A facile one-pot synthesis of novel 1,2,4-triazolo[4,3-a]pyridine derivatives containing the trifluoromethyl moiety using microwave irradiation

Article abstract of DOI:10.3184/174751915X14400874295745

A series of novel substituted 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridines are synthesised from 2,3-dichloro-5-(trifluoromethyl)pyridine, hydrazine hydrate as starting materials by multi-step reactions under microwave irradiation. Their ch

Full text of DOI:10.3184/174751915X14400874295745

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 SEPTEMBER, 521–523
RESEARCH PAPER 521
A facile one-pot synthesis of novel 1,2,4-triazolo[4,3-a]pyridine derivatives
containing the trifluoromethyl moiety using microwave irradiation
Ming-Yan Yanga, Zhi-Wen Zhaia, Zhao-Hui Suna, Shu-Jing Yub, Xing-Hai Liua*, Jian-Quan Wenga,
Cheng-Xia Tana and Wei-Guang Zhaob
aCollege of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P.R.China
bCollaborative Innovation Center of Chemical Science and Engineering, State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering
Research Center, Nankai University, Tianjin 300071, P.R. China
A series of novel substituted 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridines are synthesised from 2,3-dichloro-5-
(trifluoromethyl)pyridine, hydrazine hydrate as starting materials by multi-step reactions under microwave irradiation. Their chemical
structures can be characterised by 1H NMR, MS and elemental analysis. The title compounds exhibit weak antifungal activity.
Keywords: 1,2,4-triazolo[4,3-a]pyridine, microwave irradiation, synthesis, antifungal activity
In synthetic chemistry, green methods are attracting interest
because of their environmental benefits.1 Such methods include
catalyst free,2 supercritical fluids,3 water-phase reactions,4 ionic
liquids,5 solvent-free reactions,6 metal-free7 and ultrasound8
or microwaves irradiation.9 Nitrogen-containing heterocycles
have also proved attractive andthey have been widely used
in the medicinal, agricultural and industrial fields.10 The
1,2,4-triazoles and their fused heterocycles have received
considerable attention because of their synthetic and effective
biological importance. Reported methods of synthesising
substituted 1,2,4-triazolo[4,3-a]pyridines, include solution-
phase synthesis,11 catalysed synthesis,12 iodine mediated
synthesis,13 solvent-free synthesis,14 microwave synthesis.15 For
example, the patent EP43038516 described in 1991, that some
interesting substituted 1,2,4-triazolo[4,3-a]pyridine derivatives
were obtained using the key intermediates, substituted N-(2-
pyridyl)hydrazones. Another patent CN10200204017 also
described that triazolopyridines could be prepared from
substituted 2-hydrazinopyridines and substituted benzaldehydes
as starting materials. More recently, triazolopyridines were
synthesised from substituted 2-hydrazinopyridines and
substituted carboxylic acids using microwave or ultrasonic
methods.18,19 In our previous work, 8-chloro-[1,2,4]
triazolo[4,3-a]pyridines were synthesised using microwave
irradiation20 and showed antifungal activity. We now desribe
a series of novel 1,2,4-triazolo[4,3-a]pyridines containing the
trifluoromethyl moiety that were synthesised using microwave
irradiation.
From the hydrazine 1 the synthetic procedure leading to
compounds 2 is shown in Scheme 1. Generally, 1,2,4-triazolo-
[4,3-a]pyridines are synthesised using two steps as described
in the literature.21,22 First, the key intermediate (hydrazide or
hydrazone) is synthesised and then the fused 1,2,4-triazole
heterocycles are prepared using different conditions. Here, a
one-pot synthesis of novel 1,2,4-triazolo[4,3-a]pyridines using
a hydrazine and a carboxylic acid in POCl3 is reported under
conditions of microwave irradiation. After the reaction was
completed, the purification of these compounds is easy. We
found that the yields of the title compounds were lower than
that of our previous work where the CF3 group is absent. The
reactivity of hydrazine may be reduced by the presence of the
electron withdrawing CF3 group.
The products 2 were identified by 1H NMR and MS
1
spectra. In the H NMR spectra of the title compounds, the
CH proton signals of the pyridine moiety of title compounds
were recognised as singlets. The mass spectra of the
1,2,4-triazolo[4,3-a]pyridines 2 showed molecular ion peaks.
The measured elemental analyses were also consistent with
the corresponding calculated ones. Hence an efficient route
is established using a one-pot reaction to afford interesting
trifluoro-substituted 1,2,4-triazolo[4,3-a]pyridines
The fungicidal activities of the title compounds 2a–w against
Gibberella zeae and Alternaria alternate were determined.
The results are listed in Table 1. At a dose of 50 μg mL-1, all
compounds display weak fungicidal activity against Gibberella
zeae and Alternaria alternate.
l
C
F
3C
l
C
R
COO
H
N
P
l
OC 3
N
N
MW
N
1
NHNH2
F
3C
R
2a~2w
2a, R=4-MeOC6H4; 2b, R=2-MeC6H4; 2c, R=3-NO2C6H4; 2d, R=(CH3)2CH;
2e, R=4-MeC6H4; 2f, R=2-MeOC6H4; 2g, R=4-n-PrC6H4; 2h, R=3-MeC6H4;
2i, R=3-FC6H4; 2j, R=4-FC6H4; 2k, R=4-NO2C6H4;2l, R=4-IC6H4;
2m, R=4-ClC6H4OCH2;2n, R=3-ClC6H4; 2o, R=4-t-BuC6H4; 2p, R=4-NH2C6H4;
2q, R=4-n-BuC6H4;2r, R=4-(2-butanoic acid)C6H4; 2s, R=H; 2t, R=Me;
2u, R=2,4-Cl2C6H3; 2v, R=CH3CH2CH2; 2w, R=2-chloropyridin-3-yl
Scheme 1 The synthetic route to the title compounds.
* Correspondent. E-mail: xhliu@zjut.edu.cn

522 JOURNAL OF CHEMICAL RESEARCH 2015
Table 1 The antifungal activity of the title compounds at 50 μg mL-1
8-Chloro-3-isopropyl-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
pyridine (2d): Light yellow solid; yield 76%; m.p. 53–55°C; 1H NMR
(CDCl3, 400 MHz), δ 1.30 (d, J=8.0 Hz, 6H, –CH3), 2.17 (m, H, –
CH–), 8.02 (d, J=8.1 Hz, 2H, PyH), 8.53 (s, H, PyH); ESI-MS: 265.0
[M+H]+. Anal. calcd for C10H9ClF3N3: C, 45.56; H, 3.44; N, 15.94;
found: C, 45.78; H, 3.24; N, 16.02%.
Compound
Alternaria solani
23.8
23.8
23.8
19.0
Gibberella zeae
18.2
16.4
13.5
11.8
2a
2b
2c
2d
8-Chloro-3-(p-tolyl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
2e
2f
2g
2h
2i
2j
14.3
17.6
23.5
23.5
23.5
17.6
18.2
10.3
10.3
27.6
24.1
27.6
1
pyridine (2e): Light yellow solid; yield 61%; m.p. 92–94°C; H NMR
(CDCl3, 400 MHz), δ 2.47（t, J=8.0 Hz, 3H, –CH3), 7.27 (d, J=4.0 Hz,
2H, PhH), 7.31 (d, J=8.0 Hz, 2H, PhH), 8.00 (s, H, PyH), 8.02 (s, H,
PyH); ESI-MS: 313.0 [M+H]+. Anal. calcd for C14H9ClF3N3: C, 53.95;
H, 2.91; N, 13.48; found: C, 53.89; H, 3.18; N, 13.52%.
8-Chloro-3-(2-methoxyphenyl)-6-(trifluoromethyl)-[1,2,4]
triazolo[4,3-a]pyridine (2f): Light yellow solid; yield 34%,
2k
2l
2m
2n
17.6
23.5
17.6
13.8
10.3
10.3
6.9
1
m.p.129–132°C; H NMR (CDCl3, 400 MHz), δ 3.90 (s, 3H, –CH3),
7.13 (m, 2H, PhH), 7.57 (m, 2H, PhH), 7.77 (s, H, PyH), 8.03 (s, H,
PyH); ESI-MS: 329.0 [M+H]+. Anal. calcd for C14H9ClF3N3O: C, 51.31;
H, 2.77; N, 12.82; found: C, 51.25; H, 2.65; N, 12.99%.
8-Chloro-3- (4-propylphenyl) -6- (trifluoromethyl) -[1,2,4]
triazolo[4,3-a]pyridine (2g): Light yellow solid; yield 58%; m.p.
87–89°C; 1H NMR (CDCl3, 400 MHz), δ 0.96 (m, 3H, –CH3), 1.69 (m,
2H, CH2), 2.68 (m, 2H, –CH2–), 7.34 (d, J=8.0 Hz, 2H, PhH), 7.76 (d,
J=4.8 Hz, 2H, PhH), 8.07 (s, H, PyH), 8.52 (s, H, PyH); ESI-MS: 341.1
[M+H]+. Anal. calcd for C16H13ClF3N3: C, 56.56; H, 3.86; N, 12.37;
found: C, 56.76; H, 3.98; N, 12.54%.
8-Chloro-3-(m-tolyl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
pyridine (2h): Light yellow solid; yield 53%; m.p. 52–55°C; 1H NMR
(CDCl3,400MHz), δ 2.47(t, J=12.0 Hz, 3H, –CH3), 7.48 (m, 4H, PhH),
7.95 (s, H, PyH), 8.50 (s, H, PyH); ESI-MS: 313.0 [M+H]+. Anal. calcd
for C14H9ClF3N3: C, 53.95; H, 2.91; N, 13.48; found: C, 53.78; H, 2.79;
N, 13.64%.
17.6
2o
2p
2q
2r
2s
2t
2u
2v
2w
17.6
17.6
5.9
23.5
23.5
29.4
29.4
35.3
23.5
63.6
13.8
10.3
10.3
22.6
25.8
22.6
16.1
15.2
27.3
73.1
Chlorothalonil
Experimental
8-Chloro-3-(3-fluorophenyl)-6-(trifluoromethyl)-[1,2,4]
triazolo[4,3-a]pyridine (2i): Light yellow solid; yield 48%; m.p.
147–149°C; 1H NMR (CDCl3, 400 MHz), δ 7.52 (s, H, PyH), 7.61 (m,
4H, PhH), 8.51 (s, H, PyH); ESI-MS: 317.0 [M+H]+. Anal. calcd for
C13H6ClF4N3: C, 49.47; H, 1.92; N, 13.31; found: C, 49.66; H, 2.03; N,
13.45%.
All reagents are analytical grade. Melting points were determined
using a X-4 apparatus and were uncorrected. H NMR spectra were
measured on a Bruker Avance 400 MHz spectrometer using TMS as
an internal standard and CDCl3 as solvent. A CEM Discover Focused
Synthesiser was used for microwave reaction. Elemental analysis was
performed by a PerkinElmer 240C analyser.
1
8-Chloro-3- (4-fluorophenyl) -6- (trifluoromethyl) -[1,2,4]
triazolo[4,3-a]pyridine (2j): Light yellow solid; yield 57%; m.p.
112–114°C; 1H NMR (CDCl3, 400 MHz), δ 7.16 (m, 2H, PhH), 7.50 (s,
H, PyH), 8.13 (m, 2H, PhH), 8.45 (s, H, PyH); ESI-MS: 317.0 [M+H]+.
Anal. calcd for C13H6ClF4N3: C, 49.47; H, 1.92; N, 13.31; found: C,
49.66; H, 1.88; N, 13.34%.
Synthesis of 2a; general procedure
A CEM-designed 10-mL pressure-rated vial was charged with POCl3
(2 mL), 3-chloro-2-hydrazinyl-5-(trifluoromethyl)pyridine (211 mg,
1mmol), 4-methoxylbenzoic acid or analogous acid (1mmol). The
mixture was irradiated in a CEM Discover Focused Synthesiser (150 W,
140°C, 200 psi, 15min). The mixture was cooled to room temperature
by passing compressed air through the microwave cavity for 2 min. It
was poured into cold ice (40 mL) and the formed precipitate filtered. The
crude solid was recrystallised from EtOH to give the title compound 2a
and others. All the other compounds were synthesised according to the
same procedure.
8-Chloro-3- (4-nitrophenyl) -6- (trifluoromethyl) - [1,2,4]
triazolo[4,3-a]pyridine (2k): Light yellow solid; yield 49%; m.p.
1
117–120°C; H NMR (CDCl3, 400 MHz), δ 7.57 (s, H, PyH), 8.09
(m, 2H, PhH), 8.33 (m, 2H, PhH), 8.54 (s, H, PyH); ESI-MS: 344.0
[M+H]+. Anal. calcd for C13H6ClF3N4O2: C, 45.57; H, 1.76; N, 16.35;
found: C, 45.44; H, 1.58; N, 16.47%.
8-Chloro-3-(4-iodophenyl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
pyridine (2l): Light yellow solid; yield 44%; m.p. 127–130°C ; 1H NMR
(CDCl3, 400 MHz), δ 8.54 (s, H, PyH), 8.00 (d, J=8.0 Hz, H, PyH)
7.85(t, J=7.8 Hz, 2H, PhH), 7.55 (d, J=7.5 Hz, H, PhH), 7.37 (d, J=7.3
Hz, H, PhH); ESI-MS: 424.9 [M+H]+. Anal. calcd for C13H6ClF3IN3: C,
36.86; H, 1.43; N, 9.92; found: C, 36.99; H, 1.57; N, 10.03%.
8-Chloro-3- (4-methoxyphenyl)-6- (trifluoromethyl)-[1,2,4]
triazolo[4,3-a]pyridine (2a): Light yellow solid; yield 68%; m.p.
123–127°C; 1H NMR (CDCl3, 400 MHz), δ 3.91 (s, 3H, –CH3), 7.02 (d,
J=8.1 Hz, 2H, PhH), 7.47 (s, H, PyH), 7.90 (m, 2H, PhH), 8.84 (s, H,
PyH); ESI-MS: 329.0 [M+H]+. Anal. calcd for C14H9ClF3N3O: C, 51.31;
H, 2.77; N, 12.82; found: C, 51.43; H, 2.54; N, 12.77%.
8-Chloro-3- (4-chlorophenoxy)-6- (trifluoromethyl)-[1,2,4]
triazolo[4,3-a]pyridine (2m): Light yellow solid; yield 79%; m.p.
82–83°C ; H NMR (CDCl3, 400 MHz), δ 8.76 (s, H, PyH), 8.57 (d,
J=8.5 Hz, H, PyH), 7.00(t, J=7.0 Hz, 2H, PhH), 6.88(t, J=6.8 Hz, 2H,
PhH); ESI-MS: 385.1 [M+H]+. Anal. calcd for C13H6Cl2F3N3O: C,
44.85; H, 1.74; N, 12.07; found: C, 44.79; H, 1.86; N, 12.32%.
8-Chloro-3-(o-tolyl)-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
pyridine (2b): Light yellow solid; yield 41%; m.p. 96–97°C ; H NMR
1
1
(CDCl3, 400 MHz), δ 2.81 (d, J=8.1 Hz, 3H, –CH3,), 7.28 (d, J=4.5 Hz,
H, PhH), 7.37(t, J=7.8 Hz, H, PhH), 7.40(t, J=5.0 Hz, H, PhH), 7.48 (d,
J=7.9 Hz, H, PhH), 8.05（s, H, PyH）, 8.07（s, H, PyH）; ESI-MS: 313.0
[M+H]+. Anal. calcd for C14H9ClF3N3 C, 53.95; H, 2.91; N, 13.48; found:
C, 53.99; H, 3.01; N, 13.32%.
8-Chloro-3- (3-chlorophenyl) -6- (trifluoromethyl) -[1,2,4]
triazolo[4,3-a]pyridine (2n): Light yellow solid; yield 75%; m.p.
8-Chloro-3- (3-nitrophenyl) -6- (trifluoromethyl) - [1,2,4]
triazolo[4,3-a]pyridine (2c): Light yellow solid; yield 33%; m.p.
1
83–85°C ; H NMR (CDCl3, 400 MHz), δ 8.48 (s, H, PyH), 8.80 (d,
1
148–151°C; H NMR (CDCl3, 400 MHz), δ 7.85 (s, H, PyH), 7.86 (m,
J=8.1 Hz, H, PyH), 7.84 (d, J=7.8 Hz, H, PhH), 7.60(t, J=7.6 Hz, H,
PhH) 7.52 (s, H, PhH), 7.42 (m, H, PhH); ESI-MS: 332.9 [M+H]+.
Anal. calcd for C13H6Cl2F3N3: C, 47.01; H, 1.82; N, 12.65; found: C,
47.22; H, 1.97; N, 12.43%.
2H, PhH), 8.48 (m, 2H, PhH), 8.73 (s, H, PyH); ESI-MS: 344.0 [M+H]+.
Anal. calcd for C13H6ClF3N4O2: C, 45.57; H, 1.76; N, 16.35; found:
C,45.58; H, 1.98; N, 16.61%.

JOURNAL OF CHEMICAL RESEARCH 2015 523
8-Chloro-3-(4-(tert-butyl)phenyl)-6-(trifluoromethyl)-[1,2,4]
Antifungal activity
triazolo[4,3-a]pyridine (2o): Light yellow solid; yield 69%; m.p.
122–124°C ; H NMR (CDCl3, 400 MHz), δ 7.48 (d, J=7.4 Hz, 2H,
The antifungal activities of the title compounds against Gibberella zeae
and Alternaria alternata were evaluated, chlorothalonil was selected as
a positive control. Culture plates were cultivated at 24 1 ºC. The relative
inhibition rate of the circle mycelium compared to a blank assay was
calculated as follows: Relative ratio % = (NS − NC)/NC × 100%, where NS
is the extended diameter of the circle mycelium during the blank assay
and NC is the extended diameter of the circle mycelium during testing.
1
PhH), 7.78 (s, H, PyH), 7.81 (d, J=7.8 Hz, 2H, PhH), 9.38 (s, H, PyH);
ESI-MS: 385.1 [M+H]+. Anal. calcd for C17H15ClF3N3: C, 57.72; H,
4.27; N, 11.88; found: C, 57.83; H, 4.55; N, 12.03%.
4-(8-Chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-3-
yl)aniline (2p): Light yellow solid; yield 45%; m.p. 91–92°C ; 1H NMR
(CDCl3, 400 MHz), δ 1.28 (s, 2H, –NH2), 7.55 (m, 2H, PhH), 7.83 (m,
2H, PhH), 8.30 (s, H, PyH), 8.54 (s, H, PyH); ESI-MS: 314.0 [M+H]+.
Anal. calcd for C13H8ClF3N4: C, 49.94; H, 2.58; N, 17.92; found: C,
50.23; H, 2.81; N, 18.23%.
8-Chloro-3-(4-butylphenyl)-6-(trifluoromethyl)-[1,2,4]
triazolo[4,3-a]pyridine (2q): Light yellow solid; yield 62%; m.p.
75–78°C ; 1H NMR (CDCl3, 400 MHz), δ 0.90 (s, 3H, –CH3), 1.31 (m,
2H, –CH2–), 1.67(q, J=1.6, 2H, –CH2–), 2.67(q, J=2.6 Hz, 2H, –CH2–),
7.34 (d, J=7.3 Hz, 2H, PhH), 7.78 (d, J=7.8 Hz, H, PyH), 8.04 (d, J=8.0
Hz, 2H, PhH), 9.24 (s, H, PyH); ESI-MS: 355.1 [M+H]+. Anal. calcd for
C17H15ClF3N3: C, 57.72; H, 4.27; N, 11.88; found: C, 57.35; H, 4.54; N,
11.66%.
This work was supported financially by National Natural
Science Foundation of China (no. 21002090), The Key
Innovation Team of Science and Technology in Zhejiang
Province (2010R50018-06) and the National Key Technologies
R&D Program (2011BAE06B03-01).
Received 19 June 2015; accepted 6 August 2015
Paper 1503432 doi: 10.3184/174751915X14400874295745
Published: 1 September 2015
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2-(4-(8-Chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-
3-yl)phenyl)butanoic acid (2r): Light yellow solid; yield 44%; m.p.
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160–163°C；H NMR (CDCl3, 400 MHz), δ 1.05 (m, 3H, –CH3), 2.31
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3
4
5
8-Chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (2s):
1
6
7
8
9
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Light yellow solid; yield 23%; m.p. 122–125°C，H NMR (CDCl3, 400
MHz), δ 7.49 (s, H, PyH), 8.51 (s, H, PyH), 9.02 (s, H, Tr-H); ESI-MS:
223.0 [M+H]+. Anal. calcd for C7H3ClF3N3: C, 37.95; H, 1.36; N, 18.96;
found: C, 38.12; H, 1.39; N, 19.22%.
8-Chloro-3-methyl-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
pyridine (2t): Light yellow solid; yield 39%; m.p. 146–149°C ;
1H NMR (CDCl3, 400 MHz), δ 1.60 (s, 3H, –CH3), 8.51 (s, H, PyH),
9.02 (s, H, PyH); ESI-MS: 237.0 [M+H]+. Anal. calcd for C8H5ClF3N3:
C, 40.78; H, 2.14; N, 17.84; found: C, 40.98; H, 2.32; N, 17.68%.
8-Chloro-3-(2,4-dichlorophenyl)-6-(trifluoromethyl)-[1,2,4]
triazolo[4,3-a]pyridine (2u): Light yellow solid; yield 25%; m.p.
126–128°C ; 1H NMR (CDCl3, 400 MHz), δ 7.43 (s, H, PhH), 7.52 (d,
J=7.5 Hz, H, PhH), 7.67 (d, J=7.6 Hz, H, PhH), 7.85 (s, H, PyH), 8.08
(s, H, PyH); ESI-MS: 366.9 [M+H]+. Anal. calcd for C13H5Cl3F3N3: C,
42.60; H, 1.37; 11.46; found: C, 42.77; H, 1.56; N, 11.71%.
8-Chloro-3-propyl-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]
pyridine (2v): Light yellow solid; yield 76%; m.p. 97–99°C ; 1H NMR
(CDCl3, 400 MHz), δ 4.72(t, J=4.7 Hz, 2H, –CH2–), 5.78 (s, 3H,
–CH3), 6.88 (d, J=6.9 Hz, 2H, –CH2–), 7.53 (s, H, PyH), 8.87 (s, H,
PyH); ESI-MS: 265.0 [M+H]+. Anal. calcd for C10H9ClF3N3: C, 45.56;
H, 3.44; N, 15.94; found: C, 45.67; H, 3.51; N, 16.13%.
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