Trichloroisocyanuric acid-mediated synthesis of 1,5-fused 1,2,4-triazoles from N-heteroaryl benzamidines via intramolecular oxidative N–N bond formation

Article abstract of DOI:10.1016/j.tetlet.2019.151026

A convenient synthesis of 1,5-fused 1,2,4-triazoles from readily available N-heteroaryl benzamidines is reported. The reaction is efficiently promoted by trichloroisocyanuric acid to afford the desired products, mostly in high yields and in relatively sho

Full text of DOI:10.1016/j.tetlet.2019.151026

Journal Pre-Proof
Trichloroisocyanuric acid-mediated synthesis of 1,5-fused 1,2,4-triazoles from
N-heteroaryl benzamidines via intramolecular oxidative N–N bond formation
Ashish Bhatt, Rajesh K. Singh, Bhupendra K. Sarma, Ravi Kant
PII:
S0040-4039(19)30783-X
https://doi.org/10.1016/j.tetlet.2019.151026
TETL 151026
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 July 2019
3 August 2019
7 August 2019
Please cite this article as: Bhatt, A., Singh, R.K., Sarma, B.K., Kant, R., Trichloroisocyanuric acid-mediated
synthesis of 1,5-fused 1,2,4-triazoles from N-heteroaryl benzamidines via intramolecular oxidative N–N bond
formation, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151026
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Trichloroisocyanuric acid-mediated
synthesis of 1,5-fused 1,2,4-triazoles from N-
heteroaryl benzamidines via intramolecular
oxidative N–N bond formation
Leave this area blank for abstract info.
Ashish Bhatta*, Rajesh K. Singhb, Bhupendra K. Sarmaa and Ravi Kanta
R1
R1
transition metal free
N-N bond formation
N
NH
R2
N
N
N
Y
X
N
Y
TCCA, EtOH
78 °C, 30-45 min.
80-95%
H
R2
X
X, Y = CH or N; R1 = H, Me, Br, Cl
R2 = H, Me, OMe, Br, Cl, F, CF3, NO2

JOURNAL PRE-PROOF
1
Tetrahedron Letters
journal homepage: www.elsevier.com
Trichloroisocyanuric acid-mediated synthesis of 1,5-fused 1,2,4-triazoles from N-
heteroaryl benzamidines via intramolecular oxidative N–N bond formation
Ashish Bhatta,, Rajesh K. Singhb, Bhupendra K. Sarmaa and Ravi Kanta
a Department of Chemistry, Mewar University, Chittorgarh, (Rajasthan),312901, India
b Department of Pharmacy, Mewar University, Chittorgarh, (Rajasthan),312901, India
———
ARTICLE INFO
ABSTRACT
 Ashish Bhatt. Tel.: +91-774-284-5501; e-mail: itsbhatt2007@yahoo.co.in
Article history:
Received
A convenient synthesis of 1,5-fused 1,2,4-triazoles from readily available N- heteroaryl
benzamidines is reported. The reaction is efficiently promoted by trichloroisocyanuric acid to
Received in revised form
Accepted
Available online
afford the desired products, mostly in high yields and in relatively short time, through direct
metal-free oxidative 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 functionalities.
Keywords:
N- heteroaryl benzamidine
1,2,4-triazole
2009 Elsevier Ltd. All rights reserved.
Trichloroisocyanuric acid
Ethanol
F
F
Introduction
CF3
N
The 1,2,4-triazole nucleus is an important structural motif
present in a large number of functionalized molecules with a
wide variety of uses, including applications in medicinal
chemistry, agricultural chemistry, materials science, and
organocatalysis [1]. 1,2,4-Triazole scaffolds are found in many
biologically active molecules [2] and valuable pharmaceuticals,
including maraviroc, triazolam, sitagliptin, and penipanoid
(Figure-1)[3]. In particular, compounds containing N-fused 1,2,4-
triazoles, such as triazolopyridine 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 often been used as bioisosteres of esters and amides,
and as dipeptidomimetics in a number of pharmacologically
important molecules [5]. On the other hand, they also play
important roles as ligands in transition-metal complexes and
metal-organic frameworks, exhibiting tremendous application
prospects [6].
F
F
N
N
N
NH
N
O
N
N
NH2
O
O
F
N
maraviroc
sitagliptin
HO
Cl
N
N
N
N
N
N
N
N
NH
N
O
Cl
triazolam
OH
DL111-IT
penipanoid A
Figure 1. Representative bioactive molecules and natural
compounds possessing a 1,2,4-triazole core
In 2009, Ueda and Nagasawa [11] reported a copper-catalyzed
tandem addition−oxidative cyclization of 2-amino pyridines and
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
associated with some disadvantages, including low yields,
multistep synthetic procedures, limited scopes and inferior
regioselectivity.
aryl
nitriles
to
2-aryl-1,2,4-triazolo[1,5-a]pyridines.
Alternatively, Zhao and co-workers [12] developed a recyclable
Cu−Zn/Al−Ti catalyst for the same transformation. Recently,
Xia, Huang, and co-workers [13] described a Cu-catalyzed
oxidative cyclization of Nitriles with 2-Aminopyridines or
Amidines. However, in almost 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 they are not recyclable.
These problems are of particular environmental and economic
concerns in large-scale syntheses and in industry. Moreover,
these transition metal catalysis might cause metal contamination

JOURNAL PRE-PROOF
2
Tetrahedron
of the desired product because 1,2,4-triazoles are strong ligands
ethanol under reflux at 78 °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 satisfactory. The
progress of the reactions was monitored by TLC analysis (using
EtOAc–hexane as the eluent).
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.
However, some transition metal free synthetic methods have
also been reported to access N-fused 1,2,4-triazoles. For example,
Du, Zhao, and co-workers [14] reported a PIFA-mediated
cyclization of N-(pyridin-2-yl) amidines to 2-aryl/2-alkyl
triazolopyridines. Further, in 2015, Song, Tian and co-workers
[15] reported a new and efficient I2/KI-mediated methodology for
the synthesis of both 2-aryl and 2-alkyl substituted 1,2,4-
triazolo[1,5-a]pyridines. But these existing methods suffer from
some drawbacks in one or another respect, such as use of
expensive catalyst, formation of byproduct like 20% iodinated
product along with desired product in I2/KI-mediated
methodology, inferior regioselectivity and a limited substrate
scope.
Plausible Mechanism: Based on our experimental data and
previous report [15,22], a plausible reaction mechanism for the
formation of 1,5-fused 1,2,4-triazole 6 is proposed (Scheme 2).
According to this route, N-heteroaryl benzamidine 1 on
treatment with Trichloroisocyanuric acid first provides N-chloro
amidinium cation 2 and cyanurate anion 3 as a proton acceptor.
N-chloro amidinium 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.
O
O
Cl
Cl
Cl
O
N
N
N
N
O
_
N
O
O
N
H
Cl
H
N
Cl
N
2
N
Cl
N
4
N
Despite these elegant achievements made, it is still of
importance to develop novel and general approaches to access
this compound class.
N
NH
Ph
3
Cl
N
H
Ph
Ph
OH
N
H
O
Cl
O
1
N
N
Cl
_
N
N
O
N
Trichloroisocyanuric acid (TCCA) is a versatile reagent and is
becoming increasingly popular because of its commercial
availability at low cost. TCCA has been extensively used as an
oxidant for a wide variety of functional groups [16,17]. This
reagent also acts as a chlorinating agent [18], as oxidant for
aromatization of various nitrogen heterocycles [19], and as
oxidizing reagent to construct the C–O bond in isoxazole
synthesis [20]. However, to the best of our knowledge, there is no
report of TCCA-mediated N–N bond formation reactions.
Encouraged by the results of our previous work [21,22], in this
O
N
O
Cl
Cl
3
OH
OH
Cl
O
N
N
_
N
N
O
N
O
O
N
Cl
OH
Cl
N
N
H
O
N
O
N
N
N
N
N
6
Cl
Ph + Cl2
Ph
N
OH
5
N
N
_
O
N
OH
paper, we disclose
a new and efficient TCCA-mediated
Cl
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-heteroaryl benzamidines
through the construction of N−N bonds.
Scheme 2. Plausible mechanism for the synthesis of 1,5-fused
1,2,4-triazole from N-heteroaryl benzamidine
Table-1 Optimization of the Reaction Conditions
Result and Discussion
N
NH
N
N
Herein, we describe a convenient synthesis of 1,2,4-
triazolo[1,5-a]pyridines, as well as their pyrazido- and
pyrimidotriazole derivatives, from their corresponding N-aryl
amidines. The required substrates N- heteroaryl benzamidines
1a-t were prepared via the addition reaction of corresponding
heteroaryl amines to substituted nitriles as per the reported
literature procedure [23]. Our preliminary investigation began
with the reaction of N-(2-pyridyl) amidine 1a with TCCA (0.5
equiv.) in methanol under reflux at 65 °C. We were delighted to
observe the formation of the desired product 2a, albeit in a low
yield of 70% (Table 1, entry 1), as an isolated yield obtained
after column chromatography. Next, we optimized the reaction
conditions in order to increase the yield. Thus, different solvents
were screened under reflux condition and the results are
summarized in Table 1. It was found that ethanol was the
superior solvent in terms of the reaction time and yield of the
product (Table 1, entry 2). Once, we had established a suitable
solvent for the synthesis of 1,2,4- triazolo[1,5-a]pyridine, we
then focused on the quantity of TCCA. An increase in the
amount of TCCA (from 0.5 equiv. to 1.5 equiv.) not only
decreased the reaction time from 1.5 h to 30 minute, but also
increased the product yield from 75% to 95% (Table 1, entry 7).
Further increasing the quantity of TCCA (from 1.5 equiv. to 2
equiv.) led to a decrease in the yield to 75% (Table 1, entry 8).
Therefore, we decided to perform the subsequent reactions of the
various N- heteroaryl benzamidines with TCCA (1.5 equiv.) in
N
TCCA
N
Solvent, reflux
H
2a
1a
Entry
Solvent
TCCA (eq.)
Time
Yield
(%)
70
1
2
3
4
5
6
7
8
MeOH
EtOH
0.5
0.5
0.5
0.5
0.5
1.0
1.5
2
1.5 h
1h
75
50
45
50
85
95
75
Isopropanol
Toluene
AcOH
2.5 h
3 h
2 h
EtOH
45 min.
30 min.
15 min.
EtOH
EtOH
With the optimized reaction conditions established (Table 1,
entry 7), the scope of the newly discovered oxidative N−N bond
formation reaction was investigated (Table 2). Because 2a was
afforded in an excellent yield from its corresponding substrate
1a, the effect of substituents on the pyridine ring (R1) was first
examined. This heterocyclic ring was found to be tolerant of both

JOURNAL PRE-PROOF
3
electron-rich groups such as methyl 2b-e and electron-deficient
N
NH
groups such as halogens 2f−h. Reactions of halogen-containing
substrates provided yields slightly lower than that of the methyl-
containing substrate, 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 a substituent in
aromatic ring, this methodology is compatible with both electron-
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 transformed 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
N
N
OMe
9
30
30
92
88
N
H
OMe
2i
N
NH
N
N
F
10
11
N
H
N
F
2j
N
NH
N
N
N
N
30
87
Cl
N
H
Cl
2k
N
NH
Additionally, pyrazido- 2s and pyrimidotriazoles 2t were
prepared via the oxidative cyclization of N-pyrazyl 1s and N-
pyrimidyl substituted benzimidamides 1t, respectively, in good
yields.
N
Br
12
13
35
45
85
81
N
N
H
Br
2l
N
N
NH
N
NO2
N
N
H
2m
NO2
Table-2 Synthesis of various 1,5-fused 1,2,4-triazoles with the
scope of substituents R1 and R2 on N-heteroaryl benzamidine
R1
R1
N
NH
N
N
N
NH
R2
14
15
30
30
90
87
N
N
N
TCCA
N
N
H
Y
X
N
Y
2n
EtOH, 78 °C
R2
X
H
2
1
Cl
X, Y = CH or N, R1 = H, Me, Br, Cl
R2 = H, Me, OMe, Br, Cl, F, CF3, NO2
N
NH
N
Cl
N
N
H
N
2o
Ent
ry
Substrate (1)
Product (2)
Time
(min)
Yield
(%)
N
NH
N
N
N
N
N
NH
N
16
17
35
35
88
87
N
1
30
35
95
H
N
N
H
2a
2p
Cl
N
N
N
N
NH Cl
N
NH
2
92
N
N
N
N
H
N
N
H
2b
2q
N
N
N
NH
NH
F3C
NH CF3
3
4
30
30
93
94
N
N
N
N
H
N
18
40
84
N
H
2c
2r
N
N
N
N
N
H
N
N
NH
N
2d
N
N
19
20
30
35
91
87
N
N
H
2s
N
N
N
NH
N
N
H
N
NH
N
N
5
6
40
30
91
89
N
N
N
2e
H
N
2t
Cl
Br
Cl
N
N
N
NH
NH
N
N
H
2f
Conclusion
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 Trichloroisocyanuric acid through the
construction of N-N bond. This facile and transition-metal-free
synthetic process works well with a wide range of substituted N-
heteroaryl benzamidine. A variety of substituents are tolerated
allowing the synthesis of diverse products in good to excellent
yields. The main advantage of this procedure is to access 1,5-
fused 1,2,4-triazoles with high yields and short reaction time. The
newly developed synthetic route is believed to be valuable for the
Br
N
N
N
7
8
35
35
88
87
N
H
N
2g
Br
Br
N
N
N
NH
N
N
H
Br
Br
2h

JOURNAL PRE-PROOF
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Tetrahedron
10.1021/jo010904i
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Acknowledgments
The authors are thankful to department of chemistry, Mewar
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JOURNAL PRE-PROOF
5
Highlights
 Trichloroisocyanuric acid mediated
synthesis of 1,5-fused 1,2,4-triazoles
from N- heteroaryl benzamidines
 A transition-metal free intramolecular
oxidative N−N bond formation
 Various substituted N- heteroaryl
benzamidines tolerated and gave 1,5-
fused 1,2,4-triazoles in good yields.