A Multicomponent Electrosynthesis of 1,5-Disubstituted and 1-Aryl 1,2,4-Triazoles

Article abstract of DOI:10.1021/acs.joc.8b01808

A novel electrochemical route has been developed for the synthesis of 1,5-disubstituted and 1-aryl 1,2,4-triazoles from aryl hydrazines, paraformaldehyde, NH₄OAc, and alcohols. In this multicomponent reaction system, alcohols act as solvents as well as reactants and NH₄OAc is used as the nitrogen source. With the assistance of reactive iodide radical or I₂ and NH₃ electrogenerated in situ, this process could effectively avoid the use of strong oxidants and transition-metal catalysts and be smoothly carried out at room temperature to give a wide array of 1,2,4-triazole derivatives in good to high yields. Preliminary studies reveal that the reaction mechanism involves a radical process.

Full text of DOI:10.1021/acs.joc.8b01808

Subscriber access provided by University of Sunderland
Article
A Multicomponent Electrosynthesis of 1,5-
Disubstituted and 1-Aryl 1,2,4-Triazoles
Na Yang, and Gaoqing Yuan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01808 • Publication Date (Web): 04 Sep 2018
Downloaded from http://pubs.acs.org on September 5, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the
course of their duties.

Page 1 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
A Multicomponent Electrosynthesis of 1,5-Disubstituted
and 1-Aryl 1,2,4-Triazoles
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Na Yang, Gaoqing Yuan*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of
Chemistry and Chemical Engineering, South China University of Technology, Guangzhou,
510640, P. R. China
ABSTRACT: A novel electrochemical route has been developed for the synthesis of
1,5-disubstituted and 1-aryl 1,2,4-triazoles from aryl hydrazines, paraformaldehyde, NH4OAc and
alcohols. In this multicomponent reaction system, alcohols act as solvents as well as reactants and
NH4OAc is used as the nitrogen source. With the assistance of reactive iodide radical or I2 and
NH3 electrogenerated in situ, this process could effectively avoid the use of strong oxidants and
transition-metal catalysts and be smoothly carried out at room temperature to give a wide array of
1,2,4-triazole derivatives in good to high yields. Preliminary studies reveal that the reaction
mechanism involves a radical process.
Introduction
1,2,4-Triazoles are important skeletons in numerous agrochemicals, pharmaceuticals,
biological active compounds. A lot of compounds containing 1,2,4-triazole motif such as
1,3,5-trisubstituted and 1,5-disubstituted 1,2,4-triazoles display good anticancer, antifungal,
antibacterial and anti-inflammatory activities (Scheme 1).1 Over the past decades, much effort has
been devoted to the synthesis of substituted 1,2,4-triazoles and many synthetic methods have been
reported.2−4 But some drawbacks, such as elevated temperatures, limited substrate scope,
inconvenient starting materials or multi-step processes, still exist in some synthetic routes. In
addition, the classic C-N coupling reactions to prepare aryl-1,2,4-triazoles inevitably generated
regio isomeric triazole mixtures. Recently some novel synthetic methods have been developed for
the preparation of specific location substituted 1,2,4-triazoles, such as the transformation from
anilines, amino pyridines, and pyrimidines (Scheme 2a),5 the copper-catalyzed reaction of
amidines with solvent DMF in the presence of base and oxidant (Scheme 2b),6 copper-mediated
cyclization reaction of amine with nitriles (Scheme 2c),7 the reaction of nitriles with hydrazonoyl
chlorides through a two-step process (Scheme 2d)8 and I2-catalyzed oxidative coupling reactions
of hydrazones and amines (Scheme 2e).9 Although much progress has been made in the synthesis
of multi-substituted 1,2,4-triazoles, it is still desirable to develop a simple and efficient method for
the synthesis of specific location substituted 1,2,4-triazoles.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 15
1
2
3
4
5
Scheme 1. Some Bioactive 1,2,4-Triazole Derivatives
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Different Methods for Synthesis of Specific
Location Substituted 1,2,4-Triazoles
An electrochemical method has attracted more and more attention in organic synthesis since
electrons can act as clean and safe redox reagents to replace expensive or hazardous chemicals.
Recently, advances in synthetic organic electrochemistry have been extensively reviewed.10
Among various electrochemical strategies, reactive iodide radical or iodine electrogenerated in
situ at an anode could effectively induce or catalyze some transformations,11 which seems to be
attractive. With the help of I2 electrogenerated in situ at a graphite anode, our group has also
achieved the electrochemical conversion of CO2 with olefins or aryl hydrazines and
paraformaldehyde.12 These successful electrosynthetic examples motivate us to develop a new
electrochemical route for the synthesis of substituted 1,2,4-triazoles under mild conditions. Herein,
we report an interesting one-pot multicomponent electrochemical route to synthesize
2
ACS Paragon Plus Environment

Page 3 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
1,5-disubstituted and 1-aryl substituted 1,2,4-triazoles from aryl hydrazines, paraformaldehyde,
NH4OAc and alcohols (Scheme 2f). Although the electrochemical basic principle is similar to that
in the previous investigations, this synthetic route is novel for the preparation of substituted
7
8
9
+
1,2,4-triazoles. Differing from the previous work,5−9 the present work uses NH4 as the nitrogen
source, which further broadens a synthetic scope of 1,2,4-triazole derivatives. With the assistance
of electrochemical oxidation and electrocatalysis, this synthetic route effectively avoids the direct
use of hazardous oxidants and transition-metal catalysts.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
In this work we chose phenylhydrazine 1a, paraformaldehyde and ammonium acetate as
model substrates to start our investigation. To optimize the electrolytic conditions, the electrolysis
was carried out with constant current in an undivided cell equipped with a graphite rod anode and
a Ni plate cathode. With methanol as the solvent and NaI as the mediator, the desired product
1-phenyl-1H-1,2,4-triazole 3a was obtained in 62% yield after the electrolysis for 6 h (Table 1,
entry 1). Encouraged by this result, we replaced NaI with KI, NH4I, n-Bu4NI (TBAI), and
n-Bu4NBr (TBABr) to further examine this reaction (Table 1, entries 2–5). It was found that TBAI
gave the best result with 82% isolated yield of 3a. Solvent was also a key parameter. When MeCN,
DMF or DMSO was used as the solvent, only a trace amount of 3a was detected (Table 1, entries
6–8). In addition, we further examined the effect of ammonium salts. Using (NH4)2CO3 or NH4Cl
as the nitrogen source, the electrolytic results became unsatisfied (Table 1, entries 9 and 11).
Especially in the NH4HCO3 case, only a small amount of 3a was obtained (Table 1, entry 10).
Moreover, studies on bases indicated that strong base was more favorable to this reaction. For
example, NaOH and t-BuOK afforded the target product 3a in higher yields than weak bases
(Table 1, entries 12–15). According to our experience, I2 electrogenerated in situ at an anode could
promote some transformations effectively.12 In the absence of any iodides, only a trace amount of
3a was observed (Table 1, entry 16), indirectly indicating that reactive iodine electrogenerated in
situ could promote this transformation as well. When NH4I was used as the sole nitrogen source
without NH4OAc, a byproduct iodobenzene was obviously increased so that the yield of 3a
declined to 49% (Table 1, entry 17). Thus, NH4OAc as the nitrogen source is necessary.
Table 1. Optimization of Reaction Conditions a
Entry
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
DMF
Mediator
NaI
Ammonium Salt
NH4OAc
Base
Yield b(%)
62
1
2
3
4
5
6
7
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
KI
NH4OAc
71
NH4I
TBAI
TBABr
TBAI
TBAI
NH4OAc
78
NH4OAc
89(82)c
22
NH4OAc
NH4OAc
trace
trace
NH4OAc
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 15
1
2
3
4
5
6
7
8
9
8
DMSO
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
–
NH4OAc
(NH4)2CO3
NH4HCO3
NH4Cl
t-BuOK
t-BuOK
t-BuOK
t-BuOK
NaOH
trace
21
9
10
11
12
13
14
15
16
17
12
35
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
–
77
DBU
49
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
K2CO3
Cs2CO3
t-BuOK
t-BuOK
19
15
traced
49
NH4Ie
a Reaction conditions: phenylhydrazine 1a (1.0mmol), paraformaldehyde (1.5 mmol), ammonium salt (4.0 mmol),
mediator (0.5 equiv.), base (2.0 equiv.), solvent (20 mL), undivided cell, a graphite rod as the anode and a Ni plate
as the cathode, room temperature, current 55 mA and 6 h. b Yield was analyzed by GC-MS with n-dodecane as an
internal standard. c Isolated yield. n-Bu4NBF4 (1.0 equiv.) was used as the supporting electrolyte. NH4I (4
d
e
equiv.).
When ethanol was used as the solvent, we found that the main product was
5-methyl-1-phenyl-1H-1,2,4-triazole (Table 2, 3b). This interesting result (1,5-disubstituted
1,2,4-triazole product) encouraged us to examine the electrolytic results with various alcohols.
When 1-propanol, butanol, isobutanol, pentanol or isopentanol was used the solvent respectively,
the corresponding 1,5-disubstituted 1,2,4-triazole products were successfully obtained in good
yields as well (Table 2, 3c–3g). These results indicated that the solvent alcohols took part in the
reaction to result in the formation of 1,5-disubstituted 1,2,4-triazoles. In the present case, the
alcohols play a dual role, solvents and reactants. Notably, no corresponding product was obtained
with 2-propanol or 2-butyl alcohol as the substrate. So we deduced that the oxidation of alcohols
to aldehydes might be one of key steps in the formation of 1,5-disubstituted of 1,2,4-triazoles.
It should be pointed out that the electrical conductivity was very poor when benzyl alcohols
were used as solvents. In order to make sure that the electrosynthesis could be performed
smoothly, we used the mixture of various benzyl alcohols (10 equiv.) with MeOH (20 mL) as the
solvent to further examine the electrolysis. It was found that the benzyl alcohols bearing with
various groups could give the target products in moderate to good yields (Table 2, 3h–3u).
Moreover, the benzyl alcohols with chloro or methyl substituted group on the ortho- or
meta-position displayed higher reactivity than those on the para-position (Table 2, 3o, 3p and 3j;
or 3q, 3r and 3m). Multi-substituted benzyl alcohols could be also transformed to corresponding
1,2,4- triazoles smoothly (Table 2 3s, 3t and 3u). These experimental results demonstrated that
this electrochemical route was applicable to both aliphatic alcohols and benzyl alcohols.
Table 2. Electrolytic Results of Various Alcohols a,b
4
ACS Paragon Plus Environment

Page 5 of 15
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions: phenylhydrazine (1.0 mmol) paraformaldehyde (1.0 mmol),
NH4OAc (4.0 mmol), TBAI (0.5 equiv.), n-Bu4NBF4 (2 equiv.), aliphatic alcohol (20
mL) or benzyl alcohols (10 equiv.)/MeOH (20 mL), t-BuOK (2.0 equiv.), undivided cell,
a graphite rod as the anode and a Ni plate as the cathode, room temperature, current 55
mA and 6 h. b Isolated yield.
With methanol used as the solvent, we further examined the scope and generality of
phenylhydrazines. As shown in Table 3, various substituted phenylhydrazines could afford the
corresponding products in moderate to high yields. This process could tolerate a lot of functional
groups (Table 3, 4a–4l). In general, electron-withdrawing groups were more favorable to the
reaction than electron-donating ones in the same substituted position. In addition, phenylhydrazine
derivatives with bromo substituted on the para- and meta-position showed higher reactivity than
those on the ortho-position (Table 3, 4c, 4h and 4i). This electrochemical method was also
applicable to poly-substituted phenylhydrazine derivatives ( Table 3, 4k and 4l). However, the
yields of the target products are not more than 90%, which may be due to a side reaction of aryl
hydrazines with I2 to form iodobenzene derivatives. The side product iodobenzene was observed
in our experiments.
Table 3. Scope of Phenylhydrazine Derivativesa,b
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a Reaction conditions: phenylhydrazine derivatives 1 (1.0 mmol), paraformaldehyde (1.5
mmol), NH4OAc (4.0 mmol), TBAI (0.5 equiv.), MeOH (20 mL), t-BuOK (2.0 equiv.),
undivided cell, a graphite rod as the anode and a Ni plate as the cathode, room
temperature, current 55 mA and 6 h. b Isolated yield.
In order to demonstrate the potential practical applications of this electrochemical route, the
electrosynthesis was carried out on a gram scale. As shown in Scheme 3, when 1.1 g of 1a was
used under the standard conditions, the product 3a was obtained in 58% isolated yield with the
electrolysis prolonged to 10 h, indicating that this electrochemical route could be scaled up to a
preparing scale.
Scheme 3. Gram-Scale Experiment
Several control experiments were conducted to explore the reaction mechanism. In the
absence of ammonium salt, 2a was obtained instead of 3a (Scheme 4a), which showed that
ammonium salt was essential for the formation of 1,2,4-triazoles and 2a was likely to be an
intermediate for this electrosynthesis. 3a was not obtained under the non-electrolysis conditions
(Scheme 4b), indirectly demonstrating that the reactive iodine and NH3 electrogenerated in situ
played very important roles. Under the standard conditions, 3h was also obtained in 26% yield
with benzaldehyde as the substrate (Scheme 4c), suggesting that the alcohols might be oxidized to
aldehyde in this electrosynthesis. When a radical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT) was added to the electrolytic system
(Scheme 4d), the electrosynthesis was inhibited, which indicated that the reaction might involve a
radical pathway.
6
ACS Paragon Plus Environment

Page 7 of 15
The Journal of Organic Chemistry
1
2
3
4
5
Scheme 4. Control Experiments
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cyclic voltammetry (CV) experiments were further carried out to gain insight into the
reaction mechanism. In the blank experiment (Figure 1-Ⅰ, curve a), the peak that supposed to be
the oxidation peak of MeOH at 1.3 V vs. SCE was very weak, demonstrating that MeOH could
not be easily electro-oxidized to HCHO in the present conditions. For phenylhydrazine 1a and
paraformaldehyde (Figure 1-Ⅰ, curve b and c), oxidation peaks were hardly observed, indicating
that the electrochemical oxidation of phenylhydrazine or paraformaldehyde could be neglected.
However, an obvious oxidation peak was observed at 1.0 V vs. SCE in the presence of 1a and
paraformaldehyde at the same time (Figure 1-Ⅰ, curve e). This peak was attributed to the
oxidation of intermediate 1-methylene-2-phenylhydrazine (2a) since phenylhydrazine could easily
react with paraformaldehyde to form 2a at room temperature (Scheme 4b). In the alone n-Bu4NI
case (Figure 1-Ⅱ, curve d), a very strong oxidation peak occurred at 1.4 V vs. SCE, which was
due to the electro-oxidation of I– ions. Under the similar electrosynthetic conditions (Figure 1-Ⅰ,
curve f), the oxidation peak current at 1.0 V vs. SCE belonging to the oxidation of the intermediate
2a was quite obvious. According to these CV results, it could be concluded that the
electrochemical oxidation of I– ions at an anode was a main process and the electro-oxidation of
2a also should be considered in the present electrosynthetic system. In addition, it could be
deduced that alcohols were converted to aldehydes through the chemical oxidations instead of
electrochemical oxidations.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 15
1
2
3
4
5
6
Figure 1. Cyclic voltammograms of 0.1 mol L–1 of n-Bu4NBF4-MeOH (20 mL)-t-BuOK (2.0 mmol) solution containing different
compounds: (a) blank experiment; (b) only phenylhydrazine 1a (1.0 mmol); (c) only paraformaldehyde (1.5 mmol); (d) only n-Bu4NI
(0.5 mmol); (e) phenylhydrazine 1a (1.0 mmol) and paraformaldehyde (1.5 mmol); (f) phenylhydrazine 1a (1.0 mmol),
paraformaldehyde (1.5 mmol), NH4OAc (4.0 mmol) and n-Bu4NI (0.5 mmol); with a GC disk working electrode, Pt counter electrode
and SCE reference electrode at 100 mV/s scan rate.
7
8
9
Based on the above experiments and the previous investigations,11−16 a plausible reaction
mechanism was outlined in Scheme 5. Initially, I– ions are electro-oxidized at the anode to form a
reactive iodide radical or I2.11a,12 At the same time, phenylhydrazine easily reacts with
paraformaldehyde to produce intermediate 1-methylene-2-phenylhydrazine 2a. In the presence of
a strong base, 2a can generate 1-methylene-2-phenylhydrazine anion A,13,14 followed by the
electrochemical oxidation to yield a radical B, which is supported by the CV experiments. Then
the radical B can be converted to a resonance structural radical C.11c On the other hand, the
alcohol can be chemically oxidized to aldehyde at room temperature with the help of I2
electrogenerated at the anode.15 Subsequently, the aldehyde reacts with NH3 resulting from the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
electroreduction of NH4 ions at the cathode to form aldimine intermediate D, followed by the
reaction with I2 to generate an N-iodo aldimine intermediate E.16 The intermolecular radical
cycloaddition of radical C with E forms a radical F. The deprotonation of the radical F by an
iodide radical gives intermediate G. Finally, aromatization of G by eliminating HI generates
substituted 1,2,4-triazole 3 or 4. Moreover, the regenerated I− ions can join to the next reaction
cycle.
Scheme 5. Possible Mechanism
Conclusions
In summary, we have developed a facile electrochemical protocol for the synthesis of
1,5-disubstituted and 1-aryl 1,2,4-triazoles from aryl hydrazines, paraformaldehyde, NH4OAc and
alcohols in an undivided cell. This one-pot multicomponent electrosynthetic route has a potential
application in pharmaceutical synthesis due to its low toxic solvent, mild reaction conditions,
simplicity, readily available starting materials and a broad substrate scope.
8
ACS Paragon Plus Environment

Page 9 of 15
The Journal of Organic Chemistry
1
2
3
4
EXPERIMENTAL SECTION
5
6
7
8
General Information: Solvents and reagents were commercially available and used as received without
further treatment. Reactions were monitored by thin-layer chromatography (TLC). 1H NMR and 13C NMR spectra
were recorded using a Bruker DRX-400 spectrometer with CDCl3 or (d6-DMSO) as a solvent and TMS as an
internal standard. The chemical shifts are referenced to signals at 7.26 (or 2.5) and 77.23 (or 39.51) ppm,
respectively. Mass spectra were recorded on a Thermo Scientific ISQ gas chromatograph-mass spectrometer. The
data of HRMS was carried out on a high-resolution mass spectrometer (LCMS-IT-TOF). Melting points were
determined with a Büchi Melting Point B-545 instrument.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Electrosynthesis of Substituted 1,2,4-Triazoles: In a typical procedure,
phenylhydrazine 1a (1.0 mmol), paraformaldehyde (1.5 mmol), NH4OAc (4.0 mmol), t-BuOK (2.0 equiv.) and
TBAI (0.5 equiv.) were dissolved in a Teflon cup (50 mL) containing 20 mL of MeOH. The Teflon cup was placed
in a stainless-steel cell equipped with a graphite rod (d=0.4 cm, L=1 cm) anode and a Ni plate (area 2 cm2) cathode
connecting to a DC regulated power supply. The electrosythesis was carried out with current 55 mA at room
temperature for 6 h. After the electrolysis, the saturated aqueous Na2S2O3 solution (10 mL) was added to the
electrolyte solution and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic layer was
dried over anhydrous MgSO4. The solvent was removed under vacuum. The crude product was purified by flash
chromatography on silica gel using a mixture of petroleum ether and ethyl acetate (100:1) to give the pure target
product.
Phenyl-1H-1,2,4-triazole 3a.3b 118.6 mg, 82% yield, yellow oil; 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.55 (s, 1H), 8.08 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 7.4
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.7, 141.1, 137.1, 129.9, 128.3, 120.2.
1
5-Methyl-1-phenyl-1H-1,2,4-triazole 3b. 88.5 mg, 56% yield, brown oil; H NMR (400 MHz,
CDCl3): δ (ppm) 7.91 (s, 1H), 7.52 – 7.47 (m, 2H), 7.43 (dd, J = 7.0, 4.0 Hz, 3H), 2.51 (s, 3H);
13C NMR (100 MHz, CDCl3): δ (ppm) 152.2, 151.1, 137.6, 129.6, 128.9, 124.8, 13.3; HRMS (ESI,
m/z): Calcd. for C9H10N3 [M+H]+ 160.0869; found 160.0865.
1
5-Ethyl-1-phenyl-1H-1,2,4-triazole 3c. 116.4 mg, 67% yield, brown oil; H NMR (400 MHz,
CDCl3): δ (ppm) 7.94 (s, 1H), 7.52 – 7.40 (m, 5H), 2.81 (q, J = 7.5 Hz, 2H), 1.32 (t, J = 7.5 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 157.1, 151.2, 137.6, 129.6, 129.1, 125.2, 20.3, 12.2;
HRMS (ESI, m/z): Calcd. for C10H12N3 [M+H]+ 174.1026; found 174.1020.
1
1-Phenyl-5-propyl-1H-1,2,4-triazole 3d. 115.8 mg, 62% yield, brown oil; H NMR (400 MHz,
CDCl3): δ (ppm) 7.94 (s, 1H), 7.49 (dt, J = 13.0, 6.7 Hz, 3H), 7.41 (d, J = 7.5 Hz, 2H), 2.76 (t, J =
7.6 Hz, 2H), 1.78 (dd, J = 15.0, 7.5 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 156.2, 151.2, 137.7, 129.6, 129.2, 125.4, 28.5, 21.3, 13.9; HRMS (ESI, m/z):
Calcd. for C11H14N3 [M+H]+ 188.1182; found 188.1177.
1
5-Isopropyl-1-phenyl-1H-1,2,4-triazole 3e. 105.9 mg, 57% yield, brown oil; H NMR (400
MHz, CDCl3): δ (ppm) 7.94 (s, 1H), 7.51 – 7.46 (m, 3H), 7.39 (dd, J = 8.0, 1.4 Hz, 2H), 3.14 (dt, J
= 13.7, 6.8 Hz, 1H), 1.30 (d, J = 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ (ppm) 161.1, 151.2,
137.6, 129.7, 129.3, 125.7, 25.9, 21.8; HRMS (ESI, m/z): Calcd. for C11H14N3 [M+H]+ 188.1182;
found 188.1179.
1
5-Butyl-1-phenyl-1H-1,2,4-triazole 3f. 128.3 mg, 64% yield, brown oil; H NMR (400 MHz,
CDCl3): δ (ppm) 7.94 (s, 1H), 7.48 (dd, J = 13.4, 7.0 Hz, 3H), 7.41 (d, J = 7.7 Hz, 2H), 2.78 (t, J =
7.7 Hz, 2H), 1.79 – 1.68 (m, 2H), 1.33 (dd, J = 14.9, 7.4 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3): δ (ppm) 156.3, 151.2, 137.7, 129.6, 129.2, 125.33, 30.0, 26.3, 22.4,
13.8; HRMS (ESI, m/z): Calcd. for C12H16N3 [M+H]+ 202.1339; found 202.1334.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 15
1
2
3
4
5
6
7
8
9
5-Isobutyl-1-phenyl-1H-1,2,4-triazole 3g. 138.5 mg, 69% yield, yellow oil; 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.96 (s, 1H), 7.53 – 7.46 (m, 3H), 7.40 (d, J = 7.7 Hz, 2H), 2.67 (d, J = 7.2 Hz,
2H), 2.15 (dt, J = 13.6, 6.8 Hz, 1H), 0.90 (d, J = 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ
(ppm) 155.7, 151.2, 137.7, 129.6, 129.3, 125.7, 35.3, 28.1, 22.5; HRMS (ESI, m/z): Calcd. for
C12H16N3 [M+H]+ 202.1339; found 202.1343.
1
1,5-Diphenyl-1H-1,2,4-triazole 3h. 116.6 mg, 53% yield, yellow oil; H NMR (400 MHz,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CDCl3): δ (ppm) 8.08 (s, 1H), 7.50 – 7.45 (m, 2H), 7.41 – 7.28 (m, 8H); 13C NMR (100 MHz,
CDCl3): δ (ppm) 154.0, 151.7, 138.3, 130.1, 129.5, 129.0, 128.9, 128.7, 127.9, 125.5; HRMS (ESI,
m/z): Calcd. for C14H12N3 [M+H]+ 222.1026; found 222.1027.
1
5-(4-Fluorophenyl)-1-phenyl-1H-1,2,4-triazole 3i. 162.1 mg, 68% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ (ppm) 8.05 (s, 1H), 7.44 (ddd, J = 17.8, 5.9, 2.4 Hz, 5H), 7.32 (dd, J = 6.6,
3.0 Hz, 2H), 7.00 (t, J = 8.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 163.7 (d, J = 249.8
Hz), 153.1, 151.6, 138.2, 131.1(d, J = 8.6 Hz), 129.6, 129.2, 125.5, 124.1 (d, J = 3.4 Hz), 115.9
(d, J = 21.8 Hz); HRMS (ESI, m/z): Calcd. for C14H11FN3 [M+H]+ 240.0932; found 240.0934.
1
5-(4-Chlorophenyl)-1-phenyl-1H-1,2,4-triazole 3j. 163.9 mg, 64% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ (ppm) δ 8.07 (s, 1H), 7.42 (dd, J = 6.1, 2.4 Hz, 5H), 7.35 – 7.27 (m, 4H);
13C NMR (100 MHz, CDCl3): δ (ppm) 153.0, 151.7, 138.1, 136.4, 130.3, 129.7, 129.3, 129.0,
126.4, 125.5; HRMS (ESI, m/z): Calcd. for C14H11ClN3 [M+H]+ 256.0636; found 256.0638.
1
5-(4-Bromophenyl)-1-phenyl-1H-1,2,4-triazole 3k. 173.6 mg, 58% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ (ppm) δ 8.08 (s, 1H), 7.45 (dd, J = 13.2, 5.4 Hz, 5H), 7.35 (d, J = 8.0 Hz,
4H); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.1, 151.8, 138.1, 132.0, 130.5, 129.7, 129.4, 126.8,
125.5, 124.8; HRMS (ESI, m/z): Calcd. for C14H11BrN3 [M+H]+ 300.0131; found 300.0132.
1-Phenyl-5-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole 3l. 176.8 mg, 61% yield, yellow oil;
1H NMR (400 MHz, CDCl3): δ (ppm) 8.10 (s, 1H), 7.59 (q, J = 8.6 Hz, 4H), 7.45 – 7.41 (m, 3H),
7.35 – 7.31 (m, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.6, 151.9, 138.0, 132.0 (q, J =
32.6 Hz), 131.4, 129.8, 129.5, 129.3, 125.7 (q, J = 3.7 Hz), 125.6, 123.8 (q, J = 270.8 Hz);
HRMS (ESI, m/z): Calcd. for C15H11F3N3 [M+H]+ 290.0898; found 290.0901.
1-Phenyl-5-(p-tolyl)-1H-1,2,4-triazole 3m. 99.3 mg, 42% yield, yellow oil; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.06 (s, 1H), 7.37 (dt, J = 8.3, 4.8 Hz, 7H), 7.12 (d, J = 8.0 Hz, 2H), 2.33 (s, 3H);
13C NMR (100 MHz, CDCl3): δ (ppm) 154.1, 151.6, 140.4, 138.4, 129.5, 129.4, 129.0, 128.9,
125.5, 125.0, 21.5; HRMS (ESI, m/z): Calcd. for C15H14N3 [M+H]+ 236.1182; found 236.1184.
1
5-(4-Methoxyphenyl)-1-phenyl-1H-1,2,4-triazole 3n. 114.7 mg, 46% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ (ppm) 8.05 (s, 1H), 7.42 (d, J = 8.1 Hz, 5H), 7.37 – 7.33 (m, 2H), 6.84 (d, J
= 8.7 Hz, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 161.1, 153.9, 151.6, 138.5,
130.5, 129.6, 129.0, 125.6, 120.2, 114.2, 55.5; HRMS (ESI, m/z): Calcd. for C15H14N3O [M+H]+
252.1131; found 252.1133.
1
5-(2-Chlorophenyl)-1-phenyl-1H-1,2,4-triazole 3o. 179.2 mg, 70% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ (ppm) 8.15 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 3.7 Hz, 2H), 7.34 –
7.26 (m, 6H); 13C NMR (100 MHz, CDCl3): δ (ppm) 151.8, 151.7, 137.8, 134.0, 132.0, 131.7,
130.2, 129.3, 128.5, 128.51, 127.2, 123.8; HRMS (ESI, m/z): Calcd. for C14H11ClN3 [M+H]+
256.0636; found 256.0636.
1
5-(3-Chlorophenyl)-1-phenyl-1H-1,2,4-triazole 3p. 185.8 mg, 73% yield, yellow oil; H NMR
(400 MHz, CDCl3): δ (ppm) 8.10 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 2.9 Hz, 3H), 7.36 (s, 3H), 7.30
(d, J = 7.4 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.6, 151.7,
10
ACS Paragon Plus Environment

Page 11 of 15
The Journal of Organic Chemistry
1
2
3
4
5
137.9, 134.8, 130.2, 129.9, 129.6, 129.6, 129.4, 129.1, 126.9, 125.5; HRMS (ESI, m/z): Calcd. for
C14H11ClN3 [M+H]+ 256.0636; found 256.0633.
6
7
8
9
1-Phenyl-5-(o-tolyl)-1H-1,2,4-triazole 3q. 169.6 mg, 72% yield, yellow oil; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.14 (s, 1H), 7.36 – 7.26 (m, 6H), 7.24 (d, J = 1.5 Hz, 1H), 7.19 (dd, J = 15.3, 7.7
Hz, 2H), 2.08 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.9, 151.6, 137.9, 137.6, 130.8,
130.3, 130.3, 129.2, 128.5, 128.2, 126.1, 123.7, 19.8; HRMS (ESI, m/z): Calcd. for C15H14N3
[M+H]+ 236.1182; found 236.1181.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-Phenyl-5-(m-tolyl)-1H-1,2,4-triazole 3r. 182.9 mg, 78% yield, yellow oil; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.07 (s, 1H), 7.41 – 7.32 (m, 6H), 7.16 (t, J = 5.3 Hz, 3H), 2.28 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ (ppm) 154.1, 151.6, 138.6, 138.4, 130.9, 129.71, 129.4, 129.0, 128.5,
127.8, 126.0, 125.5, 21.4; HRMS (ESI, m/z): Calcd. for C15H14N3 [M+H]+ 236.1182; found
236.1185.
5-(2-Chloro-4-fluorophenyl)-1-phenyl-1H-1,2,4-triazole 3s. 179.8 mg, 66% yield, yellow oil; 1H
NMR (400 MHz, CDCl3): δ (ppm) 8.17 (s, 1H), 7.46 (dd, J = 8.6, 5.9 Hz, 1H), 7.38 – 7.33 (m,
3H), 7.31 – 7.27 (m, 2H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.08 (td, J = 8.2, 2.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ (ppm) 163.7 (d, J = 252.9 Hz), 151.8, 151.0, 137.7, 135.3 (d, J = 10.6
Hz), 133.4 (d, J = 9.2 Hz), 129.4, 128.7, 124.8 (d, J = 3.7 Hz), 123.8, 117.9 (d, J = 24.8 Hz),
114.8 (d, J = 21.5 Hz); HRMS (ESI, m/z): Calcd. for C14H10ClFN3 [M+H]+ 274.0542; found
274.0542.
1
5-(2,4-Dimethylphenyl)-1-phenyl-1H-1,2,4-triazole 3t. 211.2 mg, 85% yield, yellow oil; H
NMR (400 MHz, CDCl3): δ (ppm) 8.13 (s, 1H), 7.38 – 7.26 (m, 5H), 7.14 (d, J = 7.8 Hz, 1H),
7.05 – 6.98 (m, 2H), 2.34 (s, 3H), 2.05 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 154.2,
151.6, 140.3, 138.1, 137.4, 131.6, 130.3, 129.3, 128.2, 126.9, 125.5, 123.8, 21.5, 19.8; HRMS
(ESI, m/z): Calcd. for C16H16N3 [M+H]+ 250.1339; found 250.1340.
1
5-(3,5-Dichlorophenyl)-1-phenyl-1H-1,2,4-triazole 3u. 179.0 mg, 62% yield, brown oil; H
NMR (400 MHz, CDCl3): δ (ppm) 8.10 (s, 1H), 7.48 (d, J = 3.8 Hz, 3H), 7.35 (dd, J = 9.3, 5.1 Hz,
5H); 13C NMR (100 MHz, CDCl3): δ (ppm) 151.9, 151.5, 137.7, 135.5, 130.7, 130.2, 129.9, 129.8,
127.3, 125.6; HRMS (ESI, m/z): Calcd. for C14H10Cl2N3 [M+H]+ 290.0246; found 290.0245.
1
1-(4-Fluorophenyl)-1H-1,2,4-triazole 4a. 125.0 mg, 77% yield, brown solid, mp 68–70 ˚C; H
NMR (400 MHz, CDCl3): δ (ppm) δ 8.50 (s, 1H), 8.08 (s, 1H), 7.64 (dd, J = 9.0, 4.6 Hz, 2H), 7.19
(t, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ (ppm) 162.3 (d, J = 247.0 Hz), 152.9, 141.1,
133.5 (d, J = 5.3 Hz), 122.3 (d, J = 8.6 Hz), 116.9 (d, J = 23.0 Hz); HRMS (ESI, m/z): Calcd.
for C8H7FN3 [M+H]+ 164.0619; found 164.0618.
1-(4-Chlorophenyl)-1H-1,2,4-triazole 4b.3b 129.7 mg, 72% yield, white solid, mp 118–120 ˚C;
1H NMR (400 MHz, d6-DMSO): δ (ppm) 9.31 (s, 1H), 8.25 (s, 1H), 7.89 (d, J = 8.9 Hz, 2H), 7.63
(d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, d6-DMSO): δ (ppm) 152.5, 142.5, 135.6, 131.9, 129.7,
121.0.
1-(4-Bromophenyl)-1H-1,2,4-triazole 4c.3b 167.5 mg, 75% yield, yellow solid, mp 140–142 ˚C;
1H NMR (400 MHz, d6-DMSO): δ (ppm) 9.32 (s, 1H), 8.25 (s, 1H), 7.79 (dd, J = 33.9, 8.4 Hz,
4H); 13C NMR (100 MHz, d6-DMSO): δ (ppm) 152.5, 142.4, 136.0, 132.6, 121.3, 120.2.
4-(1H-1,2,4-Triazol-1-yl)benzonitrile 4d.3b 89.2 mg, 52% yield, brown solid, mp 155–157 ˚C;
1H NMR (400 MHz, CDCl3): δ (ppm) 8.68 (s, 1H), 8.12 (s, 1H), 7.83 (d, J = 10.2 Hz, 4H); 13C
NMR (100 MHz, CDCl3): δ (ppm) 153.4, 141.4, 140.1, 134.1, 120.2, 117.9, 111.9.
1-(4-(Trifluoromethyl)phenyl)-1H-1,2,4-triazole 4e. 143.3 mg, 67% yield, brown solid, mp
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 15
1
2
3
4
5
6
7
8
9
80–82 ˚C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.65 (s, 1H), 8.13 (s, 1H), 7.80 (dd, J = 26.4, 8.5
Hz, 4H); 13C NMR (100 MHz, CDCl3): δ (ppm) 153.2, 139.6, 136.5, 130.4 (q, J = 33.1 Hz),
127.3 (q, J = 3.8 Hz), 123.7 (q, J =270.5 Hz), 120.1; HRMS (ESI, m/z): Calcd. for C9H7F3N3
[M+H]+ 214.0587; found 214.0590.
1-(p-Tolyl)-1H-1,2,4-triazole 4f. 88.6 mg, 56% yield, brown solid, mp 64–66 ˚C; 1H NMR (400
MHz, CDCl3): δ (ppm) 8.60 (s, 1H), 8.14 (s, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 7.8 Hz,
2H), 2.44 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.7, 141.3, 138.4, 135.0, 130.4, 120.2,
21.1; HRMS (ESI, m/z): Calcd. for C9H10N3 [M+H]+ 160.0869; found 160.0871.
1-(4-Methoxyphenyl)-1H-1,2,4-triazole 4g.3b 92.1 mg, 53% yield, brown solid, mp 94–96 ˚C; 1H
NMR (400 MHz, CDCl3): δ (ppm) 8.44 (s, 1H), 8.03 (s, 1H), 7.52 (d, J = 8.6 Hz, 2H), 6.95 (d, J =
8.6 Hz, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm) 159.5, 152.5, 141.2, 130.6, 121.9,
114.9, 55.7.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(3-Bromophenyl)-1H-1,2,4-triazole 4h. 133.8 mg, 60% yield, yellow solid, mp 143–145 ˚C;
1H NMR (400 MHz, d6-DMSO): δ (ppm) 9.35 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.89 (d, J = 8.0
Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.1 Hz, 1H); 13C NMR (100 MHz, d6-DMSO): δ
(ppm) 152.6, 142.7, 137.9, 131.7, 130.4, 122.4, 121.8, 118.3; HRMS (ESI, m/z): Calcd. for
C8H7BrN3 [M+H]+ 223.9818; found 223.9816.
1-(2-Bromophenyl)-1H-1,2,4-triazole 4i.3b 81.9 mg, 37% yield, yellow oil; 1H NMR (400 MHz,
CDCl3): δ (ppm) 8.45 (s, 1H), 8.08 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.47 – 7.39 (m, 2H), 7.31 (t, J
= 7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.3, 144.5, 136.5, 134.0, 130.9, 128.6,
128.2, 118.8.
1-(o-Tolyl)-1H-1,2,4-triazole 4j.3b 86.4 mg, 54% yield, brown oil; 1H NMR (400 MHz, CDCl3):
δ (ppm) 8.26 (s, 1H), 8.10 (s, 1H), 7.41 – 7.27 (m, 4H), 2.20 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ (ppm) 152.2, 144.0, 136.3, 134.0, 131.7, 129.8, 127.0, 126.2, 18.0.
1
1-(3,5-Dimethylphenyl)-1H-1,2,4-triazole 4k. 111.3 mg, 64% yield, yellow oil; H NMR (400
MHz, CDCl3): δ (ppm) 8.48 (s, 1H), 8.02 (s, 1H), 7.24 (d, J = 14.7 Hz, 2H), 6.95 (s, 1H), 2.31 (s,
6H); 13C NMR (100 MHz, CDCl3): δ (ppm) 152.4, 140.9, 139.7, 136.9, 129.8, 117.8, 21.3; HRMS
(ESI, m/z): Calcd. for C10H12N3 [M+H]+ 174.1026; found 174.1025.
1-(3-Chloro-4-methylphenyl)-1H-1,2,4-triazole 4l.3b 126.9 mg, 66% yield, brown solid, mp
123–125 ˚C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.52 (s, 1H), 8.07 (s, 1H), 7.69 (s, 1H), 7.45 (d,
J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): δ (ppm)
152.8, 141.0, 136.4, 135.8, 135.6, 132.0, 120.9, 118.1, 19.9.
ASSOCIATED CONTENT
Supporting Information
1
Copies of the H NMR and 13C NMR spectra for all compounds are available in the supporting
Information
AUTHOR INFORMATION
Corresponding Author
*E-mail: gqyuan@scut.edu.cn.
Notes
12
ACS Paragon Plus Environment

Page 13 of 15
The Journal of Organic Chemistry
1
2
3
4
The authors declare no competing financial interest.
5
6
ACKNOWLEDGMENT
7
8
9
This work was supported by the National Natural Science Foundation of China (21572070) and
the National Key Research and Development Program of China (2016YFA0602900).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) (a) Lass-Flörl, C. Triazole Antifungal Agents in Invasive Fungal Infections. Drugs 2011, 71,
2405−2419. (b) Romagonli, R.; Baralidi, P. G.; Cruz-Lopez, O.; Cara, C. L.; Carrion, M. D.;
Brancale, A.; Hamel, E.; Chen, L.-C.; Bortolozzi, R.; Basso, G.; Viola, G. Synthesis and Antitumor
Activity of 1,5-Disubstituted 1,2,4-Triazoles as Cis-Restricted Combretastatin Analogues. J. Med.
Chem. 2010, 53, 4248−4258. (c) Sugane, T.; Tobe, T.; Hamaguchi, W.; Shimada, I.; Maeno, K.;
Miyata, J.; Suzuki, T.; Kimizuka, T.; Kohara, A.; Morita, T.; Doihara, H.; Saita, K.; Aota, M.;
Furutani, M.; Shimada, Y.; Hamada, N.; Sakamoto, S. Synthesis and Biological Evaluation of
3-Biphenyl-4-yl-4-phenyl-4H-1,2,4-triazoles as Novel Glycine Transporter 1 Inhibitors. J. Med.
Chem. 2011, 54, 387−391. (d) An, C.-Y.; Li, X.-M.; Li, C.-S.; Gao, S.-S.; Shang, Z.; Wang, B.-G.
Triazoles and Other N-Containing Metabolites from the Marine-Derived Endophytic Fungus
Penicillium chrysogenum EN-118. Helvetica Chimica Acta 2013, 96, 682−687. (e) Romagnoli, R.;
Baraldi, P. G.; Salvador, M. K.; Prencipe, F.; Bertolasi, V.; Cancellieri, M.; Brancale, A.; Hamel, E.;
Castagliuolo, I.; Consolaro, F.; Porcù, E.; Basso, G.; Viola, G. Synthesis, Antimitotic and
Antivascular Activity of 1-(3′,4′,5'-Trimethoxybenzoyl)-3-arylamino-5-amino-1,2,4-triazoles. J.
Med. Chem. 2014, 57, 6795−6808.
(2) (a) Potts, K. T. The Chemistry of 1,2,4-triazoles. Chem. Rev. 1961, 61, 87−127. (b) Moulin, A.;
Bibian, M.; Blayo, A. L.; Martinez, J.; Fehrentz, J. A. Synthesis of
3,4,5-Trisubstituted-1,2,4-triazoles. Chem. Rev. 2010, 110, 1809−1827. (c) Taillefer, M.; Xia, N.;
Ouali, A. Efficient Iron/Copper Co-Catalyzed Arylation of Nitrogen Nucleophiles. Angew. Chem.
Int. Ed. 2007, 46, 934−936. (d) Zhu, L.-B.; Cheng, L.; Zhang, Y.-X.; Xie, R.-G.; You, J.-S. Highly
Efficient Copper-Catalyzed N-Arylation of Nitrogen-Containing Heterocycles with Aryl and
Heteroaryl Halides. J. Org. Chem. 2007, 72, 2737−2743. (e) Cristau, H.-J.; Cellier, P. P.; Spindler,
J.-F.; Taillefer, M. Highly Efficient and Mild Copper-Catalyzed N-and C-Arylations with Aryl
Bromides and Iodides. Chem. Eur. J. 2004, 10, 5607−5622. (f) Suresh, P.; Pitchumani, K.
Per-6-amino-β-cyclodextrin as an Efficient Supramolecular Ligand and Host for Cu(I)-Catalyzed
N-Arylation of Imidazole with Aryl Bromides. J. Org. Chem. 2008, 73, 9121−9124.
(3) For the synthesis of substituted 1,2,4-triazoles: (a) Bechara, W. S.; Khazhieva, I. S.; Rodriguez,
E.; Charette, A. B. One-Pot Synthesis of 3,4,5-Trisubstituted 1,2,4-Triazoles via the Addition of
Hydrazides to Activated Secondary Amides. Org. Lett. 2015, 17, 1184−1187. (b) Shelke, G. M.;
Rao, V. K.; Jha, M.; Cameron, T. S.; Kumar, A. Microwave-Assisted Catalyst-Free Synthesis of
Substituted 1,2,4-Triazoles. Synlett. 2015, 26, 404−407. (c) Yeung, K. S.; Farkas, M. E.; Kadow, J.
F.; Meanwell, N. A. A base-catalyzed, direct synthesis of 3,5-disubstituted 1,2,4-triazoles from
nitriles and hydrazides. Tetrahedron Lett. 2005, 46, 3429−3432. (d) Castanedo, G. M.; Seng, P. S.;
Blaquiere, N.; Trapp, S.; Staben, S. T. Rapid Synthesis of 1,3,5-Substituted 1,2,4-Triazoles from
Carboxylic Acids, Amidines, and Hydrazines. J. Org. Chem. 2011, 76, 1177−1179. (e) Stocks, M.
J.; Cheshire, D. R.; Reynolds, R. Efficient and Regiospecific One-Pot Synthesis of Substituted
1,2,4-Triazoles. Org. Lett. 2004, 6, 2969−2971.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 15
1
2
3
4
5
6
7
8
9
(4) For the synthesis of 1,5-disubstituted 1,2,4-triazoles: (a) Guru, M. M.; Punniyamurthy, T.
Copper(II)-Catalyzed Aerobic Oxidative Synthesis of Substituted 1,2,3- and 1,2,4-Triazoles from
Bisarylhydrazones via C−H Functionalization/C−C/N−N/C−N Bonds Formation. J. Org. Chem.
2012, 77, 5063−5073. (b) Xu, Y.-J.; Mclaughlin, M.; Bolton, E. N.; Reamer, R. A. Practical
Synthesis of Functionalized 1,5-Disubstituted 1,2,4-Triazole Derivatives. J. Org. Chem. 2010, 75,
8666−8669. (c) Degorce, S.; Delouvrié, B.; Davey, P. R. J.; Didelot, M.; Germain, H.; Harris, C. S.;
Brempt, C. L.; Lebraud, H.; Ouvry, G. Facile, diversity-orientated one-pot synthesis of ethyl
1,5-disubstituted-1H-1,2,4-triazole-3-carboxylates. Tetrahedron Lett. 2012, 53, 6078−6082.
(5) Tam, A.; Armstrong, I. S.; La Cruz, T. E. Multicomponent Synthesis of 1-Aryl 1,2,4-Triazoles.
Org. Lett. 2013, 15, 3586−3589.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) Huang, H.-W.; Guo, W.; Wu, W.-Q.; Li, C.-J.; Jiang, H.-F. Copper-Catalyzed Oxidative
C(sp3)−H Functionalization for Facile Synthesis of 1,2,4-Triazoles and 1,3,5-Triazines from
Amidines. Org. Lett. 2015, 17, 2894−2897.
(7) Kuang, J.-Q.; Chen, B.; Ma, S.-M. Copper-mediated efficient three-component synthesis of
1,2,4-triazoles from amines and nitriles. Org. Chem. Front. 2014, 1, 186−189.
(8) Wang, L.-Y.; Tsai, H.-J.; Lin, H.-Y.; Kaneko, K.; Cheng, F.-Y.; Shih, H.-S.; Wong, F.-F.; Huang,
J.-J. One-flask synthesis of 1,3,5-trisubstituted 1,2,4-triazoles from nitriles and hydrazonoyl
chlorides via 1,3-dipolar cycloaddition. RSC Adv. 2014, 4, 14215−14220.
(9) Chen, Z.; Li, H.; Dong, W.; Miao, M.; Ren, H. I2-Catalyzed Oxidative Coupling Reactions of
Hydrazones and Amines and the Application in the Synthesis of 1,3,5-Trisubstituted
1,2,4-Triazoles. Org. Lett. 2016, 18, 1334−1337.
(10) (a) Yan, M.; Kawamata Y.; Baran, P. S. Synthetic Organic Electrochemical Methods Since
2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230−13319. (b) Francke, R.; Little,
R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem.
Soc. Rev. 2014, 43, 2492−2521. (c) Jiang, Y.-Y.; Xu, K.; Zeng, C.-C. Use of Electrochemistry in
the Synthesis of Heterocyclic Structures. Chem. Rev. 2018, 118, 4485−4540.
(11) (a) Xu, K.; Zhang, Z.-L.; Qian, P.; Zha, Z.-G.; Wang, Z.-Y. Electrosynthesis of enaminones
directly from methyl ketones and amines with nitromethane as a carbon source. Chem. Commun.
2015, 51, 11108−11111. (b) Liang, S.; Zeng, C.-C.; Luo, X.-G.; Ren, F.-Z.; Tian, H.-Y.; Sun, B.-G.;
Little, R. D. Electrochemically catalyzed amino-oxygenation of styrenes: n-Bu4NI induced C–N
followed by a C–O bond formation cascade for the synthesis of indolines. Green Chem. 2016, 18,
2222−2230. (c) Tang, S.; Gao, X.-L.; Lei, A.-W. Electrocatalytic intramolecular oxidative
annulation of N-aryl enamines into substituted indoles mediated by iodides. Chem. Commun. 2017,
53, 3354−3356.
(12) (a) Gao, X.-F.; Yuan, G.-Q.; Chen, H.-J.; Jiang, H.-F.; Li, Y.-W.; Qi, C.-R. Efficient
conversion of CO2 with olefins into cyclic carbonates via a synergistic action of I2 and base
electrochemically generated in situ. Electrochem. Commun. 2013, 34, 242−245. (b) Yang, N.; Lai,
Q.; Jiang, H.-F.; Yuan, G.-Q. A novel electrochemical conversion of CO2 with aryl hydrazines and
paraformaldehyde into 1,3,4-oxadiazol-2(3H)-one derivatives in one step. Electrochem. Commun.
2016, 72, 109−112.
(13) (a) Hou, Z.-W.; Mao, Z.-Y.; Zhao, H.-B.; Melcamu, Y. Y.; Lu, X.; Song, J.-S.; Xu, H.-C.
Electrochemical C-H/N-H Functionalization for the Synthesis of Highly Functionalized
(Aza)indoles. Angew. Chem. Int. Ed. 2016, 55, 9168–9172. (b) Xu, F.; Zhu, S.-B.; Yan, X.-M.; Xu,
14
ACS Paragon Plus Environment

Page 15 of 15
The Journal of Organic Chemistry
1
2
3
4
5
H.-C. Electrochemical Intramolecular Aminooxygenation of Unactivated Alkenes. Chem. Eur. J.
2014, 20, 12740–12744.
6
7
8
9
(14) Matsubara, Y.; Adachi, K.; Tada, H.; Kitano, K. Synthesis of 1,3,4-Oxadiazolion-2-ones by
1,3-Dipolar Addition of Carbon Dioxide with Nitrile Imine. Yakugaku zasshi 1996, 116, 255−258.
(15) (a) Miller, R. A.; Hoerrner, R. S. Iodine as a Chemoselective Reoxidant of TEMPO:
Application to the Oxidation of Alcohols to Aldehydes and Ketones. Org. Lett. 2003, 5, 285−287.
(b) Ge, W.-L.; Zhu, X.; Wei, Y.-Y. Iodine-catalyzed oxidative system for cyclization of primary
alcohols with o-aminobenzamides to quinazolinones using DMSO as the oxidant in dimethyl
carbonate. RSC Adv. 2013, 3, 10817−10822. (c) Kashparova, V. P.; Klushin, V. A.; Zhukova, I. Y.;
Kashparov, I. S.; Chernysheva, D. V.; Smirnova, N. V.; Kagan, E. Sh.; Chernyshev, V. M. A
TEMPO-like nitroxide combined with an alkyl-substituted pyridine: An efficient catalytic system
for the selective oxidation of alcohols with iodine. Tetrahedron Lett. 2017, 58, 3517−3521.
(16) Zolfigol, M. A.; Hajjami, M.; Ghorbani-Choghamarani, A. A Simple and One-pot Oxidative
Conversion of Alcohols or Aldehydes to the Nitriles using NaIO4/KI in Aqueous NH3. Bull.
Korean Chem. Soc. 2011, 32, 4191−4194.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
ACS Paragon Plus Environment