Synthesis of polysubstituted-1,2,4-triazoles

Article abstract of DOI:10.1002/jhet.1031

A new series of substituted 1,2,4-triazole derivatives have been synthesized using substituted imido derivatives and isonicotinyl hydrazine (or 4-nitrobenzoylhydrazine) as the key intermediates. These compounds include different donor or acceptor substitu

Full text of DOI:10.1002/jhet.1031

February 2013
Synthesis of Polysubstituted‐1,2,4‐Triazoles
E39
*
Guiyan Liu, Xueli Wu, and Xuefang Shi
College of Chemistry, Tianjin Key Laboratory of Structure and Performance for Functional
Molecules, Tianjin Normal University, Tianjin 300387, China
*
E-mail: xuefangshi@yahoo.com.cn
Received March 28, 2011
DOI 10.1002/jhet.1031
Published online 7 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
A new series of substituted 1,2,4‐triazole derivatives have been synthesized using substituted imido derivatives
and isonicotinyl hydrazine (or 4‐nitrobenzoylhydrazine) as the key intermediates. These compounds in-
clude different donor or acceptor substituents on the 1,2,4‐triazole derivatives. The structures of these com-
pounds were confirmed by FTIR, 1H‐NMR, 13C‐NMR, and elemental analysis.
J. Heterocyclic Chem., 50, E39 (2013).
INTRODUCTION
2a–2e [19], and 3a‐3e [19] were synthesized and
purified according to procedures in the literature. The
starting material 4‐nitrobenzoylhydrazine and 4‐
pyridinecarbonylhydrazine were also prepared according to
a literature method [20]. Compounds 4a, 4b, 4c, 4d,
4e, 4f, and 4g were prepared by refluxing a 1:1 mixture
of the corresponding 3 and isonicotinyl hydrazine (or
4‐nitrobenzoylhydrazine) in N,N‐dimethylacetamide
for several hours. After removal of the solvent,
recrystallization or column chromatography yielded
53–79% of the corresponding 1,2,4‐triazoles derivate 4
(Scheme 1).
1,2,4‐Triazole and its derivatives constitute an important
class of organic compounds with diverse biological activities.
They can be widely used in agriculture and industry, as
well as other fields [1–9]. These compounds are also very
interesting ligands because they combine the coordination
geometry of both pyrazoles and imida‐zoles with regard to
the arrangement of their three heteroatoms [10]. The
zomethine (CH═N) linkages present in the backbone provide
an attractive class of high performance materials [11]. The
synthesis of these heterocycles has received considerable at-
tention in recent years [7, 12–14]. In this article, a series of
new 3,4,5‐trisubstituted‐1,2,4‐triazole and their derivatives
have been synthesized through molecular cyclization [15].
This method is not only simple but also has a high yield com-
pared with traditional synthetic methods [2, 16]. The syn-
thetic route for the 1,2,4‐triazole derivatives is depicted in
Scheme 1.
1
In the H‐NMR spectra of compounds 4a–4f, a new
singlet peak in the region 2.28–2.37 ppm was observed
1
which is due to CH3 protons. In the H‐NMR spectra
of 5a and 5b, the CH3 protons gave a singlet peak at
2.33 and 2.34 ppm, respectively. The methoxy protons
of 4b, 4c, 4e, 4f, 5a, and 5b exhibited a signal peak
in the 3.81–3.88 ppm region. All spectra are shown in
Figure 1.
To prepare 5a and 5b, 4c and 4f had to be reduced with Zn
in CH3COOH. Purification of 5a and 5b by recrystallization
with methanol gave good yields (78% and 68%, respectively)
(Scheme 1).
RESULTS AND DISCUSSION
Synthesis. The preparation of compounds 1–5 is shown
in Scheme 1. Compounds 1a and 1b were prepared
according to a literature method [17]. Compounds 1c [18],
© 2013 HeteroCorporation

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G. Liu, X. Wu, and X. Shi
Vol 50
Scheme 1. Synthetic route of polysubstituted‐1,2,4‐triazoles derivatives.
The infrared spectra of compounds 4a–g (Table 1) exhibited
a characteristic strong absorption band at 1511–1523 cm−1
which is attributable to the C═N of the 1,2,4‐triazole residues.
CONCLUSIONS
A series of new 1,2,4‐triazole derivatives was successfully
synthesized with a mild and effective method using substi-
tuted benzoic acids as the starting material. The method has
some salient features such as faster reaction rates, high yields
and environmental friendliness. The synthesized compounds
were characterized by spectral data (1H‐NMR, 13C‐NMR, IR)
and elemental analysis.
EXPERIMENTAL
Materials. Reactions were monitored by thin layer
chromatography on 0.20 mm Anhui Liangchen silica gel plates
and the spots were detected with UV light. Silica gel (200–300
mesh) (from Anhui Liangchen Company) was used for flash
chromatography. Compounds 1a and 1b were prepared according
to a literature method [16]. Compounds 1c [17], 2a–2e [18],
and 3a−3e [18] were synthesized and purified according to
other procedures in the literature. The starting material 4‐
nitrobenzoylhydrazine and 4‐pyridinecarbonylhydrazine were
also prepared according to a literature method [19]. Other
chemicals or reagents were obtained from commercial sources.
Spectroscopic procedures. 1H‐NMR and 13C‐NMR spectra
were acquired in CDCl3 on a Varian 400 or a Varian 500
spectrometer. Unless otherwise noted, chemical shifts are reported
1
as values in ppm relative to CDCl3 (δ 7.26) for H‐NMR spectra,
and relative to CDCl3 (77.16 ppm) for 13C‐NMR spectra.
Multiplicities are described using the following abbreviations:
s = singlet, d = doublet, t = triplet, m = multiplet. Coupling
constants (J) are given in Hz at 500 MHz for the 1H‐NMR
spectra. Infrared spectra were recorded on a Perkin‐Elmer Model
1600 FTIR spectrophotometer. Elemental analyses were
determined using a Perkin‐Elmer 2400 CHN elemental analyzer.
Melting points were determined using an electrothermal digital
melting point apparatus and are uncorrected.
Synthetic procedures. All experiments were carried out in
100‐mL Synthware glass round‐bottom flasks, equipped with
magnetic stir bars. Products were identified by comparing their
IR, 1H‐NMR, and 13C‐NMR spectra and elemental analyses
with those of known samples.
Synthesis of compounds 4. A flask was charged with 3,
4‐nitrobenzoylhydrazine (or 4‐pyridinecarbonylhydrazine) and
15 mL N,N‐dimethylacetamide. The mixture was refluxed about
30 h and then cooled to room temperature after the reaction
finished. Removal of the solvent from the filtrate under vacuum
gave the crude product of 4. Compounds 4 were purified by
recrystallization or column chromatography.
4‐(4‐Chloro‐phenyl)‐3‐(4‐nitro‐phenyl)‐5‐p‐tolyl‐4H‐
[1,2,4]triazole 4a. With 3a (2.89 g, 11.00 mmol) and 4‐
nitrobenzoylhydrazine (1.97 g, 10.00 mmol). Recrystallization
with ethyl acetate: 4a (2.42 g, 62%). Yellow solid. Melting point:
250–251°C. Analytical data. Found (calcd) for: C20H15ClN4O2 C,
64.46 (64.54); H, 3.76 (3.87); N, 14.22 (14.34). 1H‐NMR
(500 MHz, CDCl3) δ (ppm): 8.20 (d, J = 9.0 Hz, 2H, CHar),
Figure 1. 1H‐NMR spectra of 4a, 4b, 4c, 4d, 4e, 4f, 4g, 5a, and 5b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

February 2013
Synthesis of Polysubstituted-1,2,4-triazoles
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Table 1
Infrared spectral data of compounds in KBr (cm−1).
No.
4a
4b
4c
4d
4e
4f
4g
5a
5b
C═N
N-H
1511
–
1515
–
1521
–
1523
–
1515
–
1519
–
1519
–
1516
3227
1514
3253
7.62 (d, J = 9.0 Hz, 2H, CHar), 7.46 (d, J = 8.5 Hz, 2H, CHar),
7.30 (d, J =8.0 Hz, 2H, CHar), 7.16 (m, 4H, CHar), 2.36 (s, 3H,
CH3). 13C‐NMR (125 MHz, CDCl3) δ (ppm): 21.3, 123.1,
123.7, 128.7, 128.9, 129.4, 130.6, 132.7, 133.2, 136.3, 140.5,
148.2, 152.5, 155.6. IR (KBr, cm−1) v: 3064, 3015, 2917,
(500 MHz, CDCl3) δ (ppm): 8.58 (d, J = 5.0 Hz, 2H, CH), 7.45
(s, 1H, CHar), 7.36 (d, J = 6.0 Hz, 2H, CH), 7.21 (m, 2H, CHar),
7.12 (d, J = 9.0 Hz, 2H, CHar), 7.07 (d, J =7.5 Hz, 1H, CHar),
6.98 (d, J = 9.0 Hz, 2H, CHar), 3.88 (s, 3H, OCH3), 2.32 (s, 3H,
CH3). 13C‐NMR (125 MHz, CDCl3) δ (ppm): 21.3, 122.2, 125.6,
125.8, 128.4, 128.9, 129.7, 130.5, 130.9, 133.1, 134.2, 136.3,
138.6, 150.2, 152.2, 155.8. IR (KBr, cm‐1) v: 3064, 3035, 2953,
1605, 1454, 1515, 1258, 1098 cm−1.
4‐(4‐Methoxy‐phenyl)‐3‐(4‐nitro‐phenyl)‐5‐m‐tolyl‐4H‐[1,2,4]
triazole 4f. With 3d (2.46 g, 9.50 mmol) and 4‐nitrobenzoylhydrazine
(1.67 g, 8.50 mmol). Recrystallization with ethyl acetate: 4f (2.04g,
62 %). Yellow solid. Melting point: 172–174°C. Analytical data.
Found (calcd) for: C22H18N4O3 C, 68.42 (68.38); H, 4.76 (4.70);
N, 14.41 (14.50). 1H‐NMR (500 MHz, CDCl3) δ (ppm): 8.18
(d, J = 8.5 Hz, 2H, CHar), 7.66 (d, J = 9.0 Hz, 2H, CHar), 7.45
(s, 1H, CHar), 7.21 (m, 2H, CHar), 7.10 (m, 3H, CHar), 6.97 (d,
J = 8.5 Hz, 2H, CHar), 3.81 (s, 3H, OCH3), 2.32 (s, 3H, CH3).
13C‐NMR (125 MHz, CDCl3) δ (ppm): 21.3, 55.6, 115.4, 123.6,
125.5, 126.3, 127.1, 128.2, 128.7, 129.2, 129.7, 130.7, 133.1,
138.4, 148.1, 160.5. IR (KBr, cm−1) v: 3096, 3064, 2998, 1621,
1482, 1519, 1249, 1115 cm−1.
4‐[4‐(4‐Chloro‐phenyl)‐5‐(4‐nitro‐phenyl)‐4H‐[1,2,4]
triazol‐3‐yl]‐pyridine 4g. With 3e (2.95 g, 9.50 mmol) and 4‐
pyridinecarbonylhydrazine (1.71 g, 8.50 mmol). Recrystallization
with ethyl acetate: 4g (1.69g, 53 %). Yellow solid. Melting point:
239–240°C. Analytical data. Found (calcd) for: C19H12ClN5O2 C,
60.36 (60.41); H, 3.16 (3.20); N, 18.51 (18.54). 1H‐NMR
(500 MHz, CDCl3) δ (ppm): 8.64 (d, J = 5.5 Hz, 2H, CH), 8.22
(d, J = 9.0 Hz, 2H, CHar), 7.64 (d, J = 9.0 Hz, 2H, CHar), 7.54
(d, J = 9.0 Hz, 2H, CH), 7.33 (d, J = 6.0 Hz, 2H, CHar), 7.19 (d,
J = 8.5 Hz, 2H, CHar). 13C‐NMR (125 MHz, CDCl3) δ (ppm):
29.6, 122.1, 123.8, 128.7, 129.4, 131.1, 132.0, 132.5, 133.6,
137.2, 158.5, 150.3, 153.1, 153.5. IR (KBr, cm−1) v: 3057, 3031,
1597, 1519, 1490, 1287, 1091 cm−1.
1601, 1486, 1511, 1286, 1094 cm−1
.
4‐[4‐(4‐Methoxy‐phenyl)‐5‐p‐tolyl‐4H‐[1,2,4]triazol‐3‐yl]‐
pyridine 4b. With 3b (1.29 g, 5.00 mmol) and 4‐
pyridinecarbonylhydrazine (0.69 g, 5.00 mmol). Purification by
flash column chromatography on silica using pentanes/ethyl
acetate (1:8) as the eluent: 4b (1.32 g, 77%). White solid. Melting
point: 178–179°C. Analytical data. Found (calcd) for: C21H18N4O
C, 73.76 (73.67); H, 5.22 (5.30); N, 16.56 (16.36). 1H‐NMR
(500 MHz, CDCl3) δ (ppm): 8.57 (d, J = 5.0 Hz, 2H, CH), 7.35
(m, 4H, CH & CHar), 7.13 (m, 4H, CHar), 6.98 (d, J =9.0 Hz,
2H, CHar), 3.88 (s, 3H, OCH3), 2.34 (s, 3H, CH3). 13C‐NMR
(125 MHz, CDCl3) δ (ppm): 21.3, 55.6, 115.3, 122.2, 123.5,
127.1, 128.5, 128.7, 129.2, 134.6, 140.1, 150.1, 160.5. IR
(KBr, cm‐1) v: 3061, 3031, 2932, 1664, 1599, 1515, 1350, 1101 cm−1.
4‐(4‐Methoxy‐phenyl)‐3‐(4‐nitro‐phenyl)‐5‐p‐tolyl‐4H‐[1,2,4]
triazole 4c. With 3b (2.50 g, 9.65 mmol) and 4‐
nitrobenzoylhydrazine (1.67 g, 8.50 mmol). Recrystallization
with ethyl acetate: 4c (2.17 g, 66%). Yellow solid. Melting point:
232–233 °C. Analytical Data. Found (calcd) for: C22H18N4O3 C,
1
63.48 (68.38); H, 4.56 (4.70); N, 14.59 (14.50). H‐NMR (500
MHz, CDCl3) δ (ppm): 8.17 (d, J = 9.0 Hz, 2H, CHar), 7.65 (d,
J = 9.0 Hz, 2H, CHar), 7.35 (d, J = 8.0 Hz, 2H, CHar), 7.14 (d,
J = 8.0 Hz, 2H, CHar), 7.10 (d, J = 9.0 Hz, 2H, CHar), 6.97 (d,
J =9.0 Hz, 2H, CHar), 3.87 (s, 3H, OCH3), 2.34 (s, 3H, CH3).
13C‐NMR (125 MHz, CDCl3) δ (ppm): 21.2, 55.9, 115.5, 124.1,
124.3, 127.3, 128.8, 129.5, 129.9, 133.7, 140.0, 143.2, 153.2,
155.7, 158.0, 160.3. IR (KBr, cm−1) v: 3074, 3025, 2927, 1604,
1524, 1461, 1259, 1105 cm−1.
4‐(4‐Chloro‐phenyl)‐3‐(4‐nitro‐phenyl)‐5‐m‐tolyl‐4H‐[1,2,4]
triazole 4d. With 3c (2.89 g, 11.00 mmol) and 4‐
nitrobenzoylhydrazine (1.97 g, 10.00 mmol). Recrystallization
with ethyl acetate: 4d (2.13 g, 55%). Yellow solid. Melting point:
166–167°C. Analytical Data. Found (calcd) for: C21H15ClN4O2 C,
64.49 (64.54); H, 3.81 (3.87); N, 14.27 (14.34). 1H‐NMR
(500 MHz, CDCl3) δ (ppm): 8.21 (d, J = 9.0 Hz, 2H, CHar), 7.62
(d, J = 9.0 Hz, 2H, CHar), 7.46 (d, J = 8.5 Hz, 2H, CHar), 7.40 (s,
1H, CHar), 7.23 (m, 2H, CHar), 7.13 (d, J =9.0 Hz, 2H, CHar), 7.01
(s, 1H, CHar), 2.32 (s, 3H, CH3). 13C‐NMR (125 MHz, CDCl3) δ
(ppm): 21.3, 123.7, 125.6, 125.9, 128.4, 128.9, 129.4, 129.7, 130.6,
131.0, 132.7, 133.2, 136.3, 138.6, 148.3, 152.6, 155.7. IR (KBr, cm‐1)
v: 3080, 3060, 2921, 1601, 1486, 1523, 1348, 1098 cm−1.
Synthesis of compounds 5. A flask was charged with 4 (2.01
g, 5.00 mmol) and Zn (0.52 g, 8.00 mmol). After the mixture was
cooled to 10–20°C, 30 mL (5.5 mmol) CH3COOH was slowly
added. The mixture was stirred for 1 h at room temperature and
then continued to be stirred for 5 h at 50°C. After the reaction
was finished, the solvent was removed from the filtrate. The
filtrate was cooled to room temperature and 10% NaOH was
added. The mixture was then extracted with ethyl acetate. The
organic extracts were concentrated under vacuum and gave the
crude product of 5. Purification of 5 by recrystallization with
methanol.
4‐[4‐(4‐Methoxy‐phenyl)‐5‐p‐tolyl‐4H‐[1,2,4]triazol‐3‐yl]‐
phenylamine 5a. 5a (1.39 g, 78%). Yellow solid. Melting point:
277–279°C. Analytical data. Found (calcd) for: C22H20N4O C,
74.19 (74.14); H, 5.71 (5.66); N, 15.69 (15.72). H‐NMR (500
MHz, CDCl3) δ (ppm): 7.92 (s, 1H, NH), 7.42 (d, J = 8.5 Hz,
2H, CHar), 7.32 (d, J = 8.0 Hz, 4H, CHar), 7.11 (d, J = 8.0 Hz,
4‐[4‐(4‐Methoxy‐phenyl)‐5‐m‐tolyl‐4H‐[1,2,4]triazol‐3‐yl]‐
pyridine 4e. With 3d (1.29 g, 5.00 mmol) and 4‐
pyridinecarbonylhydrazine (0.69 g, 5.00 mmol). Recrystallization
with ethanol: 4e (1.21g, 71 %). White solid. Melting point:
193–195°C. Analytical data. Found (calcd) for: C211H18N4O
C, 73.58 (73.67); H, 5.26 (5.30); N, 16.39 (16.36). H‐NMR
1
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G. Liu, X. Wu, and X. Shi
Vol 50
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2H, CHar), 7.06 (d, J = 8.5 Hz, 2H, CHar), 6.91 (d, J = 9.0 Hz,
2H, CHar), 3.85 (s, 3H, OCH3), 2.33 (s, 3H, CH3). IR (KBr, cm−1) v:
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Hz, 2H, CHar), 7.43 (s, 1H, CHar), 7.37 (d, J = 8.5 Hz, 2H,
CHar), 7.16 (m, 3H, CHar), 7.06 (d, J = 9.0 Hz, 2H, CHar), 6.91
(d, J = 9.0 Hz, 2H, CHar), 3.85 (s, 3H, OCH3), 2.30 (s, 3H, CH3).
IR (KBr, cm−1) v: 3253, 3117, 3097, 3046, 2920, 1603, 1469,
1514, 1255 cm−1.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet