylstyrene in the presence of trichloroacetic acid
occurred strictly regioselectively, and the correspond-
ing 2-(α,α-dimethylbenzyl)tetrazoles were formed in
71–93% yield (Scheme 3).
1-Methoxymethyl-5-phenyltetrazole (Ia). Yield
0.7 g (26%), mp 42°C. IR spectrum, ν, cm –1: 920, 940,
980, 1030, 1050, 1100, 1185, 1215, 1340, 1385, 1410,
Scheme 3.
CH2
R
N
1
+
Me
1470, 1550, 2860, 2955, 3010. H NMR spectrum, δ,
N
NH
ppm: 3.49 s (3H, CH3), 5.65 s (2H, CH2), 7.4–7.6 m
(3H, Harom), 7.85–7.9 m (2H, Harom). Found, %:
C 56.83; H 5.45; N 29.38. C9H10N4O. Calculated, %:
C 56.84; H 5.26; N 29.47.
N
R
Me
N
N
N
N
Me
2-Methoxymethyl-5-phenyltetrazol (IIa). Yield
1.4 g (53%), colorless oily substance. IR spectrum, ν,
cm–1: 930, 1030, 1050, 1070, 1120, 1140, 1180, 1195,
1340, 1390, 1470, 1540, 2860, 2950. 1H NMR
spectrum, δ, ppm: 3.46 s (3H, CH3), 5.84 s (2H, CH2),
7.4–7.5 m (3H, Harom), 8.1–8.2 m (2H, Harom). Found,
%: C 56.93; H 5.21; N 29.34. C9H10N4O. Calculated,
%: C 56.84; H 5.26; N 29.47.
IIIa–IIId
R = Me (a), Ph (b), 4-ClC6H4 (c), 2-pyridyl (d).
These results, as well as the previously obtained
data [5, 7, 8], indicate that alkylation of tetrazoles
with unsaturated compounds in the presence of acid
catalysts provides a universal method of synthesis of
2-mono- and 2,5-disubstituted tetrazoles.
1-Methoxymethyl-5-(4-methoxyphenyl)tetrazole
(Ib). Yield 0.82 g (31%), mp 89–90°C. IR spectrum, ν,
cm–1: 850, 920, 1030, 1100, 1190, 1220, 1260, 1310,
1340, 1390, 1450, 1485, 1620, 2860, 2960, 3450.
1H NMR spectrum, δ, ppm: 3.54 s (3H, CH3), 3.87 s
(3H, CH3), 5.67 s (2H, CH2), 7.02–7.07 m (2H, Harom),
7.88–7.93 m (2H, Harom). Found, %: C 54.65; H 5.39;
N 25.49. C10H12N4O2. Calculated, %: C 54.55; H 5.45;
N 25.45.
EXPERIMENTAL
The IR spectra were recorded in KBr on a UR-20
spectrometer. The H NMR spectra were measured on
a Bruker AC-200 spectrometer in acetone-d6.
1
1- and 2-Methoxymethyl-5-phenyltetrazoles
Ia–Id and IIa–IId (general procedure). A mixture of
14 mmol of 5-substituted tetrazole, 2 mmol of tetra-
butylammonium bromide, 10 ml of 10% aqueous
NaOH, and 10 ml of chloroform was stirred for 5 h at
20°C, 20 mmol of methyl chloromethyl ether in 20 ml
2-Methoxymethyl-5-(4-methoxyphenyl)tetrazole
(IIb). Yield 1.67 g (63%), mp 45-47°C. IR spectrum,
ν, cm–1: 850, 920, 1040, 1110, 1190, 1260, 1300, 1310,
1
1340, 1400, 1470, 1620, 2850, 2970, 3440. H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004

TETRAZOLES: XLVI.
553
spectrum, δ, ppm: 3.49 s (3H, CH3), 3.87 s (3H, CH3),
5.86 s (2H, CH2), 6.9–7.03 m (2H, Harom), 8.09–814 m
(2H, Harom). Found, %: C 54.71; H 5.41; N 25.42.
C10H12N4O2. Calculated, %: C 54.55; H 5.45; N 25.45.
Isomerization of tetrazoles Ib and Ic was performed
in a similar way.
2-(α,α-Dimethylbenzyl)-5-methyltetrazole (IIIa).
A mixture of 12 mmol of 5-methyltetrazole and
35 mmol of trichloroacetic acid in 20 ml of chloroform
was stirred for 5 min at 20°C. A solution of 12 mmol
of α-methylstyrene in 10 ml of chloroform was added
over a period of 20 min to the resulting suspension,
and the mixture was stirred for 6 h at 20°C. It was then
cooled to 10°C, 20 ml of 10% aqueous sodium
hydroxide and 30 ml of ethyl acetate were added, the
mixture was stirred for 0.5 h, and the organic phase
was separated, washed with water (2×30 ml), and
dried over magnesium sulfate. The solvent was
removed under reduced pressure to obtain compound
IIIa as a colorless oily substance. Yield 1.99 g (82%).
IR spectrum, ν, cm–1: 1040, 1085, 1110, 1170, 1195,
1260, 1310, 1380, 1400, 1450, 1510, 2870, 2950,
5-(4-Chlorophenyl)-1-methoxymethyltetrazole
(Ic). Yield 0.84 g (27%), mp 83°C. IR spectrum, ν,
cm–1: 920, 1005, 1020, 1330, 1420, 1470, 1610, 2850,
1
2970. H NMR spectrum, δ, ppm: 3.51 s (3H, CH3),
5.84 s (2H, CH2), 7.4–7.5 m (3H, Harom), 8.1–8.2 m
(2H, Harom). Found, %: C 48.31; H 4.07; N 25.10.
C9H9ClN4O. Calculated, %: C 48.11; H 4.01; N 24.94.
5-(4-Chlorophenyl)-2-methoxymethyltetrazole
(IIc). Yield 1.68 g (54%), mp 63°C. IR spectrum, ν,
cm–1: 915, 1015, 1095, 1180, 1210, 1280, 1330, 1370,
1
1440, 1470, 1610, 2860, 2960. H NMR spectrum, δ,
ppm: 3.50 s (3H, CH3), 6.01 s (2H, CH2), 7.60–7.65 d
(2H, Harom), 8.15–8.20 d (2H, Harom). Found, %:
C 48.35; H 4.11; N 24.98. C9H10N4O. Calculated, %:
C 48.11; H 4.01; N 24.94.
1
3000. H NMR spectrum, δ, ppm: 2.14 s (6H, 2CH3),
2.46 s (3H, CH3), 7.10–7.15 m (2H, Harom), 7.30–7.35
m (3H, Harom). Found, %: C 65.41; H 7.05; N 27.65.
C11H14N4. Calculated, %: C 65.35; H 6.93; N 27.72.
1-Methoxymethyl-5-(2-pyridyl)tetrazole (Id).
Yield 0.83 g (31%), mp 93°C. IR spectrum, ν, cm–1:
920, 1020, 1050, 1120, 1190, 1200, 1250, 1330, 1450,
1
1540, 1580, 1600, 2850, 2950, 3050. H NMR spec-
Tetrazoles IIIb–IIId were synthesized in a similar
way.
trum, δ, ppm: 3.50 s (3H, CH3), 6.05 s (2H, CH2),
7.50–7.65 m (1H, Harom), 7.97–8.06 m (1H, Harom),
8.21–8.25 d (1H, Harom), 8.75–8.79 d (1H, Harom).
Found, %: C 50.45; H 4.89; N 36.58. C8H9N5O. Cal-
culated, %: C 50.26; H 4.71; N 36.65.
2-(α,α-Dimethylbenzyl)-5-phenyltetrazole (IIIb).
Yield 2.94 g (93%), mp 51°C (from petroleum ether).
IR spectrum, ν, cm–1: 1010, 1030, 1050, 1080, 1180,
1180, 1200, 1265, 1310, 1380, 1460, 1480, 1500,
2-Methoxymethyl-5-(2-pyridyl)tetrazole (IId).
Yield 1.66 g (62%), mp 72°C. IR spectrum, ν, cm–1:
920, 990, 1000, 1030, 1050, 1070, 1100, 1190, 1210,
1260, 1310, 1440, 1480, 1540, 1595, 2850, 2950.
1H NMR spectrum, δ, ppm: 3.40 s (3H, CH3), 6.37 s
(2H, CH2), 7.60–7.69 m (1H, Harom), 8.11–8.16 m (1H,
Harom), 8.32–8.36 d (1H, Harom), 8.82–8.85 d (1H,
1
1540, 2860, 2940, 3010. H NMR spectrum, δ, ppm:
2.24 s (6H, 2CH3), 7.10–7.55 m (8H, Harom), 8.11–
8.16 m (2H, Harom). Found, %: C 72.80; H 6.15;
N 21.29. C16H16N4. Calculated, %: C 72.73; H 6.06;
N 21.21.
5-(4-Chlorophenyl)-2-(α,α-dimethylbenzyl)tetra-
zole (IIIc). Yield 2.55 g (71%), colorless oily sub-
stance. IR spectrum, ν, cm–1: 850, 1010, 1020, 1040,
1170, 1200, 1260, 1330, 1390, 1430, 1480, 1610, 2850,
Harom). Found, %: C 50.39; H 4.88; N 36.77. C8H9N5O.
Calculated, %: C 50.26; H 4.71; N 36.65.
Isomerization of 1-methoxymethyl-5-phenyl-
tetrazole (Ia). A solution of 1 mmol of 1-methoxy-
methyl-5-phenyltetrazole in 3 ml of methyl chloro-
methyl ether was heated for 10 h at 85–90°C in
a sealed ampule. Methyl chloromethyl ether was
removed under reduced pressure, the residue was
dissolved in 10 ml of chloroform, and the solution was
washed with 10% aqueuos NaOH (2×10 ml) and water
(2×10 ml) and dried over magnesium sulfate. The
solvent was removed under reduced pressure, and the
residue was 2-methoxymethyl-5-phenyltetrazole (IIa).
Yield 0.072 g (72%), colorless oily substance.
1
2960. H NMR spectrum, δ, ppm: 2.24 s (6H, 2CH3),
7.20–7.60 m (7H, Harom), 8.11–8.16 m (2H, Harom).
Found, %: C 64.40; H 5.09; N 18.85. C16H15ClN4. Cal-
culated, %: C 64.32; H 5.03; N 18.76.
2-(α,α-Dimethylbenzyl)-5-(2-pyridyl)tetrazole
(IIId). Yield 2.60 g (85%), mp 68°C (from petroleum
ether). IR spectrum, ν, cm–1: 930, 1000, 1050, 1100,
1160, 1180, 1200, 1260, 1310, 1380, 1400, 1420, 1460,
1
1500, 1600, 2860, 2940, 3000, 3020, 3080. H NMR
spectrum, δ, ppm: 2.26 s (6H, 2CH3), 7.20–7.38 m
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MYZNIKOV et al.
554
(5H, Harom), 7.45–7.52 m (1H, Harom), 7.90–8.05 m
(1H, Harom), 8.18–8.23 d (1H, Harom), 8.70–8.75 d (1H,
Harom). Found, %: C 67.70; H 5.57; N 26.49. C15H15N5.
Calculated, %: C 67.92; H 5.66; N 26.41.
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