Divergent Synthesis of Substituted Amino-1,2,4-triazole Derivatives

Article abstract of DOI:10.1055/a-1477-4630

A divergent efficient assembly of disubstituted 1,2,4-triazoles was established by cyclization of readily accessible N ′-nitro-2-hydrocarbylidene-hydrazinecarboximidamides with moderate to excellent yields under mild reaction conditions. This divergent synthetic strategy was achieved simply by varying the reaction conditions. Under acidic conditions, amino-1,2,4-triazoles were obtained by an intramolecular redox reaction involving the NO ₂group. Control experiments and DFT studies revealed that this transformation proceeds via an intramolecular 1,3-hydride transfer pathway leading to HNO ₂elimination. Under neutral conditions with water as the solvent, nitroimino-1,2,4-triazoles were obtained by oxidative intramolecular annulation under air.

Full text of DOI:10.1055/a-1477-4630

SYNTHESIS
0
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1
4
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1901–1910
paper
1901
en
F. Zhao et al.
Paper
Synthesis
Divergent Synthesis of Substituted Amino-1,2,4-triazole Derivatives
Fenghai Zhaoa
divergent access to amino-1,2,4-triazoles and nitroimino-1,2,4-triazoles
Thishana Singhb
Yumei Xiaoa
Wangcang Sua,c
Dongyan Yanga,d
Changqing Jiaa,e
Jia-Qi Li*a
NH2
N
NNO2
NH2
R2
NNO2
NH
R1
R1
R1
acidic
non-acidic
N
N
N
N
N
N
MeOH
H2O
R2
R2
NO2 eliminated
NO2 retained
NO2-promoted
intramolecular redox reaction
Zhaohai Qin*a
• DFT calculations
• metal-free • oxidant-free
• simple procedure
a Innovation Center of Pesticide Research, Department of Chemistry, College of
Science, China Agricultural University, Beijing 100193, P. R. of China
jiaqili@cau.edu.cn
b College of Agriculture, Engineering and Science, School of Chemistry and Physics,
University of KwaZulu-Natal, Durban 4000, South Africa
c Institute of Plant Protection, Henan Academy of Agricultural Sciences, Zhengzhou
450002, P. R. of China
d College of Chemistry and Chemical Engineering, Zhongkai University of Agricul-
ture and Engineering, Guangzhou, Guangdong 510225, P. R. of China
e National Engineering Research Center, Tongren Polytechnic College, Guizhou
554300, P. R. of China
Corresponding Authors
Received: 20.02.2021
Accepted after revision: 08.04.2021
Published online: 08.04.2021
bone has a perfect balance between thermal stability and a
high positive heat of formation. Amino-1,2,4-triazoles with
NO2 substituents, such as nitroamino-1,2,4-triazoles, are
used extensively as important precursors in the construc-
tion of versatile intermediates for the development of new
energetic materials.8
The most commonly used synthetic protocols for the
preparation of amino-1,2,4-triazoles involve cyclization of
hydrazonoyl derivatives and cyanamide,9 condensation of
N-cyanoimidates and mono-substituted hydrazines,10 or
cyclocondensation of amidoguanidines followed by N-sub-
stitution11 (Scheme 1). The introduction of a nitro group to
the amino group of amino-1,2,4-triazoles is usually
achieved by nitration of the amino-1,2,4-triazole with a
mixture of concentrated sulfuric and nitric acids.12 Howev-
er, these methods suffer from unsatisfactory yields, harsh
DOI: 10.1055/a-1477-4630; Art ID: ss-2021-g0077-op
Abstract A divergent efficient assembly of disubstituted 1,2,4-tri-
azoles was established by cyclization of readily accessible N′-nitro-2-hy-
drocarbylidene-hydrazinecarboximidamides with moderate to excellent
yields under mild reaction conditions. This divergent synthetic strategy
was achieved simply by varying the reaction conditions. Under acidic
conditions, amino-1,2,4-triazoles were obtained by an intramolecular
redox reaction involving the NO2 group. Control experiments and DFT
studies revealed that this transformation proceeds via an intramolecular
1,3-hydride transfer pathway leading to HNO2 elimination. Under neu-
tral conditions with water as the solvent, nitroimino-1,2,4-triazoles
were obtained by oxidative intramolecular annulation under air.
Key words 1,2,4-triazoles, divergent synthesis, redox chemistry, cy-
clization, heterocycles
Me
The development of efficient and convenient proce-
dures for the construction of N-containing heterocyclic
frameworks is one of the most important features in syn-
thetic chemistry because of the increased demand for these
structures in pharmaceutical and industrial chemicals.1
Polysubstituted 1,2,4-triazoles are an important class of
heterocyclic compounds as a result of their varied effects in
diverse domains.2 In particular, amino-1,2,4-triazole deriv-
atives have received considerable attention as valuable
building blocks for the construction of more complex struc-
tures because of their special biological, pharmacological,
and energetic activities.3 Amino-1,2,4-triazole scaffolds are
present in numerous medicinal molecules such as antibiot-
ics,4 antimalarials,5 oxytocin receptor (OTR) antagonists,6
and anticancer agents7 (Figure 1). The 1,2,4-triazole back-
OMe
MeO
HN
O
CF3
HN
OMe
N
N
F
O
N
N
N
O
N
H
N
N
N
O
F
N
H
N
Cl
H2N
N
Essramycin
Cevipabulin
antimicrotubule
Tubulin polymerization inhibitor
antimitotic and antivascular
antibiotic
F
NH2
CF3
Cl
N
N
OMe
N
N
N
N
N
HN
Cl
H
F
F
N
N
N
N
N
Cl
OMe
BCTA
anti-lung-cancer
SHR1653
OTR antagonist
DSM421
antimalarial
Figure 1 Selected natural and bioactive amino-1,2,4-triazoles
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1902
F. Zhao et al.
Paper
Synthesis
reaction conditions, a requirement for stoichiometric quan-
tities of oxidants, and low selectivities. To address these
drawbacks, a strategy to afford amino-1,2,4-triazoles deriv-
atives by direct preparation with readily accessible starting
materials, practical synthetic methods, and excellent func-
tional group compatibility is still in high demand.
ucts, as well as the design of compounds possessing poten-
tial biological activity, with the hydrocarbylidene nitrohy-
drazinecarboximidamides in hand, 4,5-disubstituted 3-
amino-1,2,4-triazoles and 1,3-disubstituted 5-nitroimino-
1,2,4-triazoles have been easily obtained in high yields un-
der mild reaction conditions. The formation of the amino-
1,2,4-triazoles occurred via an NO2-promoted intramolecu-
lar redox reaction, which has been described and investigat-
ed by both experimental studies and DFT calculations.
In our first attempt to hydrolyse the imine part and re-
lease the free amine group of guadipyr (1a)14 in 15 wt% HCl
aqueous solution (CH+ ≈ 5.0 mol·L–1, H+ is approximately
192.0 equiv relative to 1a), the desired product 2 was not
obtained (Scheme 2). Instead, compound 3a (structure un-
ambiguously determined by X-ray diffraction, Figure S2)
was obtained in moderate yield (49%), together with a sig-
nificant amount of undesired product (Figure S1).15 The
major byproduct, isolated by flash chromatography, was
compound 4 (14%). When this reaction was performed un-
der less acidic conditions, with 0.5 wt% H2SO4 aqueous solu-
tion (CH+ ≈ 5.9 × 10–2 mol·L–1, H+ is 4.0 equiv relative to 1a),
the yield of 3a decreased to 22% and the formation of 4 in-
Previous works:
H
N
N
R2
CN
NO2
N
NO2
NH2
N
HN
H2N
R2
R2
R2
R1
X
H2SO4/HNO3
(ref. 12)
N
N
N
N
N
or
N
NH
R1
(refs. 9, 10)
CN
N
N
NH2
R2HN
R1
R1
R1 OR3
R2-X
NH2
N
NH2
NH2
HN
N
HN
R1
N
(ref. 11)
O
R1
X = Cl, Br, OR3
Low selectivities
Harsh reaction conditions
Stoichiometric quantities of oxidants
This work:
NO2
NO2
N
NO2
NO2
N
N
R1
R1
N
R2CHO
MeOH
R1X/NaH
H2O
HN
N
N
N
N
N
NH2
R2
NH2
R2
HN
NH2
NH
R2
NH2
DMF
1
creased to 24% (yield measured by H NMR analysis of the
H2SO4
MeOH
NH2
Simple procedure
crude reaction mixture with 1,3,5-methoxybenzene as an
internal standard). Interestingly, when the reaction was
performed in a non-aqueous solution, such as concentrated
H2SO4 or p-toluene sulfonic acid (PTSA) in methanol (in
both cases, H+ is 2.0 equiv relative to 1a), only the desired
product 3a was detected (Figure S1). Byproduct 4 and other
Divergent synthesis
R1
N
N
N
R2
Scheme 1 Strategies for the synthesis of (nitro)amino-1,2,4-triazoles
1
Hydrocarbylidene nitrohydrazinecarboximidamides are
a class of outstanding insecticides developed by our group
and noted for their effectiveness in constructing multiple-
nitrogen-containing heterocyclic ring systems.13 We have
reported an access to 1,3-disubstituted 1,2,4-triazol-5-
amines by the cyclization of hydrocarbylidene nitrohydra-
zinecarboximidamides. These triazole compounds exhibit-
ed certain antifungal activities against plant pathogenic
fungi. However, this transformation suffered from only a
decent isolated yield and from difficult separation as a re-
sult of byproducts with similar polarities to those of the de-
sired products (Figure S1 in the Supporting Information). To
tackle this problem, we have developed an improved syn-
thetic method for the preparation of 1,3-disubstituted 5-
amino-1,2,4-triazoles in this work. As part of our continu-
ing efforts toward the practical synthesis of natural prod-
byproducts were not observed in the H NMR spectrum of
the crude product (Figure S3). We observed a linear depen-
dence between the amount of PTSA used in the reaction
and the yield of compound 3a (determined by 1H NMR
spectroscopy of the crude reaction mixture with 1,3,5-me-
thoxybenzene as an internal standard) (Figure 2). Based on
these experimental results, a plausible pathway of 1,3-hy-
dride transfer leading to the HNO2 elimination was
NO2
N
O
+
N
NH2
nBu
H
NH2
NO2
N
Cl
N
15 wt% HCl
2
N
N
NH2
nBu
NO2
N
NH2
N
H2O, 100 °C, 1.5 h
Cl
N
N
N
+
NH2
H
N
1a
Cl
N
Cl
N
nBu
3a
4
Scheme 2 Acid treatment of 1a in aqueous solution
Figure 2 Correlation between the yield of 3a and the dosage of PTSA
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

1903
F. Zhao et al.
Paper
Synthesis
NO2
N
Bn
N
N
NH2
H
H
20
18.33
III
NO2
HN
Bn
O
10.03
II-1
N
10
NH
H
N+
O-
HN
HN
NO2
Bn
H
N
N
NH
Bn
–4.51
IV
HN
0
II
NO2
N
NH2
H
0
HN
HN
–6.74
Bn
N
NH
H
V
HN
NH2
N
Bn
–10
–20
–30
–40
–60
N
N
VII
O
N
OH
basic work up
H+
H
NH
NH
NH2
Bn
N
Bn
N
N
HN
N
–38.01
VI-1
NH2
N
–39.31
VI
NO2
NO2
NO2
NH2
Bn
N
N
N
N
H+
HNO2
H2O
Bn
Bn
Bn
HN
N
N
NH2
H
N
NH2
N
H
NH2
H2O
–60.64
I
VIII
IX
VI-2
Scheme 3 Proposed reaction mechanism
proposed and investigated by using DFT calculations
(Scheme 3).
NH2
NH2
N
R2
R2
NH2
N
conditions
R1
N
NO2
5
N
N
N1
N2
N
R2
4
N
The energies of all of the structures in Scheme 3 were
calculated relative to structure II, which was the protonated
product of structure I and was assigned a Gibbs free energy
of 0 kcal·mol–1. It can cyclize to form stable structure III
(18.33 kcal·mol–1) or it can also form structure II-1. Struc-
ture III rearranges to give structure IV (–4.51 kcal·mol–1).
Structure II-1 also cyclizes to produce structure IV. A 1,3-
hydride transfer in structure IV results in structure V. The
presence of acid in the reaction mixture allows the removal
of an HNO2 molecule assisted by partial aromatization
through a five-center transition state and gives rise to
structure VI.16 According to molecular orbital theory, nitro-
gen has the ability to form four bonds. A nitrogen atom has
the electronic configuration [He] 2s22p3. Hybridization of
one s orbital and three p orbitals forms four degenerate sp3
hybrid orbitals. This is possibly the electronic nature
around the terminal NH group in structure VI. The two pro-
tons from the ring (NH) form the terminal NH3+ group, thus
leading to the formation of structure VI-1, which is slightly
higher in energy. Although it is only slightly higher in ener-
gy, this may be evidence that it is not a very stable struc-
ture. The other possible route is that only one proton from
the ring (NH) moves to the terminal N atom, forming an
NH2 group. This results in structure VI-2 with an energy of
–60.64 kcal·mol–1. Either way, the free aminotriazole VII is
formed after workup under basic conditions. In the
presence of an acid/water medium, structure I will be
3
H
R1
R1
1
3
NH2
NH2
N
NH2
N
X-ray of 3a
N
N
N
N
N
N
N
Cl
N
Cl
N
Cl
N
3a, 91% (49%)
3b, 93% (41%)
3c, 86% (42%)
NH2
N
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
N
N
Cl
3g, 83% (48%)
Cl
N
Cl
N
Cl
3d, 87% (47%)
3e, 86% (57%)
3f, 76% (49%)
NH2
N
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
3h, 81% (55%)
3i, 81% (58%)
3j, 80% (55%)
3k, 86% (55%)
NH2
N
NH2
N
NH2
N
NH2
N
N
N
N
N
N
N
N
N
3l, 90% (53%)
3m, 81% (50%)
3n, 91% (47%)
3o, 88% (52%)
Cl
OMe
Scheme 4 Substrate scope of 1,3-disubstituted 5-amino-1,2,4-tri-
azoles. Reagents and conditions: 1 (1.0 mmol), H2SO4 (1.0 mmol), MeOH
(30 mL), under air, 80 °C, 1.5 h. The yields of the isolated products are
given. In parentheses are the isolated yields obtained when 15 wt% HCl
aqueous solution (30 mL) was used in place of methanolic H2SO4.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

1904
F. Zhao et al.
Paper
Synthesis
hydrolyzed to structure VIII, which upon further reaction
with HNO2 forms structure IX.
conversion was observed (Table S1). However, the denitro
5-amino-1,2,4-triazole, compound 3a, was not observed.
Instead, compound 7, which is formed by direct cyclization
of 1a, was isolated as the main product. Compound 7 was
not stable in air and oxidized further to 5-nitroamino-
1,2,4-triazole 8a (Scheme 6).17 The structure of compound
8a was confirmed by single crystal X-ray diffraction (Figure
S2).15 Hydrogen bonding was detected in compound 1 (Fig-
ure S2a);14 however, the crystal packing of 8a revealed only
intermolecular hydrogen bonds between NH and NO2
groups. No intramolecular hydrogen bonds formed be-
tween the hydrogen atom in the NH group (N4) and the ox-
ygen atom of the nitro group (N6−O1) (Figure S2b). The re-
action was carried out in different organic solvents, and
MeCN/CsCO3 was the most effective medium (Table S1). The
use of water as a solvent in organic synthesis has attracted
much attention in green chemistry. We are pleased to re-
port that the transformation of 7a was complete after 12 h
in refluxing H2O in the absence of base and the correspond-
ing product 8a was isolated in 90% overall yield from 1a.
With an understanding of the mechanism and the opti-
mized reaction parameters in hand (Table S1), we set out to
investigate the reaction scope. A wide variety of substrates
was successfully tested by using the optimized reaction
conditions (Scheme 4). N-Heteroaryl-methyl-derived sub-
strates containing linear or branched imines gave the corre-
sponding 5-amino-1,2,4-triazoles in excellent yields (3a–
3e). Various N-aryl-methyl-substituted substrates also pro-
vided the desired products in excellent yields (3f–3l). Reac-
tions with N-alkyl-derived substrates bearing a phenyl
group (3m), electron-poor (3n), or electron-rich (3o) aro-
matic substituents on the electrophilic imine proceeded
smoothly to afford the target molecules in excellent yields.
In all transformations, the yields were significantly in-
creased in comparison to those obtained from the reaction
performed in 15 wt% HCl aqueous solution and no side re-
actions were observed.
Encouraged by these results, we extended the scope of
this transformation to the synthesis of novel 4,5-disubsti-
tuted 3-amino-1,2,4-triazoles (Scheme 5). Substrates with
N-alkyl, N-heteroaryl-methyl, or N-phenyl groups were tol-
erated in the reaction, and the corresponding products
were isolated in high yields (6a–6c). Benzaldehyde-derived
substrates furnished the desired products in high yields
(6d–6f). Compound 6g, 4,5-bis(4-chlorophenyl)-4H-1,2,4-
triazol-3-amine, was found to have much more potent anti-
cancer activity than chemotherapeutic agent 5-fluorouracil
against several lung cancer cells.6 It was successfully pre-
pared in 81% yield by using our method.
conditions a or b, air; 94% yield for condtions a, 90% yield for conditions b
NO2
NO2
NO2
N
N
N
conditions a or b
conditions a or b
N
N
N
N
N
NH
NH
nBu
NH2
nBu
HN
N2
air
Cl
N
H
nBu
Cl
N
Cl
N
1a
717
8a
65% yield
61% yield
99% yield
99% yield
a) Cs2CO3 (1.0 equiv), MeCN, 80 °C, 8 h
b) H2O, 100 °C, 12 h
Scheme 6 Neutral (or basic) treatment of 1a
Next we examined the substrate scope. A range of struc-
turally diverse substrates were successfully transformed
under the optimized reaction conditions (Scheme 7). Sub-
strates derived from linear aliphatic aldehydes furnished
the desired adducts in good to excellent yields (8a–8g, 83–
91%). Substrates bearing bulky imine moieties also fur-
nished the corresponding products in good to excellent
yields (8h–8l, 84–93%). N-Alkyl-substituted substrates de-
rived from electron-neutral, electron-deficient, and elec-
tron-rich aromatic aldehydes afforded the products in good
to excellent yields (8m–8o, 74–82%). The cyclization of 5a
was also attempted under various reaction conditions,
however, no conversion was observed (Table S1).
NH2
R2
N
NH2
N
HN
H2SO4, MeOH
80 °C, air, 1.5 h
R2
R1
N
NO2
N2
N1
3
N
N
N
R2
4
N
5
H
H
R1
R1
5
6
NH2
N
NH2
NH2
N
NH2
N
Cl
N
N
N
N
N
N
N
N
N
N
S
6a, 81%
6b, 80%
6c, 86%
6d, 88%
Cl
NH2
N
NH2
N
NH2
Cl
N
N
N
N
N
N
N
Cl
N
6f, 88%
6g, 81%
6e, 75%
Cl
To demonstrate the synthetic applicability of this proto-
col, the gram-scale preparation of 3a, 6g, and 8a was car-
ried out. There was no considerable loss in yield (Scheme
8). Finally, a control experiment was conducted to gain fur-
ther mechanistic insight to this reaction. A mixture of 1n
(1.0 mmol) and 8a (1.0 mmol) was heated in H2SO4/MeOH
under the standard reaction conditions (Scheme 9). Com-
pound 1n was converted into the corresponding product 3n
with 90% yield, and compound 8a was fully recovered. The
denitro product of 8a, compound 3a, and the cyclization
Scheme 5 Substrate scope of 4,5-disubstituted 3-amino-1,2,4-tri-
azoles. Reagents and conditions: 1 (1.0 mmol), H2SO4 (1.0 equiv), MeOH
(30 mL), under air, 80 °C, 1.5 h. The yields of the isolated products are
given.
According to the proposed reaction mechanism, a pro-
ton is critical for the dinitrogen reaction; thus, we were in-
terested in the reaction under non-acidic conditions. Inter-
estingly, when compound 1a was heated in MeCN, only 50%
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

1905
F. Zhao et al.
Paper
Synthesis
product of 1n with the NO2 group retained, compound 8n,
were not formed. These results indicate an intramolecular
denitro process for the formation of 5-amino-1,2,4-tri-
azoles. Furthermore, it shows that the denitro reaction of 5-
nitroimino-1,2,4-triazoles to 5-amino-1,2,4-triazoles could
not occur under the standard conditions.18
NO2
NNO2
4 NH
R1
N
R2
NH2
N
R2
H2O
R1
N
NO2
5
3
N
N
N1
N2
NH
R1
N
R2
100 °C, air, 12 h
H
1
8
NO2
NO2
NO2
N
N
N
N
N
N
N
N
N
N
N
NH
8a, 90% (94%)a
NH
NH
A facile protocol for the divergent synthesis of a wide
range of substituted 1,2,4-triazole amine derivatives under
simple and mild reaction conditions has been established
via a pH-dependent intramolecular annulation of easily
available N′-nitro-2-hydrocarbylidene hydrazinecarboximid-
amides. In the presence or absence of acid, the reaction pro-
ceeded smoothly to furnish a wide range of aminotriazole
or nitroiminotriazole derivatives, respectively, in moderate
to excellent yields. The formation of aminotriazoles was
achieved by an NO2-assisted intramolecular redox reaction
that led to the elimination of HNO2. This process was inves-
tigated with control experiments and DFT calculations. The
construction of nitroiminotriazoles was achieved by an en-
vironmentally benign oxidative cyclization pathway, in
which air was the sole oxidant and water was the solvent.
Further application and transformations of the products
into biologically active molecules are underway in our labo-
ratory.
N
N
Cl
Cl
N
Cl
N
Cl
N
8b, 89%
8c, 84%
X-ray of 8a
NO2
NO2
NO2
NO2
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
N
Cl
Cl
Cl
Cl
8f, 91%
8d, 90%
8e, 85%
8g, 83%
NO2
NO2
N
NO2
NH
NO2
NH
N
N
N
N
N
N
N
N
N
NH
NH
Cl
Cl
N
Cl
8h,93%
8i, 87%
8j, 84%
8k, 84%
NO2
NO2
NO2
NO2
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
N
N
8l, 84%
8m, 77%
8n, 74%
8o, 82%
Cl
OMe
Scheme 7 Substrate scope of 1,3-disubstituted 5-nitroimino-1,2,4-tri-
azoles. Reagents and conditions: 1 (1.0 mmol), H2O (30 mL), under air,
100 °C, 12 h. The yields of the isolated products are given. a In paren-
theses is the isolated yield obtained for the reaction performed with 1
(1.0 mmol), Cs2CO3 (1.0 mmol), MeCN (30 mL), under air, 80 °C, 8 h.
NO2
N
NO2
N
NH2
N
H2SO4 (1.0 equiv)
MeOH, 80 °C, 1.5 h
N
N
N
N
N
NH
NH2
nBu
N
H2O, 100 °C, 12 h
Cl
N
Cl
N
Cl
N
nBu
nBu
8a, 2.76 g (89% yield)
1a, 10 mmol
3a, 2.50 g (94% yield)
NO2
N
NH2
N
HN
N
N
N
Cl
HN
Cl
H2SO4 (1.0 equiv)
MeOH, 80 °C, 1.5 h
5g, 10 mmol
6g, 2.44g (80% yield)
Cl
Cl
Scheme 8 Gram-scale synthesis
NH2
nPr
N
N
N
NO2
N
N
N
+
NH
nBu
Cl
N
NO2
N
Cl
nPr
NO2
N
N
3n 90% yield
8a 100% recovered
NH2
H2SO4 (1.0 equiv)
MeOH, 80 °C, 1.5 h
N
N
N
+
NH
nBu
Cl
N
NO2
N
nPr
N
NH2
N
NH
N
Cl
1n (1.0 mmol)
N
+
8a (1.0 mmol)
N
Cl
N
nBu
Cl
3a not observed
8n not observed
Scheme 9 Control experiment
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

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Synthesis
13C NMR (75 MHz, DMSO-d6):  = 161.9, 158.8, 149.7, 149.2, 139.3,
132.8, 124.5, 45.9, 21.8, 12.6.
HRMS (ESI): m/z calcd for C10H12ClN5 [M + H]+: 238.0854; found:
238.0851.
All reagents and solvents were purchased and used without further
purification. Column chromatography was performed by using silica
gel (200–300 mesh). NMR spectra were obtained by using Bruker
Avance DPX300 or Bruker Avance III 500 spectrometers with TMS as
the internal standard at a constant temperature of 25 °C. Melting
points of all compounds were measured by using a Yanagimoto MFG
apparatus, and the thermometer was uncorrected. HRMS data were
obtained on a Thermo Scientific LTQ Orbitrap Discovery (Bremen,
Germany) instrument. The single-crystal structure analysis was per-
formed by using X-ray diffraction on a Rigaku Saturn 724 CCD diffrac-
tometer.
1-((6-Chloropyridin-3-yl)methyl)-3-isopropyl-1H-1,2,4-triazol-5-
amine (3d)
Yellow solid; yield: 118 mg (47%) (Method A), yield: 219 mg (87%)
(Method B); mp: 100–102 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 8.30 (d, J = 2.3 Hz, 1 H), 7.67 (dd, J =
8.3, 2.4 Hz, 1 H), 7.55 (d, J = 8.2 Hz, 1 H), 6.32 (s, 2 H), 5.11 (s, 2 H),
2.71 (hept, J = 6.9 Hz, 1 H), 1.13 (t, J = 12.6 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6):  = 156.1, 150.4, 150.3, 149.7, 139.8,
130.6, 124.6, 46.9, 26.1, 20.3.
HRMS (ESI): m/z calcd for C11H14ClN5 [M + H]+: 252.1010; found:
252.1007.
5-Amino-1,2,4-triazoles 3; General Procedure
Method A: Compound 1 (1.0 mmol) was dissolved in 15% hydrochlo-
ride aqueous solution (30 mL), and the mixture was heated at 100 ℃
for 1.5 h. The pH value of the solution was adjusted to 7 by addition of
NaHCO3, and the mixture was left to stand overnight at 0 ℃. The re-
sulting precipitate was collected and purified by silica gel column
chromatography to afford compound 3.
1-((6-Chloropyridin-3-yl)methyl)-3-(pentan-3-yl)-1H-1,2,4-tri-
azol-5-amine (3e)
Method B: Compound 1 (1.0 mmol) was dissolved in methanol (30
mL). Sulfuric acid (1.0 mmol) was added to the mixture and heated to
reflux for 1.5 h. The pH value of the solution was adjusted to 7 by ad-
dition of NaHCO3. The product was purified by silica gel column chro-
matography to afford compound 3.
White solid; yield: 160 mg (57%) (Method A), yield: 241 mg (86%)
(Method B); mp: 145–147 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 8.32 (d, J = 1.9 Hz, 1 H), 7.54 (dd, J =
8.3, 2.5 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 5.12 (s, 2 H), 4.58 (br s, 2 H),
2.46 (t, J = 7.2 Hz, 1 H), 1.68 (p, J = 7.4 Hz, 4 H), 0.88 (t, J = 7.4 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6):  = 163.5, 156.0, 149.6, 148.9, 138.9,
132.9, 124.4, 45.9, 42.3, 26.7, 12.1.
HRMS (ESI): m/z calcd for C13H18ClN5 [M + H]+: 280.1323; found:
280.1321.
3-Butyl-1-((6-chloropyridin-3-yl)methyl)-1H-1,2,4-triazol-5-
amine (3a)
White solid; yield: 130 mg (49%) (Method A), yield: 242 mg (91%)
(Method B); mp: 121–123 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, CDCl3):  = 8.28 (d, J = 2.5 Hz, 1 H), 7.52 (dd, J = 8.3,
2.5 Hz, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 5.05 (s, 2 H), 4.82 (br s, 2 H),
2.56–2.51 (t, 2 H), 1.65 (dt, J = 12.7, 7.5 Hz, 2 H), 1.36 (dq, J = 14.5, 7.3
Hz, 2 H), 0.92 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 161.9, 154.5, 151.0, 148.0, 137.6, 130.1,
124.0, 46.9, 30.0, 27.7, 22.1, 13.6.
HRMS (ESI): m/z calcd for C12H16ClN5 [M + H]+: 266.1167; found:
266.1165.
1-(2-Chlorobenzyl)-3-propyl-1H-1,2,4-triazol-5-amine (3f)
White solid; yield: 123 mg (49%) (Method A), yield: 191 mg (76%)
(Method B); mp: 125–127 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, CDCl3):  = 7.41–7.38 (m, 1 H), 7.28–7.22 (m, 2 H),
7.04 (m, 1 H), 5.16 (s, 2 H), 4.81 (s, 2 H), 2.53 (t, J = 7.6 Hz, 2 H), 1.80–
1.59 (m, 2 H), 0.96 (td, J = 7.3, 1.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 161.5, 154.4, 132.9, 132.2, 129.4, 129.3,
128.5, 127.3, 47.6, 30.2, 21.2, 13.7.
HRMS (ESI): m/z calcd for C12H15ClN4 [M + H]+: 251.1058; found:
251.1059.
1-((6-Chloropyridin-3-yl)methyl)-3-propyl-1H-1,2,4-triazol-5-
amine (3b)
White solid; yield: 103 mg (41%) (Method A), yield: 234 mg (93%)
(Method B); mp: 125–127 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1-(2-Chlorobenzyl)-3-ethyl-1H-1,2,4-triazol-5-amine (3g)
1H NMR (300 MHz, CDCl3):  = 8.34 (d, J = 1.9 Hz, 1 H), 7.56 (dd, J = 8.3,
2.5 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 5.09 (s, 2 H), 4.54 (s, 2 H), 2.56 (t,
J = 7.05 Hz, 3 H), 1.78–1.68 (m, 2 H), 1.00 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 151.8, 150.8, 150.1, 149.7, 139.1, 128.5,
124.4, 47.8, 27.5, 20.2, 13.3.
White solid; yield: 114 mg (48%) (Method A), yield: 197 mg (83%)
(Method B); mp: 153–155 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 7.41–7.04 (m, 4 H), 5.16 (s, 2 H),
4.76 (br s, 2 H), 2.59 (q, J = 7.6 Hz, 2 H), 1.26 (t, J = 7.6 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 161.9, 156.4, 135.0, 131.8, 129.5,
128.5, 127.6, 65.2, 47.1, 21.9, 15.4, 12.7.
HRMS (ESI): m/z calcd for C11H13ClN4 [M + H]+; 237.0902; found:
HRMS (ESI): m/z calcd for C11H14ClN5 [M + H]+: 252.1010; found:
252.1009.
237.0904.
1-((6-Chloropyridin-3-yl)methyl)-3-ethyl-1H-1,2,4-triazol-5-
amine (3c)
1-(2-Chlorobenzyl)-3-isopropyl-1H-1,2,4-triazol-5-amine (3h)
White solid; yield: 100 mg (42%) (Method A), yield: 205 mg (86%)
(Method B); mp: 136–138 °C; Rf = 0.3 (EtOAc/PE, 2:1).
White solid; yield: 138 mg (55%) (Method A), yield: 203 mg (81%)
(Method B); mp: 151–153 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, CDCl3):  = 8.28 (d, J = 2.5 Hz, 1 H), 7.53 (dd, J = 8.3,
2.5 Hz, 1 H), 7.32 (d, J = 8.3 Hz, 1 H), 5.05 (s, 2 H), 4.88 (s, 2 H), 2.57 (q,
J = 7.6 Hz, 2 H), 1.24 (t, J = 7.6 Hz, 3 H).
1H NMR (300 MHz, DMSO-d6):  = 7.49–7.45 (m, 1 H), 7.34–7.28 (m, 2
H), 6.71–7.68 (m, 1 H), 5.12 (s, 2 H), 4.49 (br s, 2 H), 2.75–2.66 (m, 1
H), 1.15 (d, J = 6.9 Hz, 6 H).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

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Synthesis
13C NMR (75 MHz, DMSO-d6):  = 165.6, 156.4, 135.1, 131.6, 129.5,
HRMS (ESI): m/z calcd for C11H14N4 [M + H]+: 203.1291; found:
128.2, 127.6, 47.1, 27.9, 21.3.
203.1292.
HRMS (ESI): m/z calcd for C12H15ClN4 [M + H]+: 251.1058; found:
251.1058.
3-(4-Chlorophenyl)-1-propyl-1H-1,2,4-triazol-5-amine (3n)
White solid; yield: 111 mg (47%) (Method A), yield: 216 mg (91%)
(Method B); mp: 151–152 °C; Rf = 0.4 (EtOAc/PE, 2:1).
3-Butyl-1-(4-chlorobenzyl)-1H-1,2,4-triazol-5-amine (3i)
White solid; yield: 154 mg (58%) (Method A), yield: 215 mg (81%)
(Method B); mp: 126–128 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 7.87–7.41 (m, 4 H), 6.31 (br s, 2 H),
3.85 (t, J = 6.97 Hz, 2 H), 1.75–1.68 (m, 2 H), 0.87 (t, J = 7.33 Hz, 3 H).
1H NMR (300 MHz, CDCl3):  = 7.45–7.34 (m, 2 H), 7.18 (d, J = 8.6 Hz, 2
H), 5.08 (s, 2 H), 4.40 (s, 2 H), 2.68–2.51 (m, 2 H), 1.71 (dt, J = 15.4, 7.5
Hz, 2 H), 1.42 (dq, J = 14.4, 7.3 Hz, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 156.3, 156.2, 132.94 131.2, 128.7,
127.1, 47.5, 22.3, 11.1.
HRMS (ESI): m/z calcd for C11H13Cl4 [M + H]+: 237.0902; found:
237.0905.
13C NMR (75 MHz, DMSO-d6):  = 160.7, 155.8, 136.6, 132.2, 129.5,
128.6, 48.3, 29.9, 27.9, 22.0, 14.0.
HRMS (ESI): m/z calcd for C13H17ClN4 [M + H]+: 265.1215; found:
1-Butyl-3-(4-methoxyphenyl)-1H-1,2,4-triazol-5-amine (3o)
265.1220.
White solid; yield: 128 mg (52%) (Method A), yield: 216 mg (88%)
(Method B); mp: 118–120 °C; Rf = 0.4 (EtOAc/PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 7.79–6.92 (m, 4 H), 6.20 (br s, 2 H),
3.85 (t, J = 7.05 Hz, 2 H), 3.77 (s, 3 H), 1.69–1.61 (m, 2 H), 1.33–1.23
(m, 2 H), 0.89 (t, J = 7.41 Hz, 3 H).
1-(4-Chlorobenzyl)-3-propyl-1H-1,2,4-triazol-5-amine (3j)
White solid; yield: 138 mg (55%) (Method A), yield: 201 mg (80%)
(Method B); mp: 115–117 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, CDCl3):  = 7.34–7.31 (m, 2 H), 7.15–7.12 (m, 2 H),
5.04 (s, 2 H), 4.47 (br s, 2 H), 2.53 (t, J = 7.4 Hz, 2 H), 1.77–1.65 (m, 2
H), 0.96 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 159.6, 157.1, 155.8, 126.8, 125.1,
114.0, 55.3, 45.6, 31.1, 19.5, 13.8.
HRMS (ESI): m/z calcd for C13H18N4O [M + H]+: 247.1553; found:
247.1554.
13C NMR (75 MHz, CDCl3):  = 161.3, 154.1, 133.9, 133.6, 129.0, 128.2,
49.7, 30.2, 21.3, 13.6.
HRMS (ESI): m/z calcd for C12H15ClN4 [M + H]+: 251.1058; found:
3-Amino-1,2,4-triazoles 6; General Procedure
251.1061.
Compound 5 (1.0 mmol) was dissolved in methanol (30 mL). Sulfuric
acid (1.0 mmol) was added to the mixture and heated to reflux for 1.5
h. The pH value of the solution was adjusted to 7 by addition of
NaHCO3. The product was purified by silica gel column chromatogra-
phy to afford compound 6.
1-(4-Chlorobenzyl)-3-isopropyl-1H-1,2,4-triazol-5-amine (3k)
White solid; yield: 138 mg (55%) (Method A), yield: 216 mg (86%)
(Method B); mp: 128–130 °C; Rf = 0.3 (EtOAc/PE, 2:1).
1H NMR (300 MHz, CDCl3):  = 8.51 (s, 2 H),7.53–7.40 (m, 2 H), 7.35
(d, J = 8.5 Hz, 2 H), 5.28 (s, 2 H), 2.95 (dt, J = 13.9, 7.0 Hz, 1 H), 1.22 (d,
J = 7.0 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6):  = 165.2, 155.7, 136.7, 132.2, 129.5,
128.6, 48.3, 27.9, 21.9.
5-Ethyl-4-propyl-4H-1,2,4-triazol-3-amine (6a)
White solid; yield: 125 mg (81%); mp: 176–177 °C; Rf = 0.35 (EtOAc/
PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 11.96 (s, 1 H), 3.00 (q, J = 6.6 Hz, 2
H), 2.43 (q, J = 7.6 Hz, 2 H), 1.48 (h, J = 7.3 Hz, 2 H), 1.13 (t, J = 7.6 Hz, 3
H), 0.86 (t, J = 7.4 Hz, 3 H).
HRMS (ESI): m/z calcd for C12H15ClN4 [M + H]+: 251.1058; found:
251.1059.
13C NMR (101 MHz, MeOD):  = 133.9, 122.7, 44.7, 22.5, 20.4, 11.3,
10.2.
1-Benzyl-3-isopropyl-1H-1,2,4-triazol-5-amine (3l)
HRMS (ESI): m/z calcd for C7H15N4 [M + H]+: 155.1291; found:
155.1291.
White solid; yield: 114 mg (53%) (Method A), yield: 194 mg (90%)
(Method B); mp: 155–157 °C; Rf = 0.3 (EtOAc/PE, 2:1).
4-((2-Chlorothiazol-5-yl)methyl)-5-methyl-4H-1,2,4-triazol-3-
amine (6b)
1H NMR (300 MHz, CDCl3):  = 7.39–7.31 (m, 3 H), 7.28–7.19 (m, 2 H),
5.09 (s, 2 H), 4.49 (br s, 2 H), 2.91 (dt, J = 13.9, 7.0 Hz, 1 H), 1.28 (d, J =
6.9 Hz, 6 H).
White solid; yield: 184 mg (80%); mp: 173–174 °C; Rf = 0.35 (EtOAc/
PE, 2:1).
13C NMR (75 MHz, CDCl3):  = 165.7, 154.3, 135.1, 128.8, 127.9, 126.8,
50.4, 28.0, 21.4.
1H NMR (300 MHz, DMSO-d6):  = 12.51 (s, 1 H), 7.53 (s, 1 H), 6.35 (s,
1 H), 4.40 (s, 2 H), 2.18 (s, 3 H).
13C NMR (151 MHz, DMSO-d6):  = 163.4, 153.0, 149.6, 142.0, 139.5,
HRMS (ESI): m/z calcd for C12H16N4 [M + H]+: 217.1448; found:
217.1451.
39.9, 12.9.
HRMS (ESI): m/z calcd for C7H9ClN5S [M + H]+: 230.0262; found:
3-Phenyl-1-propyl-1H-1,2,4-triazol-5-amine (3m)
230.0267.
White solid; yield: 101 mg (50%) (Method A), yield: 164 mg (81%)
(Method B); mp: 169–171 °C; Rf = 0.4 (EtOAc/PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 7.88–7.30 (m, 5 H), 6.28 (br s, 2 H),
3.86 (t, J = 6.97 Hz, 2 H), 1.78–1.66 (m, 2 H), 0.88 (t, J = 7.34 Hz, 3 H).
4-(4-Chlorophenyl)-5-ethyl-4H-1,2,4-triazol-3-amine (6c)
White solid; yield: 192 mg (86%); mp: 212–213 °C; Rf = 0.35 (EtOAc/
PE, 2:1).
13C NMR (75 MHz, DMSO-d6):  = 157.2, 156.1, 132.3, 128.6, 128.4,
125.5, 47.5, 22.4, 11.1.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

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F. Zhao et al.
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Synthesis
1H NMR (300 MHz, DMSO-d6):  = 12.89 (s, 1 H), 9.21 (s, 1 H), 7.54 (d,
J = 8.9 Hz, 2 H), 7.23 (d, J = 8.9 Hz, 2 H), 2.64 (q, J = 7.6 Hz, 2 H), 1.22 (t,
J = 7.6 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6):  = 164.9, 161.3, 146.6, 133.6, 127.2,
122.1, 24.5, 17.1.
and water (30 mL) was added. The mixture was then extracted with
ethyl acetate, and the combined organic layers were dried over mag-
nesium sulfate, filtered, and comcentrated. The residue was collected
and purified by recrystallization (ethyl acetate/PE, 1:3) to give com-
pounds 8 as solids.
HRMS (ESI): m/z calcd for C10H12ClN4 [M + H]+: 223.0745; found:
223.0747.
(E)-N-(5-Butyl-2-((6-chloropyridin-3-yl)methyl)-2,4-dihydro-3H-
1,2,4-triazol-3-ylidene)nitramide (8a)
White solid; yield: 280 mg (90%) (Method A), yield: 292 mg (94%)
(Method B); mp: 136–138 °C; Rf = 0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 11.77 (br s, 1 H), 8.47 (d, J = 2.0 Hz, 1
H), 7.77 (dd, J = 8.2, 2.5 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 5.18 (s, 2 H),
2.88–2.66 (m, 2 H), 1.82–1.64 (m, 2 H), 1.42 (dd, J = 15.0, 7.5 Hz, 2 H),
0.96 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 151.4, 150.7, 150.2, 149.6, 139.8,
130.8, 124.7, 47.4, 28.7, 25.0, 21.7, 13.7.
HRMS (ESI): m/z calcd for C12H15ClN6O2 [M + Na]+: 333.0837; found:
333.0834.
5-Phenyl-4-propyl-4H-1,2,4-triazol-3-amine (6d)
White solid; yield: 178 mg (88%); mp: 165–166 °C; Rf = 0.35 (EtO-
Ac/PE, 2:1).
1H NMR (500 MHz, DMSO-d6):  = 12.18 (s, 1 H), 7.90 (d, J = 7.7 Hz, 2
H), 7.54–7.20 (m, 3 H), 6.65 (s, 1 H), 3.11 (t, J = 7.0 Hz, 2 H), 1.55 (p, J =
7.5, 7.1 Hz, 2 H), 0.90 (q, J = 7.5 Hz, 3 H).
13C NMR (126 MHz, DMSO-d6):  = 159.0, 158.6, 132.8, 128.8, 128.6,
125.9, 45.1, 23.0, 11.8.
HRMS (ESI): m/z calcd for C11H15N4 [M + H]+: 203.1291; found:
203.1292.
(E)-N-(2-((6-Chloropyridin-3-yl)methyl)-5-propyl-2,4-dihydro-
3H-1,2,4-triazol-3-ylidene)nitramide (8b)
4-((6-Chloropyridin-3-yl)methyl)-5-phenyl-4H-1,2,4-triazol-3-
amine (6e)
White solid; yield: 264 mg (89%) (Method A); mp: 148–150 °C; Rf =
0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, DMSO-d6):  = 13.83 (br s, 1 H), 8.39 (d, J = 2.2 Hz,
1 H), 7.78 (dd, J = 8.3, 2.5 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 5.22 (s, 2 H),
2.65 (t, J = 7.4 Hz, 2 H), 1.66 (dd, J = 14.8, 7.4 Hz, 2 H), 0.89 (t, J = 7.4
Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 151.2, 150.7, 150.2, 149.6, 139.7,
131.0, 124.7, 47.5, 27.2, 20.2, 13.5.
HRMS (ESI): m/z calcd for C11H13ClN6O2 [M + Na]+: 319.0681; found:
319.0683.
White solid; yield: 215 mg (75%); mp: 215–216 °C; Rf = 0.35 (EtOAc/
PE, 2:1).
1H NMR (500 MHz, DMSO-d6):  = 12.40 (s, 1 H), 8.43 (s, 1 H), 7.89 (d,
J = 7.6 Hz, 2 H), 7.85 (dd, J = 8.2, 2.4 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H),
7.46–7.31 (m, 3 H), 7.28 (s, 1 H), 4.41 (s, 2 H).
13C NMR (126 MHz, DMSO-d6):  = 159.0, 158.6, 132.8, 128.8, 128.6,
125.9, 45.1, 23.0, 11.8.
HRMS (ESI): m/z calcd for C14H13ClN5 [M + H]+: 286.0854; found:
286.0842.
4,5-Diphenyl-4H-1,2,4-triazol-3-amine (6f)
(E)-N-(2-((6-Chloropyridin-3-yl)methyl)-5-ethyl-2,4-dihydro-3H-
1,2,4-triazol-3-ylidene)nitramide (8c)
White solid; yield: 208 mg (88%); mp: 209–210 °C; Rf = 0.35 (EtOAc/
PE, 2:1).
1H.NMR (300 MHz, DMSO-d6):  = 13.73 (s, 1 H), 9.25 (s, 1 H), 7.98 (d,
J = 7.3 Hz, 2 H), 7.56 (dd, J = 23.1, 9.1 Hz, 5 H), 7.33–7.17 (m, 2 H), 6.80
(s, 1 H).
White solid; yield: 238 mg (84%) (Method A); mp: 168–170 °C; Rf =
0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 13.84 (br s, 1 H), 8.41 (d, J = 2.0 Hz, 1
H), 7.80 (dd, J = 8.3, 2.5 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 1 H), 5.24 (s, 2 H),
2.71 (q, J = 7.5 Hz, 2 H), 1.20 (t, J = 7.6 Hz, 3 H).
HRMS (ESI): m/z calcd for C14H13N4 [M + H]+: 237.1135; found:
237.1130.
13C NMR (75 MHz, DMSO-d6):  = 152.4, 150.8, 150.2, 149.6, 139.7,
130.8, 124.6, 47.4, 19.2, 11.2.
HRMS (ESI): m/z calcd for C10H11ClN6O2 [M + Na]+: 305.0524; found:
305.0522.
4,5-Bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (6g)
White solid; yield: 247 mg (81%); mp: 220–221 °C; Rf = 0.35 (EtOAc/
PE, 2:1).
1H NMR (300 MHz, DMSO-d6):  = 13.62 (s, 1 H), 9.55 (s, 1 H), 7.99 (d,
J = 8.5 Hz, 2 H), 7.60 (t, J = 8.5 Hz, 4 H), 7.29 (d, J = 8.8 Hz, 2 H).
HRMS (ESI): m/z calcd for C14H11Cl2N4 [M + H]+: 305.0355; found:
(E)-N-(5-Butyl-2-(4-chlorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-
ylidene)nitramide (8d)
White solid; yield: 279 mg (90%) (Method A); mp: 133–135 °C; Rf =
305.0338.
0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 11.74 (br s, 1 H), 7.37–7.30 (m, 4 H),
5.14 (s, 2 H), 2.78 (t, J = 7.6 Hz, 2 H), 1.76–1.61 (m, 2 H), 1.42 (d, J = 7.4
Hz, 2 H), 0.95 (t, J = 7.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 150.6, 150.3, 134.5, 132.3, 129.8, 128.9,
50.4, 28.7, 25.4, 21.9, 13.3.
Nitroamino-1,2,4-triazoles 8; General Procedure
Method A: Compound 1 (1.0 mmol) was dissolved in H2O (30 mL). The
mixture was heated to reflux for 12 h. After evaporation of the solvent
in vacuo, the crude product was collected and purified by silica gel
column chromatography (ethyl acetate/PE, 1:1) to give compounds 8
as solids.
HRMS (ESI): m/z calcd for C13H16ClN5O2 [M + Na]+: 332.0885; found:
332.0885.
Method B: Compound 1 (1.0 mmol) was dissolved in Cs2CO3/CH3CN
(1.0 equiv; 30 mL). The mixture was heated to reflux for 8 h. The reac-
tion mixture was neutralized with concentrated hydrochloric acid,
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

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(E)-N-(2-(4-Chlorobenzyl)-5-propyl-2,4-dihydro-3H-1,2,4-triazol-
HRMS (ESI): m/z calcd for C12H14ClN5O2 [M + Na]+: 318.0728; found:
3-ylidene)nitramide (8e)
318.0726.
White solid; yield: 252 mg (85%) (Method A); mp: 166–168 °C; Rf =
0.3 (EtOAc/PE, 1:1).
(E)-N-(2-(2-Chlorobenzyl)-5-isopropyl-2,4-dihydro-3H-1,2,4-tri-
azol-3-ylidene)nitramide (8j)
1H NMR (300 MHz, CDCl3):  = 11.90 (br s, 1 H), 7.37–7.30 (m, 4 H),
5.15 (s, 2 H), 2.76 (t, J = 7.3 Hz, 2 H), 1.85–1.73 (m, 2 H), 1.02 (t, J = 7.4
Hz, 3 H).
Yellow solid; yield: 249 mg (84%) (Method A); mp: 142–144 °C; Rf =
0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, DMSO-d6):  = 13.87 (br s, 1 H), 7.51 (dd, J = 7.5,
1.8 Hz, 1 H), 7.44–7.22 (m, 2 H), 7.11 (dd, J = 7.2, 2.1 Hz, 1 H), 5.23 (s,
2 H), 3.11 (m, 1 H), 1.25 (d, J = 6.9 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6):  = 151.1, 150.6, 134.5, 133.0, 129.9,
128.9, 49.8, 27.2, 20.2, 13.5.
HRMS (ESI): m/z calcd for C12H14ClN5O2 [M + Na]+: 318.0728; found:
318.0729.
13C NMR (75 MHz, DMSO-d6):  = 155.9, 150.9, 132.7, 132.3, 130.1,
129.8, 129.6, 127.8, 48.4, 26.2, 20.4.
(E)-N-(2-(2-Chlorobenzyl)-5-propyl-2,4-dihydro-3H-1,2,4-triazol-
HRMS (ESI): m/z calcd for C12H14ClN5O2 [M + Na]+: 318.0728; found:
3-ylidene)nitramide (8f)
318.0726.
White solid; yield: 269 mg (91%) (Method A); mp: 142–148 °C; Rf =
0.3 (EtOAc/PE, 1:1).
(E)-N-(2-Benzyl-5-isopropyl-2,4-dihydro-3H-1,2,4-triazol-3-
ylidene)nitramide (8k)
1H NMR (300 MHz, DMSO-d6):  = 13.88 (br s, 1 H), 7.51–7.16 (m, 4
H), 5.23 (s, 2 H), 2.66 (t, J = 7.0 Hz, 2 H), 1.69–1.61 (m, 2 H), 0.89 (t, J =
7.7 Hz, 3 H).
White solid; yield: 219 mg (84%) (Method A); mp: 164–166 °C; Rf =
0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 11.75 (br s, 1 H), 7.40–7.33 (m, 5 H),
5.18 (s, 2 H), 3.18–3.09 (m, 1 H), 1.37 (d, J = 7.05 Hz, 6 H).
13C NMR (75 MHz, DMSO-d6):  = 151.2, 150.9, 132.7, 132.5, 130.1,
130.0, 129.8, 127.82, 48.4, 27.5, 20.3, 13.5.
13C NMR (75 MHz, CDCl3):  = 154.3, 150.5, 133.9, 128.6, 128.4, 128.4,
HRMS (ESI): m/z calcd for C12H14ClN5O2 [M + Na]+: 318.0728; found:
51.1, 26.4, 20.0.
318.0727.
HRMS (ESI): m/z calcd for C12H15N5O2 [M + Na]+: 284.1118; found:
(E)-N-(2-(2-Chlorobenzyl)-5-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-
284.1122.
ylidene)nitramide (8g)
White solid; yield: 234 mg (83%) (Method A); mp: 144–146 °C; Rf =
0.3 (EtOAc/PE, 1:1).
(E)-N-(2-((6-Chloropyridin-3-yl)methyl)-5-(pentan-3-yl)-2,4-di-
hydro-3H-1,2,4-triazol-3-ylidene)nitramide (8l)
1H NMR (300 MHz, DMSO-d6):  = 13.87 (br s, 1 H), 7.63–7.45 (m, 1
H), 7.45–7.27 (m, 2 H), 7.23–7.08 (m, 1 H), 5.23 (s, 2 H), 2.71 (q, J = 7.5
Hz, 2 H), 1.19 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 152.4, 150.9, 132.7, 132.4, 130.1,
129.9, 129.8, 127.8, 48.3, 19.3 11.3.
White solid; yield: 273 mg (84%) (Method A); mp: 144–146 °C; Rf =
0.3 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 11.55 (br s, 1 H), 8.48 (d, J = 2.0 Hz, 1
H), 7.77 (dd, J = 8.2, 2.5 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 5.21 (s, 2 H),
2.73 (t, J = 7.1 Hz, 1 H), 1.76 (tt, J = 14.4, 7.4 Hz, 4 H), 0.91 (t, J = 7.4 Hz,
6 H).
HRMS (ESI): m/z calcd for C11H12ClN5O2 [M + Na]+: 304.0572; found:
304.0577.
13C NMR (75 MHz, CDCl3):  = 152.9, 151.9, 151.8, 149.5, 149.1, 138.9,
138.6, 128.6, 124.6, 124.4, 51.4, 47.8, 40.4, 25.4, 11.3.
(E)-N-(2-((6-Chloropyridin-3-yl)methyl)-5-isopropyl-2,4-dihydro-
3H-1,2,4-triazol-3-ylidene)nitramide (8h)
HRMS (ESI): m/z calcd for C13H17ClN6O2 [M + Na]+: 347.0994; found:
347.0996.
White solid; yield: 276 mg (93%) (Method A); mp: 178–180 °C; Rf =
0.3 (EtOAc/PE, 1:1).
(E)-N-(5-Phenyl-2-propyl-2,4-dihydro-3H-1,2,4-triazol-3-
ylidene)nitramide (8m)
1H NMR (300 MHz, DMSO-d6):  = 13.82 (br s, 1 H), 8.39 (d, J = 2.3 Hz,
1 H), 7.78 (dd, J = 8.3, 2.5 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 1 H), 5.23 (s, 2 H),
3.12–3.07 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3 H).
White solid; yield: 190 mg (77%) (Method A); mp: 142–144 °C; Rf =
0.35 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 8.03–8.06 (m, 2 H), 7.54–7.57 (m, 3 H),
4.01 (t, J = 7.20 Hz, 2 H), 1.77–1.84 (m, 2 H), 0.90 (t, J = 7.50 Hz, 3 H).
13C NMR (75MHz, DMSO-d6):  = 155.9, 150.8, 150.2, 149.6, 139.7,
130.8, 124.6, 47.5, 26.3, 20.4.
13C NMR (75 MHz, CDCl3):  = 151.0, 148.9, 131.0, 129.1, 127.2, 125.3,
HRMS (ESI): m/z calcd for C11H13ClN6O2 [M + Na]+: 319.0681; found:
49.3, 21.5, 11.0.
319.0686.
HRMS (ESI): m/z calcd for C13H17ClN6O2 [M + H]+: 248.1141; found:
(E)-N-(2-(4-Chlorobenzyl)-5-isopropyl-2,4-dihydro-3H-1,2,4-tri-
248.1142.
azol-3-ylidene)nitramide (8i)
White solid; yield: 257 mg (87%) (Method A); mp: 159–161 °C; Rf =
(E)-N-(5-(4-Chlorophenyl)-2-propyl-2,4-dihydro-3o-1,2,4-triazol-
0.3 (EtOAc/PE, 1:1).
3-ylidene)nitramide (8n)
1H NMR (300 MHz, DMSO-d6):  = 13.83 (br s, 1 H), 7.45–7.42 (m, 2
H), 7.32–7.29 (m, 2 H), 5.17 (s, 2 H), 3.23–2.95 (m, 1 H), 1.25 (d, J = 6.9
Hz, 6 H).
White solid; yield: 209 mg (74%) (Method A); mp: 158–160 °C; Rf =
0.35 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 8.04–8.09 (m, 2 H), 7.60–7.64 (m, 2 H),
4.00 (t, J = 6.90 Hz, 2 H), 1.76–1.83 (m, 2 H), 0.90 (t, J = 7.50 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6):  = 155.8, 150.7, 134.5, 132.9, 129.8,
129.0, 49.9, 26.2, 20.4.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910

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Synthesis
13C NMR (75 MHz, CDCl3):  = 150.9, 148.2, 136.0, 129.2, 129.0, 124.4,
40.4, 21.5, 11.0.
HRMS (ESI): m/z calcd for C13H17ClN6O2 [M + H]+: 282.0752; found:
282.0752.
(2) (a) Li, Y.-Q.; He, Y.; Shao, T.; Pei, H.-X.; Guo, W.-K.; Mi, D.-Z.;
Krimm, I.; Zhang, Y.-J.; Wang, P.-L.; Wang, X.; Liu, M.-Y.; Yi, Z.-F.;
Chen, Y.-H. J. Med. Chem. 2019, 62, 4949. (b) Ajmal, M.; Yunus,
U.; Graham, R. M.; Leblanc, R. M. ACS Omega 2019, 4, 22280.
(c) Gao, H.-X.; Shreeve, J. M. Chem. Rev. 2011, 111, 7377.
(3) (a) Romagnoli, R.; Baraldi, P. G.; Salvador, M. K.; Prencipe, F.;
Bertolasi, V.; Cancellieri, M.; Brancale, A.; Hamel, E.;
Castagliuolo, I.; Consolaro, F.; Porcu, E.; Basso, G.; Viola, G.
J. Med. Chem. 2014, 57, 6795. (b) El-Sherief, H. A. M.; Youssif, B.
G. M.; Bukhari, S. N. A.; Abdelazeem, A. H.; Abdel-Aziz, M.;
Abdel-Rahman, H. M. Eur. J. Med. Chem. 2018, 156, 774. (c) Seth,
S.; McDonald, K. A.; Matzger, A. J. Inorg. Chem. 2017, 56, 10151.
(4) Battaglia, U.; Moody, C. J. J. Nat. Prod. 2010, 73, 1938.
(5) Ashton, T. D.; Devine, S. M.; Möhrle, J. J.; Laleu, B.; Burrows, J. N.;
Charman, S. A.; Creek, D. J.; Sleebs, B. E. J. Med. Chem. 2019, 62,
10526.
(E)-N-(5-(4-Methoxyphenyl)-2-propyl-2,4-dihydro-3H-1,2,4-tri-
azol-3-ylidene)nitramide (8o)
White solid; yield: 239 mg (82%) (Method A); mp: 148–150 °C; Rf =
0.35 (EtOAc/PE, 1:1).
1H NMR (300 MHz, CDCl3):  = 8.05–7.97 (m, 2 H), 7.10–6.97 (m, 2 H),
4.00 (t, J = 7.20 Hz, 2 H), 3.83 (s, 3 H), 1.77–1.70 (m, 2 H), 1.30–1.23
(m, 2 H), 0.90 (t, J = 7.80 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 161.7, 150.7, 148.6, 128.9, 117.5,114.5,
55.7, 47.3, 30.0, 19.3, 13.6.
HRMS (ESI): m/z calcd for C13H17ClN6O2 [M + H]+: 291.1404; found:
191.1404.
(6) Li, X.; Zhang, Z.; Chen, Y.; Wan, H.; Sun, J.; Wang, B.; Feng, B.;
Hu, B.; Shi, X.; Feng, J.; Zhang, L.; He, F.; Bai, C.; Zhang, L.; Tao,
W. ACS Med. Chem. Lett. 2019, 10, 996.
(7) Lou, K.; Yao, Y.; Hoye, A. T.; James, M. J.; Cornec, A. S.; Hyde, E.;
Gay, B.; Lee, V. M.; Trojanowski, J. Q.; Smith, A. B. III.; Brunden,
K. R.; Ballatore, C. J. Med. Chem. 2014, 57, 6116.
(8) Zhao, X. X.; Zhang, J. C.; Li, S. H.; Yang, Q. P.; Li, Y. C.; Pang, S. P.
Org. Process Res. Dev. 2014, 18, 886.
Conflict of Interest
The authors declare no conflict of interest.
(9) Yen, W.-P.; Kung, F.-C.; Wong, F. F. Eur. J. Org. Chem. 2016, 2328.
(10) Yin, P.; Ma, W.-B.; Chen, Y.; Huang, W.-C.; Deng, Y.; He, L. Org.
Lett. 2009, 11, 5482.
(11) Dolzhenko, A. V.; Pastorin, G.; Dolzhenko, A. V.; Chui, W. K.
Tetrahedron Lett. 2009, 50, 2124.
Funding Information
This work was supported by the National Key Research and Develop-
ment Plan of China (No 2016YFD0300709) and the National Natural
Science Foundation of China (No. 21402234).
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(12) Yin, P.; Parrish, D. A.; Shreeve, J. M. Angew. Chem. Int. Ed. 2014,
53, 12889.
(13) Jia, C.-Q.; Su, W.-C.; Xu, Y.-J.; Liu, J.-P.; Qin, Z.-H. Chin. J. Org.
Chem. 2016, 36, 830.
Acknowledgment
T.S. acknowledges the National Research Foundation (NRF) South Afri-
ca for a Post-PhD Thuthuka grant for financial support. All computa-
tions were performed with the computational cluster resources at the
Centre for High Performance Computing (CHPC), Cape Town, South
Africa. We are grateful to Prof. Rongzhen Liao of Huazhong University
of Science and Technology for discussion about the DFT calculations.
(14) Su, W.-C.; Zhou, Y.-H.; Ma, Y.-Q.; Wang, L.; Zhang, Z.; Rui, C.-H.;
Duan, H.-X.; Qin, Z.-H. J. Agric. Food Chem. 2012, 60, 5028.
(15) CCDC 1995578 (3a) and 1995580 (8a) contain the supplemen-
tary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/structures
(16) Wang, J.; Brower, K. R.; Naud, D. L. J. Org. Chem. 1997, 62, 9055.
(17) Intermediate 7 is unstable in air and was partially oxidized to
compound 8a during the purification. Hence, the isolated yield
of intermediate 7 is lower than that of compound 8a if com-
pound 1a is the starting material.
(18) The cyclization of 1a with PTSA in methanol was studied by
using an in situ ReactIR spectrophotometer to further under-
stand the reaction mechanism. However, besides starting mate-
rial 1a and product 3a, no intermediates were detected. This
result might be the result of the highly reactivities of the reac-
tion intermediates leading to insufficient concentrations.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1477-4630.
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References
(1) (a) Smith, C. A.; Narouz, M. R.; Lummis, P. A.; Singh, I.; Nazemi,
A.; Li, C.-H.; Crudden, C. M. Chem. Rev. 2019, 119, 4986.
(b) Ghareeb, H.; Metanis, N. Chem. Eur. J. 2020, 26, 10175.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1901–1910