A Convenient Synthesis of 1,5-Fused 1,2,4-Triazoles from N-Arylamidines via Chloramine-T Mediated Intramolecular Oxidative N-N Bond Formation

Article abstract of DOI:10.1055/s-0037-1611906

A convenient synthesis of 1,5-fused 1,2,4-triazoles from readily available N-arylamidines is reported. The reaction is efficiently promoted by chloramine-T to afford the desired products mostly in high yields and in relatively short time, through direct m

Full text of DOI:10.1055/s-0037-1611906

SYNTHESIS
0
0
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8
8
1
1
4
3
7
-
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1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
A. Bhatt et al.
Paper
Synthesis
A Convenient Synthesis of 1,5-Fused 1,2,4-Triazoles from N-Aryl-
amidines via Chloramine-T Mediated Intramolecular Oxidative
N–N Bond Formation
Ashish Bhatt*a
Rajesh K. Singhb
Ravi Kanta
0
0
0
0-0
0
0
2-1
3
6
2-8
4
2
5
R1
R1
Chloramine-T
EtOH, 80 °C
N
NH
R2
N
N
N
Y
X
N
H
Y
30–45 min
80–95%
R2
X
Bhupendra K. Sarmaa
20 examples
80–95% yield
a Department of Chemistry, Mewar University,
Chittorgarh, Rajasthan-312901, India
Itsbhatt2007@yahoo.co.in
b Department of Pharmacy, Mewar University,
Chittorgarh, Rajasthan-312901, India
X, Y = CH or N; R1 = H, Me, Br, Cl
2 = H, Me, OMe, Br, Cl, F, CF3, NO2
R
Received: 23.06.2019
F
F
Accepted after revision: 20.07.2019
Published online: 06.08.2019
DOI: 10.1055/s-0037-1611906; Art ID: ss-2019-n0223-op
CF3
N
NH
F
N
N
Abstract A convenient synthesis of 1,5-fused 1,2,4-triazoles from
readily available N-arylamidines is reported. The reaction is efficiently
promoted by chloramine-T to afford the desired products mostly in
high yields and in relatively short time, through direct metal-free oxida-
tive N−N bond formation. The mild nature of the synthesis and short
reaction time are notable advantages of the developed protocol. This
protocol is effective toward various substrates having different func-
tionalities.
O
N
N
N
N
N
NH2
O
F
maraviroc
F
sitagliptin
HO
N
O
N
Cl
N
NH
DL111-IT
N
N
N
N
O
Key words N-arylamidine, [1,2,4]triazolo[1,5-a]pyridine, [1,2,4]tri-
azolo[1,5-a]pyrazine, [1,2,4]triazolo[1,5-a]pyrimidine, chloramine-T,
ethanol
N
N
Cl
triazolam
OH
penipanoid A
The 1,2,4-triazole nucleus is an important structural
motif present in a large number of functionalized mole-
cules with a wide variety of uses, including applications in
medicinal chemistry, agricultural chemistry, materials sci-
ence, and organocatalysis.1 1,2,4-Triazole scaffolds are
found in many biologically active molecules2 and valuable
pharmaceuticals, including maraviroc, triazolam, sita-
gliptin, and penipanoid (Figure 1).3 In particular, com-
pounds containing N-fused 1,2,4-triazoles, such as triazol-
opyridine and triazolopyrazine substructures exhibit a
wide spectrum of biological activity including antifungal,
antimicrobial, antiviral, anti-inflammatory, antiasthmatic,
antiproliferative, and hypotonic.4 In addition, they have of-
ten been used as bioisosteres of esters and amides, and as
dipeptidomimetics in a number of pharmacologically im-
portant molecules.5 On the other hand, they also play im-
portant roles as ligands in transition metal complexes and
metal-organic frameworks, exhibiting tremendous applica-
tion prospects.6
Figure 1 Representative bioactive molecules and natural compounds
possessing a 1,2,4-triazole core
Due to their importance, many efficient methods have
been developed to access N-fused 1,2,4-triazoles.7 Oxidative
cyclization of N-(2-pyridyl)amidines is one of the most
straightforward strategies for the construction of the 1,2,4-
triazolo[1,5-a]pyridine framework, which previously has
been achieved by utilizing oxidants, such as NaClO/base,8
Pb(OAc)4,9 and MnO2.10 Nevertheless, these methods are as-
sociated with some disadvantages, including low yields,
multistep synthetic procedures, limited scopes, and inferior
regioselectivity.
In 2009, Ueda and Nagasawa11 reported a copper-cata-
lyzed tandem addition-oxidative cyclization of 2-aminopy-
ridines and aryl nitriles to 2-aryl-1,2,4-triazolo[1,5-a]pyri-
dines. Alternatively, Zhao and co-workers12 developed a re-
cyclable Cu–Zn/Al–Ti catalyst for the same transformation
(Scheme 1). Recently, Xia, Huang, and co-workers13 de-
scribed a Cu-catalyzed oxidative cyclization of nitriles with
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. Bhatt et al.
Paper
Synthesis
2-aminopyridines or amidines (Scheme 1). However, in al-
most all cases, copper and other transition metal catalysts
with higher loadings (typically 5–20 mol%) were used to
achieve high yields, and they are difficult to separate from
the reaction mixture and are not recyclable. These prob-
lems are of particular environmental and economic con-
cerns in large-scale syntheses and in industry. Moreover,
these transition-metal catalysis might cause metal contam-
ination of the desired product because 1,2,4-triazoles are
strong ligands for transition metals and could coordinate
with metal to form stable complexes.6c–e Therefore, it is still
of importance to develop transition-metal-free synthetic
methods to access this kind of compound class.
alkyl-substituted 1,2,4-triazolo[1,5-a]pyridines. But these
existing methods suffer from some drawbacks in one or an-
other respect, such as use of expensive catalyst, formation
of by-product like 20% iodinated product along with desired
product in I2/KI-mediated methodology, inferior regioselec-
tivity, and a limited substrate scope.
Despite these elegant achievements made, it is still of
importance to develop novel and general approaches to ac-
cess this compound class.
Chloramine-T (N-chloro-p-toluenesulfonamide sodium
salt) is a versatile reagent and is becoming increasingly
popular because of its commercial availability at low cost.
Chloramine-T has been extensively used as an oxidant to-
ward a wide variety of functional groups.16 This reagent
also acts as a chlorinating reagent,17 as an oxidant for aro-
matization,18 and as a nitrogen source that has been used
for the aziridination of alkenes.19 In particular, this oxidiz-
ing reagent has been successfully employed to construct C–
N, C–O, and C–S bonds.20 However, to the best of our knowl-
edge, there is no report of chloramine-T mediated N–N
bond formation reactions. Encouraged by our previous
work, in this paper, we disclose a new and efficient chlora-
mine-T mediated methodology for the synthesis of 2-aryl-
substituted 1,2,4-triazolo[1,5-a]pyridines, as well as their
pyrazido- and pyrimidotriazole derivatives, from N-aryl-
amidines through the construction of N–N bonds (Scheme
1).
The required substrates N-arylamidines 1 were pre-
pared via the addition reaction of corresponding aryl-
amines to substituted nitriles as per the reported literature
procedure.21 Our preliminary investigation began with the
reaction of N-(2-pyridyl)amidine 1a with chloramine-T (1
equiv) in methanol at 80 °C. We were delighted to observe
the formation of the desired product 2a, albeit in a low yield
of 65% (Table 1, entry 1). Next, the reaction conditions were
optimized in order to increase the yield. Thus, different sol-
vents were screened and the results are summarized in Ta-
ble 1. It was found that ethanol was the most superior sol-
vent in terms of the reaction time and yield of the product
(entry 2). Once, we had established a suitable solvent for
the synthesis of 1,2,4-triazolo[1,5-a]pyridine, we then fo-
cused on the quantity of chloramine-T. An increase in the
amount of chloramine-T (from 1 equiv to 2 equiv) not only
decreased the reaction time from 1.5 hours to 30 minutes,
but also increased the product yield from 75% to 95% (entry
7). Further increasing the quantity of chloramine-T (from 2
equiv to 3 equiv) led to a decrease in the yield to 80% (entry
8). Therefore, we decided to perform the subsequent reac-
tions of the various N-arylamidines with chloramine-T (2
equiv) in ethanol at 80 °C. The effect of temperature on the
reaction rate as well as on the yields of the products were
also investigated. Faster reactions occurred on increasing
the temperature but the product yields were not satisfacto-
ry. The progress of the reactions was monitored by TLC
analysis (using EtOAc–hexane as the eluent).
Ueda and Nagasawa (2009):11
CuBr (5 mol%), ZnI2 (10 mol%)
1,10-phenanthroline (5 mol%)
N
N
N
N
N
Ar
+
1,2-dichlorobenzene, air
130 °C, 24 h
Ar
NH2
60–80% yield with use of
transition metal
Du, Zhao, and co-workers (2014):14
N
N
N
NH
PhI(OCOCF3)2
R
N
hexafluoroisopropanol (HFIP)
r.t
N
R
H
70–90% yield with limited substrate
and the use of expensive catalyst
and solvent
Song, Tian and co-workers (2015):15
I
N
N
N
N
N
N
N
NH
I2/KI, K2CO3
R
R
+
DMSO, 100 °C
1.5 h
N
R
H
20% (by-product)
70%
Xia, Huang and co-workers (2019):13
Phen-MCM-41-CuBr (5 mol%)
ZnI2 (10 mol%)
N
N
N
N
Ar
+
1,2-dichlorobenzene, air
130 °C, 24 h
Ar
N
NH2
60–90% yield with use of
expensive transition-metal
catalyst
Present reported work:
R1
R1
N
NH
R2
N
N
Chloramine-T
EtOH, 80 °C
N
Y
X
N
H
Y
R2
X
80–95% yield, transition-metal-free
synthesis, low cost and cheap reagents
including solvent, and applicable with
various substrates
Scheme 1 Previously reported synthesis of 1,5-fused 1,2,4-triazoles
through the formation of N−N bond
However, some transition-metal-free synthetic meth-
ods have also been reported to access N-fused 1,2,4-tri-
azoles. For example, Du, Zhao, and co-workers14 reported a
PIFA-mediated cyclization of N-(pyridin-2-yl)amidines to 2-
aryl/2-alkyltriazolopyridines. Further, in 2015, Song, Tian
and co-workers15 reported a new and efficient I2/KI-medi-
ated methodology for the synthesis of both 2-aryl- and 2-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
A. Bhatt et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditions
Because 2a was afforded in an excellent yield from its corre-
sponding substrate 1a, the effect of substituents on the pyr-
idine ring (R1) was first examined. This heterocyclic ring
was found to be tolerant of both electron-rich groups such
as methyl 2b–e and electron-deficient groups such as halo-
gens 2f–h. Reactions of halogen-containing substrates pro-
vided yields slightly lower than that of the methyl-contain-
ing substrates, which was probably due to the relatively low
nucleophilicity of the pyridines affected by the halogens
(Table 2, entries 1–8). The substitution effect of the R2
group was then examined. It was found that when R2 is an
aryl group, this methodology is compatible with both elec-
tron-donating and electron-withdrawing groups at para-,
meta-, and ortho-positions of the benzene ring 2i–r. Even
the nitro group bearing substrate 1m was smoothly trans-
formed into the desired 1,2,4-triazolo[1,5-a]pyridine 2m
under the optimal reaction conditions. ortho-Substitution
on the 2-phenyl moiety did not affect either the reaction
rate or the yields of the products 2p–r.
N
NH
N
N
Chloramine-T
solvent, 80 °C
N
N
H
2a
1a
Entry
Solvent
Chloramine-T
(equiv)
Time
Yield (%)
1
2
3
4
5
6
7
8
MeOH
EtOH
1.0
1.0
1.0
1.0
1.0
1.5
2
1.5 h
65
75
55
45
50
85
95
80
1 h
i-PrOH
2.5 h
3 h
toluene
AcOH
EtOH
2 h
45 min
30 min
15 min
EtOH
EtOH
3
With the optimized reaction conditions established (Ta-
ble 1, entry 7), the scope of the newly discovered oxidative
N–N bond formation reaction was investigated (Table 2).
Table 2 Synthesis of Various 1,5-Fused 1,2,4-Triazoles with the Scope of Substituents R1 and R2 on N-Arylamidines
R1
R1
N
NH
R2
N
N
Chloramine-T
EtOH, 80 °C
N
Y
X
N
Y
R2
H
X
2
1
Entry
1
Substrate
Product 21
Time (min)
30
Yield (%)
95
N
NH
NH
N
N
N
N
H
2a
N
N
N
N
2
35
93
N
H
2b
2c
2d
N
NH
NH
N
N
N
N
3
4
5
30
30
40
94
95
91
N
H
N
N
N
N
H
N
N
N
N
NH
N
H
2e
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
A. Bhatt et al.
Paper
Synthesis
Table 2 (continued)
Entry
Substrate
Product 21
Time (min)
30
Yield (%)
87
Cl
Cl
N
N
NH
N
N
N
6
N
H
2f
Br
Br
NH
N
N
N
N
7
8
35
35
89
85
N
H
2g
Br
N
N
Br
N
NH
N
H
Br
N
Br
2h
2i
N
NH
N
OMe
9
30
30
30
35
90
87
86
84
N
N
H
OMe
N
N
N
N
NH
NH
NH
NH
N
N
N
N
N
N
F
10
11
12
N
H
2j
F
N
N
Cl
N
H
2k
2l
Cl
N
N
Br
N
H
Br
N
N
NO2
13
14
15
16
17
45
30
30
35
35
80
90
85
90
85
N
H
2m
NO2
N
N
N
N
NH
N
N
N
N
H
2n
Cl
NH
N
N
N
N
Cl
N
H
2o
2p
NH
N
N
N
H
Cl
NH Cl
N
N
N
N
H
2q
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

E
A. Bhatt et al.
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Synthesis
Table 2 (continued)
Entry
Substrate
Product 21
Time (min)
40
Yield (%)
81
F3C
N
NH CF3
N
N
N
18
N
H
2r
N
NH
N
N
N
19
20
30
35
90
85
N
N
N
H
2s
N
NH
N
N
N
N
N
N
H
2t
Additionally, pyrazido- 2s and pyrimidotriazoles 2t
were prepared via the oxidative cyclization of N-pyrazyl- 1s
and N-pyrimidyl-substituted benzimidamides 1t, respec-
tively, in good yields.
struction of N–N bond. This facile and transition-metal-free
synthetic process works well with a wide range of N-aryl-
substituted amidines. A variety of substituents are tolerated
allowing the synthesis of diverse products in good to excel-
lent yields. The main advantage of this procedure is to ac-
cess 1,5-fused 1,2,4-triazoles with high yields and short re-
action time. The newly developed synthetic route is be-
lieved to be valuable for the construction of building blocks
but also for medicinal chemistry studies comprising 1,5-
fused 1,2,4-triazole moiety.
Based on our experimental data and previous re-
port,8,15,22 a plausible reaction mechanism for the formation
of 1,5-fused 1,2,4-triazole 6 (≡ 2a) is proposed (Scheme 2).
According to this route, chloramine-T transfers the Cl+ ion to
the N-arylamidine 1a and generates N-chloroamidinium
cation 2′ and p-toluenesulfonamide anion 3 as a proton ac-
ceptor. N-Chloroamidinium cation, further by the cleavage
of N–Cl bond, deprotonation, and after rearomatization
provides the desired 1,5-fused 1,2,4-triazole framework 6
(≡ 2a).
All solvents and reagents were purchased from commercial sources
and used without further purification. Melting points were deter-
mined on a Stuart SMP3 melting point apparatus without correction.
IR spectra were obtained using a PerkinElmer FT-IR spectrophoto-
meter. 1H NMR and 13C NMR spectra were recorded on Bruker Avance
using the solvents indicated with 400 and 100 MHz respectively.
In conclusion, we have developed a short and efficient
synthesis of 1,5-fused 1,2,4-triazoles using a mild oxidative
cyclization method with chloramine-T through the con-
O
O
O
O
S
Cl
S
Cl
EtOH
N
· 2H2O + NaOH
N
· 3H2O
H
Na
O
O
O
O
S
S
Cl
NH
N
H
H
Cl
H
N
Cl
N
N
N
N
N
NH
3
N
H
Ph
Ph
N
Ph
O
S
O
H
O
O
4
S
_
_
1a
2'
NH2
NH
3
Cl
OH
N
N
N
N
Ph
NaCl + H2O +
N
H
Ph
N
6
5
Scheme 2 Plausible mechanism for the synthesis of 1,5-fused 1,2,4-triazoles from N-arylamidines
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

F
A. Bhatt et al.
Paper
Synthesis
High-resolution mass spectra (HRMS) were performed on a Thermo
Finnigan MAT95XP mass spectrometer. TLC was performed on silica
gel 60 F254 (Merck) TLC plates using hexane/EtOAc (7:3 v/v) as the
mobile phase. Column chromatography was carried out using Merck
silica gel (200–300 mesh) and hexane/EtOAc (7:3 v/v) as the eluent.
13C NMR (100 MHz, CDCl3):  = 164.2, 151.9, 141.0, 130.9, 129.9,
128.6, 127.2, 116.0, 115.0, 21.6.
HRMS-ESI: m/z [M + H]+ calcd for C13H11N3: 210.1026; found:
210.1023.
8-Methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2e)11
1,5-Fused 1,2,4-Triazoles 2a–t; General Procedure
White solid; yield: 45 mg (91%); mp 96–98 °C.
A stirred solution of N-arylamidine 1 (0.1 mmol, 1.0 equiv) in EtOH
(10 mL) was treated with chloramine-T trihydrate (56.3 mg, 0.2
mmol, 2.0 equiv). The reaction mixture was refluxed at 80 °C until the
starting material was completely consumed (monitored by TLC, 30
min). The mixture was quenched with sat. aq NaHCO3 (30 mL) and ex-
tracted with EtOAc (50 mL). The organic layer was washed with H2O
(40 mL), dried (Na2SO4), and evaporated. The resulting crude com-
pound was purified by silica gel column chromatography (EtOAc/hex-
ane, 3:7 v/v) to afford the desired pure 1,5-fused 1,2,4-triazole deriva-
tive 2.
IR (KBr): 3057, 2925, 1636, 1516, 758 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.43 (d, J = 6.8 Hz, 1 H), 8.31–8.29 (m, 2
H), 7.51–7.45 (m, 3 H), 7.26–7.22 (m, 1 H), 6.87 (t, J = 6.8 Hz, 1 H), 2.68
(s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.7, 152.2, 131.0, 129.9, 128.6,
128.1, 127.3, 127.0, 125.9, 113.4, 17.0.
HRMS-ESI: m/z [M + H]+ calcd for C13H11N3: 210.1026; found:
210.1027.
6-Chloro-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2f)14
2-Phenyl[1,2,4]triazolo[1,5-a]pyridine (2a)11
White solid; yield: 43.1 mg (87%); mp 165–167 °C.
White solid; yield: 47.1 mg (95%); mp 134–136 °C.
IR (KBr): 3050, 1651, 1499, 826, 714 cm–1
.
IR (KBr): 3037, 1611, 1497, 692 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.64 (s, 1 H), 8.27–8.25 (m, 2 H), 7.69
(d, J = 9.6 Hz, 1 H), 7.52–7.46 (m, 4 H).
13C NMR (100 MHz, CDCl3):  = 164.9, 150.3, 130.9, 130.34, 130.31,
128.7, 127.3, 126.6, 121.5, 116.4.
HRMS-ESI: m/z [M + H]+ calcd for C12H8ClN3: 230.0479; found:
1H NMR (400 MHz, CDCl3):  = 8.59 (dt, J = 6.8, 1.2 Hz, 1 H), 8.31–8.28
(m, 2 H), 7.75 (dt, J = 8.8, 0.8 Hz, 1 H), 7.52–7.46 (m, 4 H), 6.99 (dt, J =
1.2, 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 164.1, 151.7, 130.7, 130.1, 129.5,
128.7, 128.3, 127.3, 116.4, 113.6.
230.0477.
HRMS-ESI: m/z [M
+
H]+ calcd for C12H9N3: 196.0869; found:
196.0867.
6-Bromo-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2g)14
White solid; yield: 44.1 mg (89%); mp 165–167 °C.
5-Methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2b)23a
IR (KBr): 3042, 1628, 1502, 818, 699 cm–1
.
White solid; yield: 46 mg (93%); mp 84–86 °C.
1H NMR (400 MHz, CDCl3):  = 8.74 (d, J = 1.6 Hz, 1 H), 8.27–8.25 (m, 2
H), 7.66–7.63 (m, 1 H), 7.58–7.55 (m, 1 H), 7.52–7.47 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.7, 150.4, 133.1, 130.34, 130.29,
128.8, 128.7, 127.3, 116.8, 107.7.
HRMS-ESI: m/z [M + H]+ calcd for C12H8BrN3: 273.9955; found:
273.9953.
IR (KBr): 3041, 2912, 1624, 1503, 741 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.34–8.32 (m, 2 H), 7.63 (d, J = 8.4 Hz, 1
H), 7.52–7.40 (m, 4 H), 6.81 (dt, J = 7.2, 0.8 Hz, 1 H), 2.84 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.5, 151.8, 138.9, 131.2, 129.9,
129.3, 128.6, 127.3, 113.5, 112.8, 17.6.
HRMS-ESI: m/z [M + H]+ calcd for C13H11N3: 210.1026; found:
210.1022.
6,8-Dibromo-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2h)
White solid; yield: 42.2 mg (85%); mp 149–151 °C.
6-Methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2c)
IR (KBr): 3059, 1662, 1521, 827, 705 cm–1
.
White solid; yield: 46.5 mg (94%); mp 118–120 °C.
1H NMR (400 MHz, CDCl3):  = 8.70 (d, J = 1.6 Hz, 1 H), 8.30–8.28 (m, 2
H), 7.84 (d, J = 1.6 Hz, 1 H), 7.50–7.48 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 164.8, 149.7, 135.0, 130.6, 129.8,
128.7, 127.9, 127.6, 110.1, 106.9.
HRMS-ESI: m/z [M + H]+ calcd for C12H7Br2N3: 351.9059; found:
IR (KBr): 3054, 2931, 1641, 1511, 769 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.38 (s, 1 H), 8.28–8.26 (m, 2 H), 7.64
(d, J = 9.2 Hz, 1 H), 7.51–7.45 (m, 3 H), 7.33 (dd, J = 9.2, 1.6 Hz, 1 H),
2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.8, 150.3, 132.3, 130.9, 129.9,
128.6, 127.1, 126.3, 123.7, 115.5, 18.1.
351.9056.
HRMS-ESI: m/z [M + H]+ calcd for C13H11N3: 210.1026; found:
210.1024.
2-(4-Methoxyphenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine (2i)
White solid; yield: 44.6 mg (90%); mp 166–168 °C.
7-Methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (2d)11
IR (KBr): 3041, 2916, 1610, 1498, 1140, 810 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.36–8.35 (m, 1 H), 8.22–8.18 (m, 2 H),
7.61 (d, J = 9.2 Hz, 1 H), 7.32 (dd, J = 8.8, 1.6 Hz, 1 H), 7.03–6.99 (m, 2
H), 3.87 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.7, 161.0, 150.3, 132.3, 128.6,
126.2, 123.5, 123.4, 115.3, 114.0, 55.3, 18.1.
White solid; yield: 47.1 mg (95%); mp 141–143 °C.
IR (KBr): 3049, 2935, 1645, 1507, 781 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.44 (d, J = 7.2 Hz, 1 H), 8.28–8.26 (m, 2
H), 7.51–7.45 (m, 4 H), 6.80 (dd, J = 7.2, 2.0 Hz, 1 H), 2.47 (s, 3 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

G
A. Bhatt et al.
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Synthesis
HRMS-ESI: m/z [M + H]+ calcd for C14H13N3O: 240.1131; found:
HRMS-ESI: m/z [M + H]+ calcd for C14H13N3: 224.1182; found:
240.1127.
224.1179.
2-(4-Fluorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine (2j)
2-(3-Chlorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine (2o)
White solid; yield: 43.1 mg (87%); mp 163–165 °C.
White solid; yield: 42.1 mg (85%); mp 153–155 °C.
IR (KBr): 3068, 2931, 1635, 1511, 1224, 837, 734 cm–1
.
IR (KBr): 3026, 2916, 1629, 1494, 826, 711 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.36 (m, 1 H), 8.27–8.22 (m, 2 H), 7.62
(d, J = 8.8 Hz, 1 H), 7.34 (dd, J = 9.2, 1.6 Hz, 1 H), 7.19–7.14 (m, 2 H),
2.40 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 8.37 (s, 1 H), 8.28–8.27 (m, 1 H), 8.17–
8.12 (m, 1 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.42–7.41 (m, 2 H), 7.36 (dd, J =
9.2, 1.6 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.9 (d, 1JC,F = 247.8 Hz), 163.0, 150.3,
132.4, 129.1 (d, 3JC,F = 8.4 Hz), 127.2, 126.3, 123.8, 115.7 (d, 2JC,F = 21.6
Hz), 115.5, 18.0.
13C NMR (100 MHz, CDCl3):  = 162.5, 150.3, 134.7, 132.8, 132.6,
129.9, 129.8, 127.3, 126.3, 125.2, 124.1, 115.6, 18.1.
HRMS-ESI: m/z [M + H]+ calcd for C13H10ClN3: 244.0636; found:
244.0637.
HRMS-ESI: m/z [M + H]+ calcd for C13H10FN3: 228.0932; found:
228.0934.
6-Methyl-2-(o-tolyl)[1,2,4]triazolo[1,5-a]pyridine (2p)
2-(4-Chlorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine (2k)
White solid; yield: 44.6 mg (90%); mp 95–97 °C.
White solid; yield: 42.6 mg (86%); mp 169–171 °C.
IR (KBr): 3049, 3015, 2911, 1617, 1506, 823 cm–1
1H NMR (400 MHz, CDCl3):  = 8.41 (m, 1 H), 8.06–8.03 (m, 1 H), 7.66
(d, J = 9.2 Hz, 1 H), 7.36–7.30 (m, 4 H), 2.70 (s, 3 H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 160.0, 144.8, 132.9, 127.4, 126.4,
125.6, 125.4, 124.5, 121.5, 121.0, 118.7, 110.8, 17.0, 13.3.
.
IR (KBr): 3056, 2918, 1623, 1487, 820, 697 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.36 (s, 1 H), 8.21–8.18 (m, 2 H), 7.63
(d, J = 9.2 Hz, 1 H), 7.46–7.44 (m, 2 H), 7.35 (dd, J = 9.2, 1.6 Hz, 1 H),
2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.8, 150.3, 135.9, 132.5, 129.5,
128.9, 128.4, 126.3, 123.9, 115.5, 18.1.
HRMS-ESI: m/z [M + H]+ calcd for C14H13N3: 224.1182; found:
224.1179.
HRMS-ESI: m/z [M + H]+ calcd for C13H10ClN3: 244.0636; found:
244.0634.
2-(2-Chlorophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine (2q)
White solid; yield: 42.1 mg (85%); mp 109–110 °C.
2-(4-Bromophenyl)-6-methyl[1,2,4]triazolo[1,5-a]pyridine (2l)
IR (KBr): 3034, 2925, 1627, 1510, 839, 743 cm–1
.
White solid; yield: 41.7 mg (84%); mp 179–181 °C.
1H NMR (400 MHz, CDCl3):  = 8.45 (s, 1 H), 8.00–7.98 (m, 1 H), 7.70
(d, J = 9.2 Hz, 1 H), 7.55–7.52 (m, 1 H), 7.39–7.37 (m, 3 H), 2.43 (s, 3
H).
13C NMR (100 MHz, CDCl3):  = 162.5, 149.6, 133.1, 132.5, 132.0,
130.7, 130.5, 130.2, 126.7, 126.4, 124.0, 115.8, 18.1.
IR (KBr): 3047, 2919, 1602, 1514, 834, 703 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.36 (s, 1 H), 8.14–8.11 (m, 2 H), 7.64–
7.59 (m, 3 H), 7.35 (dd, J = 9.2, 1.6 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.9, 150.3, 132.5, 131.8, 130.0,
128.7, 126.3, 124.2, 123.9, 115.6, 18.1.
HRMS-ESI: m/z [M + H]+ calcd for C13H10BrN3: 288.0131; found:
HRMS-ESI: m/z [M + H]+ calcd for C13H10ClN3: 244.0636; found:
244.0633.
288.0129.
6-Methyl-2-[2-(trifluoromethyl)phenyl][1,2,4]triazolo[1,5-a]pyri-
6-Methyl-2-(4-nitrophenyl)[1,2,4]triazolo[1,5-a]pyridine (2m)
dine (2r)
Light yellow solid; yield: 39.6 mg (80%); mp 275–277 °C.
White solid; yield: 40.2 mg (81%); mp 80–82 °C.
IR (KBr): 3063, 2941, 1636, 1552, 1503, 1344, 850 cm–1
.
IR (KBr): 3039, 2928, 1629, 1514, 1105, 1062, 837, 795 cm–1
.
1H NMR (400 MHz, DMSO-d6):  = 8.89 (s, 1 H), 8.45–8.37 (m, 4 H),
7.84 (d, J = 8.8 Hz, 1 H), 7.62 (dd, J = 9.2, 1.6 Hz, 1 H), 2.41 (s, 3 H).
13C NMR (100 MHz, CF3CO2D):  = 153.3, 150.3, 141.8, 141.4, 132.5,
128.8, 128.7, 128.4, 124.5, 110.8, 16.2.
HRMS-ESI: m/z [M + H]+ calcd for C13H10N4O2: 255.0876; found:
1H NMR (400 MHz, CDCl3):  = 8.44–8.43 (m, 1 H), 7.88 (d, J = 7.6 Hz, 1
H), 7.84 (d, J = 7.2 Hz, 1 H), 7.70 (d, J = 9.2 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1
H), 7.59 (t, J = 7.6 Hz, 1 H), 7.40 (dd, J = 9.2, 2.0 Hz, 1 H), 2.44 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.7, 149.7, 132.6, 132.3, 131.5,
2
3
130.5, 129.4, 129.2 (q, JC,F = 31.4 Hz), 126.6 (q, JC,F = 5.4 Hz), 126.4,
124.1, 123.8 (q, 1JC,F = 272.1 Hz), 115.9, 18.1.
255.0875.
HRMS-ESI: m/z [M + H]+ calcd for C14H10F3N3: 278.0899; found:
278.0897.
6-Methyl-2-(m-tolyl)[1,2,4]triazolo[1,5-a]pyridine (2n)
White solid; yield: 44.6 mg (90%); mp 129–131 °C.
2-Phenyl[1,2,4]triazolo[1,5-a]pyrazine (2s)
IR (KBr): 3054, 3011, 2917, 1607, 1464, 833 cm–1
.
White solid; yield: 44.5 mg (90%); mp 179–181 °C.
1H NMR (400 MHz, CDCl3):  = 8.38–8.37 (m, 1 H), 8.10 (s, 1 H), 8.07
(d, J = 7.6 Hz, 1 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 7.33
(dd, J = 9.2, 1.6 Hz, 1 H), 7.27 (d, J = 7.2 Hz, 1 H), 2.45 (s, 3 H), 2.40 (s,
3 H).
IR (KBr): 3035, 1616, 1447, 709 cm–1
.
1H NMR (400 MHz, CDCl3):  = 9.30 (d, J = 1.2 Hz, 1 H), 8.56 (dd, J = 4.8,
1.6 Hz, 1 H), 8.32–8.30 (m, 2 H), 8.18 (d, J = 4.4 Hz, 1 H), 7.54–7.51 (m,
3 H).
13C NMR (100 MHz, CDCl3):  = 163.9, 150.3, 138.4, 132.4, 130.8,
130.7, 128.6, 127.8, 126.3, 124.3, 123.7, 115.5, 21.4, 18.1.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
A. Bhatt et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 165.1, 147.3, 142.7, 131.6, 130.8,
129.8, 128.9, 127.6, 121.5.
(4) (a) Collin, X.; Sauleau, A.; Coulon, J. Bioorg. Med. Chem. Lett.
2003, 13, 2601. (b) Papakonstantinou-Garoufalias, S.; Pouli, N.;
Marakos, P.; Chytyroglou-Ladas, A. Farmaco 2002, 57, 973.
(c) De Clercq, E. J. Clin. Virol. 2004, 30, 115. (d) Navidpour, L.;
Shadnia, H.; Shafaroodi, H.; Amini, M.; Dehpour, A. R.; Shafiee,
A. Bioorg. Med. Chem. 2007, 15, 1976. (e) Naito, Y.; Akahoshi, F.;
Takeda, S.; Okada, T.; Kajii, M.; Nishimura, H.; Sugiura, M.;
Fukaya, C.; Kagitani, Y. J. Med. Chem. 1996, 39, 3019. (f) Saha, A.
K.; Liu, L.; Simoneaux, R.; Decorte, B.; Meyer, C.; Skrzat, S.;
Breslin, H. J.; Kukla, M. J.; End, D. W. Bioorg. Med. Chem. Lett.
2005, 15, 5407. (g) Hester, J. B. Jr.; Rudzik, A. D.; Kamdar, B. V.
J. Med. Chem. 1971, 14, 1078.
HRMS-ESI: m/z [M
+
H]+ calcd for C11H8N4: 197.0822; found:
197.0820.
2-Phenyl[1,2,4]triazolo[1,5-a]pyrimidine (2t)23b
White solid; yield: 42.1 mg (85%); mp 184–186 °C.
IR (KBr): 3039, 1614, 1479, 1351, 769, 691 cm–1
.
1H NMR (400 MHz, CDCl3):  = 8.86 (dd, J = 6.4, 2.0 Hz, 1 H), 8.80 (dd,
J = 4.4, 2.0 Hz, 1 H), 8.36–8.34 (m, 2 H), 7.53–7.50 (m, 3 H), 7.09 (dd,
J = 6.8, 4.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 166.3, 156.1, 154.4, 135.5, 130.8,
130.2, 128.8, 127.5, 110.0.
(5) Hitotsuyanagi, Y.; Motegi, S.; Fukaya, H.; Takeya, K. J. Org. Chem.
2002, 67, 3266.
(6) (a) Liu, K.; Shi, W.; Cheng, P. Dalton Trans. 2011, 8475. (b) Wu, P.
L.; Feng, X. J.; Tam, H. L.; Wong, M. S.; Cheah, K. W. J. Am. Chem.
Soc. 2009, 131, 886. (c) Zhang, J.-P.; Lin, Y.-Y.; Huang, X.-C.;
Chen, X.-M. J. Am. Chem. Soc. 2005, 127, 5495. (d) Klingele, M.
H.; Brooker, S. Coord. Chem. Rev. 2003, 241, 119. (e) Haasnoot, J.
G. Coord. Chem. Rev. 2000, 200, 131. (f) Tao, Y.; Wang, Q.; Ao, L.;
Zhong, C.; Yang, C.; Qin, J.; Ma, D. J. Phys. Chem. C 2010, 114, 601.
(7) Holm, S. C.; Straub, B. F. Org. Prep. Proced. Int. 2011, 43, 319.
(8) Grenda, V. J.; Jones, R. E.; Gal, G.; Sletzinger, M. J. Org. Chem.
1965, 30, 259.
HRMS-ESI: m/z [M
+
H]+ calcd for C11H8N4: 197.0822; found:
197.0818.
Acknowledgment
The authors are thankful to Department of Chemistry, Mewar Univer-
sity, Chittorgarh, Rajasthan for experimental and spectroscopic analy-
sis of synthesized compounds.
(9) Potts, K. T.; Burton, H. R.; Bhattacharyya, J. J. Org. Chem. 1966,
31, 260.
Supporting Information
(10) Raval, J. P.; Desai, K. R. ARKIVOC 2005, (xiii), 21.
(11) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.
(12) Meng, X.; Yu, C.; Zhao, P. RSC Adv. 2014, 4, 8612.
(13) Xia, J.; Huang, X.; Cai, M. Synthesis 2019, 51, 2014.
(14) Zheng, Z.; Ma, S.; Tang, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
J. Org. Chem. 2014, 79, 4687.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611906.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H