Heterogeneous Copper(I)-Catalyzed Cascade Addition-Oxidative Cyclization of Nitriles with 2-Aminopyridines or Amidines: Efficient and Practical Synthesis of 1,2,4-Triazoles

Article abstract of DOI:10.1055/s-0037-1611712

The heterogeneous cascade addition-oxidative cyclization of nitriles with 2-aminopyridines or amidines was achieved in 1,2-dichlorobenzene or DMSO at 120-130 °C by using a 1,10-phenanthroline-functionalized MCM-41-supported copper(I) complex [Phen-MCM-41-

Full text of DOI:10.1055/s-0037-1611712

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
J. Xia et al.
Paper
Synthesis
Heterogeneous Copper(I)-Catalyzed Cascade Addition–Oxidative
Cyclization of Nitriles with 2-Aminopyridines or Amidines: Efficient
and Practical Synthesis of 1,2,4-Triazoles
Jianhui Xia
Phen-MCM-41-CuBr
(5 mol%)
NH2
Xue Huang
N
N
R1
R2
+
R1
Mingzhong Cai*
0
0
0
0-0
0
0
2-1
0
5
6-2
8
4
6
N
R2
N
N
ZnI2 (10 mol%), DCB
air, 130 °C, 24 h
Key Laboratory of Functional Small Organic Molecule, Ministry
of Education and College of Chemistry & Chemical Engineering,
Jiangxi Normal University, Nanchang 330022, P. R. of China
mzcai@jxnu.edu.cn
20 examples
up to 94% yield
Phen-MCM-41-CuBr
(5 mol%)
R3
HN
R3
NH2
N
N
R2
R2
N
+
.
NH HCl
Cs2CO3, DMSO
air, 120 °C, 24 h
11 examples
up to 88% yield
Recyclable copper catalyst!
Received: 23.10.2018
Accepted after revision: 05.12.2018
Published online: 18.02.2019
triazoles have been reported.8 However, most of the exist-
ing methods suffer from some drawbacks in one or another
respect, such as multistep synthetic procedures, lower
yields, a limited substrate scope, or inferior regioselectivity.
Therefore, it is highly desired to develop a simple and prac-
tical approach to 1,2,4-triazole derivatives from readily
available starting materials.
DOI: 10.1055/s-0037-1611712; Art ID: ss-2018-h0712-op
Abstract The heterogeneous cascade addition-oxidative cyclization of
nitriles with 2-aminopyridines or amidines was achieved in 1,2-dichloro-
benzene or DMSO at 120–130 °C by using a 1,10-phenanthroline-func-
tionalized MCM-41-supported copper(I) complex [Phen-MCM-41-CuBr]
as the catalyst and air as the oxidant. The approach was used to gener-
ate a wide variety of 1,2,4-triazole derivatives in mostly high yields. This
heterogeneous copper(I) catalyst could be easily prepared in a two-step
procedure from commercially or readily available and inexpensive re-
agents and it exhibited higher catalytic activity than the CuBr/1,10-
Phen system. Phen-MCM-41-CuBr was also easy to recover and was re-
cyclable up to eight times with almost consistent activity.
Recently, copper-catalyzed construction of 1,2,4-tri-
azoles from readily available starting materials has attract-
ed considerable interest because of the high efficiency and
low cost of copper catalysts.9 However, in almost all cases,
homogeneous copper catalysts with higher loadings (typi-
cally 5–20 mol%) were used to achieve high yields, and they
are difficult to separate from the reaction mixture and they
are not recyclable. These problems are of particular envi-
ronmental and economic concerns in large-scale syntheses
and in industry. Moreover, homogeneous catalysis might
cause copper contamination of the desired product because
1,2,4-triazoles are strong ligands for transition metals and
could coordinate with copper to form stable complexes.5c–e
Immobilization of the existing homogeneous copper cata-
lysts on various supports appears to be a logical solution to
these problems; the use of immobilized catalysts could en-
able facile separation, recovery, and reusability of the cop-
per catalysts, thus minimizing copper contamination of the
desired product and reducing the amount of waste generat-
ed from reaction workup.10 In recent years, some supported
copper complexes have been successfully used for the con-
struction of carbon–carbon11 and carbon–heteroatom12
bonds as highly efficient and recyclable catalysts, but the
heterogeneous copper-catalyzed synthesis of 1,2,4-tri-
azoles from readily available starting materials has received
little attention. Recently, Zhao and co-workers reported an
efficient heterogeneously catalyzed addition–oxidative cy-
clization between 2-aminopyridines or amidines and ni-
Key words copper, 1,2,4-triazole, oxidative cyclization, heteroge-
neous catalysis, cascade reaction
1,2,4-Triazoles, as highly important structural motifs,
have found broad applications in medicinal and agricultural
chemistry fields as well as in materials science.1 The com-
pounds exhibit a wide variety of biological activities, in-
cluding antifungal, antibacterial, anticancer, antimicrobial,
anti-inflammatory, antiviral, antidepressant, and anticon-
vulsant behavior.2 1,2,4-Triazole scaffolds are found in
many biologically active molecules3 and valuable pharma-
ceuticals, including maraviroc, triazolam, sitagliptin, and
deferasirox.4 1,2,4-Triazoles have also been widely used as
ligands in transition-metal complexes and metal-organic
frameworks, exhibiting tremendous application prospects.5
Based on the high importance of this scaffold and on its ap-
plications in a variety of fields, various synthetic methods
have been developed for the synthesis of 1,2,4-triazole de-
rivatives.1a,6 The most commonly investigated pathways in-
volve the intramolecular and intermolecular condensation
reactions of nitrogen-containing compounds.7 In addition,
copper-mediated or alumina-promoted synthesis of 1,2,4-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
J. Xia et al.
Paper
Synthesis
triles for the synthesis 1,2,4-triazoles using air as the oxi-
dant and copper-zinc supported on Al2O3-TiO2 as the cata-
lyst.13
OH
OH
H
H
(EtO)3Si
N
N
N
+
OH
Mesoporous silica MCM-41 has recently emerged as an
ideal support for immobilization of homogeneous catalysts
because of its unique properties such as extremely high
surface area, homogeneity of the pores, large pore volume
and high thermal stability in comparison with other solid
supports.14 In addition, nano-sized catalysts can serve as ef-
ficient bridges and fill the gap between homogeneous and
heterogeneous catalysts.15 To date, Pd,16 Rh,17 Mo,18 and
Au19 complexes immobilized on MCM-41 have been suc-
cessfully applied in organic synthesis as recyclable nanocat-
alysts. Recently, we reported the first synthesis of 1,10-
phenanthroline-functionalized MCM-41-supported cop-
per(I) complex [Phen-MCM-41-CuI] and found that it is a
highly efficient and recyclable heterogeneous catalyst for
the decarboxylative cross-coupling of potassium polyfluo-
robenzoates with aryl halides and the C–O coupling be-
tween aryl iodides and aliphatic alcohols.20 To further ex-
pand our Cu(I)-MCM-41 chemistry toolbox,11c,d,12f,h,20 herein
we report a heterogeneous copper-catalyzed cascade addi-
tion-oxidative cyclization of nitriles with 2-aminopyridines
or amidines leading to 1,2,4-triazole derivatives by using an
O
N
MCM-41
OEt
Si
H
H
O
O
N
N
N
N
1. toluene, 110 °C, 24 h
2. Me3SiCl, rt, 24 h
O
OSiMe3
Phen-MCM-41
OEt
Si
H
H
O
N
N
N
CuXn
O
CuXn
O
N
acetone
OSiMe3
reflux, 24 h
Phen-MCM-41-CuCl (A), CuXn = CuCl Phen-MCM-41-CuCl2 (D), CuXn = CuCl2
Phen-MCM-41-CuBr (B), CuXn = CuBr Phen-MCM-41-CuBr2 (E), CuXn = CuBr2
Phen-MCM-41-CuI (C), CuXn = CuI
Phen-MCM-41-Cu(OAc)2 (F), CuXn = Cu(OAc)2
Scheme 2 Preparation of the Phen-MCM-41-CuXn complexes
1,2-dichlorobenzene (DCB) at 130 °C with Phen-MCM-41-
CuCl [A] (5 mol%) as the catalyst under an air atmosphere.
The reaction was stopped 24 hours later, and 2-phe-
nyl[1,2,4]triazolo[1,5-a]pyridine 3a was obtained in 38%
yield after flash chromatography (Table 1, entry 1). To our
delight, the addition of 10 mol% ZnI2 improved the reaction
efficacy significantly, and the desired product 3a was isolat-
ed in 81% yield (entry 2).22 Other zinc salts such as ZnBr2
and ZnCl2 were less effective than ZnI2 (entries 3 and 4). To
further increase the yield, various supported copper cata-
lysts were tested, and a significant catalyst effect was ob-
served. When Phen-MCM-41-CuBr [B] was used as the cat-
alyst, the yield of 3a could be increased to 85%, while other
copper catalysts such as Phen-MCM-41-CuI [C], Phen-
MCM-41-CuCl2 [D], Phen-MCM-41-CuBr2 [E], and Phen-
MCM-41-Cu(OAc)2 [F] afforded lower yields (entries 5–9);
Phen-MCM-41-CuBr [B] was thus the best choice (entry 5).
The reaction also worked well in toluene (entry 10), but the
use of polar DMSO or DMF as the solvent resulted in a dra-
matic decrease in the yield (entries 11 and 12). The reaction
did not occur in the absence of any copper catalyst, which
revealed the special catalytic role of copper in this transfor-
1,10-phenanthroline-functionalized
MCM-41-supported
copper(I) complex [Phen-MCM-41-CuBr] as the catalyst
and air as the oxidant (Scheme 1).
NH2
Phen-MCM-41-CuBr
(5 mol%)
N
N
R1
R2
+
N
R2
R1
N
N
ZnI2 (10 mol%), DCB
air, 130 °C, 24 h
1
2
3
Phen-MCM-41-CuBr
(5 mol%)
R3
HN
R3
NH2
N
N
N
R2
R2
+
.
NH HCl
Cs2CO3, DMSO
air, 120 °C, 24 h
4
2
5
Scheme 1 Heterogeneous copper(I)-catalyzed synthesis of 1,2,4-tri-
azoles
A series of 1,10-phenanthroline-functionalized MCM-
41-supported copper(I) or (II) complexes [Phen-MCM-41-
CuXn] were prepared according to our previous procedure
as shown in Scheme 2.20b First, the mesoporous MCM-41
was condensed with 1-(1,10-phenanthrolin-5-yl)-3-(3-
(triethoxysilyl)propyl)urea21 in toluene, followed by silyla-
tion with Me3SiCl to generate the 1,10-phenanthroline-
functionalized MCM-41 [Phen-MCM-41]. The latter was
then reacted with various copper salts in acetone to afford a
series of the Phen-MCM-41-CuXn complexes as light-green
powders.
mation (entry 13). When
a homogeneous CuBr (5
mol%)/1,10-Phen (5 mol%) catalytic system was used, the
desired product 3a was isolated in 81% yield (entry 14),
which indicated that this heterogeneous Phen-MCM-41-
CuBr [B] system exhibited a slightly higher catalytic activity
than the homogeneous CuBr (5 mol%)/1,10-Phen (5 mol%)
system. When 1-(1,10-phenanthrolin-5-yl)-3-(3-(triethox-
ysilyl)propyl)urea was used as the ligand instead of 1,10-
Phen, a slightly decreased yield (78%) was also observed
(entry 15). The slightly higher activity of this heteroge-
neous catalytic system over the homogeneous analogues
may be mainly due to the efficient site isolation and the op-
In our initial screening experiments, the cascade reac-
tion of 2-aminopyridine 1a with benzonitrile 2a was inves-
tigated to optimize the reaction conditions; the results are
summarized in Table 1. The reaction was first carried out in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
J. Xia et al.
Paper
Synthesis
timal dispersion of the active sites on the inner channel
walls of the MCM-41 support with ultra-high surface area.
Finally, the amount of copper catalyst was also screened.
The use of 2.5 mol% of Phen-MCM-41-CuBr resulted in a de-
creased yield and required a longer reaction time (entry
16), whereas increasing the amount of copper catalyst
could shorten the reaction time, but did not improve the
yield significantly (entry 17). Therefore, the optimized con-
ditions for this cascade reaction are the use of Phen-MCM-
41-CuBr (5 mol%) as catalyst and ZnI2 (10 mol%) as additive
in DCB at 130 °C for 24 hours under atmospheric air (Table
1, entry 5).
a]pyridine derivatives 3b–g in 73–92% yields. These results
indicate that the electronic nature of the substituents on
the aromatic ring of the benzonitrile substrate has limited
influence on this heterogeneous copper-catalyzed cascade
reaction. But the reactivity of electron-deficient benzoni-
triles was higher than that of electron-rich derivatives, and
4-methoxybenzonitrile 2c with a strong electron-donating
group gave the desired product 3c in only 73% yield. The
meta-substituted benzonitriles 2h–j were also suitable sub-
strates and produced the expected products 3h–j in 75–94%
yields, but electron-rich 3-methoxybenzonitrile 2i dis-
played lower reactivity and furnished 3i in 75% yield. The
sterically hindered 2-fluorobenzonitrile 2k also exhibited a
lower reactivity and gave the desired product 3k in only
74% yield. In addition to aryl nitriles, heteroaryl nitriles
such as 4-cyanopyridine 2l and 2-cyanofuran 2m were also
compatible with the standard conditions and afforded the
target products 3l and 3m, respectively, in good yields.
However, when aliphatic nitriles such as acetonitrile or
benzyl cyanide were used as substrates, the reaction did
not work.
Table 1 Optimization of the Reaction Conditionsa
NH2
N
copper catalyst
Ph
+
N
Ph
N
N
solvent, additive
air, 130 °C, 24 h
N
1a
2a
3a
Entry
Copper catalyst
(mol%)
Solvent
Additive (10
mol%)
Yield
(%)b
We next examined the substrate scope of 2-aminopyri-
dines. The reaction of 2-amino-3-methylpyridine (1b) with
benzonitrile 2a gave 8-methyl-2-phenyl[1,2,4]triazolo[1,5-
a]pyridine (3n) in somewhat reduced yield (67%) due to the
steric hindrance. However, 2-amino-4-methylpyridine (1c)
displayed good reactivity and the reaction with 2a provided
the corresponding 7-methyl-2-phenyl[1,2,4]triazolo[1,5-
a]pyridine (3o) in 81% yield. In addition, halo-substituted
2-aminopyridines such as 2-amino-4-chloropyridine (1d)
and 2-amino-4-bromopyridine (1e) also reacted well in this
transformation and generated the corresponding halo-sub-
stituted 1,2,4-triazolo[1,5-a]pyridines 3p–r in 65–69%
yields. The lower yields probably reflect lower nucleophilic-
ity of 2-aminopyridines 1d and 1e because of the electron-
withdrawing nature of halogen. Notably, 1-aminoisoquino-
line 1f was also compatible with the standard conditions
and the reaction with benzonitrile furnished 2-phenyl-
[1,2,4]triazolo[5,1-a]isoquinoline (3s), which is known as a
potent nonhormonal antifertility agent,9b in 91% yield. The
reaction also worked well with 4-methylbenzonitrile 2b
and gave the target product 3t in 88% yield. The present
method thus provides a novel, highly efficient and practical
procedure for the construction of triazoloheterocycles from
readily available starting materials.
1
2
A (5)
DCB
DCB
DCB
DCB
DCB
DCB
DCB
DCB
DCB
toluene
DMSO
DMF
DCB
DCB
DCB
DCB
DCB
–
38
81
47
39
85
69
73
77
79
74
40
32
0
A (5)
ZnI2
ZnBr2
ZnCl2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
3
A (5)
4
A (5)
5
B (5)
6
C (5)
7
D (5)
8
E (5)
9
F (5)
10
11
12
13
14
15
16c
17d
B (5)
B (5)
B (5)
–
CuBr/Phen (5)
CuBr/L (5)
B (2.5)
B (10)
81
78
67
86
a Reaction conditions: 2-aminopyridine (0.6 mmol), benzonitrile (0.5
mmol), solvent (1.5 mL), under atmospheric air. L = 1-(1,10-phenanthrolin-
5-yl)-3-(3-(triethoxysilyl)propyl)urea.
b Isolated yield.
c For 36 h.
d For 15 h.
The efficiency of the heterogeneous copper(I)-catalyzed
cascade addition-oxidative coupling process for triazolohet-
erocycles prompted us to explore the construction of 1H-
1,2,4-triazoles from amidines and nitriles. In contrast to the
preparation of 1,2,4-triazolo[1,5-a]pyridines, the use of
ZnI2 in DCB proved to be unsuitable for the preparation of
1H-1,2,4-triazoles. To our delight, the addition of Cs2CO3 in
DMSO as the solvent resulted in the successful generation
of the corresponding 1H-1,2,4-triazoles from amidines 4
and nitriles 2 (Scheme 4). The reactions of benzamidine 4a
With the optimum reaction conditions in hand, we next
investigated the scope of the heterogeneous copper(I)-cata-
lyzed synthesis of 1,2,4-triazolo[1,5-a]pyridines; the results
are listed in Scheme 3. The cascade reactions of various
para-substituted benzonitriles 2b–g bearing either elec-
tron-donating or electron-withdrawing groups with 2-ami-
nopyridine 1a proceeded smoothly under the optimized
conditions to provide the corresponding 1,2,4-triazolo[1,5-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
J. Xia et al.
Paper
Synthesis
NH2
Phen-MCM-41-CuBr
(5 mol%)
N
N
R1
R2
R1
N
R2
+
N
N
ZnI2 (10 mol%), DCB
air, 130 °C, 24 h
1
2
3
N
N
N
N
N
N
N
Me
OMe
F
Cl
N
N
N
N
N
N
N
N
3a, 85%
3b, 80%
3c, 73%
3d, 84%
3e, 92%
N
N
N
N
N
N
Br
CO2Me
N
N
N
N
N
N
N
N
N
CF3
Cl
OMe
3f, 85%
3g, 91%
3h, 86%
3i, 75%
3j, 94%
Me
N
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
O
N
F
N
3k, 74%
3l, 77%
3m, 70%
3n, 67%
3o, 81%
Cl
Cl
N
N
N
Br
N
N
Me
N
N
N
N
N
Me
N
N
N
N
N
3p, 65%
3q, 67%
3r, 69%
3s, 91%
3t, 88%
Scheme 3 Heterogeneous copper(I)-catalyzed synthesis of 1,2,4-triazolo[1,5-a]pyridines. Reagents and conditions: 1 (0.6 mmol), 2 (0.5 mmol), ZnI2
(0.05 mmol), Phen-MCM-41-CuBr (5 mol%), DCB (1.5 mL), at 130 °C for 24 h under atmospheric air. Isolated yields are given.
with benzonitriles 2a or 2b afforded 1H-1,2,4-triazoles 5a
and 5b in good yields. The reaction also worked well with a
heteroaryl nitrile, 4-cyanopyridine 2l, and gave the target
Phen-MCM-41-CuBr
R3
HN
R3
NH2
N
N
(5 mol%)
product 5c in 74% yield. In terms of amidines, not only aryl
amidines but also primary, secondary, and tertiary alkyl
amidines could be employed to synthesize 1H-1,2,4-tri-
azoles. For example, the reactions of acetimidamide 4b
with electron-rich or electron-deficient benzonitriles 2b,
2e, 2f, and 2j proceeded smoothly to give the corresponding
1H-1,2,4-triazoles 5d–g in 78–88% yields. Cyclopropanecar-
boximidamide 4c displayed a similar reactivity to acetimid-
amide 4b and the reaction with 2e afforded the corre-
sponding 5-cyclopropyl-substituted triazole 5h in 83%
yield. Pivalimidamide 4d also reacted well in this transfor-
mation, thus giving the corresponding 5-(tert-butyl)-sub-
stituted triazoles 5i and 5j in good yields. Aliphatic nitriles
could also be employed as substrates, but the reactivity was
clearly lower than with aromatic nitriles. For example, the
reaction of benzamidine 4a with acetonitrile afforded the
target product 5k in only 49% yield.
To determine whether the observed activity is derived
from the Phen-MCM-41-CuBr catalyst or leached copper
species in solution, the heterogeneity of Phen-MCM-41-
CuBr was tested by hot filtration.23 For this, the reaction of
benzamidine 4a with benzonitrile 2a was carried out for 5
hours to obtain an approximately 30% conversion of 2a. The
catalyst was then removed by filtration of the reaction mix-
ture at 120 °C and the catalyst-free filtrate was allowed to
react further at 120 °C for 20 hours. In this case, no increase
R2
N
R2
+
.
NH
Cs2CO3, DMSO
air, 120 °C, 24 h
HCl
4
2
5
Ph
Ph
Ph
N
N
N
N
N
Me
N
HN
HN
HN
N
5a, 79%
5b, 81%
5c, 74%
Me
Me
Me
Me
N
N
N
Cl
Cl
Br
HN
HN
HN
N
N
N
5d, 80%
5e, 85%
5f, 78%
Me
N
N
N
N
HN
HN
HN
N
N
CF3
5g, 88%
5h, 83%
5i, 63%
Ph
N
N
Me
HN
HN
N
N
5k,a 49%
5j, 71%
OMe
Scheme 4 Heterogeneous copper(I)-catalyzed synthesis of 1H-1,2,4-
triazoles. Reagents and conditions: 4 (0.75 mmol), 2 (0.5 mmol), Cs2CO3
(1.5 mmol), Phen-MCM-41-CuBr (5 mol%), DMSO (1.5 mL), at 120 °C
for 24 h under atmospheric air. Isolated yield are given. a MeCN/DMSO
(1:3) was used as the solvent.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
J. Xia et al.
Paper
Synthesis
in conversion of 2a was observed, indicating that leached
copper species from Phen-MCM-41-CuBr (if any) are not re-
sponsible for the observed conversion. Furthermore, analy-
sis on the filtered solution by ICP-AES indicated that no Cu
metal was detected. These results demonstrated that the
catalyst was stable during the cascade cyclization reaction
and that this procedure catalyzed by Phen-MCM-41-CuBr is
unambiguously heterogeneous in nature.
A plausible mechanism for the heterogeneous cop-
per(I)-catalyzed synthesis of triazole derivatives is shown
in Scheme 5.9b,f,g First, nucleophilic attack of 2-aminopyri-
dine 1a on nitrile 2a promoted by the Phen-MCM-41-CuBr
complex occurs by forming an MCM-41-anchored four-ni-
trogen coordinated copper(I) complex intermediate A. The
latter intermediate might provide an MCM-41-anchored
cyclic copper(I) complex intermediate B after amino attacks
the carbon of cyano and subsequent proton-transfer pro-
cess. Next, intermediate B undergoes a copper-induced in-
tramolecular oxidative cyclization to produce the desired
triazolopyridine 3a and reduced copper species [Phen-
MCM-41-Cu(0)]. Finally, the reduced copper species is oxi-
dized by molecular oxygen of air to regenerate Phen-MCM-
41-CuBr and complete the catalytic cycle. The mechanism
for producing the 1,2,4-triazoles 5 from amidines 4 and
nitriles 2 might resemble that shown in Scheme 5.
CuBr was evaluated in the reaction of 2-aminopyridine (1a)
with 3-(trifluoromethyl)benzonitrile (2j); the results are il-
lustrated in Figure 1. After completion of the first reaction,
the reaction mixture was diluted with ethyl acetate. Filtra-
tion of the reaction mixture followed by washing of the re-
sulting solid with water and acetone allowed the easy re-
covery of the Phen-MCM-41-CuBr catalyst. The recovered
copper catalyst was used in the next run of the same reac-
tion process and could be recycled up to seven times with
almost consistent activity. In addition, ICP-AES analysis was
performed on the recovered catalyst after eight consecutive
runs, the copper content was found to be 0.69 mmol·g–1,
which was almost the same copper content as that of the
fresh Phen-MCM-41-CuBr. In our opinion, the excellent cat-
alytic behavior of Phen-MCM-41-CuBr should be attributed
to the efficient site isolation, to the optimal dispersion of
the active sites on the inner channel walls, and to strong in-
teraction between bidentate 1,10-phenanthroline ligand
and the copper center anchored on the MCM-41.
MCM-41
NH2
H2O
N
Ph
+
N
N
N
2a
1a
(I)
Cu
Figure 1 Recycle of heterogeneous copper catalyst
1/2 O2
In conclusion, we have developed a general, efficient
and practical method for the synthesis of 1,2,4-triazole de-
rivatives through the heterogeneous copper(I)-catalyzed
cascade addition-oxidative cyclization reaction of nitriles
with 2-aminopyridines or amidines by using molecular ox-
ygen (air at 1 atm) as the oxidant, which produces water as
the sole byproduct. The reactions generated a wide variety
of 1,2,4-triazoloheterocycles and 1H-1,2,4-triazoles in
mostly good to excellent yields and were applicable to vari-
ous nitriles and a wide range of 2-aminopyridines or ami-
dines. Furthermore, the present method offers the advan-
tages of recyclability of the copper catalyst with consistent
activity, and the copper catalyst can be easily recovered by
a simple filtration and recycled up to eight times, thereby
making this approach economically and environmentally
more acceptable.
MCM-41
MCM-41
N
N
N
N
(I)
Cu
Cu (0)
(A)
N
N
MCM-41
Ph
NH2
N
N
N
(I)
Cu
N
N
NH
N
3a
Ph
N
H
(B)
Scheme 5 Plausible mechanism for the heterogeneous copper(I)-cata-
lyzed synthesis of triazole derivatives
The lifetime of the catalyst and its level of reusability
are important factors for the practical application of a het-
erogeneous catalytic system. Under the standard reaction
conditions, the stability and recyclability of Phen-MCM-41-
All chemicals were reagent grade and used as purchased. All solvents
were dried and distilled prior to use. Phen-MCM-41-CuCl [A], Phen-
MCM-41-CuBr [B], Phen-MCM-41-CuI [C], Phen-MCM-41-CuCl2 [D],
Phen-MCM-41-CuBr2 [E], and Phen-MCM-41-Cu(OAc)2 [F] were pre-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

F
J. Xia et al.
Paper
Synthesis
1
pared according to our previous procedure,20b the copper contents
were determined to be 0.72, 0.70, 0.73, 0.67, 0.71, and 0.69 mmol·g–1
13C NMR (100 MHz, CDCl3): δ = 164.1 (d, JC–F = 248.0 Hz), 163.3,
3
,
151.7, 129.5, 129.3 (d, JC–F = 8.4 Hz), 128.3, 127.1, 116.3, 115.7 (d,
respectively. The products were purified by flash chromatography on
silica gel. Mixtures of EtOAc and hexane was generally used as eluent.
1H NMR spectra were recorded with a Bruker Avance 400 MHz spec-
trometer with TMS as internal standard in CDCl3, CD3OD or DMSO-d6
as solvent. 13C NMR spectra (100 MHz) were recorded with a Bruker
Avance 400 MHz spectrometer in CDCl3, CD3OD or DMSO-d6 as sol-
vent. Melting points were determined without correction. Copper
content was determined with an inductively coupled plasma atom
emission Atomscan 16 (ICP-AES, TJA Corporation). HRMS spectra
were recorded with a Q-Tof spectrometer with micromass MS soft-
ware using electrospray ionization (ESI).
2JC–F = 21.7 Hz), 113.6.
2-(4-Chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3e)7g
Yield: 105.6 mg (92%); white solid; mp 220–221 °C.
1H NMR (400 MHz, CDCl3): δ = 8.59 (d, J = 6.8 Hz, 1 H), 8.23 (d, J =
8.4 Hz, 2 H), 7.75 (d, J = 9.2 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.47 (d, J =
8.8 Hz, 2 H), 7.03 (t, J = 6.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 151.7, 136.1, 129.7, 129.4,
129.0, 128.6, 128.4, 116.5, 113.8.
2-(4-Bromophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3f)7g
Heterogeneous Copper-Catalyzed Synthesis of 1,2,4-Triazolopyri-
dines 3a–t; General Procedure
Yield: 116.5 mg (85%); white solid; mp 229–230 °C.
1H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 6.0 Hz, 1 H), 8.16 (d, J =
7.6 Hz, 2 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.52 (t, J =
7.4 Hz, 1 H), 7.02 (t, J = 6.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 151.7, 131.9, 129.8, 129.7,
128.9, 128.4, 124.5, 116.5, 113.8.
A 5 mL reaction tube was charged with Phen-MCM-41-CuBr (36 mg,
0.025 mmol), 2-aminopyridine 1 (0.6 mmol), nitrile 2 (0.5 mmol),
ZnI2 (16 mg, 0.05 mmol), and 1,2-dichlorobenzene (1.5 mL) under an
air atmosphere. The reaction tube was sealed and placed in an oil
bath at r.t. The reaction mixture was stirred at 130 °C for 24 h. After
cooling to r.t., the reaction mixture was diluted with EtOAc (10 mL)
and filtered. The supported copper catalyst was washed with water
(2 × 5 mL) and acetone (2 × 5 mL), and reused in the next run. The fil-
trate was concentrated in vacuo and the residue was purified by flash
column chromatography on silica gel (hexane/EtOAc, 3:2) to provide
the desired product 3.
Methyl 4-([1,2,4]Triazolo[1,5-a]pyridin-2-yl)benzoate (3g)
Yield: 115.2 mg (91%); white solid; mp 184–185 °C.
1H NMR (400 MHz, CDCl3): δ = 8.62 (d, J = 6.8 Hz, 1 H), 8.37 (d, J =
8.0 Hz, 2 H), 8.17 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.54 (t, J =
7.8 Hz, 1 H), 7.05 (t, J = 6.8 Hz, 1 H), 3.95 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.8, 163.2, 151.8, 135.0, 131.4,
130.0, 129.8, 128.4, 127.2, 116.7, 114.0, 52.2.
HRMS (ESI): m/z [M]+ calcd for C14H11N3O2: 253.0851; found:
253.0847.
2-Phenyl[1,2,4]triazolo[1,5-a]pyridine (3a)7g
Yield: 83.1 mg (85%); white solid; mp 134–135 °C.
1H NMR (400 MHz, CDCl3): δ = 8.59 (d, J = 6.8 Hz, 1 H), 8.31–8.28 (m,
2 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.55–7.46 (m, 4 H), 7.00–6.96 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 164.2, 151.7, 130.8, 130.1, 129.5,
2-(3-Chlorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3h)7g
128.7, 128.3, 127.3, 116.4, 113.6.
Yield: 98.7 mg (86%); white solid; mp 177–178 °C.
1H NMR (400 MHz, CDCl3): δ = 8.60 (d, J = 6.8 Hz, 1 H), 8.30 (s, 1 H),
8.19–8.15 (m, 1 H), 7.76 (d, J = 9.2 Hz, 1 H), 7.55–7.50 (m, 1 H), 7.45–
7.42 (m, 2 H), 7.05–7.01 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.0, 151.7, 134.8, 132.6, 130.1,
130.0, 129.7, 128.4, 127.5, 125.4, 116.6, 113.9.
2-(p-Tolyl)-[1,2,4]triazolo[1,5-a]pyridine (3b)7f
Yield: 83.4 mg (80%); white solid; mp 167–168 °C.
1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 6.8 Hz, 1 H), 8.18 (d, J =
8.0 Hz, 2 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.30 (d, J =
8.0 Hz, 2 H), 6.97 (t, J = 7.0 Hz, 1 H), 2.42 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.3, 151.7, 140.2, 129.4, 129.3,
2-(3-Methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3i)7g
128.3, 128.0, 127.3, 116.3, 113.4, 21.5.
Yield: 84.5 mg (75%); white solid; mp 106–108 °C.
1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 6.4 Hz, 1 H), 7.89 (d, J =
7.2 Hz, 1 H), 7.84 (s, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 7.47 (t, J = 7.6 Hz,
1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.01 (d, J = 7.6 Hz, 1 H), 6.96 (t, J = 6.4 Hz,
1 H), 3.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.1, 159.9, 151.6, 132.1, 129.7,
129.5, 128.3, 119.8, 116.8, 116.4, 113.6, 111.8, 55.4.
2-(4-Methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine (3c)9b
Yield: 82.2 mg (73%); white solid; mp 134–135 °C.
1H NMR (400 MHz, CDCl3): δ = 8.57 (d, J = 6.8 Hz, 1 H), 8.23 (dd, J = 6.8,
2.0 Hz, 2 H), 7.72 (d, J = 9.2 Hz, 1 H), 7.50–7.46 (m, 1 H), 7.03–6.95 (m,
3 H), 3.88 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.2, 161.3, 151.7, 129.4, 128.8,
128.2, 123.4, 116.2, 114.1, 113.3, 55.3.
2-(3-(Trifluoromethyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine (3j)9b
Yield: 123.7 mg (94%); white solid; mp 164–165 °C.
1H NMR (400 MHz, CDCl3): δ = 8.61 (d, J = 6.8 Hz, 1 H), 8.58 (s, 1 H),
8.48 (d, J = 8.0 Hz, 1 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.72 (d, J = 8.0 Hz,
2-(4-Fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3d)7g
Yield: 89.5 mg (84%); white solid; mp 173–174 °C.
1H NMR (400 MHz, CDCl3): δ = 8.56 (d, J = 6.8 Hz, 1 H), 8.27 (dd, J = 8.4,
1.6 Hz, 2 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.17 (t, J =
8.6 Hz, 2 H), 6.97 (t, J = 6.8 Hz, 1 H).
1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.57–7.52 (m, 1 H), 7.05 (t, J = 7.0 Hz,
1 H).
2
13C NMR (100 MHz, CDCl3): δ = 162.9, 151.8, 131.7, 131.3 (q, JC–F
=
32.4 Hz), 130.4, 129.9, 129.2, 128.4, 126.6 (q, 3JC–F = 3.6 Hz), 124.3 (q,
3JC–F = 3.9 Hz), 124.0 (q, 1JC–F = 270.8 Hz), 116.6, 114.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
J. Xia et al.
Paper
Synthesis
2-(2-Fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (3k)9b
13C NMR (100 MHz, CDCl3): δ = 165.4, 151.8, 140.6, 136.0, 129.5,
128.4, 127.5, 127.3, 115.3, 114.9, 21.5.
Yield: 78.9 mg (74%); white solid; mp 171–172 °C.
HRMS (ESI): m/z [M]+ calcd for C13H10ClN3: 243.0563; found:
243.0574.
1H NMR (400 MHz, CDCl3): δ = 8.67 (d, J = 6.8 Hz, 1 H), 8.26 (td, J = 7.6,
1.6 Hz, 1 H), 7.80 (d, J = 9.2 Hz, 1 H), 7.56–7.51 (m, 1 H), 7.48–7.43 (m,
1 H), 7.32–7.22 (m, 2 H), 7.06–7.01 (m, 1 H).
7-Bromo-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (3r)
13C NMR (100 MHz, CDCl3): δ = 160.8 (d, 1JC–F = 257.3 Hz), 160.8 (d, 3JC–
2
3
Yield: 94.5 mg (69%); white solid; mp 187–188 °C.
= 4.9 Hz), 151.1, 131.5 (d, JC–F = 8.5 Hz), 131.0 (d, JC–F = 2.6 Hz),
129.7, 128.5, 124.3 (d, JC–F = 3.6 Hz), 118.9 (d, JC–F = 11.1 Hz), 116.8,
F
3
2
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 7.2 Hz, 1 H), 8.28–8.23 (m,
2 H), 7.93 (d, J = 1.6 Hz, 1 H), 7.51–7.47 (m, 3 H), 7.10 (dd, J = 7.2,
2.0 Hz, 1 H).
116.6, 113.8.
2-(Pyridin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (3l)7g
13C NMR (100 MHz, CDCl3): δ = 165.1, 152.2, 130.4, 128.8, 128.5,
Yield: 75.5 mg (77%); white solid; mp 190–192 °C.
127.4, 123.6, 118.8, 117.6.
1H NMR (400 MHz, CDCl3): δ = 8.77 (d, J = 5.6 Hz, 2 H), 8.63–8.60 (m,
1 H), 8.14 (d, J = 5.6 Hz, 2 H), 7.81–7.78 (m, 1 H), 7.58–7.53 (m, 1 H),
7.07 (t, J = 6.8 Hz, 1 H).
HRMS (ESI): m/z [M]+ calcd for C12H8BrN3: 272.9902; found:
272.9905.
13C NMR (100 MHz, CDCl3): δ = 161.9, 151.7, 150.4, 138.3, 130.0,
2-Phenyl[1,2,4]triazolo[5,1-a]isoquinoline (3s)9b
128.5, 121.3, 116.8, 114.4.
Yield: 111.6 mg (91%); white solid; mp 152–153 °C.
1H NMR (400 MHz, CDCl3): δ = 8.72–8.68 (m, 1 H), 8.37–8.31 (m, 3 H),
7.81–7.78 (m, 1 H), 7.72–7.67 (m, 2 H), 7.52–7.44 (m, 3 H), 7.21 (d, J =
7.2 Hz, 1 H).
2-(Furan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (3m)
Yield: 64.8 mg (70%); white solid; mp 126–127 °C.
1H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 6.8 Hz, 1 H), 7.72 (d, J =
8.8 Hz, 1 H), 7.62 (d, J = 1.6 Hz, 1 H), 7.53–7.48 (m, 1 H), 7.21–7.19 (m,
1 H), 7.02–6.97 (m, 1 H), 6.59–6.57 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 150.3, 131.4, 131.1, 129.9,
129.8, 128.7, 128.4, 127.2, 124.6, 124.4, 122.3, 114.0.
13C NMR (100 MHz, CDCl3): δ = 157.0, 151.3, 146.2, 144.1, 129.9,
2-(p-Tolyl)-[1,2,4]triazolo[5,1-a]isoquinoline (3t)
128.4, 116.3, 113.8, 111.7, 111.3.
HRMS (ESI): m/z [M]+ calcd for C10H7N3O: 185.0589; found: 185.0587.
Yield: 114.1 mg (88%); white solid; mp 198 °C.
1H NMR (400 MHz, CDCl3): δ = 8.72–8.69 (m, 1 H), 8.33 (d, J = 7.2 Hz,
1 H), 8.23 (d, J = 8.4 Hz, 2 H), 7.83–7.78 (m, 1 H), 7.72–7.67 (m, 2 H),
7.32 (d, J = 7.6 Hz, 2 H), 7.21 (d, J = 7.2 Hz, 1 H), 2.43 (s, 3 H).
8-Methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (3n)24
13C NMR (100 MHz, CDCl3): δ = 163.4, 150.2, 139.9, 131.4, 129.8,
Yield: 70.1 mg (67%); white solid; mp 100–101 °C.
1H NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 6.4 Hz, 1 H), 8.32–8.28 (m,
2 H), 7.51–7.41 (m, 3 H), 7.17–7.15 (m, 1 H), 6.79 (t, J = 7.0 Hz, 1 H),
2.64 (s, 3 H).
129.4, 128.3, 128.2, 127.2, 127.1, 124.6, 124.5, 122.3, 113.8, 21.5.
HRMS (ESI): m/z [M]+ calcd for C17H13N3: 259.1109; found: 259.1106.
13C NMR (100 MHz, CDCl3): δ = 163.6, 152.1, 131.1, 129.9, 128.6,
Heterogeneous Copper-Catalyzed Synthesis of 1H-1,2,4-Triazoles
128.1, 127.4, 127.0, 125.8, 113.4, 17.0.
5a–j; General Procedure
A 5 mL reaction tube was charged with Phen-MCM-41-CuBr (36 mg,
0.025 mmol), amidine 4 (0.75 mmol), nitrile 2 (0.5 mmol), Cs2CO3
(489 mg, 1.5 mmol), and DMSO (1.5 mL) under an air atmosphere. The
reaction tube was sealed and placed in an oil bath at r.t. The reaction
mixture was stirred at 120 °C for 24 h. After cooling to r.t., the reac-
tion mixture was diluted with EtOAc (10 mL) and filtered. The sup-
ported copper catalyst was washed with water (2 × 5 mL) and acetone
(2 × 5 mL), and reused in the next run. The filtrate was washed with
5% aqueous NaHCO3 and brine. The organic layer was dried over Mg-
SO4 and concentrated in vacuo and the residue was purified by flash
column chromatography on silica gel (hexane/EtOAc, 3:2) to provide
the desired product 5.
7-Methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (3o)24
Yield: 84.7 mg (81%); white solid; mp 139–140 °C.
1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J = 6.8 Hz, 1 H), 8.27 (d, J =
7.6 Hz, 2 H), 7.52–7.43 (m, 4 H), 6.82 (d, J = 6.8 Hz, 1 H), 2.48 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.1, 151.9, 141.0, 130.9, 130.0,
128.7, 127.3, 116.1, 115.0, 21.6.
7-Chloro-2-phenyl[1,2,4]triazolo[1,5-a]pyridine (3p)9b
Yield: 74.6 mg (65%); white solid; mp 189–190 °C.
1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 7.2 Hz, 1 H), 8.27–8.23 (m,
2 H), 7.73 (d, J = 2.0 Hz, 1 H), 7.52–7.45 (m, 3 H), 6.96 (dd, J = 7.2,
2.0 Hz, 1 H).
3,5-Diphenyl-1H-1,2,4-triazole (5a)9f
Yield: 87.4 mg (79%); white solid; mp 190–191 °C.
13C NMR (100 MHz, CDCl3): δ = 165.3, 151.9, 136.2, 130.4, 128.8,
128.4, 127.4, 115.5, 115.1.
1H NMR (400 MHz, CDCl3): δ = 8.09–7.99 (m, 4 H), 7.49–7.38 (m, 6 H).
13C NMR (100 MHz, CD3OD): δ = 160.6, 131.1, 130.3, 130.0, 127.6.
7-Chloro-2-(p-tolyl)-[1,2,4]triazolo[1,5-a]pyridine (3q)
Yield: 81.6 mg (67%); white solid; mp 217 °C.
5-Phenyl-3-(p-tolyl)-1H-1,2,4-triazole (5b)9g
1H NMR (400 MHz, CDCl3): δ = 8.45 (dd, J = 7.2, 0.4 Hz, 1 H), 8.13 (dd,
J = 6.4, 1.6 Hz, 2 H), 7.70 (d, J = 1.6 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 2 H),
6.93 (dd, J = 7.2, 2.4 Hz, 1 H), 2.41 (s, 3 H).
Yield: 95.3 mg (81%); white solid; mp 189 °C.
1H NMR (400 MHz, DMSO-d6): δ = 14.44 (br, 1 H), 8.13–8.08 (m, 2 H),
8.02–7.96 (m, 2 H), 7.54–7.46 (m, 3 H), 7.37–7.32 (m, 2 H), 2.36 (s,
3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
J. Xia et al.
Paper
Synthesis
13C NMR (100 MHz, CD3OD): δ = 159.4, 158.9, 140.1, 129.6, 129.2,
5-(tert-Butyl)-3-(3-methoxyphenyl)-1H-1,2,4-triazole (5j)9b
128.5, 126.2, 125.8, 20.1.
Yield: 82.1 mg (71%); colorless oil.
1H NMR (400 MHz, DMSO-d6): δ = 13.65 (br, 1 H), 7.59 (d, J = 7.2 Hz,
1 H), 7.53–7.51 (m, 1 H), 7.39–7.34 (m, 1 H), 6.98–6.93 (m, 1 H), 3.82
(s, 3 H), 1.37 (s, 9 H).
4-(5-Phenyl-1H-1,2,4-triazol-3-yl)pyridine (5c)9b
Yield: 82.2 mg (74%); white solid; mp 241–242 °C.
1H NMR (400 MHz, DMSO-d6): δ = 8.73 (d, J = 5.6 Hz, 2 H), 8.10 (d, J =
8.0 Hz, 2 H), 8.01 (d, J = 6.0 Hz, 2 H), 7.60–7.53 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 165.4, 160.6, 159.9, 133.6, 130.2,
118.7, 114.8, 111.3, 55.6, 32.2, 29.5.
13C NMR (100 MHz, DMSO-d6): δ = 167.4, 150.9, 137.7, 132.0, 130.7,
129.5, 129.1, 126.7, 120.6.
3-Methyl-5-phenyl-1H-1,2,4-triazole (5k)9b
Yield: 58.5 mg (49%); white solid; mp 162–164 °C.
5-Methyl-3-p-tolyl-1H-1,2,4-triazole (5d)
1H NMR (400 MHz, CD3OD): δ = 7.87–7.83 (m, 2 H), 7.37–7.31 (m,
Yield: 69.3 mg (80%); white solid; mp 192 °C.
3 H), 2.36 (s, 3 H).
1H NMR (400 MHz, DMSO-d6): δ = 13.60 (br, 1 H), 7.89 (d, J = 8.0 Hz,
13C NMR (100 MHz, CDCl3): δ = 160.5, 156.0, 129.6, 128.8, 127.4,
2 H), 7.29–7.23 (m, 2 H), 2.40 (s, 3 H), 2.34 (s, 3 H).
126.4, 12.5.
13C NMR (100 MHz, DMSO-d6): δ = 161.4, 153.8, 138.4, 129.6, 126.1,
21.3, 12.1.
Funding Information
HRMS (ESI): m/z [M]+ calcd for C10H11N3: 173.0953; found: 173.0948.
We thank the National Natural Science Foundation of China (No.
21462021), the Natural Science Foundation of Jiangxi Province of Chi-
na (No. 20161BAB203086) and Key Laboratory of Functional Small
Organic Molecule, Ministry of Education (No. KLFS-KF-201704) for fi-
3-(4-Chlorophenyl)-5-methyl-1H-1,2,4-triazole (5e)9b
Yield: 82.3 mg (85%); white solid; mp 174–175 °C.
1H NMR (400 MHz, CD3OD): δ = 7.83 (d, J = 8.4 Hz, 2 H), 7.34 (d, J =
8.4 Hz, 2 H), 2.37 (s, 3 H).
nancial support.
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
4
6
2
0
2
1)NaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
J
i
a
n
g
x
iPro
v
i
n
c
e
of
C
h
i
n
a
(2
0
1
6
1
B
A
B
2
0
3
0
8
6)K
e
y
L
a
b
oratoryof
F
u
n
cti
o
n
a
lS
m
al Org
a
n
i
c
M
o
l
e
c
u
l
e
,
M
i
n
i
stryof
E
d
u
c
ati
o
n
(K
L
F
S-KF-2
0
1
7
0
4)
13C NMR (100 MHz, CD3OD): δ = 159.0, 155.3, 135.0, 128.5, 127.4,
10.5.
Supporting Information
3-(4-Bromophenyl)-5-methyl-1H-1,2,4-triazole (5f)9b
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611712.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
Yield: 92.8 mg (78%); white solid; mp 183–185 °C.
1H NMR (400 MHz, CD3OD): δ = 7.87 (d, J = 8.4 Hz, 2 H), 7.60 (d, J =
8.4 Hz, 2 H), 2.48 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 159.4, 155.3, 131.6, 129.2, 127.6,
References
123.2, 10.5.
(1) (a) Moulin, A.; Bibian, M.; Blayo, A.-L.; El Habnouni, S.;
Martinez, J.; Fehrentz, J.-A. Chem. Rev. 2010, 110, 1809. (b) Al-
Soud, Y. A.; Heydel, M.; Hartmann, R. W. Tetrahedron Lett. 2011,
52, 6372. (c) Kaur, R.; Dwivedi, A. R.; Kumar, B.; Kumar, V. Anti-
Cancer Agents Med. Chem. 2016, 16, 465. (d) Keri, R. S.; Patil, S.
A.; Budagumpi, S.; Nagaraja, B. M. Chem. Biol. Drug Des. 2015,
86, 410. (e) Paprocka, R.; Wiese, M.; Eljaszewicz, A.; Helmin-
Basa, A.; Gzella, A.; Modzelewska-Banachiewicz, B.;
Michalkiewicz, J. Bioorg. Med. Chem. Lett. 2015, 25, 2664.
(2) (a) Kumar, S. S.; Kavitha, H. P. Mini-Rev. Org. Chem. 2013, 10, 40.
(b) Kathiravan, M. K.; Salake, A. B.; Chothe, A. S.; Dudhe, P. B.;
Watode, R. P.; Mukta, M. S.; Gadhwe, S. Bioorg. Med. Chem. 2012,
20, 5678. (c) Lass-Florl, C. Drugs 2011, 71, 2405. (d) Plech, T.;
Luszczki, J. J.; Wujec, M.; Flieger, J.; Pizori, M. Eur. J. Med. Chem.
2013, 60, 208. (e) Holla, B. S.; Poojary, K. N.; Rao, B. S.;
Shivananda, M. K. Eur. J. Med. Chem. 2002, 37, 511.
5-Methyl-3-(3-trifluoromethylphenyl)-1H-1,2,4-triazole (5g)9b
Yield: 99.9 mg (88%); white solid; mp 170–171 °C.
1H NMR (400 MHz, CD3OD): δ = 8.30 (s, 1 H), 8.24 (d, J = 7.6 Hz, 1 H),
7.71 (d, J = 8.0 Hz, 1 H), 7.65 (t, J = 7.6 Hz, 1 H), 2.51 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 159.4, 155.2, 131.4, 130.8 (q, JC–F
2
=
=
3
1
32.2 Hz), 129.3, 129.2, 125.5 (q, JC–F = 3.7 Hz), 124.1 (q, JC–F
271.1 Hz), 122.5 (q, 3JC–F = 3.9 Hz), 10.3.
3-(4-Chlorophenyl)-5-cyclopropyl-1H-1,2,4-triazole (5h)9b
Yield: 91.2 mg (83%); white solid; mp 202–203 °C.
1H NMR (400 MHz, DMSO-d6): δ = 13.76 (br, 1 H), 7.95 (dd, J = 6.6,
1.8 Hz, 2 H), 7.50 (d, J = 8.4 Hz, 2 H), 2.13–2.01 (m, 1 H), 1.06–0.99 (m,
2 H), 0.98–0.92 (m, 2 H).
13C NMR (100 MHz, CD3OD): δ = 161.4, 135.0, 131.0, 128.8, 128.5,
127.5, 7.2, 6.9.
(3) (a) Sebeika, M. M.; Jones, G. B. Curr. Org. Synth. 2014, 11, 732.
(b) Maddila, S.; Pagadala, R.; Jonnalagadda, S. B. Lett. Org. Chem.
2013, 10, 693.
(4) (a) Haycock-Lewandowski, S. J.; Wilder, A.; Ahman, J. Org.
Process Res. Dev. 2008, 12, 1094. (b) Turner, K. Org. Process Res.
Dev. 2012, 16, 727. (c) Siddaiah, V.; Basha, G. M.; Srinuvasarao,
R.; Yadav, S. K. Catal. Lett. 2011, 141, 1511. (d) Hansen, K. B.;
Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.; Palucki, M.; Rivera,
N.; Steinhuebel, D.; Armstrong, J. D.; Askin, D.; Grabowski, E. J.
Org. Process Res. Dev. 2005, 9, 634.
5-(tert-Butyl)-3-phenyl-1H-1,2,4-triazole (5i)9b
Yield: 63.4 mg (63%); white solid; mp 145–146 °C.
1H NMR (400 MHz, CD3OD): δ = 7.98 (d, J = 6.4 Hz, 2 H), 7.47–7.40 (m,
3 H), 1.42 (s, 9 H).
13C NMR (100 MHz, CD3OD): δ = 167.3, 159.8, 129.2, 128.5, 128.3,
126.2, 32.0, 28.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

I
J. Xia et al.
Paper
Synthesis
(5) (a) Liu, K.; Shi, W.; Cheng, P. Dalton Trans. 2011, 8475. (b) Wu, P.
L.; Feng, X. J.; Tam, H. L.; Wong, M. S.; Cheah, K. W. J. Am. Chem.
Soc. 2009, 131, 886. (c) Zhang, J.-P.; Lin, Y.-Y.; Huang, X.-C.;
Chen, X.-M. J. Am. Chem. Soc. 2005, 127, 5495. (d) Klingele, M.
H.; Brooker, S. Coord. Chem. Rev. 2003, 241, 119. (e) Haasnoot, J.
G. Coord. Chem. Rev. 2000, 200, 131. (f) Tao, Y.; Wang, Q.; Ao, L.;
Zhong, C.; Yang, C.; Qin, J.; Ma, D. J. Phys. Chem. C 2010, 114, 601.
(6) (a) Yeung, K.-S.; Farkas, M. E.; Kadow, J. F.; Meanwell, N. A. Tetra-
hedron Lett. 2005, 46, 3429. (b) Yaseen, A.; Al-Soud, M. H.;
Hartmann, W. Tetrahedron Lett. 2011, 52, 6372. (c) Paulvannan,
K.; Chen, T.; Ron, H. Tetrahedron 2000, 56, 8071. (d) Reichelt, A.;
Falsey, J. R.; Rzasa, R. M.; Thiel, O. R.; Achmatowicz, M. M.;
Larsen, R. D.; Zhang, D. Org. Lett. 2010, 12, 792. (e) Wang, L. Y.;
Tsai, H. J.; Lin, H. Y.; Kaneko, K.; Cheng, F. Y.; Wong, F. F.; Huang,
J. J. RSC Adv. 2014, 4, 14215. (f) Zhang, Q.; Keenan, S. M.; Peng,
Y.; Nair, A. C.; Yu, S. J.; Howells, R. D.; Welsh, W. J. J. Med. Chem.
2006, 49, 4044. (g) Stocks, M. J.; Cheshire, D. R.; Reynolds, R. D.
Org. Lett. 2004, 6, 2969. (h) Li, Z.-H.; Wong, M. S.; Fukutani, H.;
Tao, Y. Org. Lett. 2006, 8, 4271.
(7) (a) Devine, P. N.; Volante, R. P. Org. Lett. 2003, 5, 2271. (b) Chen,
X. M.; Zhang, J. P.; Zheng, S. L.; Huang, X. C. Angew. Chem. Int. Ed.
2004, 43, 206. (c) Castanedo, G.; Seng, P. S.; Blaquiere, N.; Trapp,
S.; Staben, S. T. J. Org. Chem. 2011, 76, 1177. (d) Bechara, W. S.;
Khazhieva, I. S.; Rodriguez, E.; Charette, A. B. Org. Lett. 2015, 17,
1184. (e) Chen, Z.; Li, H.; Dong, W.; Miao, M.; Ren, H. Org. Lett.
2016, 18, 1334. (f) Song, L.; Tian, X.; Lv, Z.; Li, E.; Wu, J.; Liu, Y.;
Yu, W.; Chang, J. J. Org. Chem. 2015, 80, 7219. (g) Zheng, Z.; Ma,
S.; Tang, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem.
2014, 79, 4687. (h) Inturi, S. B.; Kalita, B.; Ahamed, A. J. Tetrahe-
dron Lett. 2016, 57, 2227. (i) Guirado, A.; Lopez-Caracena, L.;
Loppez-Sanchez, J. I.; Sandoval, J.; Vera, M.; Bautista, D.; Galvez,
J. Tetrahedron 2016, 72, 8055. (j) Wang, H.; Ren, Y.; Wang, K.;
Man, Y.; Xiang, Y.; Li, N.; Tang, B. Chem. Commun. 2017, 53,
9644.
2008, 14, 6713. (c) Lipshutz, B. H.; Taft, B. R. Angew. Chem. Int.
Ed. 2006, 45, 8235. (d) Wang, D.; Etienne, L.; Echeverria, M.;
Moya, S.; Astruc, D. Chem. Eur. J. 2014, 20, 4047.
(11) (a) Wu, Q.; Wang, L. Synthesis 2008, 2007. (b) Zhang, L.; Li, P.;
Wang, L. Lett. Org. Chem. 2006, 3, 282. (c) Xiao, R.; Yao, R.; Cai,
M. Eur. J. Org. Chem. 2012, 4178. (d) Zhao, H.; Huang, B.; Wu, Y.;
Cai, M. J. Organomet. Chem. 2015, 797, 21.
(12) (a) Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079.
(b) Benyahya, S.; Monnier, F.; Taillefer, M.; Chi Man, M. W.; Bied,
C.; Ouazzan, F. Adv. Synth. Catal. 2008, 350, 2205. (c) Benyahya,
S.; Monnier, F.; Chi Man, M. W.; Bied, C.; Ouazzan, F.; Taillefer,
M. Green Chem. 2009, 11, 1121. (d) Phan, N. T. S.; Nguyen, T. T.;
Nguyen, V. T.; Nguyen, K. D. ChemCatChem 2013, 5, 2374.
(e) Chouhan, G.; Wang, D.; Alper, H. Chem. Commun. 2007, 4809.
(f) Zhao, H.; He, W.; Yao, R.; Cai, M. Adv. Synth. Catal. 2014, 356,
3092. (g) Magne, V.; Garnier, T.; Danel, M.; Pale, P.; Chassaing, S.
Org. Lett. 2015, 17, 4494. (h) Zhao, H.; He, W.; Wei, L.; Cai, M.
Catal. Sci. Technol. 2016, 6, 1488.
(13) Meng, X.; Yu, C.; Zhao, P. RSC Adv. 2014, 4, 8612.
(14) (a) Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C.; Beck,
J. S. Nature 1992, 359, 710. (b) Corma, A. Top. Catal. 1997, 4, 249.
(c) Martin-Aranda, R. M.; Cejka, J. Top. Catal. 2010, 53, 141.
(15) Shylesh, S.; Schunemann, V.; Thiel, W. R. Angew. Chem. Int. Ed.
2010, 49, 3428.
(16) (a) Mehnert, P. C.; Weaver, D. W.; Ying, J. Y. J. Am. Chem. Soc.
1998, 120, 12289. (b) Mukhopadhyay, K.; Sarkar, B. R.;
Chaudhari, R. V. J. Am. Chem. Soc. 2002, 124, 9692. (c) Cai, M.;
Zheng, G.; Ding, G. Green Chem. 2009, 11, 1687. (d) Cai, M.;
Peng, J.; Hao, W.; Ding, G. Green Chem. 2011, 13, 190. (e) Havasi,
F.; Ghorbani-Choghamarani, A.; Nikpour, F. New J. Chem. 2015,
39, 6504. (f) Hao, W.; Liu, H.; Yin, L.; Cai, M. J. Org. Chem. 2016,
81, 4244.
(17) Shyu, S.-G.; Cheng, S.-W.; Tzou, D.-L. Chem. Commun. 1999,
2337.
(8) (a) Kuang, J.; Chen, B.; Ma, S. Org. Chem. Front. 2014, 1, 186.
(b) Neuhaus, W. C.; Moura-Letts, G. Tetrahedron Lett. 2016, 57,
4974.
(18) (a) Nunes, C. D.; Valente, A. A.; Pillinger, M.; Fernandes, A. C.;
Romao, C. C.; Rocha, J.; Goncalves, I. S. J. Mater. Chem. 2002, 12,
1735. (b) Jia, M.; Seifert, A.; Thiel, W. R. Chem. Mater. 2003, 15,
2174.
(19) (a) Corma, A.; Gutierrez-Puebla, E.; Iglesias, M.; Monge, A.;
Perez-Ferreras, S.; Sanchez, F. Adv. Synth. Catal. 2006, 348, 1899.
(b) Villaverde, G.; Corma, A.; Iglesias, M.; Sanchez, F. ACS Catal.
2012, 2, 399. (c) Yang, W.; Zhang, R.; Yi, F.; Cai, M. J. Org. Chem.
2017, 82, 5204.
(20) (a) Lin, Y.; Cai, M.; Fang, Z.; Zhao, H. RSC Adv. 2016, 6, 85186.
(b) Lin, Y.; Cai, M.; Fang, Z.; Zhao, H. RSC Adv. 2017, 7, 34722.
(21) Li, M.-J.; Chen, Z.; Wing-Wah Yam, V.; Zu, Y. ACS Nano 2008, 2,
905.
(9) (a) Kauffmann, T.; Albrecht, J.; Berger, D.; Legler, J. Angew. Chem.
Int. Ed. Engl. 1967, 6, 633. (b) Ueda, S.; Nagasawa, H. J. Am. Chem.
Soc. 2009, 131, 15080. (c) Li, Z.; Zhang, Z.; Zhang, W.; Liu, Q.;
Liu, T.; Zhang, G. Synlett 2013, 24, 2735. (d) Xu, H.; Jiang, Y.; Fu,
H. Synlett 2013, 24, 125. (e) Sudheendran, K.; Schmidt, D.; Frey,
W.; Conrad, J.; Beifuss, U. Tetrahedron 2014, 70, 1635. (f) Xu, H.;
Ma, S.; Xu, Y.; Bian, L.; Ding, T.; Fang, X.; Zhang, W.; Ren, Y. J.
Org. Chem. 2015, 80, 1789. (g) Wang, F.; You, Q.; Wu, C.; Min, D.;
Shi, T.; Kong, Y.; Zhang, W. RSC Adv. 2015, 5, 78422. (h) Guru, M.
M.; Punniyamurthy, T. J. Org. Chem. 2012, 77, 5063.
(10) (a) Girard, C.; Onen, E.; Aufort, M.; Beauviere, S.; Samson, E.;
Herscovici, J. Org. Lett. 2006, 8, 1689. (b) Chassaing, S.; Sido, A. S.
S.; Alix, A.; Kumarraja, M.; Pale, P.; Sommer, J. Chem. Eur. J.
(22) Demko, Z. P.; Sharpless, B. K. J. Org. Chem. 2001, 66, 7945.
(23) Lempers, H. E. B.; Sheldon, R. A. J. Catal. 1998, 175, 62.
(24) Zhang, G.; Hu, Y. J. Heterocycl. Chem. 2007, 44, 919.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I