Microwave-assisted synthesis of 1-aryl-5-(trifluoromethyl)-1H-tetrazoles

Article abstract of DOI:10.1016/j.jfluchem.2014.07.025

This general protocol provides a wide variety of 5-substituted-1H- tetrazoles in good yields under mild reaction conditions. An efficient, green, and convenient method for the preparation of new 5-substituted-tetrazoles via microwave-assisted 1,3-dipolar cycloaddition reaction of N-aryl-2,2,2- trifluoroacetimidoyl chlorides and sodium azide in acetonitrile without assistance of any catalyst has been reported. The FT-IR, ¹⁹F NMR, ¹H NMR, ¹³C NMR, HMBC spectra, elemental analysis, and single-crystal X-ray analysis confirm the structures of the products.

Full text of DOI:10.1016/j.jfluchem.2014.07.025

Journal of Fluorine Chemistry 166 (2014) 84–87
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Microwave-assisted synthesis of
1-aryl-5-(trifluoromethyl)-1H-tetrazoles
b
Fariba Rahmani a, Ali Darehkordi a, , Behrouz Notash
*
a Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
b Department of Chemistry, Shahid Beheshti University, G.C. Tehran 1983963113, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
This general protocol provides a wide variety of 5-substituted-1H-tetrazoles in good yields under mild
reaction conditions. An efficient, green, and convenient method for the preparation of new
5-substituted-tetrazoles via microwave-assisted 1,3-dipolar cycloaddition reaction of N-aryl-2,2,2-
trifluoroacetimidoyl chlorides and sodium azide in acetonitrile without assistance of any catalyst has
been reported. The FT-IR, 19F NMR, 1H NMR, 13C NMR, HMBC spectra, elemental analysis, and single-
crystal X-ray analysis confirm the structures of the products.
Received 7 July 2014
Received in revised form 25 July 2014
Accepted 26 July 2014
Available online 5 August 2014
Keywords:
ß 2014 Elsevier B.V. All rights reserved.
5-Substituted-1H-tetrazoles
N-Aryl-2,2,2-trifluoroacetimidoyl chlorides
1-Aryl-5-(trifluoromethyl)-1H-tetrazoles.
1. Introduction
However, many of these protocols have some disadvantages,
such as the use of toxic metals, strong Lewis acid, expensive
Tetrazoles are a class of heterocycles with a wide range of
applications that are receiving considerable attention. This
functional group has a role in coordination chemistry as ligands,
in materials science as specialty explosives and information
recording systems, as good potential inhibitors, and as inter-
mediates in a variety of synthetic transformations [1–3]. Moreover,
the tetrazole groups have found use in pharmaceuticals as
lipophilic spacers and carboxylic acid surrogates. Also the tetrazole
ring appears in some well-known drugs [4]. The outstanding
achievements of the pharmaceutical chemistry in the last decade
are due in no small way to the creation of novel drugs containing a
tetrazole ring as structural fragment. Tetrazoles have not been
found in nature. With rare exceptions these compounds do not
exhibit appreciable biological activity, but they are at the same
time resistant to biological degradation. It is this property that
makes it possible to use tetrazoles as isosteric substituents of
various functional groups in the development of biologically active
substances [5]. Therefore, a number of methods have been
reported for the preparation of tetrazoles [6]. One of the major
synthetic routes to tetrazole formation is the [2 + 3] cycloaddition
of an organonitrile and an azide salt [7–9].
reagents, low yield, harsh reaction conditions, water sensitivity,
and the presence of hydrazoic acid, which is toxic and explosive.
Thus, the development of a convenient and safe process for the
preparation of new tetrazole derivatives containing fluorine atom
is an interesting subject for investigation.
Microwave irradiation has long been considered as a green
technology because it often allows solvent-free reactions and its
level of energy consumption is low compared with more
traditional methods [10–17].
The short reaction time and expanded reaction range offered by
microwave-assisted organic synthesis are suited to the increased
demands in industry. In particular, there is a requirement in the
pharmaceutical industry for a higher number of novel chemical
entities to be produced, which requires chemists to employ a
number of resources to reduce the time for the production of
compounds.
Although there are many methods for the preparation of
tetrazole compounds; and the synthesis of different tetrazole
derivatives have been reported in literature, but there are a few
reports for synthesis of their trifluoromethylated derivatives [18].
In continuing of our studies [19–21], we now report synthesis of 1-
aryl-5-(trifluoromethyl)-1H-tetrazoles derivatives using reaction
of trifluoroacetimidoyl chloride derivatives with sodium azide in
acetonitrile by two methods: (a) in acetonitrile at room tempera-
ture and (b) in acetonitrile using microwave irradiation, in one pot
reaction.
*
Corresponding author. Tel.: +98 3913202440; fax: +98 3913202429.
E-mail addresses: darehkordi@vru.ac.ir, adarehkordi@yahoo.com
(A. Darehkordi).
http://dx.doi.org/10.1016/j.jfluchem.2014.07.025
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

F. Rahmani et al. / Journal of Fluorine Chemistry 166 (2014) 84–87
85
Table 1
Model reaction, conditions, and yield.
.
Scheme 1. Synthesis of trifluoromethylated tetrazoles derivatives.
Entry
Solvent
Conditions
Yield (%)
the interesting and remarkable biological activities of tetrazoles,
we require the synthesis of the tetrazole-annulated trifluoro-
methyl derivative with the following structure (see Scheme 1).
In this research, imidoyl halides are obtained via refluxing a
mixture of trifluoroacetic acid and a primary amine in carbon
tetrachloride in the presence of triethylamine and triphenylpho-
sphine [21,22]. A variety of acetymidoyl chlorides were examined
to generate the desired coupled products.
1
2
3
4
5
6
CH3CN
THF
RT, 7 h
RT, 7 h
RT, 7 h
RT, 7 h
RT, 7 h
RT, 7 h
78
56
Toluene
CH2Cl2
DMF
43
46
31
H2O
No reaction
2. Results and discussion
New 5-substituted-tetrazoles via microwave-assisted 1,3-
dipolar cycloaddition reaction of N-aryl-2,2,2-trifluoroacetimidoyl
chlorides and sodium azide in acetonitrile without using any
Trifluoromethylated tetrazoles are very important due to the
various and high biological properties. In this research, to increase
Table 2
Synthesis of 1-aryl-5-(trifluoromethyl)-1H-tetrazoles 3a–3j.
Compound
R1
Product
Room temperature
Microwave condition
Melting point (8C)
Time
6
Isolated yield (%)
Microwave irradiation time (min)
10
Isolated yield (%)
95
3a
H
84
Yellow oil
3b
3c
2-Br
7
7
78
10
10
92
90
63–64
2,4-dimethy
76
Yellow oil
3d
3e
4-Cl
6
8
78
69
10
9
95
94
Yellow oil
4-CH3
Yellow oil[23]
3f
2-CF3
7
68
8
97
73–74
3g
3h
4-NO2
8
8
71
75
8
96
94
70–71
4-OCH3
10
Yellow oil
3i
3j
2-OCH3
8
8
76
78
10
10
94
95
Yellow liquid
105–106
Naphthalene

86
F. Rahmani et al. / Journal of Fluorine Chemistry 166 (2014) 84–87
4. Conclusion
In conclusion, we described a microwave-assisted 1,3-dipolar
cycloaddition reaction for the synthesis of trifluoromethylated
tetrazole derivatives in the absence of any catalyst. The use of
microwave conditions not only made the reaction feasible, but also
added additional beneficial features to the reaction such as
shortened reaction time. This new process provided an environ-
mentally useful conventional organic solvent, easy work up, and
reduced waste production by the lack of catalysts or additive agents.
5. Experimental
5.1. General methods
Fig. 1. The ORTEP diagram of 3b. Thermal ellipsoids are at 30% probability level.
Ethos 1 advanced Microwave Digestion system Milestone was
used for synthesis of compounds. Melting points were determined
on a Melt-Tem II melting point apparatus and are uncorrected. IR
spectra were obtained on a Matson-1000 FT-IR spectrometer.
Peaks are reported in wave numbers (cmÀ1). All of the NMR spectra
were recorded on a Bruker model DRX-300 AVANCE (1H: 300 13C:
catalysts have been reported. Organic solvents are very important
as liquid medium for reactions to take place, and after the synthesis
of a chemical product for extraction, separation, purification, and
drying. In search of an effective solvent and to optimize the
experimental conditions, the reaction of N-(2-bromophenyl)-
2,2,2-trifluoroacetimidoyl chloride and sodium azide was consid-
ered as the model reaction, reaction was carried out with magnetic
stirring for 7 h at room temperature (Table 1). The reaction in
CH3CN proceeded in excellent yield (entry 1). On the other hand,
the reactions in THF, toluene, CH2Cl2, and DMF resulted in
moderate and insufficient yields (entries 2–5). We then examined
the generality of the reaction in CH3CN. As a refinement of our
method, we next sought to carry out the reaction under microwave
irradiation. As shown in Table 2, these reactions normally
proceeded in improved yields compared to the previous method,
and with the obvious advantage of a faster and more convenient
operation. As summarized in Table 2, a variety of substituents, both
electron withdrawing and electron releasing, could be accommo-
dated without significant differences in reaction time or yield.
Besides the much milder conditions and shortened reaction times,
our method also represents a considerable improvement in yield.
Another advantage of this reaction is easy purification of products
without using chromatography or recrystallization. The crude
product was simply washed with n-hexane for purification. This is
an important advantage to reduce costs in industry. The present
study revealed the results using a wide variety of imidoyl chloride
75, 19F: 235 MHz) NMR spectrometer. Chemical shifts of 1H and 13
C
NMR are reported in parts per million (ppm) from tetramethylsi-
lane (TMS) as an internal standard in DMSO-d6 or CDCl3 as a
solvent and 19F NMR are reported in parts per million (ppm) from
CFCl3 as an internal standard in DMSO-d6 or CDCl3 as a solvent. The
crystallographic information file has been deposited with the
Cambridge Data Centre, CCDC 1006291.
BB. X-STEP32 Version 1.07b, Crystallographic Package; Stoe & Cie
GmbH: Darmstadt, Germany, 2000.
5.2. General procedure A
A mixture of acetimidoyl chloride (1 mmol), sodium azide
(1 mmol), and acetonitrile (5 mL) was stirred at room temperature
for appropriate time (6–8 h), after completion of the reaction, as
indicated by TLC, the reaction mixture was filtered. After removing
the solvent under reduced pressure, if necessary, the crude
products were purified by washing with n-hexane to give the
target product 3a–3j (69–84%).
5.3. General procedure B
a
straightforward procedure with much milder conditions,
shortened reaction times, simple purification, and a high yield.
X-ray crystallographic analysis revealed the structure of
compound 3b as depicted in Fig. 1.
A mixture of acetimidoyl chloride (1 mmol), sodium azide
(1 mmol), and acetonitrile (3 mL) was irradiated in a microwave
oven at 300 W for 8–10 min, after completion of the reaction, as
indicated by TLC, the reaction mixture was filtered. After removing
the solvent under reduced pressure, if necessary, the crude
products were purified by washing with n-hexane to give the
target product 3a–3j (90–95%).
3. X-ray crystallography
X-ray data for 3b: C8H4N4BrF3, M = 293.05, orthorhombic
system, space group P212121, a = 6.0152(12), b = 9.3822(19),
3
c = 17.933(4) A; V = 1012.1(4) A , Z = 4, Dcalcd = 1.923 g cmÀ3
,
m(Mo–
5.4. Characterization
˚
˚
Ka
) = 4.082 mmÀ1, crystal dimension of 0.40 Â 0.35 Â 0.35 mm. The
X-ray diffraction measurement was made on a STOE IPDS-2T
5.4.1. 1-phenyl-5-(trifluoromethyl)-1H-tetrazole (3a)
diffractometer with graphite monochromated Mo–K
structure was solved by using SHELXS.
a
radiation. The
Prepared according to General Procedure A and B, pale yellow
oil, (yield: 95%). IR (neat, cmÀ1): 3071, 1531, 1499, 1H NMR (DMSO,
The data reduction and structure refinement was carried out
with SHELXL using the X-STEP32 crystallographic software
package. The non-hydrogen atoms were refined anisotropically
by full matrix least-squares on F2 values to final R1 = 0.0684,
wR2 = 0.1481, and S = 1.026 with 145 parameters using 2657
300 MHz)
(DMSO, 75 MHz):
129.79, 129.76, 125.05, 117.73 (q, J = 270.0 Hz), 19F NMR (DMSO,
235 MHz) 59.78 ppm. Elemental analysis: value calculated for
d
7.72–7.78 (m, 2 H), 7.70–7.74 (m, 3 H), 13C NMR
d
145.90 (q, J = 42.0 Hz), 132.41, 131.59, 131.58,
d
C8H5F3N4: C, 44.87%; H, 2.35%; N, 26.16%; value found: C, 44.47%;
H, 2.24%; N, 26.55%.
independent reflection (u range = 3.14–29.148). Hydrogen atoms
were added in idealized positions. The crystallographic informa-
tion file has been deposited with the Cambridge Data Centre, CCDC
1006291. X-STEP32 Version 1.07b, Crystallographic Package; Stoe &
Cie GmbH: Darmstadt, Germany, 2000.
5.4.2. 1-(2-bromophenyl)-5-(trifluoromethyl)-1H-tetrazole (3b)
Prepared according to General Procedure A and B, white
powder, m.p = 63–64 8C (yield: 92%). IR (neat, cmÀ1): 3080, 1537,

F. Rahmani et al. / Journal of Fluorine Chemistry 166 (2014) 84–87
87
1490. 1H NMR (DMSO, 300 MHz):
(m, 2 H). Elemental analysis: value calculated for C8H4BrF3N4: C,
32.79%; H, 1.38%; N, 19.12%; value found: C, 32.54%; H, 1.44%; N,
19.35%.
d
8.04–8.01 (m, 2 H), 7.76–7.69
C, 44.27%; H, 2.89%; N, 22.95%; value found: C, 43.81%; H, 2.81%; N,
22.35%.
5.4.9. 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole (3i)
Prepared according to General Procedure A and B, pale yellow
oil (yield: 97.6%)._IR (neat, cmÀ1): 1601, 1563, 1506, and 1470. 1H
5.4.3. 1-(2,4-dimethylphenyl)-5-(trifluoromethyl)-1H-tetrazole(3c)
Prepared according to General Procedure A and B, yellow oil, IR
NMR (DMSO, 300 MHz):
(dd, J = 7.8, 1.7 Hz, 1 H), 7.14-7.08 (m, 2 H), 3.79 (s, 3H). 13C NMR
(DMSO, 75 MHz): 153.55, 147.00 (q, J = 41.5 Hz), 133.19, 127.22,
121.00, 120.59, 117.60 (q, J = 270.4 Hz), 112.07, 55.76. Elemental
analysis: value calculated for C9H7F3N4O: C, 44.27%; H, 2.89%; N,
22.95%; value found: C, 44.35%; H, 3.18%; N, 23.05%.
d 7.59 (ddd, J = 7.8, 7.5, 1.7 Hz, 1 H), 7.36
(neat, cmÀ1): 3091, 1543, and 1487. 1H NMR (CDCl3, 300 MHz)
d:
2.17, 2.30(s, 6H, CH3), 7.02–7.20(m, 3 H, Ar). Elemental analysis:
value calculated for chemical formula: C10H9F3N4: C, 49.59%; H,
3.75%; N, 23.13%; value found C, 49.21%; H, 3.88%; N, 23.44%.
d
5.4.4. 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-tetrazole (3d)
Prepared according to General Procedure A and B, pale yellow
oil (yield: 92.2%). IR (neat, cmÀ1): 3101, 1531, and 1497. 1H NMR
5.4.10. 1-(naphthalen-1-yl)-5-(trifluoromethyl)-1H-tetrazole (3j)
Prepared according to General Procedure A and B, white
powder, m.p. = 105–106 8C (yield: 94.1%). IR (KBr, cmÀ1): 3067,
(DMSO, 300 MHz):
d
7.60–7.56 (m, 2 H), 7.47–7.43 (m, 2 H). 13C
146.02 (q, J = 42.0 Hz), 138.13, 130.94,
NMR (DMSO, 75 MHz):
d
1599, and 1531. 1H NMR (DMSO, 300 MHz):
d
8.11 (d, J = 8.3 Hz,
1H) 7.96 (d, J = 8.3 Hz, 1H), 7.62–7.50 (m, 4H), 7.02 (d, J = 8.3 Hz,
1H). 13C NMR (DMSO, 75 MHz):
147.68 (q, J = 42.0 Hz), 133. 91,
130.25, 126.48, 117.75 (q, J = 270.9 Hz). Elemental analysis: value
calculated for C8H4ClF3N4: C, 38.65%; H, 1.62%; N, 22.93%; value
found: C, 38.51%; H, 1.74%; N, 22.40%.
d
132.55, 128.81, 128.73, 128.46, 128.40, 127.64, 125.10, 124.63,
120.74, 117.74 (q, J = 270.9 Hz). Elemental analysis: value calcu-
lated for C12H7F3N4: C, 54.55%; H, 2.67%; N, 21.21%; value found: C,
54.27%; H, 2.66%; N, 21.21%.
5.4.5. 1-(4-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole (3e)
Prepared according to General Procedure A and B, pale yellow
oil (yield: 97.3%). IR (neat, cmÀ1): 3045, 2930, 1531, and 1514. 1H
NMR (DMSO, 300 MHz):
NMR (DMSO, 75 MHz):
d
7.37–7.31 (m, 4 H), 2.42 (s, 3 H). 13C
145.96 (q, J = 41.2 Hz), 142.28, 130.33,
Acknowledgment
d
129.95, 124.83, 117.81 (q, J = 270.9 Hz), 21.10. Elemental analysis:
value calculated for C9H7F3N4: C, 47.37%; H, 3.09%; N, 24.98%;
value found: C, 46.89%; H, 2.63%; N, 24.64%
We gratefully acknowledge, the Vail-e-Asr University of
Rafsanjan Faculty Research Grant for financial support.
References
5.4.6. 1-(2-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-1H-
tetrazole (3f)
[1] J.R. Li, Y. Tao, Q. Yu, X.H. Bu, H. Sakamoto, S. Kitagawa, Chem-Eur. J. 14 (2008)
2771–2776.
[2] S.J. Wittenberger, Org. Prep. Proced. Int. 26 (1994) 499–531.
[3] P.N. Gaponik, S.V. Voitekhovich, O.A. Ivashkevich, Russ. Chem. Rev. 75 (2006)
507–516.
[4] R.D. Smith, J.V. Denuncia, R.J. Lee, D.D. Christ, A.T. Chiu, D.J. Carini, W.F. Herblin,
P.B.M.W.M. Timmermans, R.R. Wexler, Methods Neurosci. 13 (1993) 258–261.
[5] L.V. Myznikov, A. Hrabalek, G.I. Koldobskii, Chem. Heterocycl. Comp. 43 (2007)
1–9.
[6] A.R. Katritzky, C. Cai, N.K. Meher, Synthesis (2007) 1204–1208.
[7] P. Magnus, G.M. Taylor, J. Chem. Soc. 1 (1991) 2657–2661.
[8] T. Jin, S. Kamijo, Y. Yamamoto, Tetrahedron Lett. 45 (2004) 9435–9437.
[9] L. Lang, B. Li, W. Liu, L. Jiang, Z. Xu, G. Yin, Chem. Commun. (2010) 448–450.
[10] A. de la Hoz, A. Dı´az-Ortiz, A. Moreno, F. Langa, Eur. J. Org. Chem. 22 (2000) 3659–
3673.
[11] L. Perreux, A. Loupy, Tetrahedron 57 (2001) 9199–9223.
[12] P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57 (2001) 9225–9283.
[13] V. Santagada, E. Perissutti, G. Caliendo, Curr. Med. Chem. 9 (2002) 1251–1283.
[14] A. Loupy, Microwaves in Organic Synthesis, Wiley-VCH, Weinheim, 2002.
[15] B.L. Hayes, Aldrichim. Acta 37 (2004) 66–76.
[16] C.O. Kappe, Angew. Chem. Int. Ed. 43 (2004) 6250–6281.
[17] J. Tierney, P. Lindstrom, Microwave-Assisted Organic Synthesis, Blackwell,
London, 2005.
[18] K. Uneyama, F. Yamashita, K. Sugimoto, O. Morimoto, Tetrahedron Lett. 31 (1990)
2717–2720.
[19] A. Darehkordi, M. Javanmiri, S. Ghazi, S. Assar, J. Fluorine Chem. 132 (2011)
263–268.
Prepared according to General Procedure A and B, white powder
m.p. = 73–74 8C (yield: 97%). IR (neat, cmÀ1): 3091, 1612, and 1547,
1H NMR (DMSO, 300 MHz):
d
8.22–8.16 (m, 2 H), 8.01–8.05 (m,
2 H). 13C NMR (DMSO, 75 MHz):
d
135.12, 134.14, 130.62, 129.25,
28.63, 128.55, 124.97, 120.63, 120.09, 115.76. Elemental analysis:
value calculated for C9H4F6N4: C, 38.31%; H, 1.43%; N, 19.86%;
value found: C, 38.12%; H, 1.58%; N, 19.73%.
5.4.7. 1-(4-nitrophenyl)-5-(trifluoromethyl)-1H-tetrazole(3g)
Prepared according to General Procedure A and B, white
powder, m.p. = 70–71?C (yield: 97%). IR (neat, cm-1): 3091, 1612,
and 1547, 1H NMR (DMSO, 300 MHz):
d 8.56–8.53 (d, J = 8.7 Hz,
2H), 8.01–8.05 (d, J = 8.4 Hz, 2H). Elemental analysis: value
calculated for C8H4F3N5O2: C, 37.08%; H, 1.56%; N, 27.02%; value
found: C, 37.21%; H, 1.54%; N, 27.21%.
5.4.8. 1-(4-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole (3h)
Prepared according to General Procedure A and B, pale yellow
oil (yield: 98.3%). IR (neat, cmÀ1): 1609, 1533, 1514, and 1466. 1H
NMR (DMSO, 300 MHz):
d
7.38 (d, J = 8.7 Hz, 2 H), 7.06 (d,
161.
J = 8.7 Hz, 2 H), 3.89 (s, 3 H). 13C NMR (DMSO, 75 MHz):
d
[20] A. Darehkordi, F. Rahmani, V. Hashemi, Tetrahedron Lett. 54 (2013) 4689–4692.
[21] A. Darehkordi, H. Khabazzadeh, K. Saidi, J. Fluorine Chem. 126 (2005) 1140–1143.
[22] K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem. 58
(1993) 32–35.
72, 146.03 (q, J = 42.1 Hz), 126.51, 124.95, 117.81 (q, J = 270.6 Hz),
114.87, 55.72. Elemental analysis: value calculated for C9H7F3N4O: