Cu2O acting as a robust catalyst in CuAAC reactions: Water is the required medium

Article abstract of DOI:10.1039/c0gc00848f

Cu₂O as the catalyst in water was found to be quite robust for the azide-alkyne cycloaddition (AAC) reaction, which was verified by a wide variety of applicable azides and alkynes. Water was proved to play an essential role because of a significant rate acceleration compared with reactions using organic solvents and conducted under neat conditions. The high catalytic performance of Cu₂O/H₂O system was further argued by decreasing the catalyst loading to ppm levels. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00848f

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COMMUNICATION
Cu2O acting as a robust catalyst in CuAAC reactions: water is the required
medium†
Kai Wang, Xihe Bi,* Shuangxi Xing, Peiqiu Liao, Zhongxue Fang, Xianyu Meng, Qian Zhang,* Qun Liu and
Yu Ji
Received 25th November 2010, Accepted 23rd December 2010
DOI: 10.1039/c0gc00848f
Cu2O as the catalyst in water was found to be quite
robust for the azide-alkyne cycloaddition (AAC) reaction,
which was verified by a wide variety of applicable azides
and alkynes. Water was proved to play an essential role
because of a significant rate acceleration compared with
reactions using organic solvents and conducted under neat
conditions. The high catalytic performance of Cu2O/H2O
system was further argued by decreasing the catalyst loading
to ppm levels.
catalyst for organic reactions such as coupling and cycloaddition
reactions, some of which can be performed in water,6 so we
envisaged that water might be a required medium for Cu2O-AAC
reactions. Further studies realized this hypothesis. In this con-
text, we wish to report that Cu2O as the catalyst in water is quite
robust for the CuAAC reactions, which was verified by the wide
range of applicable organic azides and alkynes. Water was proved
to play an essential role in Cu2O-AAC because a significant rate
acceleration was observed in the presence of water compared
with reactions using organic solvents and conducted under neat
conditions. The high catalytic efficiency of Cu2O/H2O system
was further argued by catalyst loadings as low as 100 part per
million (ppm) under neat conditions. A plausible mechanism
on the water-acceleration effect was also tentatively suggested.
During our preparation of this manuscript, Kong and co-
workers reported polyvinylpyrrolidone (PVP) stabilized Cu2O
nanoparticles as catalyst for the CuAAC reaction in water,
however, an additional operation for preparing the PVP-coated
Cu2O nanoparticles was required; moreover, only a limited set
of azides and alkynes were tested in their protocol.7
Initially, the survey of reaction parameters including copper
catalysts and solvents was performed using the cycloaddi-
tion of tosyl azide 1a with phenylacetylene 2a as a model
reaction, because N-sulfonyl triazoles 3 have been proved
convenient precursors of azavinyl carbenes in metal-catalyzed
transannulation,8 while only a few of procedures for their
synthesis are available to date.4b,9 Therefore it is highly desirable
to search for a simple, practical and efficient catalyst system.
As shown in Table 1, in the presence of 20 mol% lutidine,
CuI promotes the cycloaddition both in CHCl3 and in water;
without the lutidine, the full conversion can not occur in water
(entries 1–3). CuCl could result in a complete conversion with
a good yield, but would require a longer reaction time (entry
4). Other cuprous salts and complexes, and cupric compounds
showed little or no catalytic effect, similar to the situation
without catalyst (entries 5–9). To our delight, Cu2O catalyzed
this reaction in water within a very short period of time, affording
an excellent yield of 3a (entry 10). Noticeably, there was no
amide by-product formed in this process through the three-
component reactions of alkynes, sulfonyl azides and H2O as
reported by Chang et al.10 Using high purity Cu2O (99.99%)
Since the seminal discovery of the Cu(I)-catalyzed azide–alkyne
cycloaddition (CuAAC) by the groups of Sharpless and Meldal
independently, this ‘near–perfect’ bond–forming reaction has
found a myriad of applications in chemistry, biology, and materi-
als science.1 A plethora of copper catalytic systems have been uti-
lized to catalyze this transformation including the combination
of copper with other elements such as Cu(II)/sacrificial reducing
agent, Cu(0)/oxidizing agent or Cu(I)/auxiliary ligand, and
the use of Cu(I) species alone.2 Despite these catalytic systems
available, it still appeals as a more simple and practical catalyst
for this reaction. Compared with other cuprous species, Cu2O is
the most readily available and above all an inexpensive catalyst.
For a long time, the surface of Cu2O has been assumed to be
the catalytically active species in metallic Cu(0)-catalyzed AAC
reactions,3 supported by experimental evidence; for example,
the catalytic activity of metallic Cu by washing with dilute
HCl showed a dramatic drop.3a Unfortunately, reactions directly
catalyzed by Cu2O powder were usually met with incomplete
conversion and poor yields even after longer reaction times.4
Until now, the catalytic capability of Cu2O in the CuAAC
reactions has yet been thoroughly exploited because of lacking
appropriate reaction conditions.
As our continued interest in developing and applying smart
organic reactions to label biomolecules under bio-compatible
conditions,5 we noted that Cu2O has been emerging as a versatile
Department of Chemistry, Northeast Normal University, Changchun,
130024, China. E-mail: bixh507@nenu.edu.cn, zhangq651@nenu.edu.cn
† Electronic supplementary information (ESI) available: Experimental
procedures, analytical data, and spectra copies of all compounds. See
DOI: 10.1039/c0gc00848f
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Table 1 Cycloaddition of tosyl azide 1a with phenylacetylene 2a under
trizaole 3a can be detected from the reaction mixture of alkyne 1a
varying conditionsa
with tosyl azide 2a in the presence of 10 mol% Cu2O under neat
conditions in 6 h, and most starting materials were left, where
the reaction has been carried out in a glove box to minimize the
impact of water (entry 1). Once small amount of water (100 ml,
5.5 mmol) was added, the conversion quickly completed within
2.5 h, yielding 89% of 3a (entry 2), so the rate acceleration
is not simply a consequence of the increased concentration of
the reacting species. Undoubtedly, water plays a crucial role in
the Cu2O-AAC reaction. Next, we varied the amount of Cu2O
and the reaction temperature in the presence of 100 ml H2O. It
was found that a slight increase in the reaction temperature
can compensate for the decrease in reaction rate caused by
reducing the catalyst. Delightfully, a small amount (100 ppm)
of Cu2O still effectively catalyzed a complete conversion within
Entry
Cat.
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
CuIc
CHCl3
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
DMSO
CHCl3
THF
CH3OH
12
12
12
24
12
12
12
12
12
4
80
79
CuIc
CuI
45 (55)d
70
CuCl
CuBr
[(IPr)2Cu]PF6
CuCl2
CuO
trace
0
0
0
0
90
91
trace
20 (80)d
trace
trace
9
no
10
11
12
13
14
15
Cu2O
Cu2Oe
Cu2O
Cu2O
Cu2O
Cu2O
◦
12 h at 50 C, yielding 87% of 3a. This is comparable with the
3
catalytic efficiency of some Cu(I) complexes (entries 3–5).12 The
results listed in Table 4 show some of the azide-alkyne reactions
under neat conditions in the presence of a trace amount of
water (100 ml) at low Cu2O loading (100 ppm). All of reactions
proceeded smoothly, affording good to excellent yields of the
corresponding triazoles 3 and 4.
12
12
12
12
a Reactions were performed with phenylacetylene (1.2 mmol), tosyl azide
(1 mmol), and [Cu] (10 mol%) in solvent (1 mL) at room temperature.
b Isolated yields. c 20 mol% lutidine was added. d Recovery of tosyl azide
in bracket, determined by 1H NMR analysis of the crude reaction
mixture. e High purity of Cu2O (99.99%) was used.
Water appears to act as an activator for Cu2O catalyst. To gain
some insight into the activation pathway of water, we carried
out a deuterium experiment. Reaction of tosyl azide 1a with
phenylacetylene 2a in D2O offered the desired triazole 3a-D
with 92% d-incorporation at the 5-position (eqn (1)). Based on
this information as well as the results of theoretical calculation
on the reaction mechanism from other groups,2,13 we tentatively
suggested that water might actively take part in the formation
of the transion-state complex of azide and alkyne on the surface
of Cu2O, and somehow stabilize it, finally assist the reaction
by speeding up the protiolysis step that cleaves the Cu–C bond
of Cu-triazolyl intermediate, leading to the regeneration of the
catalytically active Cu(I) species.
only slightly increased the rate, thus negating the influence of
metal impurities (entry 11). In contrast, the representative polar,
nonpolar, and protonic organic solvents instead of water all gave
poor yields or trace amount of triazole 3a (entries 12–15). Water
was therefore established as an appropriate reaction medium for
efficient Cu2O-AAC reactions.11
Next, the reaction scope catalyzed by Cu2O in water was
investigated. As shown in Table 2, a wide variation of azides
and alkynes efficiently fused and produced the corresponding
N-sulfonyl triazoles 3 and N-aryl/alkyl triazoles 4 in good to
excellent yields. For the synthesis of N-sulfonyl triazoles 3, either
varying the substituent on the phenyl acetylene or using fused
aromatic alkynes did not induce appreciable changes in the reac-
tion efficiency (3b–3g). By comparison, the reaction of aliphatic
alkynes is a little slower, albeit yielding triazoles 3h–3n in good
to high yields. A range of functional groups including halo-,
cyclopropyl-, ethoxy-, amide, ether and double bonds were
well tolerated. In addition to the tosyl azide, 4-chlorophenyl,
2-naphthyl, methyl, as well as bulky camphor sulfonyl azides
were all suitable to this Cu2O-catalyzed procedure in water (3o–
3r). The chemoselective formation of triazole 4a, leaving the
sulfonyl azide intact, demonstrated a much higher reactivity for
alkyl azide. Thus, the reactions for the synthesis of N-aryl/alkyl
triazoles 4 generally proceeded much faster, and also displayed
higher functional group tolerance, for example, hydroxyl, ester,
and triethylsilyl groups were all tolerated (4b–4j). These results
demonstrated that Cu2O as catalyst in water is quite robust
for AAC reactions, featuring a wide scope of substrates, clean
conversion and high reaction efficiency in open-air conditions.
The outstanding catalytic performance of Cu2O under an ‘in
water’ environment led us to investigate the effectofwater, as well
as the possibility of decreasing the amount of catalyst used in
the transformation. As shown in Table 3, only a trace amount of
(1)
In conclusion, we have demonstrated that Cu2O acted as a
robust catalyst in water for CuAAC reactions making a wide
variety of triazoles, without additional stabilizing ligands. Due
to the simplicity and practicality of the Cu2O/H2O catalyst
system, our findings are striking in terms of further advancing
the application of CuAAC click chemistry, particularly under ‘in
water’ conditions. Further studies to clarify the mechanism of
the water-accelerated Cu2O-AAC reaction in combination with
theoretical calculations are underway.
This work was supported by NSFC (20902010), the State Key
Laboratory of Bio-organic and Natural Products Chemistry,
Key Laboratory of Natural Resources of Changbai Mountain
& Functional Molecules (Yanbian University), Jilin Provincial
Natural Science Foundation (20101537), Young Scientific Re-
search Foundation of Jilin Province (20090138) and Science
Foundation for Young Teachers of Northeast Normal Univer-
sity (09QNJJ013).
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Table 2 Cu2O-catalyzed azide-alkyne cycloaddition with a wide variety of alkynes and azides in watera
a (a) Reagents and Conditions: alkynes (1.2 mmol), azides (1.0 mmol), Cu2O (0.1 mmol), water (1 mL), RT; (b) The 1,4-regioselectivity of 4b was
confirmed by an NOE study; (c) The reaction for 4g was performed at 50 ◦C.
Table 4 Cu2O-AAC reaction under neat conditionsa
Table 3 Condition optimization for the cycloaddition of phenylacety-
lene 1a with tosyl azide 2a under neat conditionsa
Entry Cu2O (mol%) Water (ml)b Temp. (◦C) Time (h) Yield (%)c
1
2
3
4
5
10
10
1
0.1
0
RT
RT
40
50
50
6
2.5
5
7
12
traced
89
91
88
87
100
100
100
100
100 ppm
a Reactions were performed with tosyl azide 1a (0.5 mmol), phenyl-
acetylene 2a (0.6 mmol). b Water was used as an additive. c Isolated
yields. d Determined by 1H NMR spectroscopic analysis of the crude
reaction mixture.
a Reagents and Conditions: alkynes (0.6 mmol), azides (0.5 mmol), Cu2O
(100 ppm), water (100 ml), 50 ◦C.
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