An improved protocol for the preparation of 5-substituted tetrazoles from organic thiocyanates and nitriles

Article abstract of DOI:10.1055/s-0033-1340616

Organic thiocyanates and nitriles are converted efficiently into the corresponding 5-substituted 1H-tetrazoles by treatment with zinc(II) chloride and sodium azide in aliphatic alcohols. The presented procedure provides mild reaction conditions, short reaction times, and good to excellent yields for a wide range of substrates, including deactivated aliphatic nitriles and thermally unstable thiocyanates. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340616

PAPER
▌781
paper
An Improved Protocol for the Preparation of 5-Substituted Tetrazoles from
Organic Thiocyanates and Nitriles
Preparation of 5-Substituted Tetrazoles
Svetlana Vorona, Tatiana Artamonova, Yuri Zevatskii, Leonid Myznikov*
Saint Petersburg State University of Technology and Design, ul. Bolshaya Morskaya 18, 191186 Saint Petersburg, Russian Federation
Fax +7(812)5719584; E-mail: Myznikov_lv@mail.ru
Received: 01.11.2013; Accepted after revision: 19.12.2013
Table 1 Experimental Data for the Formation of 5-Phenyltetrazole
Abstract: Organic thiocyanates and nitriles are converted efficient-
from Benzonitrile
ly into the corresponding 5-substituted 1H-tetrazoles by treatment
with zinc(II) chloride and sodium azide in aliphatic alcohols. The
Entry Reagent(s)
Solvent
Temp Time Yield
presented procedure provides mild reaction conditions, short reac-
tion times, and good to excellent yields for a wide range of sub-
strates, including deactivated aliphatic nitriles and thermally
unstable thiocyanates.
(°C)
(h)
(%)
1
2
3
4
5
6
7
NaN3, NH4Cl
NaN3, ZnBr2
NaN3, Et3N·HCl
NaN3, Et3N·HCl
NaN3, CuSO4
NaN3
DMF1
H2O3
125
100
100
100a
140
190
85
7
24
8
~100
76
Key words: tetrazoles, nitriles, thiocyanates, cycloaddition, azides,
zinc salts
4
PhNO2
PhNO2
96
5
2
93
DMSO6
NMP7
1
98
Tetrazoles have been known for more than one hundred
years. They are used in pharmaceuticals, high energy ma-
terials and for certain other purposes. The primary method
for the preparation of 5-substituted tetrazoles is via the re-
action of aliphatic or aromatic nitriles with salts of hydra-
zoic acid in the presence of various reactants and
catalysts. All of these methods are based on the funda-
mental work of Finnegan, who reported the formation of
tetrazoles from nitriles in the presence of sodium azide
and ammonium chloride.1 Numerous modifications of
Finnegan’s method have been described, including the use
of various solvents, the replacement of ammonium chlo-
ride with triethylammonium chloride and the utilization of
Lewis acids as catalysts.2 However, all of these methods
require harsh conditions and prolonged reaction times.
This statement is best illustrated by the literature experi-
mental data for the reaction of benzonitrile with sodium
azide (Table 1).
0.33
18
96
TMSN3, TBAF
no solvent8
86
a Reaction under microwave conditions.
In order to elaborate a practical synthesis of thiotetrazoles,
we decided to further investigate the work of Sharpless3
devoted to the zinc-catalyzed cycloaddition of azides to
nitriles in aqueous medium. We found that the Sharpless
method could be substantially improved by using aliphat-
ic alcohols as solvents. In the case of thiocyanates, the re-
action temperature and time could be decreased to 50 °C
and 1.5 hours, respectively (Scheme 1).
NaN3 (1.2 equiv)
ZnCl2 (1 equiv)
H
S
S
N
R
R
N
N
N
1a–f
i-PrOH, 50 °C, 1.5 h
N
As shown in Table 1, none of the reported conditions uti-
lize a temperature below 100 °C, except for the reaction
with the organic silicon azide (Table 1, entry 7). Reduc-
2a–f
Scheme 1 Synthesis of thiotetrazoles by reaction of the correspond-
tion of the reaction time could only be achieved by in- ing thiocyanates with ZnCl2 and NaN3 in i-PrOH
creasing the temperature, or by the application of
microwave activation.5,9 The use of high temperatures and
Our initial efforts were focused on studying the reaction
prolonged reaction times made no substantial difference
when the starting nitrile and the corresponding tetrazole
were stable under the reaction conditions, but in the case
of thiocyanates, prolonged heating at 85 °C led to decom-
position of the reactants and the reaction products. As a
result, none of the methods presented in Table 1 gave sat-
isfactory results for the preparation of thiotetrazoles from
thiocyanates.
of benzyl thiocyanate with zinc(II) chloride (ZnCl2) and
sodium azide (NaN3) in various solvents (Table 2). As
shown in Table 2, aliphatic alcohols were the best media
for the reaction of benzyl thiocyanate with sodium azide
in the presence of zinc salts, while solvents commonly
used for tetrazole preparation showed lower efficiency. It
is interesting to note that the yields of the expected tetra-
zole were substantially lower in the case of methanol and
sterically hindered tert-butyl alcohol (t-BuOH).
Next, we investigated the reaction of benzyl thiocyanate
with sodium azide in isopropyl alcohol (i-PrOH) in the
presence of different Lewis acids. The formation of 5-
SYNTHESIS 2014, 46, 0781–0786
Advanced online publication: 21.01.2014
DOI: 10.1055/s-0033-1340616; Art ID: SS-2013-Z0723-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

782
S. Vorona et al.
PAPER
alyst at 50 °C. In addition, no significant difference in the
catalytic activity between zinc(II) chloride and zinc(II)
bromide was observed. Complete conversion of benzyl
thiocyanate could only be achieved with one equivalent of
the zinc salt. The reaction was incomplete after four hours
at 50 °C with 0.5 equivalents of zinc(II) chloride. During
the reaction, a large amount of a precipitate containing
zinc salts was formed, and for this reason, vigorous stir-
ring was essential.
Table 2 Comparison of the Effect of Solvents on the Reaction of
Benzyl Thiocyanate with ZnCl2 (1 equiv) and NaN3 (1.2 equiv)a
Entry
Solvent
Yield (%)b
1
2
MeCN
DMSO
DMF
16
trace
trace
trace
no reaction
48
3
4
H2O
To clarify the scope and limitations of the zinc(II) chlo-
ride mediated reaction, various structurally diverse thio-
cyanates were reacted with sodium azide, in isopropyl
alcohol, to give the corresponding tetrazoles in good
yields after a short reaction time at 50 °C (Table 3). Only
in the case of extremely unstable thiocyanate 1f and thio-
tetrazole 2f did the yield not exceed 50% (Table 3, entry
6).
5
AcOH
MeOH
EtOH
6
7
89
8
i-PrOH
n-PrOH
n-BuOH
t-BuOH
92
9
88
Having established that our approach was suitable for the
preparation of thiotetrazoles, we decided to investigate the
reactions with a variety of aliphatic and aromatic nitriles,
using alcohols as the solvent. However, the temperature
that could be reached in isopropyl alcohol was insufficient
for rapid conversions. The optimal reaction conditions
were determined as 95 °C for aromatic nitriles in n-propyl
alcohol (n-PrOH), and 110 °C for aliphatic nitriles in n-
butyl alcohol (n-BuOH) (Scheme 2).
10
11
82
39
a Reactions were conducted at 50 °C for 1.5 h.
b Yield of isolated product.
(benzylsulfanyl)-1H-tetrazole (2c) was not detected in the
presence of iron(III) chloride (FeCl3), aluminum chloride
(AlCl3), copper(II) bromide (CuBr2), copper(I) bromide
(Cu2Br2), and zinc oxide (ZnO), or in the absence of a cat-
Table 3 Reactions of Thiocyanates with ZnCl2 (1 equiv) and NaN3 (1.2 equiv)a
Entry
Thiocyanate
Product
Yield (%)b
84
Mp (°C)
93
H
N
S
S
1
1a
2ac
N
N
N
N
N
H
N
S
S
2bc
2c
82
92
166–167
138
N
2
3
1b
1c
N
HO
N
HO
H
N
S
S
N
N
N
S
N
O
O
H
S
N
4
5
6
1d
1e
1f
2d
2e
91
77
47
149–150
87
N
N
N
S
N
H
N
S
N
N
N
N
N
N
O
O
H
N
S
2fc
H2N
151
S
H2N
N
N
a Reactions were conducted in i-PrOH at 50 °C for 1.5 h.
b Yield of isolated product.
c Product isolated by extraction.
Synthesis 2014, 46, 781–786
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of 5-Substituted Tetrazoles
783
tions. All the tested aliphatic and aromatic nitriles gave
moderate to excellent yields of the corresponding tetra-
zoles within a comparatively short reaction time.
H
NaN3 (1.2 equiv)
ZnCl2 (1 equiv)
R1
N
N
R1
N
R2OH, 95–110 °C
R2 = n-Pr, n-Bu
N
N
3a–j
4a–j
It is important to note that our procedure eliminates the
necessity to use a pressure reactor for aliphatic nitriles, in-
cluding acetonitrile. The high reactivity of the zinc(II)
chloride–sodium azide (ZnCl2–NaN3) system in alcohols
can be illustrated by the reaction with 1,2-dicyanobenzene
(3i). The reaction of 3i with zinc(II) chloride (2 equiv) and
sodium azide (2.4 equiv) gave ditetrazole product 4i (Ta-
ble 4, entry 9), while the use zinc(II) chloride (1 equiv)
Scheme 2 Synthesis of tetrazoles by reaction of the corresponding
nitriles with ZnCl2 and NaN3 in aliphatic alcohols
Table 4 lists the different 5-substituted tetrazoles obtained
using the presented procedure, and indicates the versatili-
ty of the reaction under the appropriate reaction condi-
Table 4 Reactions of Aliphatic and Aromatic Nitrilesa
Entry
Substrate
Time (h)
Product
Yield (%)b
51
Mp (°C)
147
H
N
1
3a
MeCN
10
4ac
N
N
N
N
H
N
2
3
4
5
3b
3cd
3d
3e
EtCN
10
10
10
2
4bc
4cc
4dc
4e
53
53
65
81
93–94
214–215
39–40
N
N
N
H
N
NC
CN
N
N
N
N
NH
N
N
N
H
N
CN
CN
N
N
N
H
N
123–124
N
N
HN
CN
N
N
6
7
8
3f
1
1
7
4f
85
80
95
216
N
HN
CN
CN
N
N
3g
3h
4g
4h
225–226
234
O2N
O2N
N
HN
N
N
MeO
MeO
N
HN
N
N
CN
CN
N
9
3id
1
4i
90
232
H
N
N
N
N
HN
CN
N
10
3j
0.5
4j
N
91
212–213
N
N
a Reaction conditions: ZnCl2 (1 equiv), NaN3 (1.2 equiv); entries 1–4: n-BuOH, 110 °C; entries 5–10: n-PrOH, 95 °C.
b Yield of isolated product.
c Product isolated by extraction.
d ZnCl2 (2 equiv) and NaN3 (2.4 equiv) were used.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 781–786

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S. Vorona et al.
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R1
O
H
R1
N3
H
NaN3
ZnCl2
n-R2OH
R1
R1
R2
N
N
R1
N
•ZnCl2
•ZnCl2
•ZnCl2
N
N
– n-R2OH
NH
NH
N
N
N
N
Scheme 3 The proposed mechanism for the formation of tetrazoles in aliphatic alcohols
Reaction Workup; General Procedure
and sodium azide (1.2 equiv) led to a mixture of the start-
ing material, and mono- and ditetrazole products.
When the starting material had been consumed (monitored by
TLC), the solvent was evaporated under reduced pressure. Next, 5%
NaOH (50 mL) was added and the mixture was stirred for 20 min,
until the original precipitate had dissolved and a suspension of
Zn(OH)2 had formed. The suspension was filtered, and the solid
washed with 5% NaOH (10 mL). The pH of the filtrate was adjusted
to 1.0 with concd HCl, which caused the tetrazole product to precip-
itate. The tetrazole was filtered, washed with 9% HCl (2 × 10 mL)
and dried. In the cases where precipitation did not occur after acid-
ification (as indicated in Tables 3 and 4), the products were isolated
by extraction with EtOAc (3 × 10 mL), followed by evaporation un-
der reduced pressure.
It is clear that in the present case, reduction of the temper-
ature and reaction time can only be achieved through a
multi-step reaction mechanism. The dependence of the re-
activity of the zinc(II) chloride–sodium azide system on
the structure of the alcohol prompted us to include the sol-
vent in the reaction mechanism.
Taking into account the published data on the synthesis of
tetrazoles from imino ethers,10 we have proposed the fol-
lowing reaction mechanism (Scheme 3). The first step of
the reaction is the zinc-catalyzed in situ formation of an
imino ether, which subsequently reacts with sodium azide
to form the corresponding tetrazole. The lower efficiency
in the case of the reaction in methanol can be explained by
the high stability of the intermediate under the reaction
conditions, since the nucleophilicities of methoxide and
azide ions are comparable. Steric hindrance leads to a de-
crease in the product yields in the case of tert-butyl alco-
hol.
5-(Phenylsulfanyl)-1H-tetrazole (2a)
Yield: 1.11 g (84%); white solid; mp 93–94 °C (toluene) (Lit.14 92–
93 °C).
IR (KBr): 3057, 2851, 2795, 2652, 2618, 2548, 1851, 1514, 1477,
1441, 1371, 1317, 1066, 1033, 1000, 982, 753, 687 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.34–7.40 (m, 3 H, ArH),
7.46–7.50 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 129.55, 130.37, 132.41,
153.75 (one carbon atom resonance was not detected).
Anal. Calcd for C7H6N4S: C, 47.18; H, 3.39; N, 31.44; S, 17.99.
Found: C, 47.34; H, 3.31; N, 31.37; S, 18.08.
In conclusion, an efficient synthesis of 5-substituted 1H-
tetrazoles has been developed. The presented approach
has several advantages, such as short reaction times, good
to excellent yields of the products and mild reaction con-
ditions. This procedure allows the use of various sub-
strates, including deactivated aliphatic nitriles and
thermally unstable thiocyanates.
4-(1H-Tetrazol-5-ylsulfanyl)phenol (2b)
Yield: 1.05 g (82%); white solid; mp 166–167 °C (H2O).
IR (KBr): 3366, 3233, 3014, 2872, 2783, 2666, 2542, 1907, 1597,
1582, 1499, 1440, 1371, 1317, 1246, 1220, 1041, 833, 700, 537
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 6.81 (d, J = 8.0 Hz, 2 H, ArH),
7.40 (d, J = 8.0 Hz, 2 H, ArH), 10.01 (s, 1 H, OH).
Compounds 1a, 1b and 1f were prepared using known proce-
dures.11–13 All other chemicals were of reagent grade quality and
were obtained from Sigma-Aldrich, and used without further puri-
fication. All the reaction mixtures were stirred magnetically. The
progress of the reactions was monitored by TLC on Merck Silica gel
60 F254 aluminum-backed SiO2-coated sheets; compounds were
made visual by UV irradiation (254 nm). Melting points were deter-
mined on a Kofler hot stage microscope and are uncorrected. IR
spectra were recorded on a Shimadzu FTIR-8400s spectrophotom-
eter. 1H and 13C NMR spectra were recorded on a JEOL JNM-ECX
400A (400 MHz) spectrometer; chemical shifts were indirectly ref-
erenced to TMS through the solvent signal. ESI-MS experiments
were performed using a Bruker MaXis 4G spectrometer. Mass spec-
tra were obtained by direct infusion of a solution of the sample in
MeCN into the detector. Elemental analysis was performed on a
LECO CHNS-932 analyzer.
13C NMR (100 MHz, DMSO-d6): δ = 116.07, 117.42, 136.51,
155.33, 159.70.
MS (ESI): m/z (%) = 195.0 (100%) [M + H]+.
Anal. Calcd for C7H6N4OS: C, 43.29; H, 3.11; N, 28.85; S, 16.51.
Found: C, 43.42; H, 3.19; N, 28.71; S, 16.38.
5-(Benzylsulfanyl)-1H-tetrazole (2c)
Yield: 1.18 g (92%); white solid; mp 138 °C (EtOH) (Lit.15 134–
135 °C).
IR (KBr): 3061, 2895, 2812, 2653, 2545, 2490, 1532, 1493, 1454,
1433, 1362, 1318, 1236, 1079, 1037, 980, 776, 704, 571, 475 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.47 (s, 2 H, CH2), 7.20–7.28
(m, 3 H, ArH), 7.35–7.37 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 36.51, 128.20, 129.09,
129.45, 137.22, 154.23.
5-(Substituted sulfanyl)-1H-tetrazoles 2a–f; General Procedure
NaN3 (8.9 mmol) and ZnCl2 (7.4 mmol) were added to a solution of
the appropriate thiocyanate (7.4 mmol) in i-PrOH (25 mL). The re-
action mixture was stirred vigorously at 50 °C for 1.5 h.
Anal. Calcd for C8H8N4S: C, 49.98; H, 4.19; N, 29.14; S, 16.68.
Found: C, 49.90; H, 4.30; N, 29.01; S, 16.79.
1-Phenyl-2-(1H-tetrazol-5-ylsulfanyl)ethanone (2d)
Yield: 1.13 g (91%); white solid; mp 149–150 °C (EtOAc).
5-Substituted-1H-tetrazoles 4a–j; General Procedure
NaN3 (11.6 mmol) and ZnCl2 (9.7 mmol) were added to a solution
of the appropriate nitrile (9.7 mmol) in n-PrOH or n-BuOH (25
mL). The temperatures, reaction times and solvents are listed in Ta-
ble 4. Vigorous stirring was essential.
IR (KBr): 3438, 3066, 2922, 2792, 2738, 1679, 1597, 1582, 1518,
1450, 1386, 1355, 1330, 1307, 1203, 1045, 1000, 888, 748, 688,
639 cm–1.
Synthesis 2014, 46, 781–786
© Georg Thieme Verlag Stuttgart · New York

PAPER
Preparation of 5-Substituted Tetrazoles
5,5′-Methanediylbis(1H-tetrazole) (4c)
785
1H NMR (400 MHz, DMSO-d6): δ = 5.06 (s, 2 H, CH2), 7.54 (t, J =
16.0 Hz, 2 H, ArH), 7.67 (t, J = 8.0 Hz, 1 H, ArH), 8.01 (d, J = 8.0
Hz, 2 H, ArH).
Yield: 1.22 g (53%); white solid; mp 214–215 °C (MeCN–CCl4)
(Lit.16 214 °C).
13C NMR (100 MHz, DMSO-d6): δ = 40.93, 128.98, 129.42,
134.45, 135.65, 154.40, 193.26.
MS (ESI): m/z (%) = 221.0 (100) [M + H]+.
IR (KBr): 3435, 3118, 2997, 2880, 2758, 2704, 2474, 1642, 1567,
1550, 1405, 1362, 1272, 1242, 1105, 1074, 1010, 923, 859, 754,
647, 418 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.71 (s, 2 H, CH2).
13C NMR (100 MHz, DMSO-d6): δ = 19.49, 152.89.
Anal. Calcd for C9H8N4OS: C, 49.08; H, 3.66; N, 25.44; S, 14.56.
Found: C, 48.91; H, 3.47; N, 25.58; S, 14.59.
Anal. Calcd for C3H4N8: C, 23.69; H, 2.65; N, 73.66. Found: C,
23.68; H, 2.64; N, 73.68.
5-(Hexylsulfanyl)-1H-tetrazole (2e)
Yield: 1.01 g (77%); colorless solid; mp 87 °C (CCl4) (Lit.15 85 °C).
IR (KBr): 3062, 2948, 2930, 2857, 2697, 2556, 2497, 1522, 1464,
1431, 1358, 1313, 1253, 1041, 987, 891, 848, 818 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 0.80 (t, J = 12.0 Hz, 3 H, CH3),
1.18–1.22 (m, 4 H, CH2CH2), 1.28–1.36 (m, 2 H, CH2), 1.58–1.65
(m, 2 H, CH2), 3.18 (t, J = 12.0 Hz, 2 H, CH2).
5-Butyl-1H-tetrazole (4d)
Yield: 0.98 g (65%); white solid; mp 39–40 °C (CCl4–hexane)
(Lit.17 40–42 °C).
IR (KBr): 3453, 2960, 2877, 2740, 2610, 2473, 2349, 1835, 1583,
1550, 1468, 1406, 1260, 1108, 1045, 987, 933, 740 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 0.79 (t, J = 16.0 Hz, 3 H, CH3),
1.17–1.27 (m, 2 H, CH2), 1.56–1.63 (m, 2 H, CH2), 2.79 (t, J = 16.0
Hz, 2 H, CH2), 15.93 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 13.81, 21.97, 22.85, 29.56,
156.34.
13C NMR (100 MHz, DMSO-d6): δ = 14.35, 22.47, 28.02, 29.54,
31.15, 32.46, 154.63.
Anal. Calcd for C7H14N4S: C, 45.13; H, 7.58; N, 30.08; S, 17.21.
Found: C, 45.30; H, 7.72; N, 29.91; S, 17.14.
2-(1H-Tetrazol-5-ylsulfanyl)acetamide (2f)
Anal. Calcd for C5H10N4: C, 47.60; H, 7.99; N, 44.41. Found: C,
47.86; H, 7.74; N, 44.30.
The workup procedure excluded basification due to hydrolysis of
the amide group. After evaporation of the solvent under reduced
pressure, 9% HCl (50 mL) was added, and the mixture was stirred
for 10 min until no solid was longer present. The product was iso-
lated by extraction with EtOAc (3 × 10 mL), followed by evapora-
tion under reduced pressure.
5-Benzyl-1H-tetrazole (4e)
Yield: 1.11 g (81%); white solid; mp 123–124 °C (EtOAc) (Lit.17
123–124 °C).
IR (KBr): 2982, 2852, 2704, 2593, 1661, 1596, 1534, 1494, 1453,
1382, 1241, 1176, 1108, 1054, 1000, 915, 734, 710, 695, 633, 570
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 4.26 (s, 2 H, CH2), 7.20–7.32
(m, 5 H, ArH), 16.18 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 29.43, 127.55, 129.19,
Yield: 0.64 g (47%); white solid; mp 151 °C (MeCN).
IR (KBr): 3349, 3005, 2928, 2787, 2730, 2546, 2359, 1680, 1613,
1494, 1414, 1368, 1316, 1263, 1244, 1157, 1121, 1061, 1039, 981,
901, 859, 800, 684, 660 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.97 (s, 2 H, CH2), 7.26 (s, 1
H, CONH2), 7.67 (s, 1 H, CONH2).
136.45, 155.77 (one carbon atom resonance was not detected).
13C NMR (100 MHz, DMSO-d6): δ = 36.33, 154.57, 168.87.
MS (ESI): m/z (%) = 160.0 (100) [M + H]+.
Anal. Calcd for C8H8N4: C, 59.99; H, 5.03; N, 34.98. Found: C,
60.09; H, 5.00; N, 35.07.
Anal. Calcd for C3H5N5OS: C, 22.64; H, 3.17; N, 44.00; S, 20.15.
Found: C, 22.55; H, 3.10; N, 44.17; S, 20.21.
5-Phenyl-1H-tetrazole (4f)
Yield: 1.21 g (85%); white solid; mp 216 °C (EtOAc) (Lit.3 215–
216 °C).
5-Methyl-1H-tetrazole (4a)
Yield: 1.04 g (51%); white solid; mp 147 °C (EtOAc–hexane) (Lit.3
146 °C).
IR (KBr): 3413, 3128, 3055, 2981, 2908, 2839, 2686, 2611, 2543,
2482, 2376, 1604, 1564, 1483, 1407, 1288, 1255, 1163, 1083, 1056,
1035, 993, 783, 725, 703, 688 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.49–7.50 (m, 3 H, ArH),
IR (KBr): 3159, 3021, 2957, 2879, 2805, 2748, 2710, 2648, 2604,
2498, 2451, 2348, 1829, 1582, 1565, 1426, 1385, 1257, 1112, 1054,
995, 924, 685 cm–1.
7.98–8.00 (m, 2 H, ArH), 15.78 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 124.67, 127.47, 129.82,
131.63, 155.81.
1H NMR (400 MHz, DMSO-d6): δ = 2.44 (s, 3 H, CH3), 15.86 (s, 1
H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 8.85, 152.66.
Anal. Calcd for C7H6N4: C, 57.53; H, 4.14; N, 38.34. Found: C,
57.47; H, 4.18; N, 38.30.
Anal. Calcd for C2H4N4: C, 28.57; H, 4.80; N, 66.64. Found: C,
28.64; H, 4.93; N, 66.53.
5-(4-Nitrophenyl)-1H-tetrazole (4g)
Yield: 1.03 g (80%); off-white solid; mp 225–226 °C (EtOAc) (Lit.3
220 °C).
5-Ethyl-1H-tetrazole (4b)
Yield: 0.94 g (53%); white solid; mp 93–94 °C (EtOAc–hexane)
(Lit.9 95–96 °C).
IR (KBr): 3443, 3326, 3216, 3104, 2915, 2607, 1959, 1605, 1551,
1514, 1340, 1288, 1244, 1134, 1109, 1088, 997, 853, 730, 499 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.16–8.19 (m, 2 H, ArH),
8.30–8.33 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 124.99, 128.58, 131.08,
IR (KBr): 3116, 3001, 2941, 2869, 2709, 2613, 2445, 1805, 1571,
1471, 1402, 1307, 1253, 1051, 973, 912, 810, 445 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 1.21 (t, J = 16.0 Hz, 3 H, CH3),
2.80–2.86 (m, 2 H, CH2), 15.90 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 12.13, 16.94, 157.49.
149.12, 155.87.
Anal. Calcd for C7H5N5O2: C, 43.98; H, 2.64; N, 36.64. Found: C,
44.09; H, 2.75; N, 36.51.
Anal. Calcd for C3H6N4: C, 36.73; H, 6.16; N, 57.11. Found: C,
36.92; H, 6.30; N, 57.01.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 781–786

786
S. Vorona et al.
PAPER
5-(4-Methoxyphenyl)-1H-tetrazole (4h)
Yield: 1.25 g (95%); white solid; mp 234 °C (EtOAc) (Lit.3 231–
232 °C).
Acknowledgment
We are grateful to the CJSC NOVBYTCHIM for funding and assis-
tance.
IR (KBr): 3078, 2984, 2922, 2840, 2716, 2641, 2477, 1877, 1617,
1501, 1443, 1406, 1298, 1265, 1183, 1056, 1032, 992, 835, 752,
698, 615, 522 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 3.77 (s, 3 H, CH3), 7.07 (d, J =
4.0 Hz, 2 H, ArH), 7.92 (d, J = 12.0 Hz, 2 H, ArH), 16.47 (s, 1 H,
NH).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
13C NMR (100 MHz, DMSO-d6): δ = 55.88, 115.27, 116.79,
129.13, 155.24, 161.95.
(1) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem.
Soc. 1958, 80, 3908.
(2) Roh, J.; Vavrova, K.; Hrabalek, A. Eur. J. Org. Chem. 2012,
31, 6101.
Anal. Calcd for C8H8N4O: C, 54.54; H, 4.58; N, 31.80. Found: C,
54.59; H, 4.66; N, 31.89.
5,5′-Benzene-1,2-diylbis(1H-tetrazole) (4i)
Yield: 1.50 g (90%); white solid; mp 232 °C (EtOH) (Lit.3 228–
230 °C).
(3) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66,
7945.
(4) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis 1998,
910.
(5) Roh, J.; Artamonova, T. V.; Vavrova, K.; Koldobskii, G. I.;
Hrabalek, A. Synthesis 2009, 2175.
IR (KBr): 3386, 3245, 3056, 2981, 2908, 2844, 2756, 2700, 2611,
2504, 2457, 1998, 1589, 1546, 1469, 1380, 1255, 1236, 1064, 985,
906, 829, 775, 744, 707, 526, 433 cm–1.
(6) Akhlaghinia, B.; Rezazadeh, S. J. Braz. Chem. Soc. 2012,
23, 2197.
(7) Palde, P. B.; Jamison, T. F. Angew. Chem. Int. Ed. 2011, 50,
3525.
(8) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.;
Vaccaro, L. J. Org. Chem. 2004, 69, 2896.
(9) Yoneyama, H.; Usami, Y.; Komeda, S.; Harusawa, S.
Synthesis 2013, 45, 1051.
(10) Benson, F. R. Chem. Rev. 1947, 41, 1.
(11) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii,
P. V. Mendeleev Commun. 2006, 16, 250.
(12) Mahajan, U. S.; Akamanchi, K. G. Synth. Commun. 2009,
39, 2674.
(13) Shiryaev, A. K.; Moiseev, I. K. Russ. J. Org. Chem. 2001,
37, 746.
(14) Lieber, E.; Enkoji, T. J. Org. Chem. 1961, 26, 4472.
(15) LeBlanc, B. W.; Jursic, B. S. Synth. Commun. 1998, 28,
3591.
(16) Zubarev, V. Yu.; Trifonov, R. E.; Poborchii, V. V.;
Ostrovskii, V. A. Chem. Heterocycl. Compd. 2006, 42, 469.
(17) Jin, T.; Kitahara, F.; Kamijo, S.; Yamamoto, Y. Tetrahedron
Lett. 2008, 49, 2824.
1H NMR (400 MHz, DMSO-d6): δ = 7.74–7.78 (m, 2 H, ArH),
7.88–7.92 (m, 2 H, ArH).
13C NMR (100 MHz, DMSO-d6): δ = 125.03, 131.32, 131.82,
155.24.
Anal. Calcd for C8H6N8: C, 44.86; H, 2.82; N, 52.32. Found: C,
44.93; H, 2.88; N, 52.25.
2-(1H-Tetrazol-5-yl)pyridine (4j)
After basification, the pH of the filtrate was adjusted to 6–7 with 9%
HCl, which caused the tetrazole to precipitate. The tetrazole was fil-
tered, washed with H2O (2 × 10 mL) and dried.
Yield: 1.28 g (91%); white solid; mp 212–213 °C (H2O) (Lit.3
211 °C).
IR (KBr): 3240, 3055, 1611, 1571, 1528, 1469, 1444, 1400, 1295,
1260, 1171, 1138, 1059, 1027, 803, 757, 731, 649 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.57 (t, J = 12.0 Hz, 1 H, ArH),
8.02 (t, J = 4.0 Hz, 1 H, ArH), 8.17 (d, J = 8.0 Hz, 1 H, ArH), 8.73
(d, J = 4.0 Hz, 1 H, ArH), 16.86 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 123.12, 126.61, 138.74,
144.18, 150.56, 155.31.
Anal. Calcd for C6H5N5: C, 48.98; H, 3.43; N, 47.60. Found: C,
49.15; H, 3.58; N, 47.46.
Synthesis 2014, 46, 781–786
© Georg Thieme Verlag Stuttgart · New York