Copper(I) oxide and benzoic acid 'on water': A highly practical and efficient catalytic system for copper(I)-catalyzed azide-alkyne cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2011.05.061

A simple combination of Cu₂O and PhCO₂H 'on H ₂O' has been developed as a highly practical and efficient catalytic system for copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). It not only provides a further evidence

Full text of DOI:10.1016/j.tetlet.2011.05.061

Tetrahedron Letters 52 (2011) 3782–3785
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Tetrahedron Letters
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Copper(I) oxide and benzoic acid ‘on water’: a highly practical and
efficient catalytic system for copper(I)-catalyzed azide–alkyne cycloaddition
⇑
⇑
Changwei Shao, Rui Zhu, Sheng Luo, Qun Zhang, Xinyan Wang , Yuefei Hu
Department of Chemistry, Tsinghua University, Beijing 100084, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 March 2011
Revised 3 May 2011
Accepted 13 May 2011
Available online 20 May 2011
A simple combination of Cu2O and PhCO2H ‘on H2O’ has been developed as a highly practical and efficient
catalytic system for copper(I)–catalyzed azide–alkyne cycloaddition (CuAAC). It not only provides a fur-
ther evidence for the strategy of carboxylic acids-promoted CuAAC, but also offers significant advantages
to CuAAC because Cu2O is one of the most stable and cheapest Cu(I) sources; PhCO2H is one of the struc-
turally simplest bidentate ligands; and water is the most ‘green’ solvent.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzoic acid
Copper(I) oxide
Catalysis
Click chemistry
Since copper(I)–catalyzed azide–alkyne cycloaddition (CuAAC)
was reported independently by the groups of Sharpless1 and
Meldal2 in 2002, great efforts have been made to understand
the nature of CuAAC.3 As shown in Scheme 1, a widely accepted
three-step catalytic cycle mechanism of CuAAC was proposed by
Sharpless in his first CuAAC article.1
roles7a in this process: (a) it serves as a bidentate ligand to promote
the formation of dinuclear alkynyl–copper(I) intermediate 4a (step
I); (b) MeCO2H (7a) in situ generated in the reaction serves as a
highly active promoter to cycloaddition (step II) and protonation
of C–Cu bond (step III). This is the first example that the ligand
could promote all three key steps in CuAAC catalytic cycle.
In 2004, Fokin reported first that the efficiency of CuAAC could
be enhanced significantly by ligands.4 Since then, many efficient
ligand-mediated CuAAC procedures were developed,5,6 in which
the ligands may be useful to dissociate the stable cluster of Cu(I)
sources into the active Cu(I) species, or protect Cu(I) species from
oxidation and disproportionation. Three years later, Straub6i also
proved that the protonation of C–Cu bond in intermediate 5 was
inefficient using H2O or RC„CH as a proton source, but it was
highly efficient in MeCO2H (in few minutes). Although Straub’s re-
sults clearly indicated that ‘step III’ in CuAAC mechanism may not
be benefited from the most reported ligands because they are all
basic or neutral compounds, unfortunately, less attention was paid
to the protonation of C–Cu bond in the design of ligands and cata-
lysts in CuAAC studies.
Recently, we reported that copper(I) carboxylates (6) were
highly efficient catalysts for CuAAC.7b As shown in Scheme 2, by
using 0.01 equiv of copper(I) acetate {6a, as a polymeric dinuclear
complex [(MeCO2Cu)2]n}, the cycloaddition of phenylethyne (1a)
and benzyl azide (2a) gave 1-benzyl-4-phenyl-1,2,3-trizole (3a)
in 98% yield in 8 min. We also revealed that MeCOÀ2 plays dual
During the further studies on the CuAAC catalyzed by copper(I)
carboxylates (6), we observed two interesting phenomena as
shown in Scheme 3. (a) By using H2O as a solvent, [(MeCO2Cu)2]n
(6a) was hydrolyzed quickly to red Cu2O and MeCO2H (7a).8 But,
the desired product 3a was still obtained in 95% yield in 11 min.
(b) By using the reference methods, [(MeCO2Cu)2]n (6a),9 (PhCO2-
Cu)4 (6b),10 [(CF3CO2Cu)4]n (6c),11 and [(t-BuCO2Cu)5]n (6d)12 were
prepared from Cu2O and the corresponding carboxylic acid anhy-
drides. However, regardless of the purities of 6a–d, they all exhib-
ited similarly excellent catalytic activity. These phenomena
strongly implied that the uses of pre-prepared 6a–d may be not
[CuLn]+
R1
N
N
N
RC CH (1)
R
(3)
R1N3 (2)
R1
N
Step II
RC C-CuLn
N
N
Cycloaddition
(4)
R
CuLn
⇑
Corresponding authors. Tel.: +86 10 62795380; fax: +86 10 62771149 (Y.H.).
E-mail addresses: wangxinyan@mail.tsinghua.edu.cn (X. Wang), yfh@mail.
(5)
tsinghua.edu.cn (Y. Hu).
Scheme 1. A three-step catalytic cycle of CuAAC.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.061

C. Shao et al. / Tetrahedron Letters 52 (2011) 3782–3785
3783
Table 1
BnN3 (2a), [(MeCO2Cu)2]n (6a)
(0.01 equiv), C6H12, rt, 8 min
N
Effects of the carboxylic acids 7a–k on CuAACa
Bn
N
N
PhC CH (1a)
98%
Entry
RCO2H (7a–k)
Time (min)
Yield of 3ab (%)
Ph
6a
6a
3a
1
2
3
4
5
6
7
8
MeCO2H (7a)
8
2
8
6
7
8
7
98
97
96
98
98
95
93
98
98
35
28
MeCO2H
(7a)
HCO2H (85% aq) (7b)
MeCH2CH2CO2H (7c)
Me2CHCO2H (7d)
t-BuCO2H (7e)
H2C@CH(CH2)8CO2H (7f)
CF3CO2H (7g)
C6H5CO2H (7h)
HO2CCH2CH2CO2H (7i)
HO2CCO2H (7j)
[(PhC CCu)2]n ( 4a)
Scheme 2. Copper(I) acetate-catalyzed highly efficient CuAAC.
9c
10
360
360
9
10
11
6a (0.01 equiv), H2O, rt, 11 min
L
-Proline (7k)
95%
a
+
1a
2a
3a
The neat mixture of 1a (2 mmol), 2a (2.1 mmol), Cu2O (0.01 equiv) and RCO2H
6b-d in different purities
(0.01 equiv), neat, rt, 1-3 min
(7a–k, 0.02 equiv) was stirred at 25 °C.
b
Isolated yields.
The reaction time was obtained by using one drop of H2O.
94-96%
c
Scheme 3. Two interesting phenomena.
100
97
96
95
95
necessary and they may be replaced with a simple combination of
Cu2O and RCO2H (7). Since 6a is a very expensive commercial prod-
uct and the preparation of 6b–d suffers from very tedious purifica-
tions, plus the fact that all of them are chemically unstable in
storage, therefore, studies on the combination of Cu2O/RCO2H (7)
are practically important for the understanding and applications
of CuAAC.
92
90
80
70
60
50
40
30
20
10
0
47
41
In literature, polyvinylpyrrolidone coated nanoparticles of Cu2O
have been reported to catalyze CuAAC efficiently, but the commer-
cial Cu2O showed very weak catalytic activity.13 We also proved
that, when the neat mixture of 1a, 2a and Cu2O (0.01 equiv) was
stirred at room temperature for 43 h, the substrates were slowly
converted into 3a in 97% yield (Scheme 4). To our delight, when
the same mixture was treated with a catalytic amount of MeCO2H
(7a, 0.02 equiv), 3a was obtained in 98% yield within 8 min.
Since copper(I) carboxylates 6a–d have proved to be excellent
catalysts for CuAAC,7b we predicted that the combination of Cu2O
and RCO2H (7) may be a general catalytic system for CuAAC. Thus,
different carboxylic acids were tested. As shown in Table 1, the
combinations of Cu2O and aliphatic acids (7a–g, entries 1–7)
showed highly efficient catalytic activity in neat conditions, but
benzoic acid (7h, entry 8) had lower activity (38 min). Realizing
the solid 7h could not react efficiently with solid Cu2O, one drop
of H2O was added and the same reaction finished within 9 min.
As was expected, 7i (entry 9) gave the excellent results because
it is a bis(carboxylic acid). However, both 7j and k (entries 10
and 11) gave poor yields of 3a, even prolonged reaction times were
used. Those results may be caused by the fact that they have strong
chelating ability to Cu(I) ion, by which the catalytic cycle of Cu(I)
ion is retarded.7a,14
25
23
22
2:1
1:1
1:2
1:4
1:8
Ratios of Cu2O:HOAc (0.005 equiv.of Cu2O)
Reaction Time (min)
Yields of 3a (%)
Figure 1. Effects of the ratios of Cu2O:7a on CuAAC.
Table 2
Effects of the solvents on the reactivity of Cu2O/7aa
Entry
Solvent (2.0 mL)
Time (min)
Yield of 3ab (%)
1
2
3
4
5
6
7
8
H2O
120
120
120
120
120
120
120
120
98
65
56
45
20
18
15
8
MeCN
CH2Cl2
MeCOMe
C6H12
EtOH
t-BuOH
THF
a
The mixture of 1a (2 mmol), 2a (2.1 mmol), Cu2O (0.01 equiv) and 7a
As shown in Figure 1, by using a lower loading of Cu2O
(0.005 equiv), the best results (97%, 22 min) were obtained by
using 1:2 (by mole) of Cu2O:7a, which may result from the fact that
this ratio could generate the maximal catalyst 6a. However, lower
catalytic activity was observed by using large excess of 7a. For
example, reaction time was doubled when 1:8 ratio of Cu2O:7a
was used. As was expected, all ratios of Cu2O:7a (1:1–1:8) gave
(0.02 equiv) in solvent was stirred at 25 °C.
b
Isolated yields.
nearly identical excellent results with a higher loading of Cu2O
(0.01 equiv).
Since CuAAC is a highly exothermic reaction, the reaction in a
solvent was tested for the safe reason. To our disappointment,
the combination of Cu2O/7a in solvents did not match its highly
catalytic activity in neat conditions. As shown in Table 2, low cat-
alytic activities were observed in all testing solvents (entries 1–8).
Although H2O was the best solvent (entry 1), its reaction time was
15 times longer than that in neat conditions.
However, when MeCO2H (7a) was replaced with PhCO2H (7h),
the same reaction in H2O finished in only 8 min to give 3a in 98%
yield. To understand this result, the reaction was monitored care-
Cu2O (0.01 equiv), neat, rt, 43 h
97%
1a
2a
3a
+
Cu2O (0.01 equiv), MeCO2H
(7a, 0.02 equiv), neat, rt, 8 min
98%
Scheme 4. Cu2O and Cu2O/7a catalyzed CuAAC.

3784
C. Shao et al. / Tetrahedron Letters 52 (2011) 3782–3785
Cu2O (0.01 equiv), 7h (0.02
equiv), H2O, rt, 5-18 min
88~98%
N
R
N
N
+
RN3
PhC CH
2a-l
3a-l
1a
Ph
N3
N3
N3
N3
O2N
Br
Br
2a, 8 min
(3a, 98%)
2b, 8 min
(3b, 91%)
2c, 6 min
(3c, 94%)
2d, 7 min
(3d, 90%)
N3
N3
N3
2
N3
4
2e, 17 min
(3e, 93%)
2h, 18 min
(3h, 92%)
2f, 10 min
(3f, 91%)
2g, 16 min
(3g, 88%)
O
O
O
N3
N3
N3
NC
N3
Ph
EtO
2i, 7 min
(3i, 97%)
2j, 5 min
(3j, 90%)
2k, 6 min
(3k, 93%)
2l, 6 min
(3l, 94%)
Figure 2. Cu2O powders on the interface between two phases.
Scheme 5. Cu2O/7h catalyzed CuAAC.
fully and two interesting phenomena were observed as shown in
Figure 2. (a) After 1a, 2a and Cu2O were added into H2O, a two-
phase system formed and the organic layer was surrounded by
H2O. (b) Cu2O powders were not precipitated in H2O, but they were
spread on the interface between two phases. Thus, the protocol in
H2O actually was still a ‘neat condition’ for the reactants 1a, 2a,
and Cu2O, but not for the carboxylic acids because they have differ-
ent distributions between H2O and organic layer. Therefore, the big
reactivity difference between 7a and h may simply result from
their solubility in H2O.
According to this opinion, it may be expected that the hydro-
philic carboxylic acids lead to lower reactivity and the hydrophobic
carboxylic acids lead to higher reactivity. For example, each of 7a,
b, e, or h has high activity in neat conditions (see Table 1). But, the
activity of 7a and b was reduced significantly in H2O (Table 3, en-
tries 1 and 2) because they are miscible with H2O in all propor-
tions. Both 7e and h still kept high activity (entries 3 and 4)
because they have poor solubility in H2O (2.17 g and 0.34 g/
100 mL H2O, respectively). As was expected, 7h in all testing or-
ganic solvents exhibited low activity because all reactants were di-
luted by organic solvents (entries 5–11).
It is valuable to note that the reaction was not sensitive to the
amount of H2O and the similar results were obtained by using
0.5–2.0 mL of H2O for 1.0 mmol of 1a. This result also suggests that
the reaction may proceed ‘on water’ rather than ‘in water’. We also
observed that the temperature of H2O increased quickly during the
reaction, but it usually was below 40 °C.
Finally, the substrate scopes were tested under our optimized
conditions [0.01 equivalent of Cu2O, 1:2 (by mole) of Cu2O:7h]. As
shown in Scheme 5, all cycloadditions of phenylethyne (1a) and dif-
ferent azides (2a–l) proceeded efficiently. Unlike the catalyst 6a,7b
the effects of azide structures on the rates were very small. For
example, benzyl azides (2a–d) and alkyl azides (2f–h) gave very
close rates and yields. It was similar to the catalyst 6a, the azides
(2i–l) substituted by electron-withdrawing group at a-carbon gave
the excellent results.
As shown in Scheme 6, the structure of alkyne has significant ef-
fects on this catalytic system. All hydrophobic alkynes (1b–e)
showed very high efficiency, while the hydrophilic alkynes (1f–i)
showed relatively low efficiency. It was interesting to observe that
both propynoic acid (1f) and its ester (1g) showed similar effi-
ciency. Although the acylated derivatives 1h and i were very good
substrates, their parent compounds prop-2-yn-1-ol and prop-2-yn-
1-amine just gave moderate results (78% in 14 h and 64% in 16 h,
respectively), which may be caused by the coordination between
Cu(I) ion with hydroxyl or amine group.
In conclusion, it is well known that the efficiency of CuAAC can
be enhanced by ligands, but the protonation of C–Cu bond in
CuAAC catalytic cycle could not be benefited from these existing
ligands because they are all basic or neutral compounds. Recently,
we discovered that copper(I) carboxylates are excellent catalysts
for CuAAC, and the carboxylic acids could promote a fast proton-
ation of C–Cu bond in CuAAC intermediate. However, copper(I) car-
boxylates are chemically unstable and their preparations usually
associate with very tedious purifications. In this letter, we found
that the pre-prepared copper(I) carboxylates can be replaced with
a simple combination of Cu2O and the corresponding carboxylic
acids. Finally, the combination of Cu2O/PhCO2H (7h) ‘on H2O’
was developed as a highly practical and efficient catalytic system
for CuAAC. This catalytic system not only provides a further evi-
Table 3
Effects of the solvents on the reactivity of Cu2O/7a
Cu2O (0.01 equiv), 7h (0.02
equiv), H2O, rt, 5-115 min
Entry RCO2H (7a, b, e, h) Solvent
Time
(min)
Yield of 3ab (%)
N
Bn
(2.0 mL)
N
N
+
BnN3
RC CH
90~97%
1
2
3
4
5
6
7
8
7a
7b
7e
7h
7h
7h
7h
7h
7h
7h
7h
H2O
H2O
H2O
H2O
MeCN
MeCOMe
CH2Cl2
C6H12
THF
120
110
15
8
60
60
60
60
60
60
60
98
96
98
98
85
72
65
58
46
26
22
2a
1b-i
R
3m-t
F
MeO
1b, 9 min
(3m, 95%)
1c, 11 min
(3n, 97%)
1d, 6 min
(3o, 92%)
1e, 5 min
(3p, 91%)
9
10
11
O
O
t-BuOH
EtOH
EtO
MeO2CO
1h, 73 min
HO
BocHN
1i, 115 min
1f, 55 min
(3q, 90%)
1g, 45 min
(3r, 92%)
a
The mixture of 1a (2 mmol), 2a (2.1 mmol), Cu2O (0.01 equiv) and
(0.02 equiv) in solvent was stirred at 25 °C.
7
(3s, 93%)
(3t, 91%)
b
Isolated yields.
Scheme 6. Cu2O/7h catalyzed CuAAC.

C. Shao et al. / Tetrahedron Letters 52 (2011) 3782–3785
3785
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also offers significant advantages to CuAAC because Cu2O is one of
the most stable and cheapest Cu(I) sources; PhCO2H is one of the
structurally simplest bidentate ligands; and H2O is the most ‘green’
solvent.
Acknowledgment
This work was supported by the NNSFC (21072112).
Supplementary data
Supplementary data (Experiments, characterization, 1H and 13
C
NMR spectra for products 3a–t) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.05.061.
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