Tetrazoles: L. Microwave-activated alkylation of 5-aryltetrazoles and 1-substituted tetrazole-5-thiones with 1,3-dibromo-2,2-bis(bromomethyl)propane

Article abstract of DOI:10.1134/S1070428006120128

Alkylation of 5-aryltetrazoles and 1-substituted tetrazole-5-thiones with 1,3-dibromo-2,2-bis(bromomethyl)propane in dimethylformamide in the presence of sodium hydroxide leads to the formation of tetrakis(5-aryltetrazol-2-ylmethyl) methanes and tetrakis(

Full text of DOI:10.1134/S1070428006120128

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 12, pp. 1834–1837. © Pleiades Publishing, Inc., 2006.
Original Russian Text © M.V. Zatsepina, A. Hrabalek, T.V. Artamonova, G.I. Koldobski, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42,
No. 12, pp. 1844–1847.
Tetrazoles: L.* Microwave-Activated Alkylation
of 5-Aryltetrazoles and 1-Substituted Tetrazole-5-thiones
with 1,3-Dibromo-2,2-bis(bromomethyl)propane
M. V. Zatsepinaa, A. Hrabalekb, T. V. Artamonovaa, and G. I. Koldobskiia
a St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: koldobsk@tu.spb.ru
b Faculty of Pharmacy, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove, 50005 Czech Republic
e-mail: hrabalek@faf.cuni.cz
Received May 16, 2006
Abstract—Alkylation of 5-aryltetrazoles and 1-substituted tetrazole-5-thiones with 1,3-dibromo-2,2-bis-
(bromomethyl)propane in dimethylformamide in the presence of sodium hydroxide leads to the formation of
tetrakis(5-aryltetrazol-2-ylmethyl)methanes and tetrakis(1-R-tetrazol-5-ylsulfanylmethyl)methanes, respec-
tively. Microwave activation considerably shortens the reaction time and increases the yield.
DOI: 10.1134/S1070428006120128
We previously showed that alkylation of 1-aryl-4,5-
dihydro-1H-tetrazol-5-ones and 1-phenyl-4,5-dihydro-
1H-tetrazole-5-thione with tetrakis(2-chloroacetoxy-
methyl)methane provides a simple and effective proce-
dure for the preparation of tetrazole-containing sub-
strates which can be used in divergent syntheses of
dendrimers [1]. In the present work we examined the
alkylation of a series of 5-aryltetrazoles and 1-substi-
tuted 4,5-dihydro-1H-tetrazole-5-thiones with 1,3-di-
bromo-2,2-bis(bromomethyl)propane under conditions
of conventional heating and microwave activation. It is
known that the use of microwave activation in organic
synthesis makes it possible to considerably increase
the reaction rate and yield and in some cases to im-
prove the selectivity [2–5].
in most cases these reactions give rise to mixtures of
isomeric 1,5- and 2,5-disubstituted tetrazoles which are
often difficult to separate [6, 7]. However, contrary to
the expectations, the reaction of 5-aryltetrazoles Ia–Id
with 1,3-dibromo-2,2-bis(bromomethyl)propane in di-
methylformamide in the presence of sodium hydroxide
gave only the corresponding 2,5-disubstituted deriva-
tives IIa–IId in 80–87% yield (Scheme 1).
The product structure was determined on the basis
of detailed analysis of their 13C NMR spectra. Accord-
ing to published data for numerous 1,5- and 2,5-disub-
stituted tetrazole derivatives, the positions of the C5
signal in their 13C NMR spectra differ considerably: it
is located at about δC 150 and 160 ppm, respectively
[8]. Therefore, isomeric 1,5- and 2,5-disubstituted
tetrazoles can be distinguished with a high reliability.
In the 13C NMR spectra of all compounds IIa–IId, the
While studying alkylation of 5-substituted tetra-
zoles with alkyl halides, one should keep in mind that
Scheme 1.
RC6H4
C6H4R
N
N
N
N
N
N
N
N
N
HN
N
NaOH, DMF
N
N
N
N
+
C(CH2Br)4
N
RC6H4
N
N
N
N
RC6H4
C6H4R
Ia–Id
IIa–IId
R = H (a), 4-F (b), 4-Br (c), 4-O2N (d).
* For communication XLIX, see [1].
1834

TETRAZOLES: L.
1835
Scheme 2.
N
N
N
N
N
N
N
N
R
R
R
R
S
S
N
N
NaOH, DMF
+
C(CH2Br)4
N
S
S
S
R
N
H
N
N
N
N
N
N
N
N
IIIa–IIIf
III, R = Me (a), cyclohexyl (b), Ph (c), 4-BrC6H4 (d), 2,4,6-Me3C6H2 (e), 1-naphthyl (f).
C5 atom of the heteroring resonated in the region
δC 162.7–167.2 ppm, indicating that these compounds
are 2,5-disubstituted isomers. Presumably, the ob-
served regioselectivity is determined by specific steric
structure of the alkylating agent.
It should be emphasized that the alkylation of
5-aryltetrazoles with 1,3-dibromo-2,2-bis(bromo-
methyl)propane occurs at a fairly high temperature
(120–130°C) and requires a long time (20–27 h). Such
relatively severe conditions considerably restrict the
synthetic potential of the proposed procedure for the
preparation of polytetrazoles. These obstacles may be
circumvented by carrying out the process under condi-
tions of microwave activation. The microwave-assisted
alkylation of 5-aryltetrazoles with 1,3-dibromo-2,2-bis-
(bromomethyl)propane required much shorter time, the
yield of the target products slightly increased, while
the selectivity of the process did not change (see table).
tion products increased. For example, in the alkylation
of 1-phenyl-4,5-dihydro-1H-tetrazole-5-thione [9] the
reaction time shortened from 5 to 1 h, and the yield
increased from 66 to 91%. Regardless of the reaction
conditions and substrate structure, the alkylation of
1-substituted tetrazole-5-thiones was characterized by
high regioselectivity: in all cases, only the correspond-
ing sulfanyl derivatives were formed. Our results are
consistent with published data on the alkylation of
1-alkyl(aryl)tetrazole-5-thiones with various haloal-
kanes and sulfuric acid esters [10, 11].
Thus we have shown that alkylation of 5-aryltetra-
zoles and 1-substituted tetrazole-5-thiones with halo-
alkanes under conditions of microwave activation is
a promising method for the preparation of tetrazole-
containing compounds with a complex structure.
EXPERIMENTAL
Analogous results were obtained in the alkylation
of 1-substituted tetrazole-5-thiones with the same
reagent. The reaction occurred at 110°C in 4–10 h, and
the corresponding sulfanyl-substituted tetrazoles IIIa–
IIIe were formed in 60–94% yield (Scheme 2). An ex-
ception was tetrazole IIIf whose yield was as low as
43%; presumably, the reason is steric effect of the sub-
stituent at N1 (R = 1-naphthyl) in the heteroring. When
the reaction was performed under microwave irradia-
tion, the rate of the process and the yield of the alkyla-
The IR spectra were recorded on a Shimadzu FTIR-
8400s spectrometer from samples prepared as KBr
1
pellets. The H and 13C NMR spectra were measured
from solutions in CDCl3 (compound IIa) or DMSO-d6
(IIb–IId, IIIa–IIIf) on a Bruker AC-400 spectrometer.
The elemental compositions were determined on
a LECO 932 CHNS(O) analyzer. A Milestone P/N
44072 microwave furnace was used to perform micro-
wave-assisted reactions.
Alkylation of 5-aryltetrazoles Ia–Id with 1,3-dibromo-2,2-bis(bromomethyl)propane under conditions of conventional
heating and microwave activation
Thermal reaction
time, h
Microwave activation
time, h
Compound no.
temperature, °C
yield, %
temperature, °C
yield, %
120
130
130
130
20
20
24
27
87
85
87
80
120
130
130
130
02
10
05
17
93
89
90
82
IIa
IIb
IIc
IId
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006

ZATSEPINA et al.
1836
1313, 1346, 1428, 1465, 1522, 1606, 3018, 3043, 3099,
Tetrakis(5-phenyl-2H-tetrazol-2-ylmethyl)-
1
methane (IIa). a. A mixture of 1.80 mmol of 1,3-di-
bromo-2,2-bis(bromomethyl)propane, 9 mmol of
5-phenyltetrazole, 9 mmol of NaOH, and 15 ml of
DMF was stirred for 20 h at 120°C. The solvent was
removed under reduced pressure, 50 ml of a 5% aqu-
eous solution of sodium hydroxide was added to the
residue, and the precipitate was filtered off, washed
with 50 ml of water, and dried in air. Yield 87%,
mp 157–159°C (from acetonitrile). IR spectrum, ν,
cm–1: 691, 731, 788, 881, 923, 1004, 1024, 1039, 1073,
1199, 1283, 1356, 1451, 1467, 1530, 2972, 3013,
3013. H NMR spectrum, δ, ppm: 8.30–8.05 m (16H,
Harom), 5.65 s (8H, CH2). 13C NMR spectrum, δC, ppm:
162.7, 148.6, 132.3, 127.7, 124.5, 54.5, 43.7. Found,
%: C 48.06; H 2.68; N 33.76. C33H24N20O8. Calculated,
%: C 47.83; H 2.92; N 33.80.
Tetrakis(1-methyl-1H-tetrazol-5-ylsulfanyl-
methyl)methane (IIIa). A mixture of 1.80 mmol of
1,3-dibromo-2,2-bis(bromomethyl)propane, 9 mmol of
1-methyl-4,5-dihydro-1H-tetrazole-5-thione, 9 mmol
of NaOH, and 15 ml of DMF was stirred for 6 h at
110°C. The solvent was removed under reduced pres-
sure, 50 ml of a 5% aqueous solution of sodium
hydroxide was added to the residue, and the precipitate
was filtered off, washed with 50 ml of water, and dried
in air. Yield 73%, mp 236–237°C (from DMF). IR spec-
trum, ν, cm–1: 701, 830, 848, 1029, 1078, 1172, 1227,
1278, 1391, 1410, 1467, 1654, 1676, 2934, 2954, 2981.
1H NMR spectrum, δ, ppm: 3.92 s (12H, CH3), 3.74 s
(8H, CH2). 13C NMR spectrum, δC, ppm: 153.5, 44.7,
39.03, 34.0. Found, %: C 30.19; H 4.08; N 41.79;
S 23.65 C13H20N16S4. Calculated, %: C 29.53; H 3.81;
N 42.39; S 24.26.
1
3035, 3071. H NMR spectrum, δ, ppm: 8.15–7.40 m
(20H, Harom), 5.30 s (8H, CH2). 13C NMR spectrum, δC,
ppm: 165.8, 130.8, 128.9, 127.0, 126.4, 53.8, 43.9.
Found, %: C 60.82; H 4.58; N 34.55. C33H28N16. Cal-
culated, %: C 61.10; H 4.35; N 34.55.
b. A mixture of 1.80 mmol of 1,3-dibromo-2,2-bis-
(bromomethyl)propane, 9 mmol of 5-phenyltetrazole,
9 mmol of NaOH, and 15 ml of DMF was stirred for
20 h at 120°C under microwave irradiation (65 W).
The mixture was then treated as described above in a
to isolate 93% of compound IIa with mp 157–159°C
(from acetonitrile).
Tetrazoles IIIb and IIId–IIIf were synthesized in
a similar way.
Tetrazoles IIb–IId were synthesized in a similar
way.
Tetrakis(1-cyclohexyl-1H-tetrazol-5-ylsulfanyl-
methyl)methane (IIIb). Reaction time 4 h (110°C).
Yield 94%, mp 175–176°C (from acetonitrile). IR spec-
trum, ν, cm–1: 753, 818, 850, 895, 1003, 1084, 1152,
1192, 1204, 1275, 1374, 1391, 1410, 1430, 1453, 1467,
Tetrakis[5-(4-fluorophenyl)-2H-tetrazol-2-yl-
methyl]methane (IIb). Reaction time 20 h (130°C).
Yield 85%, mp 197–198°C (from EtOAc–EtOH, 1:2).
IR spectrum, ν, cm–1: 524, 617, 682, 759, 844, 1033,
1095, 1157, 1238, 1357, 1427, 1469, 1542, 1612, 2927,
1
1
2858, 2935. H NMR spectrum, δ, ppm: 4.35–4.20 m
2962, 3008, 3066, 3089. H NMR spectrum, δ, ppm:
7.94–7.26 m (16H, Harom), 5.52 s (8H, CH2). 13C NMR
spectrum, δC, ppm: 167.2, 132.6, 127.0, 120.3, 119.7,
57.9, 47.4. Found, %: C 49.63; H 3.20; N 31.45.
C33H24N16. Calculated, %: C 55.00; H 3.36; N 31.10.
(4H, C61H3 11), 3.80 s (8H, CH2), 2.00–1.15 m (40H,
C6H11). C NMR spectrum, δ, ppm: 152.2, 57.7, 44.7,
31.8, 24.6. Found, %: C 50.05; H 6.47; N 28.44;
S 15.82. C33H52N16S4. Calculated, %: C 49.47; H 6.54;
N 27.97; S 16.01.
Tetrakis[5-(4-bromophenyl)-2H-tetrazol-2-yl-
methyl]methane (IIc). Reaction time 24 h (130°C).
Yield 87%, mp 214–215°C (from DMF–acetonitrile,
1:3). IR spectrum, ν, cm–1: 507, 681, 753, 834, 1013,
1001, 1013, 1036, 1071, 1135, 1190, 1271, 1354, 1415,
Tetrakis(1-phenyl-1H-tetrazol-5-ylsulfanyl-
methyl)methane (IIIc). A mixture of 1.80 mmol of
1,3-dibromo-2,2-bis(bromomethyl)propane, 9 mmol of
1-phenyl-4,5-dihydro-1H-tetrazole-5-thione, 9 mmol
of NaOH, and 15 ml of DMF was stirred for 1 h at
110°C under microwave activation (60 W). The sol-
vent was removed under reduced pressure, 50 ml of
a 5% aqueous solution of sodium hydroxide was added
to the residue, and the precipitate was filtered off,
washed with 50 ml of water, and dried in air. Yield
91%, mp 158°C (from propan-2-ol).
1
1456, 1606, 2961, 2999. H NMR spectrum, δ, ppm:
7.94–7.63 m (16H, Harom), 5.54 s (8H, CH2). 13C NMR
spectrum, δC, ppm: 163.2, 132.0, 128.1, 125.5, 123.9,
53.9, 43.7. Found, %: C 41.33; H 2.21; N 23.51.
C33H24N16. Calculated, %: C 41.10; H 2.51; N 23.24.
Tetrakis[5-(4-nitrophenyl)-2H-tetrazol-2-yl-
methyl]methane (IId). Reaction time 27 h (130°C).
Yield 80%, mp 230–232°C (from DMF). IR spectrum,
ν, cm–1: 690, 734, 854, 865, 1013, 1036, 1109, 1288,
Tetrakis[1-(4-bromophenyl)-1H-tetrazol-5-yl-
sulfanylmethyl]methane (IIId). Reaction time 4 h
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006

TETRAZOLES: L.
1837
(110°C). Yield 60%, mp 190–191°C (from DMF–
ethanol, 5:1). IR spectrum, ν, cm–1: 551, 827, 1007,
1072, 1244, 1273, 1289, 1386, 1427, 1492, 1654, 2980,
N 23.09; S 12.73. C49H36N16S4. Calculated, %: C 60.23;
H 3.71; N 22.93; S 13.12.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 06-03-32286a).
1
3059, 3093. H NMR spectrum, δ, ppm: 7.90–7.50 m
(16H, Harom), 3.80 s (8H, CH2). 13C NMR spectrum, δC,
ppm: 154.2, 133.2, 132.2, 127.1, 124.3, 44.8. Found,
%: C 36.53; H 2.25; N 20.59. C33H24Br4N16S4. Cal-
culated, %: C 36.26; H 2.20; N 20.51.
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Tetrakis[1-(2,4,6-trimethylphenyl)-1H-tetrazol-
5-ylsulfanylmethyl]methane (IIIe). Reaction time
10 h (110°C). Yield 84%, mp 238–239°C (from DMF).
IR spectrum, ν, cm–1: 584, 620, 730, 854, 973, 1013,
1032, 1093, 1165, 1240, 1282, 1395, 1438, 1488, 1608,
1
2862, 2922, 2953, 2980, 3028. H NMR spectrum, δ,
ppm: 7.15 s (8H, Harom), 3.85 s (8H, CH2), 2.35 (12H,
CH3), 1.75 (24H, CH3). 13C NMR spectrum, δC, ppm:
155.5, 141.7, 135.4, 129.8, 128.0, 44.6, 20.93, 16.81.
Found, %: C 57.60; H 6.07; N 24.18; S 13.78.
C45H52N16S4. Calculated, %: C 57.18; H 5.54; N 23.71;
S 13.57.
Tetrakis[1-(1-naphthyl)-1H-tetrazol-5-ylsulfanyl-
methyl]methane (IIIf). Reaction time 5 h (110°C).
Yield 43%, mp 209–211°C (from DMF–ethanol, 7:1).
IR spectrum, ν cm–1: 577, 665, 774, 800, 855, 960,
971, 1052, 1085, 1124, 1242, 1262, 1349, 1395, 1408,
1426, 1465, 1509, 1598, 1668, 2931, 2972, 3019, 3065.
1H NMR spectrum, δ, ppm: 8.30–7.15 m (28H, Harom),
3.80 s (8H, CH2). 13C NMR spectrum, δC, ppm: 156.2,
133.9, 132.2, 128.8, 128.7, 128.5, 128.1, 127.4, 126.0,
125.7, 121.5, 44.6, 38.7. Found, %: C 60.66; H 4.03;
p. 469.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 12 2006