A highly efficient synthesis of N-glycosyl-1,2,3-triazoles using a recyclable cellulose-copper(0) catalyst in water

Article abstract of DOI:10.1016/j.catcom.2016.02.015

Cellulose supported copper(0) was used as a highly active heterogeneous catalyst to synthesize N-glycosyl-1,2,3-triazoles from glycosyl azides and alkynes. Cellulose-Cu(0) catalysed the cycloaddition reaction to produce the corresponding products in good

Full text of DOI:10.1016/j.catcom.2016.02.015

A highly efficient synthesis of N-glycosyl-1,2,3-triazoles using a recyclable
cellulose-copper(0) catalyst in water
Wenbo Yu, Luxia Jiang, Chao Shen, Weiming Xu, Pengfei Zhang
PII:
DOI:
Reference:
S1566-7367(16)30062-0
doi: 10.1016/j.catcom.2016.02.015
CATCOM 4597
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
15 September 2015
14 February 2016
17 February 2016
Please cite this article as: Wenbo Yu, Luxia Jiang, Chao Shen, Weiming Xu,
Pengfei Zhang, A highly efficient synthesis of N-glycosyl-1,2,3-triazoles using a re-
cyclable cellulose-copper(0) catalyst in water, Catalysis Communications (2016), doi:
1
0.1016/j.catcom.2016.02.015
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ACCEPTED MANUSCRIPT
A highly efficient synthesis of N-glycosyl-1,2,3-triazoles using a
recyclable cellulose-copper (0) catalyst in water
a, b
b
c
b
b,*
Wenbo Yu , Luxia Jiang , Chao Shen , Weiming Xu and Pengfei Zhang
a
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
3
10014, China
b
College of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 310016, China
c
College of Biology and Environmental Engineering, Zhejiang Shuren University,
Hangzhou 310015, China
Abstract:
Cellulose supported copper (0) was used as a highly active heterogeneous catalyst
to synthesize N-glycosyl-1,2,3-triazoles from glycosyl azides and alkynes.
Cellulose-Cu(0) catalysed the cycloaddition reaction to produce the corresponding
products in good to excellent yields in water. This heterogeneous catalyst has the
advantages of high catalytic reactivity and low copper leaching. The separation and
reuse of the catalyst are easy and efficient.
Corresponding author Tel.: +86 571 28862867; fax: +86 571 28862867.
E-mail address: chxyzpf@hotmail.com.

ACCEPTED MANUSCRIPT
1
. Introduction
The Cu (I)-catalysed azide-alkyne cycloaddition (CuAAC) to generate
,2,3-triazoles has been one of the most desired examples of click chemistry, which
1
was proposed in 2001 by Sharpless and co-workers [1-3]. The applications of this
approach have dramatically increased in different areas, such as drug discovery [4],
material science [5] and chemical biology [6]. Cu(I) salts in the presence of a base or
Cu(II) salts that are coupled with reducing agents are commonly used catalyst systems
for this reaction. Despite many obvious advantages, the CuAAC reaction has a
non-ignorable limitation: there is a significant amount of toxic, coloured, and
expensive copper complexes, which are difficult to remove from the end products [7].
Immobilizing the copper catalyst on a heterogeneous support is one of the main
strategies to circumvent the aforementioned problems [7]. Therefore, various
heterogeneous supports have been applied to immobile types of copper catalysts to
improve this click-type reaction, such as organic polymers [8], zeolites [9], charcoal
[
[
10-11], alumina [12], silica [13], magnetic materials [14] and polysaccharides
15-16]. In particular, supported copper nanoparticles can make the reaction more
efficient [17]. Among these supports, polysaccharides have obvious advantages for
environment-friendly chemistry because they are abundant in nature, biodegradable,
and nontoxic. Cellulose is the most common polysaccharide, and the use of cellulose
as a metal-supported material for catalytic reactions has been explored in some cases
[
18-21]. However, the application of this heterogeneous catalyst in click chemistry,
particularly for specific substrates, such as drug, sugar, and so on, requires further
improvement.
Click chemistry is also a powerful tool for carbohydrate drug development [22].
N-glycosyl-1,2,3,-triazole derivatives, which are prepared from easily available
glycosyl azides and alkynes by the CuAAC reaction, exhibit various activities [23-24].
Our group has synthesized a series of glucosyl triazoles in a CuSO and sodium
4
ascorbate system [25]. However, when this method was used to synthesize other
glycosyl triazoles, such as arabinosyl derivatives, the yield was not satisfactory. In
fact, because of the complexities of the carbohydrate configurations, the conditions of

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the CuAAC reaction for diverse glycosyl azides and alkynes are not always moderate.
In several cases, the reaction has high temperatures, a long reaction time and a low
yield [22, 26-27]. To our surprise, there are few reports on the development or
application of the new catalytic method to synthesize glycosyl triazoles [28-29].
Continuing our longstanding interest in catalysis and carbohydrate chemistry
[
30-31], herein, we describe an efficient and recyclable catalytic system for the
CuAAC reaction using a cellulose-supported Cu(0) catalyst (cellulose-Cu(0)) and its
application in the synthesis of N-glycosyl triazoles.
2
Experimental
2
.1. Materials
Microcrystalline cellulose was purchased from J&K Scientific (Shanghai, China).
Cu(NO ) ·3H O, and sugars and alkynes were purchased from Aladdin Reagent
3
2
2
(Shanghai, China). Other chemicals were commercially obtained and used without
prior purification.
2
.2. Catalyst preparation
Microcrystalline cellulose (5 g) was suspended in 50 mL of water. To this
suspension, 1.0 g of Cu(NO ) ·3H O was added and stirred for 15 min. Then,
3
2
2
hydrazine hydrate (80%, 1.5 mL) was slowly added dropwise to the above reaction
mixture under continuous stirring for 12 h at room temperature. The catalyst was
filtered in a nitrogen atmosphere, washed several times with distilled water and
acetone and dried in vacuum at 50 °C [18].
2
.3. Characterization
ICP-AES metal determinations were performed using a Perkin-Elmer Optima
100 XL inductively coupled plasma atomic emission spectrometer. X-ray
3
photoelectron spectrographs (XPS) were recorded using an ESCALAB-250Xi
instrument. The melting points were recorded using a X5-Data microscopic melting
1
13
point apparatus. H NMR and C NMR spectra were recorded using a Bruker
Advance 500 spectrometer at ambient temperature. GC-MS and ESI-HRMS were
acquired using Agilent 5975 and Agilent 1290-6530 UPLC-Q-TOF spectrometers.
Transmission electron microscopy (TEM) images were taken using a FEI T20

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microscope.
.4. Synthesis of 2,3,4-tri-O-acetyl-α-L-arabinopyranosyl azide
,2,3,4-Tetra-O-acetyl-α/β-L-arabinopyranose (16.24 g, 50 mmol), 125 mL of
CH Cl and 5.5 mL of water were added to a flask with an ice-water bath. Then,
2
1
2
2
phosphorus tribromide (21.87 g, 80 mmol) was slowly dropped into the mixture while
o
stirring. The reaction was performed at 0 C for 12 h and monitored using TLC
(petroleum ether- ethyl acetate=2:1). After the reaction completed, the reaction
solution was diluted with 250 mL of CH Cl . The organic layer was washed with cold
2
2
water (250 mL×2), saturated with NaHCO (250 mL×2), and brined. Then, the
3
organic phase was dried with Mg SO , filtered and evaporated under reduced pressure
2
4
to generate 2,3,4-tri-O-acetyl-α-L-arabinopyranosyl bromide (crude product). The
crude residue was purified by recrystallization from diethyl ether, and white
needle-like crystals were obtained (12 g, 70% yield).
A mixture of 2,3,4-tri-O-acetyl-α-L-arabinopyranosyl bromide (16.96 g, 50 mmol),
sodium azide (6.5 g, 10 mmol), Tetrabutylammonium hydrogen sulphate (TBAHS,
2
.55 g, 7.5 mmol, 1 M aq Na CO (300 mL) and CH Cl (250 mL) was stirred in a
2 3 2 2
round bottomed flask for 2 h. The reaction was monitored using TLC (petroleum
ether- ethyl acetate=3:1). After the reaction completes, the solution was poured into a
beaker containing CH Cl (250 mL), stirred and separated. The organic layer was
2
2
washed with water (250 mL×3) and brine (250 mL). The aqueous phase was extracted
with CH Cl (50 mL×3). The combined organic layers were dried (MgSO ) and
2
2
4
filtered and the solvent was evaporated under reduced pressure to yield crude
,3,4-tri-O-acetyl-α-L-arabinopyranosyl azide. A white solid (16 g) was obtained by
recrystallization using EtOH in an 85% yield.
2
2
.5. General experimental procedure to synthesize N-glycosyl triazoles
Azide (1.0 mmol) and alkyne (1.0 mmol) were suspended in 1.0 mL of water, and
the cellulose-Cu(0) catalyst (137 mg, 0.730 mmol copper per gram, 10 mol %) was
o
added. The reaction was performed at 60 C and monitored using the thin-layer
chromatographic technique. After the reaction completed, the mixture was allowed to
cool to room temperature. Then, the reaction mixture was filtered, and the filter was

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subsequently washed with ethyl acetate (3×5 mL). The organic extracts were
combined, washed with water and dried over MgSO . The solvent was removed, and
4
further purification was performed using column chromatography.
2
.6. Catalyst recycling experiment
The reactions were performed for 12 h. After the post treatment process of the
reaction, the catalyst was recovered, washed with water and acetone twice, and dried
in vacuum for 3 h at 50 °C. Then, it was reused for the next cycle.
3
. Results and discussion
3
.1. Catalyst synthesis and characterization
Cellulose-Cu(0) was prepared following the method reported by Reddy’s group
[
18]. To characterize the cellulose-Cu(0) catalyst, we studied the oxidation state of the
Cu of the catalyst using XPS (Fig. 1 A). The binding energy of Cu 2p3/2 showed a
peak at 932.68 eV, which is typically attributed to Cu(0) [18]. The TEM analysis
shows that the average diameter of the copper nanoparticles was approximately 5-10
nm and that the dispersion of Cu particles on the cellulose support was good (Fig. 2).
ICP-AES analysis was applied to measure the copper-loading levels of the prepared
catalyst, which shows the presence of 0.730 mmol of copper per gram.
Fig.1
Fig.2
3
.2. Synthesis and characterization of glycosyl azides
Scheme 1
After preparing and characterizing the cellulose-Cu(0) catalyst, we focused on
evaluating the catalyst reactivity for the catalysing synthesis of N-glycosyl triazoles
Scheme 1 A). First, we synthesized glycosyl azides as the corresponding substrate.
(
According to the reported method [32], β-glucopyranosyl azide 1b-1c was obtained
through treatments of compound 4b-4c with TMSN /SnCl (Scheme 1 C). However,
3
4
when we used this method to synthesize arabinopyranosyl azide, a new challenge
emerged. The pure desired product α-L-arabinopyranosyl azide could not be obtained
1
through recrystallization or chromatography. The H NMR spectrum of the

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arabinopyranosyl azide that was obtained through this synthesis route showed impure
signals that always accompanied the pure ones (see supplementary information). To
solve this problem, another reported synthesis route [33] was used (Scheme 1 B), and
the results were satisfying. O-acetyl-α-L-arabinopyranosyl azide 1a was prepared
from per-O-acetyl-L-arabinose 4a through bromination and a substituted reaction of
azide, and the single configuration product was obtained with recrystallization. The
1
impure signals disappeared in the H NMR analysis of 1a, and the value of the vicinal
coupling constant of the anomeric proton (J=7.96) confirmed the α-configuration of
1
a (see supporting information) [34].
3
.3. Catalytic studies
In our previous studies, we found that the coupling of CuSO with the reducing
4
agent Na-ascorbate, which is one of the most commonly used catalytic systems for
CuAAC, did not efficiently catalyse the reaction of O-acetyl-α-L-arabinopyranosyl
azide 1a and phenyl acetylene 2a: only a 54% yield of the arabinopyranosyl triazole
3
a was obtained after a 24-hour reaction (Table 1, entry 10). Hence, the cycloaddition
of 1a and 2b was performed as a model reaction to test the catalytic activities of the
prepared cellulose-Cu(0) catalyst. First, the model reaction was accomplished in
different media with 10% mol of cellulose-Cu(0) at room temperature, and the results
were encouraging (Table 1, entries 1-6). Compared with the typical catalyst (Table 1,
entry 10), cellulose-Cu(0) performed well in all of the selected solvents, among which
acetonitrile was the most appropriate reaction media for the model reaction. Water is
the ideal environmentally friendly reaction solvent, but cellulose-Cu(0) was less
efficient in water than in other organic solvents, such as dichloromethane and
acetonitrile. In consideration of green-chemistry, we attempted to improve the
catalytic activity of cellulose-Cu(0) in water and found that when the temperature
reached 60 °C, a satisfactory yield of the desired product was obtained (Table 1, entry
7
). In addition, only a small quantity of the product was obtained when cellulose and
CuI or Cu(NO ) were added in situ (Table 1, entry 8-9).
3
2
Table 1

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To study the effect of catalyst loading, three parallel reactions were performed
with 1 mol %, 5 mol %, and 10 mol % cellulose-Cu(0) loading. The yields of 3a were
detected using GC-MS after 3, 6, 12, and 24 hours. The study reveals that reducing
the amount of cellulose-Cu(0) causes a decrease in product yields (Fig. 3). However, a
long reaction time can minimize the negative effect of the low catalyst dosage. An
excellent yield can be obtained using only 1 mol % catalyst after a 24-hour reaction.
Fig.3
To further investigate the scope of the cycloaddition reactions catalysed by
cellulose-Cu(0), we performed the reactions with different glycosyl azides and
terminal alkynes under the optimized reaction conditions (water as the solvent, 10
mol% of cellulose-Cu(0) as the catalyst, and completing the reaction at 60 °C in 12 h).
The results are summarized in Table 2. The results show that this method has a good
compatibility for various substituted glycosyl azides. The reaction of α-L-
arabinopyranosyl azide and β- D-glucopyranosyl azides with phenyl acetylene had a
similarly good yield (Table 2, entries 1, 6 and 11). Different phenyl-acetylene-bearing
groups smoothly reacted with glycosyl azides to afford the corresponding products in
good to high yields. The electronic effect of phenyl acetylene on the reaction was not
evident (Table 2, entries 1-3, 6-8 and 11-13). We also used 3-butyn-1-ol as an
aliphatic reactant and obtained a favourable result (Table 2, entries 4, 9 and 14). The
heterocycle-substituted compound, which was 2-pyridyl acetylene, afforded the
corresponding products (3e, 3j and 3o) in excellent yields (92%-94%).
Table 2
Recoverability and reusability are important indicators of the supported catalyst
evaluation. When water is used as the reaction media, both the product and the
cellulose-Cu(0) catalyst are insoluble, so after the reaction completed, the catalyst was
separated by filtration with the product and unreacted reactants. The catalyst was
sequentially washed with ethyl acetate, water and acetone, and the dried catalyst could
be used for the next cycle. There was no significant loss of catalyst in quantity. Then,
the reusability of the catalyst was examined in the cycloaddition reaction, and the
results are shown in Fig. 4. These studies indicate that cellulose-Cu(0) maintains its

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catalytic activity after five reuses. However, the yields of the fifth cycle decreased by
approximately 10 percent compared to that of the first use of the catalyst. Copper
leaching from the heterogeneous catalyst may decrease the catalyst activity. The
reaction solution of every cycle was analysed using ICP-AES, and a notably small
amount of copper ions (0.3-1.9 ppm) was detected. The results show that the copper
leaching was negligible and did not affect the catalyst activity. Thus, we speculate that
the change of the valence state of the used catalyst may be responsible for the slight
yield decrease. To verify this speculation, XPS was used to scan the spent
cellulose-Cu(0) catalyst, and two peaks at 933.28 and 934.88 eV were found (Fig. 1
B). These peaks indicate that the reused cellulose-Cu(0) contains Cu(I) and Cu(II).
The clear effect of the oxidation states of the catalyst and the catalytic activities
require further investigation.
Fig.4
Although there are many reports on the synthesis and applications of
N-glycosyl-1,2,3-triazoles, few new catalysts or methods have been applied to
synthesize glycosyl triazoles. The reported protocols to synthesize
N-glycosyl-1,2,3-triazoles are summarized in Table 3. The typical catalytic system,
which is Cu SO with Na-ascorbate or CuI with DIPEA, requires a long reaction
2
4
time or a high temperature to perform the reaction. The complex of Cu and ligands is
a more efficient catalyst for the reaction. However, considering the environmental
and economic benefits, the supported Cu catalyst has a unique advantage. Our
developed protocol is easy to operate and more efficient and adaptable than the
commonly used system to synthesize glycosyl triazoles.
Table 3
4
. Conclusion
In conclusion, we have reported a simple, efficient and eco-friendly protocol that
uses cellulose-Cu(0) as a catalyst for the heterogeneously catalysed cycloaddition
reaction of glycosyl azides with terminal alkynes to generate the corresponding
triazoles in good to excellent yields. The reaction was performed in water, and no

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external ligand or base was required. The cellulose-Cu(0) catalysts in this catalytic
system are easily recoverable and efficiently reusable.
Acknowledgments
This work was supported by the Zhejiang Provincial Natural Science Foundation of
China (No. LZ13B020001), the Major Scientific and Technological Innovation
projects of Hangzhou City (No. 20122511A43) and the Key-Sci-Tech Innovation
Team of Zhejiang Province (No. 2010R50017).
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A)
B)
Fig.1 A) XPS spectrum of the cellulose-Cu(0) catalyst B) XPS spectrum of the spent
cellulose-Cu(0) catalyst
Fig.2 TEM images of cellulose-Cu(0)

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Scheme 1 A) Cellulose-Cu(0) catalyzed the cycloaddition of glycosyl azides and terminal alkynes; B)
Synthesis of arabinopyranosyl azide; C) Synthesis of glucopyranosyl azide
Fig. 3 Influence of different cellulose-Cu(0) loading. Reaction conditions: 1a (0.5 mmol), phenyl
o
acetylene 2a (0.5 mmol), cellulose-Cu(0) ,water (1 mL), at 60 C. GC-MS yield (using n-dodecane
as an internal standard).

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Fig. 4 Recycling of the cellulose-Cu(0) in the synthesis of 3a (Table 2, entry 1). The Cu in reaction
solution for each cycle was: 0.3, 0.3, 0.7, 1.2, 1.9 ppm.

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a
Table 1 Optimization of reaction conditions
b
Entry
Catalyst (mol %)
cellulose-Cu(0) (10%)
cellulose-Cu(0) (10%)
cellulose-Cu(0) (10%)
cellulose-Cu(0) (10%)
cellulose-Cu(0) (10%)
cellulose-Cu(0) (10%)
cellulose-Cu(0) (10%)
Cu(NO ) ·3H O (10%), cellulose
Solvent
Dichloromethane
Toluene
Time (h)
10
Yield (%)
92%
1
2
3
4
5
6
7
8
9
10
89%
Ethanol
10
67%
Acetonitrile
Acetone
10
93%
10
92%
Water
10
81%
c
Water
12
93%
d
Acetonitrile
Acetonitrile
24
Trace
Trace
54 %
3
2
2
d
CuI (10%), cellulose
CuSO ·5H O, sodium ascorbate
24
1
0
t-Butanol/H O
24
4
2
2
a
Reaction conditions: O-acetyl-α-L-arabinopyranosyl azide 1a (1 mmol), phenyl acetylene 2a (1
mmol), catalyst (10 mol %), solvent(1 mL), at room temperature.
b
Isolated yield.
c
The reaction was performed at 60 °C.
d
100 mg cellulose was added.

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a
Table 2 Reaction between glycosyl azides and alkynes
Entry
Gly
R
Product
Yield(%)
93
1
3a
2
3
4
5
3b
3c
3d
3e
84
87
89
94
6
7
8
9
3f
3g
3h
3i
89
83
85
85
1
1
0
1
3j
92
90
3k

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1
1
1
1
2
3
4
5
3l
3m
3n
3o
80
85
83
94
a
Reaction conditions: O-acetyl-α-L-arabinopyranosyl azide 1a (1 mmol), phenyl acetylene 2a (1
o
mmol), cellulose-Cu(0) (10% mmol), water (1 mL), at 60 C.
b
Isolated yield.

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Table 3 Comparison of the developed protocol with other reported method in the
synthesis of glycosyl triazoles
Ref
No Glycosyl azide
.
Alkyne
Cataly Conditio Tim Yield
.
st (mol%)
ns
e
(%)
(
h)
1
glucopyranosyl
azide
phenyl acetylene
phenyl acetylene
CuSO ·5H O
H O/EtO
24
60
27
4
2
2
o
20% , sodium
ascorbate
H, 70 C
2
3
xylopyranosyl
azide
CuI 50%, iPr NEt DMF,N2,
1
80
99
26
15
2
o
100 C
glucopyranosyl 2-methylbut-3-yn-2
Functionalized
chitosan-CuI
H O/EtO
2
12
o
azide
-ol
H, 70 C
0
.1%
4
glucopyranosyl
bromide, NaN3
phenyl acetylene
Cu nanoparticles H O, 100
16
70
98
29
28
2
o
on activated
carbon 0.5%
C
5
6
arabinopyranos
yl azide
phenyl acetylene
phenyl acetylene
C H COOCu(PPh CH Cl , rt
5
3
7
2
2
3)2 1%
glycopyranosyl
azide
cellulose-Cu(0)
10%
H O, 60
12
90-9 this
2
o
C
3
wor
k
17

ACCEPTED MANUSCRIPT
Graphical abstract
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ACCEPTED MANUSCRIPT
Highlights
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Cellulose supported Cu nanoparticles were prepared as a heterogeneous catalyst.
Cellulose-Cu(0) catalyzed the reaction of glycosyl azides and alkynes efficiently.
The catalytic reaction was carried out in water without external ligands or base.
The heterogeneous catalyst was easily recoverable and efficiently reusable.
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