Highly active binuclear Cu(II) catalyst bearing an unsymmetrical bipyridine-pyrazole-amine ligand for the azide-alkyne cycloaddition reaction

Article abstract of DOI:10.1016/S1872-2067(15)61121-4

Ligands containing NH groups often show special characteristics. In this paper, a well-defined dinuclear Cu(II) complex bearing an unsymmetrical bipyridine-pyrazole-amine ligand was synthesized by the condensation of N–H to release H₂O. Using sodium L-ascorbate as a reductant, the binuclear complex showed excellent activity in 1,3-dipolar cycloaddition reactions between alkynes and azides to obtain 1,4-disubstituted triazoles in 95%–99% isolated yields.

Full text of DOI:10.1016/S1872-2067(15)61121-4

Chinese Journal of Catalysis 37 (2016) 1446–1450
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Communication
Highly active binuclear Cu(II) catalyst bearing an unsymmetrical
bipyridine‐pyrazole‐amine ligand for the azide‐alkyne cycloaddition
reaction
Baofeng Han, Xiao Xiao, Lan Wang, Wenjing Ye*, Xiaoping Liu#
Key Laboratory of Structure‐Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, Liaoning,
China
A R T I C L E I N F O
A B S T R A C T
Article history:
Ligands containing NH groups often show special characteristics. In this paper, a well‐defined dinu‐
clear Cu(II) complex bearing an unsymmetrical bipyridine‐pyrazole‐amine ligand was synthesized
by the condensation of N–H to release H2O. Using sodium L‐ascorbate as a reductant, the binuclear
complex showed excellent activity in 1,3‐dipolar cycloaddition reactions between alkynes and az‐
ides to obtain 1,4‐disubstituted triazoles in 95%–99% isolated yields.
Received 12 March 2016
Accepted 18 April 2016
Published 5 September 2016
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Keywords:
N‐heterocycle ligand
Cu complex
Published by Elsevier B.V. All rights reserved.
1,3‐Dipolar cycloaddition
Alkynes
Azides
The Cu(I)‐catalyzed Huisgen 1,3‐dipolar cycloaddition reac‐
tion between alkynes and azides (CuAAC) for constructing tri‐
azole cycles, which was independently reported by Sharpless et
al. [1] and Meldal et al. [2] in 2002, represents the most effi‐
cient essence of “click chemistry” proposed by Sharpless et al.
[3] in 2001. This reaction has been widely applied in medicinal,
bioorganic, and materials chemistry, as well as many other
areas of research over the last decade [4,5]. Although the
CuSO4/sodium ascorbate system is still the most frequently
used method, numerous efficient catalysts have been devel‐
oped for improving the present reaction conditions [6]. For
example, the use of ligands decreases the amount of Cu catalyst
needed and enhances its catalytic activity owing to stabilization
of the Cu(I) center [7‒14]. Moreover, various Cu complexes,
especially Cu(I) complexes bearing different ligands such as
amines [7,8], N‐heterocycles [9‒11], N‐heterocycle carbenes
(NHCs) [12], phosphines, and phosphonites [13,14], have been
developed and have shown satisfactory results. Complexes of
other metals such as Ru [15], Ag [16], and Ln [17] can also
promote the 1,3‐dipolar cycloaddition reaction to generate
triazoles. In addition, several recyclable heterogeneous cata‐
lysts have been reported in recent years [18].
The ligands most frequently used in 1,3‐dipolar cycloaddi‐
tion reaction between alkynes and azides are symmetrical pol‐
ydentate nitrogen ligands such as tris‐(benzyltriazolylme‐
thyl)amine (TBTA) [19,20]. Recently, we found that transi‐
* Corresponding author. Tel: +86‐23‐23986403; E‐mail: yewenjing@syphu.edu.cn
# Corresponding author. Tel: +86‐23‐23986403; E‐mail: lxp19730107@163.com
This work was supported by the China Postdoctoral Science Foundation (2013M541254), the National Natural Science Foundation of China
(21502120), the Program for Innovative Research Team of the Ministry of Education and the Program for Liaoning Innovative Research Team in
University.
DOI: 10.1016/S1872‐2067(15)61121‐4 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 37, No. 9, September 2016

Baofeng Han et al. / Chinese Journal of Catalysis 37 (2016) 1446–1450
1447
Scheme 1. Ligand bearing an NH group.
tion‐metal complex catalysts with pyrazole and benzimidazole
ligands containing an NH moiety could significantly accelerate
the reaction rate [21,22]. In this paper, we synthesize a highly
active binuclear Cu catalyst bearing an unsymmetrical bipyri‐
dine‐pyrazole‐amine ligand and investigate its catalytic activity
on the 1,3‐dipolar cycloaddition reaction between alkynes and
azides. As far as we known, this is one of a few examples of the
CuAAC reaction using a binuclear Cu complex as a catalyst
[9,12,23,24]. The ligand is shown in Scheme 1.
Fig. 1. The molecular structure of 8.
The ligand was a known compound reported by Reedijk’s
group [25] and was synthesized through improved methods
(Scheme 2). Acetal 1 was treated with N,N‐dimethylformamide
dimethyl acetal under reflux and the resulting intermediate
was condensed with hydrazine hydrate to produce pyrazole 2
[26]. Pyrazole 2 was deprotected using acetic acid (AcOH) to
yield pyrazolyl carboxaldehyde 3 [26]. Amine 6 was prepared
from aldehyde 5 and amine 4 [27]. The condensation of 3 and 6
in CH2Cl2, followed by reduction with NaBH(OAc)3 gave the
ligand 7 (HNpy2pz) [28]. With the aim of obtaining a highly
active Cu(I) complex catalyst, Cu(CH3CN)4PF6 was chosen as
the Cu precursor, which was reacted with ligand 7. To a MeOH
(10 mL) solution of ligand 7 (2.5 mmol, 0.686 g) an equimolar
amount of Cu(CH3CN)4PF6 (2.5 mmol, 0.915 g) in MeOH (40
mL) was added with stirring. The solution was stirred at room
temperature for 16 h in air. The final green solution was con‐
centrated to give a green powder. The product was recrystal‐
lized from CH3CN‐hexane‐Et2O (1:1:3) to obtain green crystals.
The crystals were collected by filtration, washed with hexane
and dried in vacuo (0.870 g, 71% yield). Crystals suitable for
X‐ray diffraction were obtained by layering hexane/Et2O over
an acetonitrile solution at 2–6 °C. HRMS: Calcd. for
deposition number CCDC 1444219. To our surprise, a binuclear
Cu(II) complex 8 was obtained instead of the designed Cu(I)
complex, whereby the Cu(I) center was oxidized to Cu(II) by air
in the presence of the NH group in the pyrazole (Eq. (1)). The
unit cell of 8 contained a dinuclear cation [Cu(Npy2pz)]22+, and

the corresponding anions were two PF6 which were omitted
for clarity (Fig. (1)). Reedijk’s group [25] had reported a similar

binuclear complex in which ClO4 was an anion instead of PF6 .
The catalytic performance of the binuclear complex 8 was
investigated and the 1,3‐dipolar cycloaddition reaction be‐
tween phenylacetylene and benzyl azide was selected as the
model reaction for exploring the optimal conditions (Table 1).
First, different solvents were screened and it was found that
MeOH was a suitable solvent. The reaction gave poor results if
water, toluene, or even CH2Cl2 were used as solvents, maybe
because of the poor solubility of catalyst 8 in them (Table 1,
entries 1–3). The catalyst loading was then screened and 0.1
mol% loading gave the highest yield of 99% after 16 h (Table 1,
Table 1

C32H32Cu2F6N10P1 [M–PF6 ]+: 827.1045; Found: 827.1040. The
Cycloaddition reaction between phenylacetylene and benzyl azide.
N
N
X‐ray crystallographic files, in CIF format, are available from
the Cambridge crystallographic data center upon quoting the
Cat.
N
N3
+
L-Ascorbate Na
solvent
1a
3a
2a
N2, 25 o
C
NaAsc
(mol%)
Isolated
yield (%)
Entry
Cat. (mol%)
Solvent Time (h)
1
2
3
4
5
6
7
8 (0.1)
8 (2)
1
10
1
1
1
CH2Cl2
toluene
H2O
MeOH
MeOH
MeOH
MeOH
16
16
16
16
12
12
16
6
52
17
99
96
8 (0.1)
8 (0.1)
8 (0.1)
8 (0.05)
8 (2)
Scheme 2. Synthesis of tripodal N4 ligand 7. (i) a. N,N‐dimethylforma‐
mide dimethyl acetal, reflux, 3 h; b. NH2NH2·H2O, 40 ºC, 18 h, 61% for
two steps. (ii) AcOH/H2O (1:4), 0 ºC, 9 h, 53%. (iii) NaBH4, MeOH, rt,
overnight, 73%. (iv) NaBH(OAc)3 (3.0 eq.), CH2Cl2, rt, 48 h, 51%.
1
—
34
trace
Reaction conditions: phenylacetylene 1.0 mmol, benzyl azide 1.0 mmol,
solvents 1.5 mL, N2, 25 °C.

1448
Baofeng Han et al. / Chinese Journal of Catalysis 37 (2016) 1446–1450
entry 4). The Cu(II) complex‐8‐catalyzed 1,3‐dipolar cycloaddi‐
tion reaction between phenylacetylene and benzyl azide did
not work in the absence of sodium L‐ascorbate (Table 1, entry
7). This was consistent with the reported results that Cu(I) was
the real active catalyst [5]. Moreover, to avoid the oxidation of
the Cu(I) catalyst by air, the cycloaddition reaction should be
performed under a N2 atmosphere. A reaction in air did not
give the expected 1,4‐diphenyl triazole product.
Next, the CuAAC reactions between various alkynes (1a–q)
and benzyl azide (2a) were explored under the optimal condi‐
tions (Table 2). Phenylacetylene, 3‐fluorophenyl, 4‐chloro‐
phenyl, and n‐hexyl acetylene substrates showed the highest
reactivity. At 0.1 mol% catalyst loading, their corresponding
triazoles were obtained in more than 99% yields (Table 2, en‐
tries 1, 3, 6, and 16). Using 0.2 mol% of catalyst, the other
halogeno‐ and methyl‐phenylacetylene substrates gave the
products in more than 95% yields (Table 2, entries 2, 4, 5, and
7–9). The electron‐rich alkyne needed a higher catalyst loading
of 0.3 mol%, which gave a 99% yield (Table 2, entry 10). The
heterocycle alkynes also showed excellent reactivity, giving
99% and 97% yields (Table 2, entries 11 and 12). We were
pleased that the catalytic activity was not affected by the hy‐
droxyls on the substrate. The reaction of propargyl alcohol with
benzyl azide produced the corresponding 1,4‐disubstituted
triazole in 96% yield (Table 2, entry 13). Both alcohol 1n and
the ester 1o gave 99% yields but they needed a 0.3‐mol% cata‐
Table 2
The Cu catalyzed 1,3‐dipolar cycloaddition reaction of various alkynes.
Isolated
yield (%)
Isolated
yield (%)
Entry
1a
Alkyne
Product
Entry
10b
Alkyne
Product
N
N
N
N
N
N
99
99
1a
1j
MeO
MeO
3a
3j
N
N
N
N
N
F
F
N
2
96
>99
97
11
99
97
N
1k
N
1b
3b
3k
N
N
N
N
N
N
F
F
F
3a
12
S
S
1c
1l
3c
N
3l
N
N
N
N
N
N
N
HO
HO
4
13
96
1d
1m
1n
1o
1p
F
3d
3m
N
N
N
N
Cl
Cl
N
HO
HO
5
>99
>99
95
14b
15b
16a
17b,c
99
1e
3e
3n
N
N
N
N
N
N
N
N
N
N
EtO
EtO
6a
99
O
1f
O
Cl
Cl
3f
3o
N
N
N
N
n-Hexyl
t-Bu
n-Hexyl
t-Bu
7
>99
97
1g
1h
1i
Br
Br
3g
N
3p
N
N
N
Me
Me
8
98
1q
3h
N
3q
N
9
>99
Me
Me
3i
Reaction conditions: alkynes 1.0 mmol, benzyl azide 1.0 mmol, Cat. 8 (0.2 mol%), sodium L‐ascorbate 2 mol%, MeOH 1.5 mL, N2, 25 °C, 16 h.
a Cat. 8 0.1 mol%, sodium L‐ascorbate 1 mol%. b Cat. 8 0.3 mol%, sodium L‐ascorbate 3 mol%. c 1q is 1.2 mmol.

Baofeng Han et al. / Chinese Journal of Catalysis 37 (2016) 1446–1450
1449
Scheme 4. Cycloaddition reaction between trimethylsilylacetylene and benzyl azide.
SiMe3‐deprotection reaction in which they needed a base addi‐
tive such as K2CO3.
In conclusion, a binuclear Cu(II) complex bearing an un‐
symmetrical bipyridine‐pyrazole‐amine ligand was synthesized
from a Cu(I) precursor in air. The complex was an excellent
catalyst in the CuAAC reaction between alkynes and azides; at a
catalyst loading of 0.1–0.3 mol% all of the 1,4‐disubstituted
triazoles were obtained in isolated yields above 95%.
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Graphical Abstract
Chin. J. Catal., 2016, 37: 1446–1450 doi: 10.1016/S1872‐2067(15)61121‐4
Highly active binuclear Cu(II) catalyst bearing an unsymmetrical
bipyridine‐pyrazole‐amine ligand for the azide‐alkyne cycloaddition
reaction
Baofeng Han, Xiao Xiao, Lan Wang, Wenjing Ye*, Xiaoping Liu*
Shenyang Pharmaceutical University
Binuclear Cu(II) complex bearing an unsymmetrical bipyridine‐pyra‐
zole‐amine ligand was synthesized. The complex was an excellent catalyst in
the CuAAC reaction. At 0.1–0.3 mol% catalyst loading all the 1,4‐disubstitut‐
ed triazoles were obtained in 95–99% isolated yields.

1450
Baofeng Han et al. / Chinese Journal of Catalysis 37 (2016) 1446–1450
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