Copper-mediated sequential C-N and N-N bond formation: Facile synthesis of symmetrical 1,2,4-triazoles

Article abstract of DOI:10.1055/s-0033-1338985

Via a one-pot process, catalyzed by Cu(OAc)₂, a series of 3,5-disubstituted 4H-1,2,4-triazoles was conveniently and efficiently synthesized by using low-toxicity, stable, readily available, inexpensive amidine hydrochloride. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338985

LETTER
▌2735
lCettoerpper-Mediated Sequential C–N and N–N Bond Formation: Facile Synthesis
of Symmetrical 1,2,4-Triazoles
1,2,4-Triazole Synthesis
Zhonglian Li, Zhiguo Zhang,* Wei Zhang, Qingfeng Liu, Tongxin Liu, Guisheng Zhang*
Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang, Henan 453007, P. R. of China
Fax +86(373)3325250; E-mail: zhangzg@htu.edu.cn; E-mail: zgs6668@yahoo.com
Received: 26.06.2013; Accepted after revision: 09.09.2013
just when we prepared this manuscript, Fu et al. also re-
Abstract: Via a one-pot process, catalyzed by Cu(OAc)2, a series
ported a similar strategy of dimerization of amidines for
of 3,5-disubstituted 4H-1,2,4-triazoles was conveniently and effi-
the synthesis of the DHT via sequential intermolecular
ciently synthesized by using low-toxicity, stable, readily available,
coupling and intramolecular aerobic oxidative dehydroge-
nation.12 In this paper, we describe our recent effort to the
symmetrical 1,2,4-triazole derivatives during which an
anaerobic cascade reaction of deamination and N–N bond
coupling by using amidine hydrochloride in the presence
of copper took place.
inexpensive amidine hydrochloride.
Key words: 1,2,4-triazoles, copper, amidine hydrochloride, N–N
bond coupling, de-amine reaction
1,2,4-Triazole-containing compounds are widely used in
pesticides,1 plant growth regulators,2 medicines3 (such as
some well-known triazole fungicides), dyes,4 metal com-
plexes,5 industrial additives, and functional materials.6
They are also important intermediates in organic synthe-
sis. As an important part of the triazole family, 3,5-disub-
stituted 4H-1,2,4-triazoles (DHTs) have attracted much
attention over the past decades. A number of reports have
discussed the certain efficient method for the DHTs syn-
thesis. Among them, two of the most extensively used
methods for the preparation of DHTs involved the intra-
and intermolecular cyclization of acyclic nitrogen-con-
taining amidine and/or hydrazine derivatives7 and the re-
arrangement reaction of the five- and six-membered
cyclic nitrogen-containing compounds8 under acid-cata-
lyzed (Brønsted acid or Lewis acid)9 and/or alkali-cata-
lyzed conditions (pyridine, hydrazine hydrate, sodium
hydroxide, potassium carbonate, etc.).3,10 However, the
cases of the transition-metal-catalyzed DHTs synthesis
were relatively rare.5,7a Here are several worthy of men-
tioning examples of Cu-catalyzed reactions: Chen et al.
prepared two interesting CuI-DHT coordination polymers
by an unprecedented copper-mediated cycloaddition of
nitriles and ammonia at 160 °C in three days, in which the
CuII not only acted as a catalyst but also as a coordination
center of the metal complexes.5 Another CuI-catalyzed
oxidative synthesis of DHT derivatives was reported by
Nagasawa’s group in 2009. Via a procedure of initial am-
idine C–N formation followed by intramolecular oxida-
tive N–N bond formation, they achieved the catalytic
cycle by using molecular oxygen as the oxidant.7a In 2005,
Chen et al. disclosed that one-pot solvothermal treatments
of organonitriles, ammonia and CuII salts yielded CuI and
DHTs. The mechanism was confirmed by several crystals
of isolated copper complex intermediate.11 Very recently,
Relying on the features of multiple oxidation states, cop-
per catalysts are widely used in redox reactions, non-re-
dox reactions, single electron transfer processes and
synergistic catalysis13 to construct the carbon–carbon
bond, carbon–heteroatom bond and heteroatom–heteroat-
om bond formation.14 Combined with our recent research
for the direct synthesis of heterocyclic compounds from
acyclic acetoacetamides precursors,15 we used benzimid-
amide 1a as the model for the dimerization. The screening
of the reaction conditions (Table 1) showed that 3,5-di-
phenyl-4H-1,2,4-triazole 2a can be finally obtained in
86% yield by treating 1a (1.0 mmol) with Cu(OAc)2 (0.2
mmol), K2CO3 (2.0 mmol), 1,10-phenanthroline (Phen,
0.1 mmol) in anhydrous DMF (2.0 mL) under an inert at-
mosphere at 130 °C for 24 hours (entry 3). It resulted in a
slightly lower yield of 2a when the reactions were per-
formed at lower temperature at 110 °C (1a was recovered
in 14% yield) or when the amount of the Cu(OAc)2 was
increased or decreased (entries 1, 2 and 4). The lack of any
catalytic components, ligand, copper salt or alkali, also
dramatically affected the yield of 2a (entries 5–7). Direct
use of commercially available DMF as the solvent, under
the conditions of nitrogen protection or open-air, led to a
competitive yield in comparison to the optimal conditions
(entry 3 vs. entries 8 and 9). Additionally, we considered
that the reaction mixture contains chloride ions, so CuCl2
was also tested for this dimerization; as a result, a slightly
lower yield (83%) was obtained (entry 10). We then per-
formed the reaction in the presence of CuI, which also
gave a slightly lower yield of 2a (entry 11).16
NH
N
K2CO3 (2.0 equiv)
NH2 ⋅HCl
DMF (anhyd), N2 balloon
R
R
130 °C, 4.0 h
1s: R = NH2
1t: R = OH
3a: 92%
3b: 94%
SYNLETT 2013, 24, 2735–2739
Advanced online publication: 28.10.2013
DOI: 10.1055/s-0033-1338985; Art ID: ST-2013-W0590-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Scheme 1 4-Amino-/hydroxybenzimidamide intramolecular elimi-
nation of ammonia

2736
Z. Li et al.
LETTER
Table 1 Survey of Reaction Conditionsa
yields (compounds 2b–2d and 2g–2i). Additionally, as an
extension of this dimerization approach, some prepared
compounds, such as 2l, could be used in further function-
alization reactions of the Ullmann reaction, Castro–
Stephens coupling, Kumada coupling, Heck reaction etc.
and 2m could be widely used in nitrogen-containing com-
pounds synthesis, especially after Béchamp reduction.17
Surprisingly, the reaction was almost completely shut
down when aliphatic acetimidamide hydrochloride 1o
was employed for the screening, even using stronger base
(such as Cs2CO3) or higher temperature (such as 145 °C or
reflux). We deduced that the most likely reason may be
due to the low reactivity of 1o. So, we added the benzam-
idine to the reaction mixture in batches under the standard
conditions. As a result, we got a cross-coupling product
3-methyl-5-phenyl-4H-1,2,4-triazole (2p) in the yield of
68% after 48 hours. Surprisingly, it failed to provide the
desired cross-coupling products 2q and 2r when cyclo-
propylcarbamidine hydrochloride (1q) and 2,2,2-trimeth-
ylacetamidine hydrochloride (1r) were used. These
results exhibited the limitation of this method and also it
indicated that the current optimal conditions were too
mild to fit the aliphatic amidine derivatives to self-dimer-
ize.
N
N
NH
metal, base
Ph
Ph
N
Ph
NH2⋅HCl
1a
ligand, solvent, temp
H
2a
Entry Catalyst
(equiv)
Base
Ligand Time
(h)
Yield
(%)b
1
Cu(OAc)2 (0.1)
Cu(OAc)2 (0.2)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
Phen
Phen
Phen
Phen
Phen
Phen
–
24
24
24
24
24
24
32
24
24
24
24
72
75c
86
72
0d
2
3
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.3)
–
4
5
6
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
CuCl2 (0.2)
46
72
78e
74f
83
82
7
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
Phen
Phen
Phen
Phen
9
10
11
CuI (0.2)
Inspired by compound 2m, we intended to introduce the
amino or hydroxyl group directly to DHTs. Unexpectedly,
under the optimal conditions, the reaction only provided
benzonitrile derivatives 3a (80%) and 3b (86%) undergo-
ing an intramolecular elimination of ammonia process
rather than an intermolecular dimerization to DHTs 2
when 4-aminobenzimidamide (1s) and 4-hydroxybenz-
imidamide (1t) were used as the models (Table 1, entry 3).
And the yields of them could be further improved to 92%
a Unless otherwise indicated, all reactions were carried out with 1a
(1.0 mmol), base (2.0 equiv), ligand (0.1 equiv) and DMF (2.0 mL) at
130 °C under dry nitrogen.
b Isolated yield.
c Reaction was carried out at 110 °C and 14% 1a was recovered.
d Compound 1a (95%) was recovered.
e Reaction was performed in commercially available DMF in N2.
f Reaction was carried out in the open air, and commercially available
DMF was used directly as the solvent.
The optimal conditions for this dimerization were finally
identified as Cu(OAc)2 (0.2 mmol), K2CO3 (2.0 mmol),
Phen (0.1 mmol) in anhydrous DMF (2.0 mL) in N2 atmo-
sphere at 130 °C (Table 1, entry 3). Consequently, we test-
ed the universality of this dimerization of acetoacetamides
under the optimal conditions by using aryl-substituted
amidine hydrochloride (Table 2). Notably, a variety of
substrates 1a–n could be easily converted into the corre-
sponding DHTs 2a–n in moderate to good yields (41–
90%). Various electron-donating groups (EDG) substitu-
ent (Me, OMe, OEt; compounds 2b–f) and electron-with-
drawing groups (EWG) substituent (F, Cl, Br, CF3 NO2;
compounds 2g–n) on the aryl group were completely tol-
erated in the current transformation, including unsubsti-
tuted benzene ring (compound 2a). However, the position
of the substituents on the aryl group (para, meta and ortho
position) affected the yields of 2 dramatically, and para-
and meta-substituted substrates gave relatively higher
Cu(OAc)2
2
Phen
N
N
N
II
Cu
N
N
H
C
R
R
N
N
II
– NH3
Cu
AcO OAc
A
N
N
II
1
Cu
N
N
R
R
NH2 H2N
B
Scheme 3 A plausible mechanism
Cu, DMSO
Cs2CO3, DMSO
N
N
NH
120 °C, O2, 48 h
120 °C, N2, 24 h
NH
N
NH2 NH
NH2⋅HCl
1b
4b (44%)
2b (68%)
Scheme 2 The work of Fu et al.
Synlett 2013, 24, 2735–2739
© Georg Thieme Verlag Stuttgart · New York

LETTER
1,2,4-Triazole Synthesis
2737
and 94% in the presence of K2CO3, respectively,16 as (Table 1, entry 4). We deduced the proposed mechanism
shown in Scheme 1. It is well known that benzonitriles according to the conditions screened in Table 1 together
could be constructed via an intramolecular elimination of with some previous literature results. In a simplified, gen-
ammonia of aryl amidines,18 but so far it is very rare to erally accepted mechanistic model (Scheme 3), amidine 1
achieve such transformation in the presence of the unpro- initially reacts with copper(II) complexes7a,20 A to gener-
tected amino or hydroxyl group.19
ate the chain copper–ammonia 1:2 complexes transition
state B under alkaline conditions. Then, B affords a six-
membered metallacycle species C via an intramolecular
ammonia elimination.11,21 Subsequently, the product
DHTs 2 is generated in a manner of direct N–N bond for-
mation,22 and simultaneously, the copper complexes de-
part into the next coming catalytic cycle.
Fu et al. demonstrated that the intermediate N-[amino(p-
tolyl)methylene]-4-methylbenzimidamide (4b) could be
obtained in a yield of 44% by treatment of 4-methyl-
benzamidine hydrochloride (1b) with Cs2CO3 in DMSO
under N2, then the target product 2b was provided in 68%
yield when 4b was treated in the presence of Cu powder
under O2 (Scheme 2).12 But for our strategy, any interme- In summary, we have developed a convenient method for
diates, as direct evidence for the mechanism of the self- the synthesis of symmetrical 1,2,4-triazole via dimeriza-
condensation, were not isolated in the control experiments tion of amidine hydrochloride in the presence of
of quenching the reaction in two hours (Table 1, entry 3) Cu(OAc)2.23 Although the mechanism of this reaction
or performing the reaction at slightly lower temperature cannot explain why the aliphatic-substituted amidine hy-
Table 2 Self-Assembly of Amidine Hydrochloride 1a,b
Cu(OAc)2 (0.2 equiv)
NH
N
N
K2CO3 (2.0 equiv)
R
R
R
NH2
⋅HCl
N
H
2
Phen (0.1 equiv)
DMF, N2, 130 °C
1
N
N
N
N
N
N
N
H
N
N
H
H
2a, 24 h, 86%
2b, 24 h, 90%
2c, 48 h, 77%
OEt
N
EtO
N
N
N
N
N
MeO
OMe
N
H
N
H
N
H
2d, 36 h, 53% c)
2f, 24 h, 41% c
2e, 24 h, 67%
N
N
N
N
N
N
F
F
N
N
N
H
H
H
F
F
F
F
2g, 24 h, 83%
2h, 24 h, 82%
2i, 24 h, 52%c
N
N
N
N
N N
F3C
CF3
N
H
N
N
H
H
Cl
Cl
Br
Br
2l, 24 h, 72%
2j, 24 h, 80%
2k, 24 h, 78%
N
N
F3C
CF3
N
N
N
N
N
H
N
H
N
O2N
NO2
H
F3C
CF3
2o, 48 h, trace
2m, 24 h, 85%
2n, 24 h, 75%
N
N
N
N
N
N
N
N
N
H
H
H
2p, 48 h, 68%
2q, 48 h, 0%
2r, 48 h, 0%
a All reactions were carried out with amidine hydrochloride 1 (1.0 mmol), Cu(OAc)2 (0.2 mmol), K2CO3 (2.0 mmol), Phen (0.1 mmol) in DMF
(2.0 mL) in N2 atmosphere at 130 °C, unless otherwise indicated.
b Isolated yield.
c Some unidentified mixture was obtained simultaneously.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2735–2739

2738
Z. Li et al.
LETTER
(16) See the Supporting Information for more information.
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(b) Rosenberg, M. G.; Brinker, U. H. J. Org. Chem. 2003,
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449.
drochloride 1 did not work well, as an optional method for
the symmetrical 1,2,4-triazole synthesis, the process
avoided using the carcinogenic hydrazine24 and volatile
reactants such as ammonia used in the traditional meth-
ods.
Acknowledgment
(19) Ashley, J. N.; Barber, H. J.; Ewins, A. J.; Newbery, G.; Self,
A. D. H. J. Chem. Soc. 1942, 103.
We thank the NSFC (21002051, 21172056, 21302044 and
21272057), PCSIRT (IRT1061), the China Postdoctoral Science
Foundation funded project (2012M521397, 2013T60701 and
2013M530339), and the Key Project of Henan Educational Com-
mittee (13A150546) for financial support of this research.
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6421.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(21) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem.
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(23) General Procedure for the Synthesis of Compounds
2a–o: To a round-bottom flask (25 mL) equipped with a
spherical condenser (40 cm length) were added amidine
hydrochloride 1 (1.0 mmol), Cu(OAc)2 (0.2 equiv), K2CO3
(2.0 equiv), 1,10-phenanthroline (0.1 equiv) and anhyd
DMF (2.0 mL). Then the mixture was well stirred at 130 °C
under an inert atmosphere. After cooling off, the mixture
was filtered through a pad of celite eluting with CH2Cl2 (3 ×
6 mL). The volatiles were removed under reduced pressure
and the residue was purified by a short flash silica gel
column chromatography to give compound 2. 2a: white
solid; eluent: petroleum ether–EtOAc (3:1). Yield: 86%; mp
191–192 °C. 1H NMR (400 MHz, CD3OD): δ = 8.05 (d, J =
6.4 Hz, 4 H), 7.41–7.49 (m, 6 H). 13C NMR (100 MHz,
CD3OD): δ = 160.53, 131.02, 130.17, 129.89, 127.56.
HRMS (ESI): m/z [M + H]+ calcd for C14H11N3: 222.1026;
found: 222.1026.
General Procedure for the Synthesis of Compounds 2p:
To a round-bottom flask (25 mL) equipped with a spherical
condenser (40 cm length) were added acetimidamide
hydrochloride 1p (94.5 mg, 1.0 mmol), benzimidamide
hydrochloride 1a (0.5 equiv), Cu(OAc)2 (37 mg, 0.2 mmol),
K2CO3 (276 mg, 2.0 mmol), 1,10-phenanthroline (20 mg,
0.1 mmol) and anhyd DMF (2.0 mL). Then the mixture was
well stirred at 130 °C under an inert atmosphere. The other
two batches of benzimidamide hydrochloride 1a (0.5 equiv
for each) were added to the mixture every 8.0 h. After 48 h
(total reaction time), the reaction mixture was cooled,
filtered through a pad of celite eluting with CH2Cl2 (3 × 6
mL). The volatiles were removed under reduced pressure
and the residue was purified by short flash silica gel column
chromatography to give compound 2p as a white solid;
eluent: petroleum ether–EtOAc (2:1). Yield: 68%; mp 161–
163 °C. 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 6.0 Hz,
2 H), 7.44 (d, J = 6.0 Hz, 3 H), 2.53 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 161.04, 155.71, 130.08, 129.73, 128.89,
126.44, 12.81. HRMS (ESI): m/z [M + H]+ calcd for C9H9N3:
160.0869; found: 160.0874.
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General Procedure for the Synthesis of Compounds 3a,b:
To a round-bottom flask (25 mL) equipped with a spherical
condenser (40 cm length) were added amidine hydrochloride
1s or 1t (1.0 mmol), Cu(OAc)2 (0.2 equiv), K2CO3 (2.0
equiv), 1,10-phenanthroline (0.1 equiv) and anhyd DMF
Synlett 2013, 24, 2735–2739
© Georg Thieme Verlag Stuttgart · New York

LETTER
(2.0 mL). Then the mixture was well stirred at 130 °C under
1,2,4-Triazole Synthesis
2739
CDCl3): δ = 7.35 (d, J = 8.8 Hz, 2 H), 6.62 (d, J = 8.4 Hz, 2
H), 4.28 (s, 2 H). 13C NMR (100 MHz, CDCl3): δ = 150.80,
133.67, 120.41, 114.33, 99.30. 3b: white solid; yield: 86%;
mp 110–113 °C. 1H NMR (400 MHz, CDCl3): δ = 7.55 (d,
J = 8.8 Hz, 2 H), 6.95 (d, J = 8.8 Hz, 2 H). 13C NMR (100
MHz, CDCl3): δ = 160.57, 134.47, 119.42, 116.63, 102.80.
(24) Toth, B. In Vivo 2000, 14, 299.
an inert atmosphere. After cooling off, the mixture was
filtered through a pad of celite eluting with CH2Cl2 (3 × 6
mL). The volatiles were removed under reduced pressure
and the residue was purified by a short flash silica gel
column chromatography to give compound 3a or 3b. 3a:
yellow solid; yield: 80%; mp 81–83 °C. 1H NMR (400 MHz,
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2735–2739

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