Copper-catalyzed synthesis of 1,2,4-triazoles via sequential coupling and aerobic oxidative dehydrogenation of amidines

Article abstract of DOI:10.1055/s-0032-1317692

A convenient, efficient, and practical copper-catalyzed one-pot method for the synthesis of 1,2,4-triazoles has been developed via reactions of amidines. The procedure underwent sequential base-promoted intermolecular coupling (nucleophilic substitution) between two amidines and intramolecular aerobic oxidative dehydrogenation, and the inexpensive, convenient, and efficient method for the synthesis of 1,2,4-triazoles will attract much attention in academic and industrial research. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317692

LETTER
▌125
lCettoerpper-Catalyzed Synthesis of 1,2,4-Triazoles via Sequential Coupling and
Aerobic Oxidative Dehydrogenation of Amidines
Synthesis of 1,2,4-Triazoles
Hao Xu,a,b Yuyang Jiang,c Hua Fu*a,c
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
b
School of Chemistry and Chemical Engineering, Henan University, Kaifeng 475001, P. R. of China
c
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057,
P. R.of China
Received: 09.10.2012; Accepted after revision: 31.10.2012
azoles via sequential coupling and aerobic oxidative
Abstract: A convenient, efficient, and practical copper-catalyzed
dehydrogenation of amidines.
one-pot method for the synthesis of 1,2,4-triazoles has been devel-
oped via reactions of amidines. The procedure underwent sequential
base-promoted intermolecular coupling (nucleophilic substitution)
between two amidines and intramolecular aerobic oxidative dehy-
drogenation, and the inexpensive, convenient, and efficient method
for the synthesis of 1,2,4-triazoles will attract much attention in ac-
ademic and industrial research.
Reaction of benzamidine hydrochloride (1a) with cyclo-
propanecarboxamidine hydrochloride (1i) was used as the
model to optimize reaction conditions including the cata-
lysts, bases, solvents, temperature, and reaction time. As
shown in Table 1, the copper-catalyzed one-pot synthesis
of 3-cyclopropyl-5-phenyl-1H-1,2,4-triazole (2i) under-
went sequential two-step procedures: intermolecular cou-
pling (nucleophilic substitution) between two amidines
and intramolecular aerobic oxidative dehydrogenation.
The first-step coupling was performed at 120 °C for
24 hours under N2 atmosphere, and the second step, the
intramolecular formation of the N–N bond, was carried
out at 120 °C for 24 hours under O2. In order to prevent
homogeneous coupling of benzamidine hydrochloride
(1a; we found that aromatic amidines easily self-coupled),
1a was added (3 × 0.25 mmol) every eight hours. Seven
copper catalysts (0.1 equiv) were screened by using two
equivalents of Cs2CO3 as the base (relative to amount of
1i), and DMSO as the solvent (Table 1, entries 1–7), and
Cu powder exhibited the highest activity (Table 1, entry
7). Only trace amount of target product was observed in
the absence of copper catalyst (Table 1, entry 8). Other
bases were determined (Table 1, entries 9–12), and they
were inferior to Cs2CO3 (compare entries 7, 9–12, Table
1). Affect of solvents was also investigated (compare en-
tries 7, 13–15, Table 1), and DMSO provided the highest
efficiency. We attempted different temperature (Table 1,
entries 16 and 17), and 120 °C was suitable (Table 1, com-
pare entries 7, 16, and 17). The second step, the aerobic
oxidative dehydrogenation, was elongated to 48 hours,
and a higher yield was afforded (Table 1, entry 18). When
the one-pot, two-step reaction was performed under N2
(Table 1, entry 19) or air (Table 1, entry 20), lower yields
were provided. We changed amount of 1a (Table 1,
entries 21 and 22), and the results showed that four equiv-
alents of 1a (1a was added by ratio of 2:1:1) gave 2i in
72% yield (Table 1, entry 22).
Key words: copper, aerobic oxidative, dehydrogenation, amidines,
1,2,4-triazoles
Nitrogen heterocycles occur widely in various natural
products and biologically active molecules.1 The 1,2,4-tri-
azole derivatives are widely used in medicinal chemistry,
materials science, and organocatalysis, and their synthesis
has attracted much attention.2 The common methods are
from intramolecular cyclizations of N-acylamidorazones
that are prepared via couplings of hydrazines and carbox-
ylic acid derivatives,3 but they often provide 1,2,4-tri-
azoles in low yields. Therefore, it is highly desired to
develop a simple and practical approach to 1,2,4-triazole
derivatives. Recently, transition-metal-catalyzed aerobic
oxidative formation of bonds is a focal field,4 and some ni-
trogen heterocycles, such as benzimidazoles,5 carba-
zoles,6 indazoles,7 N-methoxylactams,8 and indolines,9
have been prepared via the aerobic oxidative strategy, in
which expensive palladium-, rhodium-, and ruthenium-
based catalysts are often necessary. During the past few
years, there have been excellent progress in copper-cata-
lyzed cross-couplings with inexpensive and low toxic
copper-catalysts, and wide application with good func-
tional tolerance has been explored.10,11 Recently, several
efficient copper-catalyzed aerobic oxidative methods for
the synthesis of nitrogen heterocycles have been devel-
oped by us12 and other groups.13 Nagasawa and coworkers
have developed an efficient copper-catalyzed synthesis of
1,2,4-triazole derivatives via coupling of amidines with
nitriles.14 Herein, we report a novel, convenient, and effi-
cient copper-catalyzed one-pot synthesis of 1,2,4-tri-
With the optimum reaction conditions in hand, the scope
of the copper-catalyzed one-pot synthesis of 1,2,4-tri-
azoles was investigated. As shown in Table 2, the exam-
ined substrates provided moderate to good yields.
Aromatic amidines self-coupled to give homogeneous
SYNLETT 2013, 24, 0125–0129
Advanced online publication: 04.12.2012
DOI: 10.1055/s-0032-1317692; Art ID: ST-2012-W0864-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

126
H. Xu et al.
LETTER
Table 1 Copper-Catalyzed One-Pot Synthesis of 3-Cyclopropyl-5-
phenyl-1H-1,2,4-triazole (2i) via Reaction of Benzamidine Hydro-
chloride (1a) with Cyclopropanecarboxamidine Hydrochloride (1i):
Optimization of Conditionsa (continued)
products (Table 2, entries 1–5). Heterogeneous reactions
of aromatic amidines with aliphatic amidines were also
performed well (Table 2, entries 6–19), but aromatic am-
idines were required to add to the system (3×) by the ratio
(2:1:1) every eight hours in order to prevent self-reaction
of the aromatic amidines. In the copper-catalyzed reac-
tion, no ligand or additive was needed. The reactions
could tolerate some functional groups including C–Cl
bond (Table 2, entries 3, 14–16), nitro (Table 2, entry 4),
and N-heterocycle (Table 2, entries 5, 17–19) in the sub-
strates.
(1) cat., base,
solvent, temp,
T-1, N2
NH2•HCl
NH2•HCl
N
+
N
HN
(2) temp, T-2, O2
N
NH
H
1a
1i
2i
O2
N
NH
Table 1 Copper-Catalyzed One-Pot Synthesis of 3-Cyclopropyl-5-
phenyl-1H-1,2,4-triazole (2i) via Reaction of Benzamidine Hydro-
chloride (1a) with Cyclopropanecarboxamidine Hydrochloride (1i):
Optimization of Conditionsa
NH3
H2O
NH2
I-1
Entry Catalyst
Base
Solvent
Temp T-1 (h)/ Yield
(°C)
(1) cat., base,
solvent, temp,
T-1, N2
T-2 (h) (%)b
NH2•HCl
NH2•HCl
N
21
22
Cu
Cu
Cs2CO3
Cs2CO3
DMSO
DMSO
120
120
24/48
24/48
64e
72f
+
N
HN
(2) temp, T-2, O2
N
NH
H
1a
1i
2i
a Reaction conditions: benzamidine hydrochloride (1a, 3 × 0.25
mmol) was added (3×) every 8 h, cyclopropanecarboxamidine hydro-
chloride (1i, 0.5 mmol), catalyst (0.1 mmol), base (2 mmol), solvent
(1.5 mL), under nitrogen atmosphere for the first step, under oxygen
balloon (1 bar) for the second step.
O2
N
NH
NH3
H2O
NH2
b Isolated yield.
I-1
c Under O2 for the two steps.
d Under air for the two steps.
Entry Catalyst
Base
Solvent
Temp T-1 (h)/ Yield
e Conditions: 1a (3 × 0.5 mmol) and Cs2CO3 (2.5 mmol) were added
(3×) every 8 h.
(°C)
T-2 (h) (%)b
f Conditions: 1a (1 mmol+2 × 0.5 mmol) and Cs2CO3 (3.0 mmol) were
added (3×) every 8 h.
1
2
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
120
120
120
120
120
120
120
120
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/24
24/48
72
31
38
38
33
27
21
44
trace
17
CuBr
CuCl
Cu2O
CuO
Table 2 Copper-Catalyzed One-Pot Synthesis of 1,2,4-Triazoles via
Sequential Coupling and Aerobic Oxidative Dehydrogenation of
Amidinesa
3
4
R2
(1) Cu, Cs2CO3, DMSO
120 °C, 24 h, N2
5
N
NH2⋅HCl
NH2⋅HCl
R1
+
R1
6
Cu(OAc)2 Cs2CO3
N
HN
R2
N
(2) 120 °C, 48 h, O2
NH
H
7
Cu
–
Cs2CO3
Cs2CO3
NaOAc
K2CO3
K3PO4
1
1
2
8
Entry
1
R1
1
R2
2
Yield
(%)b
9
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
10
11
12
13
14
15
16
17
18
19
20
35
34
28
5
1
2
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
Ph
1a
1b
1c
1d
1e
1f
Ph
2a
2b
2c
2d
2e
2f
62
61
60
64
53
80
45c
40c
72
49
4-MeC6H4
4-ClC6H4
3-O2NC6H4
4-pyridyl
Ph
4-MeC6H4
4-ClC6H4
3-O2NC6H4
4-pyridyl
Me
KOt-Bu DMSO
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dioxane
o-xylene 120
4
34
42
trace
38
52
28c
41d
5
DMF
120
90
6
DMSO
DMSO
DMSO
DMSO
DMSO
7
Ph
1g
1h
1i
Et
2g
2h
2i
140
120
120
120
8
Ph
n-Pr
9
Ph
c-Pr
10
Ph
1j
t-Bu
2j
72
Synlett 2013, 24, 125–129
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,2,4-Triazoles
127
Table 2 Copper-Catalyzed One-Pot Synthesis of 1,2,4-Triazoles via
Sequential Coupling and Aerobic Oxidative Dehydrogenation of
Amidinesa (continued)
The synthesized N-[amino(m-tolyl)methylene]-4-methyl-
benzamidine was treated in the presence of Cu powder un-
der O2, and the target product 2b was provided in 68%
yield (Scheme 1, ii). Therefore, a possible mechanism for
the synthesis of 1,2,4-triazoles is proposed in Scheme 2.
Amidine hydrochlorides transformed into free amidines
in the presence of base (Cs2CO3), and intermolecular nu-
cleophilic attack of amino in one amidine to carbon in an-
other one leads to intermediate I. Treatment of I with
copper in the presence of O2 provides Cu(III) complex II
(the similar metal complexes have been reported in the
previous literature15), and reductive elimination of II af-
fords the target product (2)14 leaving Cu(I) complex III.
Further, reaction of III with I regenerates II, and the tar-
get product 216 continuously is provided in the catalytic
cycle.
R2
(1) Cu, Cs2CO3, DMSO
120 °C, 24 h, N2
N
NH2⋅HCl
NH2⋅HCl
R1
+
R1
N
HN
R2
N
(2) 120 °C, 48 h, O2
NH
H
1
1
2
Entry
1
R1
1
R2
2
Yield
(%)b
11
12
13
14
15
16
17
18
19
1b
1b
1b
1c
1c
1c
1e
1e
1e
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-pyridyl
4-pyridyl
4-pyridyl
1f
1g
1i
1f
1i
1j
1f
1i
1j
Me
2k
2l
85
42c
91
75
78
51
70
84
86
Et
c-Pr
Me
2m
2n
2o
2p
2q
2r
2s
In summary, we have developed a convenient, efficient,
and practical copper-catalyzed one-pot method for the
synthesis of 1,2,4-triazoles. The protocol uses readily
available substituted amidines as the starting materials, in-
expensive Cu powder as the catalyst, and economical and
environment friendly oxygen as the oxidant, and the cor-
responding 1,2,4-triazoles were obtained in moderate to
good yields. The procedure underwent sequential base-
promoted intermolecular coupling (nucleophilic substitu-
tion) between two amidines and intramolecular aerobic
oxidative dehydrogenation, and the inexpensive, conve-
nient, and efficient method for the synthesis of 1,2,4-tri-
azoles will attract much attention in academic and
industrial researches because of the wide application of
these compounds in various fields.
c-Pr
t-Bu
Me
c-Pr
t-Bu
a Reaction conditions: amidine-1 + amidine-2 (1.0 mmol) for entries
1–5, amidine-1 (2.0 mmol) for entries 6–19 [added (3×: 1 mmol + 2×
0.5 mmol) every 8 h], amidine-2 (0.5 mmol) for entries 6–19, Cu
powder (0.1 mmol), Cs2CO3 (1.5 mmol for entries 1–5; 3.0 mol for
entries 6–19), DMSO (1.5 mL), reaction temperature (120 °C), reac-
tion time (24 h for the first step; 48 h for the second step), under ni-
trogen atmosphere for the first step, under oxygen balloon (1 bar) for
the second step.
b Isolated yield.
c Conditions: 0.5 mL t-BuOH were added.
Acknowledgment
We explored the reaction mechanism for the synthesis of The authors wish to thank the National Natural Science Foundation
of China (Grant Nos. 20972083 and 21172128), and the Ministry of
Science and Technology of China (Grant No. 2012CB722605) for
financial support.
1,2,4-triazoles. As shown in Scheme 1, treatment of 4-
methylbenzamidine hydrochloride (1b) was first carried
out in the presence of Cs2CO3 in DMSO under N2 (no ad-
dition of Cu powder), and N-[amino(m-tolyl)methylene]-
4-methylbenzamidine (I-2) was obtained in 44% yield (I-
2 was purified by recrystallization which led to the loss of
some product because of its high polarity, Scheme 1, i).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
NH2⋅HCl
Cs2CO3, DMSO
120 °C, 24 h, N2
N
(i)
NH
NH2 NH
1b
I-2 (44% yield)
Cu, DMSO
N
N
(ii)
120 °C, 48 h, O2
N
N
NH2 NH
H
I-2
2b (68% yield)
Scheme 1 (i) Treatment of 4-methylbenzamidine hydrochloride (1b) in the presence of Cs2CO3 in DMSO under N2 leading to N-[amino(3-
tolyl)methylene]-4-methylbenzamidine (I-2); (ii) copper-catalyzed aerobic oxidation of I-2 leading to 2b in the presence of Cu powder under O2
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 125–129

128
H. Xu et al.
LETTER
R1
N
R2
NH2•HCl
NH
Cu
NH2•HCl
NH2
NH
base
NH3
base
R1
+
R1
H2N
R2
NH2 NH
HN
R2
NH
I
H
N
R1
R2
N
NH
R2
Cu, base, O2
H2O
I, base, O2
N
N
II
R1
Cu
N
H
III
R2
N
H2O
NH
N
R1
R1
N
R2
N
H
N
H
II
2
Scheme 2 Possible mechanism for synthesis of 1,2,4-triazoles
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(16) General Procedure for the Synthesis of Compounds 2a–s
A 10 mL Schlenk tube was charged with a magnetic stirrer
and DMSO (1.5 mL). For entries 1–5 in Table 2, aromatic
amidine (1 mmol), Cu powder (0.1 mmol, 6.4 mg), and
Cs2CO3 (2 mmol, 489 mg) were added to the tube. The
mixture was stirred at 120 °C for 24 h under nitrogen
atmosphere, and then the nitrogen atmosphere was changed
into oxygen atmosphere (other conditions were kept). The
following aerobic oxidative intramolecular formation of N–
N bond was carried out at 120 °C for 48 h. The resulting
mixture was cooled to r.t. and filtered, and the solid was
washed with EtOAc (3 × 3 mL). The combined filtrate was
concentrated by a rotary evaporator, and the residue was
purified by column chromatography on silica gel using PE–
EtOAc as eluent to give the desired target product. For
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Synlett 2013, 24, 125–129
© Georg Thieme Verlag Stuttgart · New York

LETTER
aliphatic amidine (0.5 mmol), Cu powder (0.1 mmol, 6.4
Synthesis of 1,2,4-Triazoles
129
3-(4-Chlorophenyl)-5-cyclopropyl-4H-1,2,4-triazole
mg), and Cs2CO3 (3.0 mmol, 978 mg) were added to the
tube. The mixture was stirred at 120 °C under nitrogen
atmosphere, and additional aromatic amidine (2 × 0.5 mmol)
was added to the resulting solution after 8 h and 16 h,
respectively. The reaction was performed for a total 24 h
under nitrogen atmosphere, and then the nitrogen
atmosphere was changed into oxygen atmosphere (other
conditions were kept). The following aerobic oxidative
intramolecular formation of N–N bond was carried out at
120 °C for 48 h. The workup procedure was similar to that
of entries 1–5 in Table 2. Data for three representative
examples are given here.
(2o)14
Eluent: PE–EtOAc (6:1); yield 85 mg (78%); white solid;
mp 203–205 °C (lit.14 mp 202–203 °C). 1H NMR (600 MHz,
DMSO-d6): δ = 13.71 (s, 1 H), 7.91 (d, 2 H, J = 8.9 Hz),
7.57–7.40 (m, 2 H), 2.09–1.96 (m, 1 H), 1.06–0.80 (m, 4 H).
13C NMR (150 MHz, DMSO-d6): δ = 160.2, 160.1, 133.7,
131.0, 129.2, 127.9, 8.6, 7.5. ESI-MS: m/z = 220.2 [M + H]+;
m/z = 242.0 [M + Na]+.
4-(5-Methyl-4H-1,2,4-triazol-3-yl)pyridine (2q)17
Eluent: PE–EtOAc (4:1); yield 56 mg (70%); white solid;
mp 104–106 °C (lit.17 mp 207–209 °C). 1H NMR (600 MHz,
DMSO-d6): δ = 13.94 (s, 1 H), 8.81–8.55 (m, 2 H), 7.91 (d,
2 H, J = 3.4 Hz), 2.44 (s, 3 H). 13C NMR (150 MHz, DMSO-
d6): δ = 159.4, 154.8, 150.8, 139.1, 120.5, 12.2. ESI-MS: m/z
= 161.2 [M + H]+; m/z = 183.1 [M + Na]+.
3-Methyl-5-phenyl-4H-1,2,4-triazole (2f)14
Eluent: PE–EtOAc (1:1); yield 64 mg (80%); white solid;
mp 163–165 °C (lit.14 mp 163–165 °C). 1H NMR (600 MHz,
DMSO-d6): δ = 13.75 (s, 1 H), 7.95 (d, 2 H, J = 7.56 Hz),
7.44–7.33 (m, 3 H), 2.35 (s, 3 H). 13C NMR (150 MHz,
DMSO-d6): δ = 160.8, 154.3, 131.7, 129.3, 129.1, 126.2,
126.1, 12.5. ESI-MS: m/z = 160.3 [M + H]+; m/z = 182.2 [M + Na]+.
(17) Lipinski, C. A.; Lamattina, J. L.; Oates, P. J. J. Med. Chem.
1986, 29, 2154.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 125–129

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