One-pot synthesis of N-fused 1,2,4-triazoles and related heterocycles via I2/TBHP-mediated oxidative C–N bond formation

Article abstract of DOI:10.1016/j.tetlet.2018.10.019

A metal-free iodine/TBHP-mediated oxidative C–N bond formation for the one-pot synthesis of N-fused 1,2,4-triazoles and related heterocycles via cyclization has been developed. This reaction which is amenable to scale-up affords the corresponding products with good to excellent yields and tolerates a wide range of functional groups.

Full text of DOI:10.1016/j.tetlet.2018.10.019

Accepted Manuscript
One-pot synthesis of N-fused 1,2,4-triazoles and related heterocycles via I2/
TBHP-mediated oxidative C-N bond formation
Yachuang Wu, Yifeng Yang, Yinliang Qi, Shimei Du, Yongsheng Zhang, Liang
Ding, Yanfang Zhao
PII:
S0040-4039(18)31227-9
https://doi.org/10.1016/j.tetlet.2018.10.019
TETL 50329
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
24 August 2018
7 October 2018
11 October 2018
Please cite this article as: Wu, Y., Yang, Y., Qi, Y., Du, S., Zhang, Y., Ding, L., Zhao, Y., One-pot synthesis of N-
fused 1,2,4-triazoles and related heterocycles via I2/TBHP-mediated oxidative C-N bond formation, Tetrahedron
Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.10.019
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One-pot synthesis of N-fused 1,2,4-triazoles and related heterocycles via I2/TBHP-mediated oxidative C-N bond
formation
Yachuang Wu,a Yifeng Yang,a Yinliang Qi,a Shimei Du,a Yongsheng Zhang,a Liang Ding,a Yanfang Zhao*a
aKey Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of
Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
e-mail address: yanfangzhao@126.com (Y. Zhao).
Abstract
A metal-free iodine/TBHP-mediated oxidative C-N bond formation for the one-pot synthesis of
N-fused 1,2,4-triazoles and related heterocycles via cyclization has been developed. This reaction which is
amenable to scale-up affords the corresponding products with good to excellent yields and tolerates a wide
range of functional groups.
Keywords：One-pot; 1,2,4-Triazoles; I2/TBHP; C-N bond formation.
Introduction
1,2,4-Triazole-fused heterocycles are widely found in natural products and drugs with a broad
spectrum of biological activities, such as antibacterial,1 anti-HIV,2 anti-inflammatory,3 and antiepileptic
activities,4 (Fig. 1).
Figure 1. Selected biologically active 1,2,4-triazole-fused heterocycles
Various methods for synthesizing 1,2,4-triazole-fused heterocycles have been reported in the literature
(Scheme 1). Vidavalur and co-workers reported a novel strategy to obtain N-fused 1,2,4-triazoles from
iodobenzene and 2-hydrazinopyridines using molybdenum hexacarbonyl as a convenient and reliable solid
source of carbon monoxide (Scheme 1, Method A).5 Djuric and co-workers described the one step
construction of 1,2,4-triazole-fused heterocycles from carboxylic acids and 2-hydrazinopyridine using a
PS-PPh3 resin combined with microwave heating (Scheme 1, Method B).6 Zhang and co-workers reported a
method to synthesize 1,2,4-triazole-fused heterocycles from N'-(pyridin-2-yl)benzohydrazide by dehydration
in acetic acid under microwave irradiation at 180 °C.7 Roberts and co-workers reported a mild
N,N'-carbonyldiimidazole (CDI) mediated cyclization reaction for the same transformation.8 The oxidative
cyclization of 2-(2-arylidenehydrazinyl) pyridines represents the most commonly used method for the
synthesis of 1,2,4-triazole-fused heterocycles (Scheme 1, Method C). The oxidative cyclization of
2-(2-arylidenehydrazinyl) pyridines utilizing reagents such as hypervalent iodine,9 chloramine T,10 ceric
ammonium nitrate,11 and RuCl3/potassium peroxomonosulphate12 or under mild electrolytic conditions13 has
been reported in the literature. However, there are some disadvantages to these methodologies, such as the
use of
Molecular iodine has widely been used in organic chemistry due to the advantages of being
inexpensive and less toxic.14 A number of methodologies using this reagent have been developed for the
synthesis of heterocycles via carbon-heteroatom and carbon-carbon bond construction.15

efficient I2/TBHP-mediated one-pot protocol for the synthesis of 1,2,4-triazole-fused heterocycles in
moderate to good yields.
Synthesis of 1,2,4-triazole-fused heterocycles
Scheme 1.
Results and Discussion
Initially, benzaldehyde (1a) and 2-hydrazinopyridine (2a) were chosen as model substrates for
optimization of the reaction conditions. 2-Hydrazinopyridine (2a) was prepared in high yield by
condensation of the corresponding aryl halide with hydrazine. The I2/tert-butyl hydroperoxide (TBHP)
system has been widely reported in the literature for the construction of C-N bonds.16 However, the desired
product 3a was formed in only 40% yield when the reaction was performed using I2 (0.2 equiv.) as a catalyst
and TBHP (2 equiv.) as an oxidant in 1,4-dioxane at room temperature for 2 h (Table 1, entry 1). Several
other catalysts such as KI, tetrabutylammonium iodide (TBAI), N-iodosuccinimide (NIS), CuI and
PhI(OAc)2 in the presence of TBHP (Table 1, entries 2−6) were tested, but they exhibited lower catalytic
activities. Screening of the reaction temperature from 40 °C to 100 °C indicated that raising the temperature
to 60 °C increased the yield of 3a to 65 % (Table 1, entry 8), but raising the temperature to 80 °C and 100 °C
had no further effect on the yield compared with 60 °C (Table 1, entries 9-10). Next, commonly used
solvents were screened which revealed that using 1,4-dioxane afforded the best yield of 65% (Table 1,
entries 11-15). To our surprise, when 1.0 equivalents of potassium carbonate (K2CO3) as a base was added to
the reaction system, the desired product (3a) was obtained in 95% yield (Table 1, entry 18). Thus, the
optimal reaction conditions were 1a (1 equiv.), 2a (1 equiv.), I2 (0.2 equiv.), TBHP (2 equiv., 70% in water),
K2CO3 (1 equiv.) in 1,4-dioxane at 60 °C for 1 h (Table 1, entry 18).
Table 1. Optimization of the reaction conditionsa

Entry
Catalyst
(equiv.)
Oxidant
(equiv.)
Base
Solvent
Temp
(°C)
Time (h)
Yieldb
(%)
(equiv.)
1
2
I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
—
—
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
EtOH
r.t.
r.t.
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
1
1
1
40
25
KI
3
TBAI
—
r.t.
Trace
32
4
NIS
—
r.t.
5
CuI
—
r.t.
20
6
PhI(OAc)2
—
r.t.
Trace
50
7
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
—
40
8
—
60
65
9
—
80
60
10
11
12
13
14
15
16c
17c
18c
19c
—
100
60
58
—
52
—
H2O
60
30
—
DMSO
60
45
—
DCM
reflux
60
42
—
EtOAc
48
KI
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
60
75
KAc 3
K2CO3
Na2CO
60
82
60
95
60
1
88
b
c
aReagents and conditions: 1a (1 mmol), 2a (1 mmol), catalyst (0.2 mmol), oxidant (2 mmol), solvent (10 mL). Isolated yield. base (1.0 equiv.) was added to the
reaction system.
With the optimized reaction conditions for C-N bond formation identified, the substrate scope was
investigated to determine the generality of this method (Scheme 2). A series of substituted benzaldehydes
with ortho-, meta- or para-substituents were explored and gave the desired 1,2,4-triazole-fused heterocycles
(3a-m) in 72-95% yield. Compounds 3g, 3i and 3k were also obtained in good yields, which indicated that
the transformation is not affected by steric hindrance. However, the reaction of nitro-substituted substrates
3d, 3l and 3m showed an obvious decrease in yield, which indicated that this reaction is affected by
electronic factors and electron-withdrawing substituents are unfavorable. Moreover, cinnamic aldehyde and
isobutyraldehyde can be converted into the corresponding 1,2,4-triazole-fused heterocycles in good yields.
Next, we explored the substrate scope of 2-hydrazinopyridine and its derivatives (Scheme 3). Under the
optimized reaction conditions, all substrates were converted into the desired 1,2,4-triazole-fused
heterocycles (3p-v) in 92-97% yield. To our delight, the reaction performed on a 10 g (50 mmol) scale
afforded 3a in 94% yield, which indicated that the reaction is practical.
Scheme 2. Substrate scope for the synthesis of 1,2,4-triazole-fused heterocyclesa,b

a Reagents and conditions：1 (1 mmol) , 2 (1 mmol), I2 (0.2 mmol), TBHP (2 mmol, 70% in water), K2CO3 (1 mmol), 1,4-dioxane, 60 °C, 1 h; b Isolated yield.
Scheme 3. Substrate scope for the synthesis of 1,2,4-triazole-fused heterocyclesa,b
a Reagents and conditions：1 (1 mmol), 2 (1 mmol), I2 (0.2 mmol), TBHP (2 mmol, 70% in water), K2CO3 (1 mmol), 1,4-dioxane, 60 °C, 1 h; b Isolated yield.
In order to explore the reaction mechanism, various control experiments were conducted.
(E)-2-(2-Benzylidenehydrazinyl) pyridine was converted into the corresponding 1,2,4-triazole-fused
heterocycle in 96% yield under the optimised reaction conditions (Scheme 4). When the reaction was

conducted in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydroxytoluene
(BHT) as radical scavengers, compound 3a was obtained in 93% and 91% yield, respectively, which
indicated that the reaction did not proceed via a radical mechanism. When the reaction was conducted
without TBHP, compound 3a was obtained in only 22% yield. No desired product was detected when the
reaction was performed without I2, which indicated that I2 is necessary to this reaction and TBHP plays a
supporting role.
Scheme 4. Control experiments
Based on our experimental results and previous investigations,17 a plausible mechanism was proposed
(Scheme 5). First, intermediate A was formed by the condensation reaction between benzaldehyde (1) and
2-hydrazinopyridine (2), then intermediate B was formed via a base-promoted oxidative iodination of A.
Second, intermediate B underwent cyclization via nucleophilic substitution to obtain the desired
intermediate C. Finally, intermediate C was deprotonated by the iodine anion and converted into compound
3a. During the reaction, the eliminated HI was oxidized to I2 by TBHP and the catalytic cycle was achieved.
Scheme 5. Proposed mechanism for the formation of 2a

Conclusion
In summary, we have developed an efficient one-pot synthesis of 1,2,4-triazole-fused heterocycles via
I2/TBHP-mediated oxidative C-N bond formation. This novel reaction works well with a wide range of
substrates and can be conducted on gram scale.
Acknowledgements
The work was supported by the Program for Innovative Research Team of the Ministry of Education
and Program for Liaoning Innovative Research Team in University (IRT1073).
Notes and references
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Highlights
1, One-pot protocol for the synthesis of 1,2,4-triazole-fused heterocycles.
2, Wide substrate scope, short reaction time and high reaction yields.
3, The reaction can be conducted on gram scale.

An iodine/TBHP-mediated one-pot oxidative C-N bond formation for the synthesis of N-fused 1,2,4-triazoles and related
heterocycles is developed.