Practical synthesis of 5-substituted tetrazoles under microwave irradiation

Article abstract of DOI:10.1055/s-0029-1216840

5-Substituted tetrazoles were prepared by treatment of nitriles with sodium azide and triethylammonium chloride in nitrobenzene in a microwave reactor. This practical method combines the advantages of previous procedures, including good-to-excellent yields, short reaction times, and easy isolation of the product. Moreover, sterically hindered tetrazoles, as well as those deactivated by electron-donating groups, can be prepared. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216840

PAPER
2175
Practical Synthesis of 5-Substituted Tetrazoles under Microwave Irradiation
5
-Substitu
a
ted Tetrazo
r
les oslav Roh,*a Tatjana V. Artamonova,b Kateꢀina Vávrová,a Grigorii I. Koldobskii,b Alexandr Hrabáleka
a
Faculty of Pharmacy, Centre for New Antivirals and Antineoplastics, Charles University,
Heyrovského 1203, 50005 Hradec Kralove, Czech Republic
Fax +420(495)067166; E-mail: jaroslav.roh@faf.cuni.cz
b
St. Petersburg State Institute of Technology, Moskovskii pr. 26, 190013 St. Petersburg, Russian Federation
Received 16 February 2009
nometallic side products, problems can occur in purifying
the products.
Abstract: 5-Substituted tetrazoles were prepared by treatment of
nitriles with sodium azide and triethylammonium chloride in ni-
trobenzene in a microwave reactor. This practical method combines
the advantages of previous procedures, including good-to-excellent
yields, short reaction times, and easy isolation of the product. More-
over, sterically hindered tetrazoles, as well as those deactivated by
electron-donating groups, can be prepared.
Microwave (MW) irradiation of the reactants in hydro-
philic media (water, N,N-dimethylformamide, dioxane,
1,2-dimethoxyethane, or ionic liquids) has also been used
recently, but with the exception of shorter reaction times,
substantial optimization has not been achieved.7 All the
methods are efficient only for the preparation of tetrazoles
from sterically unhindered nitriles or those bearing an
electron-accepting substituent attached to the nitrile
group. Otherwise, long reaction times and more-forcing
reaction conditions have to be used to achieve reasonable
yields.
Key words: tetrazoles, microwave irradiation, sodium azide, het-
erocycles, nitriles
The preparation of variously substituted tetrazoles has
been the subject of intense investigation, especially over
the past few decades. These heterocycles have found
widespread use as ligands in coordination chemistry, in
the photographic industry, as components of special ex-
plosives,1 and, above all, in pharmaceutical chemistry.
The first attempts to optimize their preparation were made
by Finnegan and coworkers2 50 years ago, and various
modifications of their method, which is based on the reac-
tion of nitriles with sodium azide in N,N-dimethylform-
amide, have been used. However, this method is not
optimal, particularly when sterically hindered nitriles or
those with electron-donating substituents are used as start-
ing materials, or when the tetrazoles that are obtained are
very hydrophilic. In such cases, difficulties in isolating the
products or the extreme duration of the reaction can be se-
rious drawbacks.
The aim of this study was to find a practical method for
synthesis of tetrazoles that combines the advantages of
previous procedures, namely good yields in short times,
versatility, and easy isolation of the products.
The general reaction is outlined in Scheme 1. To take ad-
vantage of MW irradiation, we focused our attention on
the use of hydrophobic solvents with large dipole mo-
ments. Toluene, as employed by Koguro et al.,8 is unsuit-
able because of its low absorption of MW radiation
(m = 1.0 × 1030 Cm). Chlorobenzene and anisole gave
slightly higher yields. As shown in Table 1, nitrobenzene
was found to be the solvent of choice because of its high
dipole moment and its minimal water solubility, which fa-
cilitates the extraction of tetrazoles, in the form of their
salts, into aqueous solution. Moreover, there is no need to
use dried solvents, as shown by entry 7 in Table 1.
Wiberg and Michaud were the first to use a Lewis acid in
a nonaqueous medium for tetrazole synthesis,3 but this
modification did not make the procedure more economi-
cal. Later, Demko and Sharpless4 published an improved
method, but they did not succeed in shortening the reac-
tion times; also, the reaction of less-reactive nitriles re-
quired temperatures as high as 170 °C in an autoclave.
N
HN
NaN3, Et3N⋅HCl
CN
N
R
PhNO2, MW
N
R
Scheme 1
The latest reports describe the use of organometallic re-
agents that serve as donors of the azide anion.5 However,
not even the use of these reagents markedly decreases the
reaction times that are necessary to obtain good yields of
tetrazoles; furthermore, the reagents suffer the combined
disadvantages of being both costly and toxic. Moreover,
because of the production of equimolar amounts of orga-
The reactions were carried out in a microwave reactor at a
constant temperature, as measured at the surface of the re-
action flask by an external infrared thermometer (see
Table 2 and Table 3). The average MW power values are
given in Tables 2 and 3, which present an overview of the
preparation of water-insoluble and water-soluble tetra-
zoles, respectively. The advantages of this method are a
substantial decrease in reaction times compared with the
method of Koguro et al.,8 good-to-excellent yields, and, in
most cases, isolation of the products by simple aqueous
SYNTHESIS 2009, No. 13, pp 2175–2178
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x.
x
x
.
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0
0
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Advanced online publication: 27.05.2009
DOI: 10.1055/s-0029-1216840; Art ID: P02809SS
© Georg Thieme Verlag Stuttgart · New York

2176
J. Roh et al.
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Table 2 Water-Insoluble Tetrazoles
Table 1 Conversion of Benzonitrile into 5-Phenyl-1H-tetrazole
(1a) in the Presence of Sodium Azide (1.3 equiv) and Triethylammo-
nium Chloride (1.3 equiv) under Microwave Irradiation
Set temp Average Time Tetrazole
Yield
(%)a
(°C)
power (W)(h)
Entry Solvent
m (1030 Cm)a Temp (°C) Time (h) Yield (%)
H
N
1a 100
75
75
75
2
3
1
93
91
92
1
2
3
4
5
6
7
PhCl
5.6
4.2
14.0
5.6
4.2
14.0
–
100
100
100
100
100
100
100
0.5
0.5
0.5
2
49
56
56
83
87
93
88
N
N
N
PhOMe
PhNO2
PhCl
H
N
1b 100
N
N
N
H
N
PhOMe
PhNO2
2
1c
100
N
N
O2N
2
N
N
b
HN
HN
PhNO2
2
N
a See reference 6,
N
N
1d 100
75
75
6
4
90
b Saturated with H2O.
N
N
extraction with recycling of the solvent and without the
need for column chromatography.
N
HN
N
1e
100
H2N
81
30
The second notable advantage of this method is the possi-
bility of converting electron-rich nitriles (alkyl or cy-
cloalkyl nitriles) or sterically hindered nitriles (e.g.,
adamantane-1-carbonitrile) into the corresponding tetra-
zoles. For example, 5-undecyl-1H-tetrazole (1i), the con-
ventionally preparation of which requires refluxing for
three days in toluene,9 was obtained in 60% yield in 12
hours (Table 2). 2,4-Dimethoxybenzonitrile, a nitrile
whose reactivity is decreased by both steric hindrance and
the presence of electron-donating groups, was successful-
ly converted into 5-(2,4-dimethoxyphenyl)-1H-tetrazole
(1f) (Table 2). Tetrazoles 1g, 1o, and 1p, which contain
chemically sensitive ester bonds, could also be prepared
(Tables 2 and 3); interestingly, no hydrolysis products
were detected in the reaction mixtures.
N
N
MeO
HN
N
1fb 125
100
75
4
3
N
MeO
N
HN
N
1g 100
1h 100
85
O
N
O
N
HN
75
75
2
80
60
N
N
H
N
1i
100
12
N
Me(CH2)10
It should also be emphasized that previously described
methods for the synthesis of 5-substituted tetrazoles that
use ammonium azide suffer from the problem of sublima-
tion of the highly explosive and toxic salt from the reac-
tion mixture and its crystallization in the condenser. With
our method, this sublimation does not occur even at longer
reaction times, thereby increasing the overall safety of the
procedure.
N
N
H
N
1jb 100
75
8
32
N
N
N
N
N
H
N
S
N
N
N
1k 80
50
75
4
8
83
54
N
N
In conclusion, a practical method has been developed for
the preparation of 5-substituted tetrazoles that combines
the advantages of previous methods. Note that the proce-
dure can be scaled up to 100-gram amounts of the starting
nitriles without decreasing the yields.
H
N
1l
100
N
N
N
a Isolated yields.
Reactants for the preparation of tetrazoles 1g, 1k, and 1p were pre-
pared according to known procedures.10,11 All other chemicals were
purchased from Sigma-Aldrich (Schnelldorf, Germany). Melting
points were recorded on a Kofler apparatus and are uncorrected. 1H
NMR and 13C NMR spectra were recorded on a Varian Mercury-Vx
BB 300 spectrometer. Microwave reactions were conducted in a
Milestone MicroSYNTH Ethos 1600 URM apparatus.
b 2 equiv each of NaN3 and Et3N·HCl were used.
Tetrazoles 1a–p: General Procedure
Et3N·HCl (10.5 mmol) and NaN3 (10.5 mmol) were added to the so-
lution of the nitrile (8 mmol) or dinitrile (4 mmol) in PhNO2 (30
mL), and the mixture was heated with continuous stirring in the mi-
crowave reactor under the conditions summarized in Tables 2
and 3.
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5-Substituted Tetrazoles
2177
13C NMR (75 MHz, DMSO-d6): d = 112.0, 114.4, 116.8, 124.7,
Table 3 Water-Soluble Tetrazoles
130.1, 149.7, 155.8.
Set temp Average
Time Tetrazole
Yield
(%)a
(°C)
power (W) (h)
5-(2,4-Dimethoxyphenyl)-1H-tetrazole (1f)
Yield: 30%; mp 175 °C (EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 3.84 (s, 3 H), 3.95 (s, 3 H),
6.70–6.77 (m, 2 H), 8.02 (d, J = 8.5 Hz, 1 H).
N
HN
N
1m 100
75
4
78
N
N
N
13C NMR (75 MHz, DMSO-d6): d = 55.8, 56.0, 98.7, 105.1, 106.7,
130.7, 151.2, 158.1, 163.4.
NH
N
N
HN
1n
1o
80
50
75
8
4
59
69
Anal. Calcd. for C9H10N4O2: C, 52.42; H, 4.89; N, 27.17; O, 15.52.
Found: C, 51.97; H, 4.59; N, 26.90.
N
N
N
HN
O
100
1H-Tetrazol-5-ylmethyl Benzoate (1g)
N
Yield: 85%; mp 120–122 °C (no recrystallization).
1H NMR (300 MHz, DMSO-d6): d = 5.68 (s, 2 H), 7.51–7.59 (m, 2
H), 7.65–7.73 (m, 1 H), 8.00–8.05 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 56.1, 128.9, 129.1, 129.7,
N
N
MeO
HN
N
1p
100
75
4
71
O
N
O
134.1, 153.3, 165.4.
a Isolated yields.
5-Benzyl-1H-tetrazole (1h)
Yield: 80%; mp 121–123 °C (H2O).
1H NMR (300 MHz, DMSO-d6): d = 4.28 (s, 2 H), 7.22–7.37 (m, 5
H).
13C NMR (75 MHz, DMSO-d6): d = 29.1, 127.2, 128.8, 128.9,
136.1, 155.4
Water-Insoluble Tetrazoles
The mixture was extracted with H2O or 2% aq NaOH (3 × 20 mL).
The combined aqueous extracts were extracted with Et2O (2 × 20
mL) and then acidified with aq HCl. The resultant precipitate was
filtered off and crystallized. In some cases, the reaction mixture be-
came dark, and consequently the isolated product was yellow-
brown. Simple crystallization with charcoal afforded pure products.
5-Undecyl-1H-tetrazole (1i)
Yield: 60%; mp 72–73 °C (MeCN).
1H NMR (300 MHz, CDCl3): d = 0.83 (t, J = 6.5 Hz, 3 H), 1.15–1.30
(m, 16 H), 1.58–1.73 (m, 2 H), 2.84 (t, J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.2, 22.3, 22.9, 27.2, 28.5, 28.8,
5-Phenyl-1H-tetrazole (1a)
Yield: 93%; mp 217–218 °C (H2O–EtOH).
1H NMR (300 MHz, DMSO-d6): d = 7.54–7.64 (m, 3 H), 7.98–8.06
(m, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 124.3, 127.2, 129.6, 131.5,
155.4.
28.9, 29.1, 29.2, 31.5, 156.1.
Anal. Calcd for C12H24N4: C, 64.24; H, 10.78; N, 24.97. Found: C,
64.26; H, 10.82; N, 24.93.
5-(Adamantan-1-yl)-1H-tetrazole (1j)
Yield: 32%; mp 250 °C (EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 1.68–1.78 (m, 6 H), 1.96 (m,
6 H), 2.00–2.08 (m, 3 H).
5-(4-Tolyl)-1H-tetrazole (1b)
Yield: 91%; mp 244–245 °C (H2O–EtOH).
1H NMR (300 MHz, DMSO-d6): d = 2.37 (s, 3 H), 7.39 (d, J = 8.0
Hz, 2 H), 7.91 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 21.2, 121.5, 127.1, 130.2,
13C NMR (75 MHz, DMSO-d6): d = 27.6, 32.3, 36.0, 40.7, 163.2.
Anal. Calcd for C11H16N4: C, 64.68; H, 7.89; N: 27.43. Found: C,
64.29; H, 7.73; N: 27.15.
141.4, 155.3.
5-(4-Nitrophenyl)-1H-tetrazole (1c)
Yield: 92%; mp 218–219 °C (H2O–EtOH).
1H NMR (300 MHz, DMSO-d6): d = 8.28 (d, J = 9.0 Hz, 2 H), 8.42
(d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 124.8, 128.4, 130.8, 148.9,
1-Phenyl-5-[(1H-tetrazol-5-ylmethyl)sulfanyl]-1H-tetrazole
(1k)
Yield: 83%; mp136–137 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): d = 4.90 (s, 2 H), 7.60–7.75 (m, 5
H).
155.6.
13C NMR (75 MHz, DMSO-d6): d = 153.9, 153.3, 133.1, 131.0,
130.3, 124.7, 25.3
5,5'-(1,2-Phenylene)bis(1H-tetrazole) (1d)
Yield: 90%; mp 232–233 °C (EtOH).
1H NMR (300 MHz, DMSO-d6): d = 7.76–7.85 (m, 2 H), 7.86–7.95
(m, 2 H).
5-Cyclohexyl-1H-tetrazole (1l)
Yield: 54%; mp 131 °C (H2O).
1H NMR (300 MHz, DMSO-d6): d = 1.1–2.1 (m, 10 H), 2.90–3.05
(m, 1 H).
13C NMR (75 MHz, DMSO-d6): d = 124.7, 131.0, 131.6, 155.0.
13C NMR (75 MHz, DMSO-d6): d = 25.2, 25.4, 30.9, 32.9, 159.8.
3-(1H-Tetrazol-5-yl)aniline (1e)
Yield: 81%; mp 199–201 °C (H2O).
1H NMR (300 MHz, DMSO-d6): d = 6.74 (d, J = 8.0 Hz, 1 H), 7.08–
7.28 (m, 3 H).
Water-Soluble Tetrazoles
The mixture was extracted with H2O (3 × 15 mL). The resulting
aqueous phase was washed with Et2O (2 × 20 mL) then acidified
with HCl, saturated with NaCl, and extracted with EtOAc (3 × 20
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J. Roh et al.
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mL). The combined organic extracts were evaporated, and the crude
product was crystallized.
References
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5,5¢-Ethane-1,2-diylbis(1H-tetrazole) (1m)
Yield: 78%; mp 247 °C (i-PrOH or EtOH).
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13C NMR (75 MHz, DMSO-d6): d = 21.0, 155.0.
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Yield: 59%; mp 147 °C (EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 2.47 (s).
13C NMR (75 MHz, DMSO-d6): d = 8.6, 152.4.
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Yield: 69%; mp 153–155 °C (EtOAc).
1H NMR (300 MHz, DMSO-d6): d = 3.66 (s, 3 H), 4.18 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 29.5, 52.6, 150.7, 168.4.
(1H-Tetrazol-5-yl)methyl Acetate (1p)
Yield: 71%; oil.
1H NMR (300 MHz, DMSO-d6): d = 2.1 (s, 3 H), 5.4 (s, 2 H).
13C NMR (75 MHz, DMSO-d6): d = 20.6, 55.1, 153.3, 170.1.
Acknowledgment
This work was supported by the Czech Science Foundation (203/07/
1302), by the Ministry of Education of the Czech Republic (project
no. MSM0021620822 and Research Centre for New Antivirals and
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Synthesis 2009, No. 13, 2175–2178 © Thieme Stuttgart · New York