Microwave-assisted arylation of 5-substituted tetrazoles

Full text of DOI:10.1134/S1070428010040366

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 4, pp. 612–614. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © Yu.A. Efimova, T.V. Artamonova, G.I. Koldobskii, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 4,
pp. 618–620.
SHORT
COMMUNICATIONS
Microwave-Assisted Arylation of 5-Substituted Tetrazoles
Yu. A. Efimova, T. V. Artamonova, and G. I. Koldobskii†
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 190013 Russia
e-mail: efimova84@mail.ru
Received December 15, 2009
DOI: 10.1134/S1070428010040366
Despite considerable interest in 2,5-disubstituted
tetrazoles as potential substrates for the synthesis of
biologically active substances, methods for their pre-
paration have been developed to insufficient extent.
Arylation of tetrazole and 5-substituted tetrazoles is
one of the least studied reactions of these compounds.
On the other hand, it may underlie a promising
procedure for the preparation of difficultly accessible
2-substituted tetrazoles. Known methods for arylation
of 5-substituted tetrazoles [1, 2] lead to formation of
mixtures of isomeric 1,5- and 2,5-disubstituted deriva-
tives. However, in some cases such reactions are char-
acterized by high selectivity. For example, the aryla-
tion of 5-substituted tetrazolates [3–6] with diaryliodo-
nium salts in the presence of different catalysts gives
only 2,5-disubstituted tetrazoles. The arylation of
5-aryltetrazoles with 2,4-dinitrofluorobenzene also
occurs at the 2-position of the tetrazole ring with high
selectivity [7].
tetrazoles occurred under analogous conditions despite
microwave activation or conventional heating. Obvi-
ously, the reason is low nucleophilicity of tetrazolate
ion and competing reaction of 4-nitrofluorobenzene
with DMF.
We presumed that arylation of 5-alkyl(aryl)tetra-
zoles could be accomplished in another polar solvent,
dimethyl sulfoxide. In fact, the arylation of 5-aryltetra-
zoles with 4-nitrofluorobenzene in DMSO in the pres-
ence of sodium hydroxide under microwave activation
or without it (on heating) gave only the corresponding
2,5-diaryltetrazoles. Our results showed that micro-
wave irradiation increases the yield of the arylation
products by a factor of 1.5 to 3. Below are given the
yields of 2,5-diaryltetrazoles IIId–IIIg obtained in
microwave-assisted reaction and under conventional
heating, respectively, %: IIId, 55, 40; IIIe, 77, 40;
IIIf, 67, 40; IIIg, 60, 21. High yields of the arylation
products under microwave activation made it possible
to simplify the isolation procedure and avoid addi-
tional purification. Thus microwave-assisted arylation
of 5-aryltetrazoles with 4-nitrofluorobenzene in
DMSO in the presence of sodium hydroxide may be
regarded as one of the simplest and effective proce-
dures for the synthesis of 2,5-diaryltetrazoles.
In continuation of our studies on the synthesis of
functionally substituted tetrazoles under conditions of
microwave activation [8, 9], we examined arylation of
5-aryl(alkyl)tetrazoles with 4-nitrofluorobenzene in
DMF in the presence of sodium hydroxide under
microwave irradiation. We previously showed [2] that
the arylation of 5-methylsulfanyltetrazole with 4-nitro-
fluorobenzene in DMF in the presence of sodium hy-
droxide yields a mixture of 1,5- and 2,5-disubstituted
isomers. However, no arylation of 5-alkyl- or 5-aryl-
The arylation of 5-methyl-, 5-benzyl-, and
5-(4-chlorobenzyl)tetrazoles in all cases afforded mix-
tures of isomeric 1- and 2-aryl-5-alkyltetrazoles. The
ratio of isomeric tetrazoles IIa:IIIa was 2:3, and the
R
NO2
H
N
NO2
R
R
NaOH, DMSO
N
N
+
+
N
N
N
N
NO2
N
N
N
F
N
N
Ia–Ig
IIa–IIc
IIIa–IIIg
R = Me (a), PhCH2 (b), 4-ClC6H4CH2 (c), 4-MeOC6H4 (d), 4-MeC6H4 (e), Ph (f), 4-ClC6H4 (g).
†
Deceased.
612

MICROWAVE-ASSISTED ARYLATION OF 5-SUBSTITUTED TETRAZOLES
613
ratio of 5-benzyl- and 5-(4-chlorobenzyl)-substituted
derivatives IIb:IIIb and IIc:IIIc was 1:2. In these
cases, microwave irradiation did not affect the selec-
tivity of arylation to an appreciable extent, but the
yield of isomeric products was higher. The overall
yields of 1,5- and 2,5-disubstituted tetrazoles IIa–IIc
and IIIa–IIIc under microwave irradiation and in con-
ventional thermal reactions were, respectively, %:
IIa+IIIa, 74, 56; IIb+IIIb, 82, 78; IIc+IIIc, 81, 64.
column chromatography on silica gel using ethyl
acetate–carbon tetrachloride (2:3) as eluent.
5-Benzyl-1-(4-nitrophenyl)tetrazole (IIb).
mp 114–115°C (from ethanol) [11]. IR spectrum, ν,
cm–1: 3439, 3123, 3113, 3095, 3067, 3032, 3007, 2925,
2867, 1615, 1599, 1528, 1507, 1493, 1456, 1427, 1381,
1363, 1347, 1316, 1301, 1280, 1264, 1149, 1113, 1097,
1081, 1074, 1040, 1028, 1012, 1002, 987, 963, 894,
859, 845, 795, 754, 738, 725, 712, 696, 690, 676, 578,
1
5-Methyl-1-(4-nitrophenyl)tetrazol (IIa) and
5-methyl-2-(4-nitrophenyl)tetrazole (IIIa). 5-Meth-
yltetrazole (Ia), 0.4 g (5 mmol), was dissolved in
15 ml of DMSO, 0.5 g (3.5 mmol) of 4-nitrofluoro-
benzene and 0.2 g (5 mmol) of sodium hydroxide were
added, and the mixture was stirred for 3 h in a micro-
wave reactor at 90°C (50 W). The mixture was cooled
to 20°C and diluted with 50 ml of cold water, the
resulting suspension was acidified with hydrochloric
acid to pH 2, and the precipitate was filtered off,
treated with 10 ml of a 1% solution of sodium
hydroxide to remove unreacted 5-methyltetrazole,
washed with water, and dried in air. Overall yield 74%.
The isomeric products were separated by column
chromatography on silica gel using ethyl acetate–
carbon tetrachloride (2:3) as eluent.
544, 517, 501. H NMR spectrum (acetone-d6), δ,
ppm: 4.51 s (2H, CH2), 7.18–7.22 m (2H, Harom), 7.24–
7.38 m (3H, Harom), 7.93 d (2H, Harom), 8.50 d
(2H, Harom).
5-Benzyl-2-(4-nitrophenyl)tetrazole (IIIb).
mp 109°C (from propan-2-ol). IR spectrum, ν, cm–1:
3438, 3113, 3084, 3031, 2956, 2853, 1612, 1594, 1525,
1501, 1454, 1426, 1410, 1382, 1367, 1343, 1315, 1293,
1278, 1212, 1172, 1122, 1108, 1092, 1074, 1031, 1011,
1
993, 863, 857, 832, 751, 733, 717, 700, 682. H NMR
spectrum (acetone-d6), δ, ppm: 4.43 s (2H, CH2), 7.27–
7.30 t (1H, Harom), 7.34–7.38 t (2H, Harom), 7.43 d (2H,
Harom), 8.44 d (2H, Harom), 8.55 d (2H, Harom). Found,
%: C 59.62; H 3.82; N 24.75. C14H11N5O2. Calculated,
%: C 59.79; H 3.91; N 24.91.
5-(4-Chlorobenzyl)-1-(4-nitrophenyl)tetrazole
(IIc). mp 188–189°C (from acetonitrile). IR spectrum,
ν, cm–1: 3442, 3121, 3110, 3090, 3067, 2977, 2922,
2854, 1613, 1598, 1524, 1508, 1490, 1440, 1429, 1416,
1407, 1361, 1344, 1313, 1294, 1280, 1266, 1165, 1150,
1108, 1092, 1182, 1040, 1014, 1009, 993, 957, 912,
859, 832, 825, 784, 753, 727, 716, 695, 684, 646, 549,
524, 505, 460. 1H NMR spectrum (acetone-d6), δ, ppm:
4.53 s (2H, CH2), 7.26 d (2H, Harom), 7.33 d (2H,
5-Methyl-1-(4-nitrophenyl)tetrazole (IIa).
mp 130°C (from toluene) [10]. IR spectrum, ν, cm–1:
3438, 3118, 3090, 3070, 3004, 2925, 2853, 1926, 1612,
1598, 1530, 1521, 1502, 1411, 1386, 1361, 1344, 1315,
1304, 1290, 1278, 1178, 1122, 1104, 1079, 1041, 1011,
983, 958, 856, 825, 754, 734, 716, 701, 689, 682, 528,
1
502. H NMR spectrum (CDCl3), δ, ppm: 2.72 s (3H,
CH3), 7.77 d (2H, Harom), 8.48 d (2H, Harom). 13C NMR
spectrum (CDCl3), δC, ppm: 10.15 (CH3), 125.00
(CHarom), 125.45 (CHarom), 138.58 (Carom),148.20 (C5),
151.46 (Carom).
H
arom), 7.97 d (2H, Harom), 8.52 d (2H, Harom). 13C NMR
spectrum (acetone-d6), δC, ppm: 29.81 (CH2), 125.41
(CHarom), 126.79 (CHarom), 128.89 (CHarom), 130.94
(CHarom), 132.91 (Carom), 133.77 (Carom), 139.11 (Carom),
148.92 (C5), 154.55 (Carom). Found, %: C 53.38;
H 3.43; N 22.11. C14H10ClN5O2. Calculated, %:
C 53.25; H 3.17; N 22.19.
5-Methyl-2-(4-nitrophenyl)tetrazol (IIIa).
mp 155–156°C (from ethanol). IR spectrum, ν, cm–1:
3430, 3119, 3086, 3061, 3042, 3016, 2917, 2853, 2794,
1948, 1806, 1617, 1596, 1527, 1497, 1431, 1377, 1366,
1353, 1339, 1314, 1302, 1258, 1212, 1177, 1110, 1096,
1051, 1016, 971, 862, 853, 751, 743, 711, 693, 682,
5-(4-Chlorobenzyl)-2-(4-nitrophenyl)tetrazole
(IIIc). mp 144°C (from acetonitrile). IR spectrum, ν,
cm–1: 3436, 3115, 3090, 3083, 3055, 2922, 2853, 1615,
1594, 1525, 1507, 1490, 1433, 1421, 1407, 1382, 1368,
1340, 1314, 1293, 1230, 1186, 1173, 1109, 1095, 1084,
1015, 1010, 996, 914, 864, 854, 801, 749, 735, 711,
683, 625, 517, 485. 1H NMR spectrum (acetone-d6), δ,
ppm: 4.44 s (2H, CH2), 7.39 d (2H, Harom), 7.46 (2H,
1
533, 504, 496. H NMR spectrum (CDCl3), δ, ppm:
2.67 s (3H, CH3), 8.31–8.34 d (2H, Harom), 8.42–8.45 d
(2H, Harom). 13C NMR spectrum (CDCl3), δC, ppm:
10.98 (CH3), 120.12 (CHarom), 125.40 (CHarom), 140.55
(Carom), 147.55 (Carom), 164.16 (C5). Found, %:
C 46.57; H 3.42; N 34.18. C8H7N5O2. Calculated, %:
C 46.83; H 3.41; N 34.15.
Tetrazoles IIb/IIIb and IIc/IIIc were synthesized in
a similar way. Individual isomers were isolated by
H
arom), 8.42 d (2H, Harom), 8.54 d (2H, Harom). 13C NMR
spectrum (acetone-d6), δC, ppm: 31.06 (CH2), 120.72
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 4 2010

EFIMOVA et al.
614
(CHarom), 125.77 (CHarom), 128.83 (CHarom), 130.90
(CHarom.), 132.58 (Carom), 135.79 (Carom), 140.84
(Carom), 148.33 (Carom), 166.56 (C5). Found, %:
C 53.32; H 3.21; N 22.15. C14H10ClN5O2. Calculated,
%: C 53.25; H 3.17; N 22.19.
P/N 44072 reactor. The elemental compositions were
determined on a LECO CHNS(O)-932 analyzer. The
ratios of isomeric 1- and 2-(4-nitrophenyl)-5-alkyl-
tetrazoles were determined from the intensity ratio of
signals from methyl or methylene protons on C5 as
average of three measurements. 5-Alkyl(aryl)tetrazoles
Ia–Ig were synthesized as described in [13, 14]. The
purity of the isolated compounds was checked by TLC
on Silufol UV-254 plates using ethyl acetate–carbon
tetrachloride (2:3) as eluent. The procedures for aryla-
tion under microwave irradiation and under conven-
tional heating were similar.
Tetrazoles IIId–IIIf were synthesized in a similar
way; the reaction mixtures were stirred for 2 h
at 100°C.
5-(4-Methoxyphenyl)-2-(4-nitrophenyl)tetrazole
(IIId). Yield 55%, mp 182°C (from ethyl acetate) [12].
IR spectrum, ν, cm–1: 3437, 3120, 3088, 3064, 3004,
2943, 2845, 1613, 1598, 1582, 1521, 1499, 1475, 1431,
1344, 1251, 1211, 1181, 1174, 1106, 1019, 1006, 985,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 08-03-00342a).
1
856, 841, 750, 680, 640, 611, 534. H NMR spectrum
(CDCl3), δ, ppm: 3.89 s (3H, OCH3), 7.05 d (2H,
Harom), 8.19 d (2H, Harom), 8.39–8.46 m (4H, Harom).
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5-(4-Methylphenyl)-2-(4-nitrophenyl)tetrazole
(IIIe). Yield 77%, mp 170–171°C (from ethyl acetate)
[12]. IR spectrum, ν, cm–1: 3121, 3088, 3030, 2925,
2855, 1678, 1597, 1529, 1498, 1398, 1311, 1247, 1132,
1110, 1068, 1041, 1028, 1016, 987, 953, 881, 855, 827,
798, 748, 721, 690, 680, 661, 609, 500. 1H NMR spec-
trum (CDCl3), δ, ppm: 2.45 s (3H, CH3), 7.35 d (2H,
Harom), 8.15 d (2H, Harom), 8.41–8.48 m (4H, Harom).
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ppm: 120.25 (CHarom), 125.43 (CHarom) 126.37 (Carom),
127.21 (CHarom), 129.07 (CHarom), 131.09 (CHarom),
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(IIIg). Yield 60%, mp 184–185°C (from ethyl acetate)
[12]. IR spectrum, ν, cm–1: 3436, 3372, 3121, 3092,
1607, 1596, 1532, 1494, 1471, 1458, 1432, 1411, 1366,
1351, 1339, 1311, 1211, 1111, 1092, 1022, 1011, 991,
1
859, 853, 841, 754, 748, 683, 566. H NMR spectrum
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Harom), 8.41–8.49 m (4H, Harom).
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