A supported copper hydroxide on titanium oxide as an efficient reusable heterogeneous catalyst for 1,3-dipolar cycloaddition of organic azides to terminal alkynes

Article abstract of DOI:10.1002/chem.200901444

An easily prepared supported copper hydroxide on titanium oxide (Cu(OH)_x/TiO₂) showed high catalytic performance for the 1,3-dipolar cycloaddition of organic azides to terminal alkynes in non-polar solvents under anaerobic conditions. The reactions of various combinations of organic azides (four examples, including aromatic and aliphatic ones) and terminal alkynes (eleven examples, including aromatic, aliphatic, and double bond-containing ones) exclusively proceeded to give the corresponding 1,4-disubstituted-1,2,3triazole derivatives in a completely regioselective manner. For the transfor-mation of benzyl azide and ethynylbenzene with 0.12 mol% of Cu(OH)_x/ TiO₂, the turnover frequency was 505 h^-1 and the turnover number reached up to 800. These values were the highest among those with previously reported heterogeneous catalysts including Cu(OHyAl₂O₃. The observed catalysis was truly heterogeneous and the retrieved catalyst after the reaction could be reused at least three times with retention of its high catalytic performance. It was confirmed by the UV/ Vis spectrum of Cu(OH)/TiO₂ and the amount of diyne formed that the Cu" species in Cu(OH)_x/TiO₂ were reduced to Cu^I species by the alkyne-alkyne homocoupling at the initial stage of the reaction (during the pretreatment of Cu(OH)/TiO₂ with an alkyne). The catalytic reaction rate for the 1,3-dipolar cycloaddition linearly increased with an increase in the amount of in situ generated Cu ^I species. Therefore, the in situ generated Cu1 species would be the catalytically active species for the present 1,3-dipolar cycloaddition.

Full text of DOI:10.1002/chem.200901444

DOI: 10.1002/chem.200901444
A Supported Copper Hydroxide on Titanium Oxide as an Efficient Reusable
Heterogeneous Catalyst for 1,3-Dipolar Cycloaddition of Organic Azides to
Terminal Alkynes
Kazuya Yamaguchi,[a, b] Takamichi Oishi,[a] Tatsuyori Katayama,[a] and
Noritaka Mizuno*[a, b]
Abstract: An easily prepared support-
ed copper hydroxide on titanium oxide
(Cu(OH)x/TiO2) showed high catalytic
performance for the 1,3-dipolar cyclo-
addition of organic azides to terminal
alkynes in non-polar solvents under
anaerobic conditions. The reactions of
various combinations of organic azides
(four examples, including aromatic and
aliphatic ones) and terminal alkynes
(eleven examples, including aromatic,
aliphatic, and double bond-containing
ones) exclusively proceeded to give the
corresponding 1,4-disubstituted-1,2,3-
triazole derivatives in a completely re-
gioselective manner. For the transfor-
mation of benzyl azide and ethynylben-
zene with 0.12 mol% of Cu(OH)x/
TiO2, the turnover frequency was
505 hꢀ1 and the turnover number
reached up to 800. These values were
the highest among those with previous-
ly reported heterogeneous catalysts in-
cluding Cu(OH)x/Al2O3. The observed
catalysis was truly heterogeneous and
the retrieved catalyst after the reaction
could be reused at least three times
with retention of its high catalytic per-
formance. It was confirmed by the UV/
Vis spectrum of Cu(OH)x/TiO2 and the
amount of diyne formed that the CuII
species in Cu(OH)x/TiO2 were reduced
to CuI species by the alkyne–alkyne ho-
mocoupling at the initial stage of the
reaction (during the pretreatment of
Cu(OH)x/TiO2 with an alkyne). The
catalytic reaction rate for the 1,3-dipo-
lar cycloaddition linearly increased
with an increase in the amount of in
situ generated CuI species. Therefore,
the in situ generated CuI species would
be the catalytically active species for
the present 1,3-dipolar cycloaddition.
Keywords: alkynes · azides · copper
hydroxide · dipolar cycloaddition ·
heterogeneous catalysis
Introduction
of organic azides or terminal alkynes, this uncatalyzed trans-
formation usually requires high reaction temperatures (typi-
cally more than 808C) and results in the formation of a ca.
1:1 mixture of 1,4- and 1,5-regioisomers.[1] The groups of
Sharpless[3a] and Meldal[3b] have independently reported the
copper-catalyzed Huisgen 1,3-dipolar cycloaddition, so-
called “click reaction”. The 1,3-dipolar cycloaddition is dra-
matically accelerated by the presence of copper catalysts
and is totally regioselective, affording the corresponding 1,4-
disubstituted-1,2,3-triazole derivatives. Since the reaction
typically shows 100% chemoselectivity, 100% regioselectivi-
ty, and 100% atom economy, it has become attractive in
many fields of organic synthesis, combinatorial chemistry,
polymer chemistry, supramolecular chemistry, biochemistry,
and drug discovery.[4]
Huisgen 1,3-dipolar cycloaddition of organic azides to termi-
nal alkynes is one of the most important synthetic routes to
1,2,3-triazole derivatives,[1] which have been utilized as dyes,
photostabilizers, agrochemicals, and biochemicals.[2] Al-
though Huisgen cycloaddition shows high chemoselectivity
because many functional groups are intact in the presence
[a] Dr. K. Yamaguchi, T. Oishi, T. Katayama, Prof. Dr. N. Mizuno
Department of Applied Chemistry, School of Engineering
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
Fax : (+81)3-5841-7220
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp
It is widely accepted that CuI catalysts are required for
the click reaction.[3–6] The CuI species are generally prepared
by the in situ reduction of CuII salts with agents such as
sodium ascorbate and ascorbic acid or by the in situ oxida-
tion of Cu0 clusters.[3–6] Also, CuI complexes with stabilizing
[b] Dr. K. Yamaguchi, Prof. Dr. N. Mizuno
Core Research for Evolutional Science and Technology (CREST)
Science and Technology Agency (JST)
4-1-8 Honcho, Kawaguchi, Saitama, 332-0012 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901444.
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FULL PAPER
ligands are very useful and have been reported to be active
for the 1,3-dipolar cycloaddition.[5] Very recently, we have
reported that the copper-substituted silicotungstate
(TBA)4[g-H2SiW10O36Cu
2ACHTUGNRTEN(NUNG m-1,1-N3)2] (TBA=tetra-n-butyl-
ACHTUNGTRENNUNGammonium) could act as an efficient homogeneous catalyst
and showed the extremely high turnover frequency (TOF)
and turnover number (TON) for the 1,3-dipolar cycloaddi-
tion under solvent-free conditions.[5k]
As for the 1,3-dipolar cycloaddition, most of the reported
copper-catalyzed systems are homogeneous and have serious
shortcomings in the difficulty in catalyst/product(s) separa-
tion, reuse of (expensive) catalysts, and/or indispensability
of additives, such as reducing agents, stabilizing ligands, and
bases. In contrast, the heterogeneous systems with solid cat-
alysts have significant advantages in catalyst/product(s) sep-
aration and reuse of catalysts.[7] Cu0 nanocluster,[6a] Cu0/C,[6b]
Cu0/boehmite,[6c] Cu0/Al2O3,[6d] CuII-ALG (ALG=alginate-
based biopolymer),[6e] CuI-USY (USY=ultra stable Y-zeo-
Figure 1. Organic azides and terminal alkynes used.
A
Results and Discussion
of previously reported heterogeneous catalysts for the 1,3-
dipolar cycloaddition. However, the TOFs and TONs are
still not so high (TOF: 0.6–120 hꢀ1, TON: 5–80) and addi-
tives such as bases are necessary to attain high yields in
some cases.[6] Therefore, the development of efficient addi-
tive-free reusable heterogeneous catalysts with high TOFs
and TONs is desirable from the standpoint of green chemis-
try[8] and can solve the above-mentioned problems.
Effect of solvents and catalysts on the 1,3-dipolar cycloaddi-
tion: First, the effect of solvents on the Cu(OH)x/TiO2-cata-
lyzed 1,3-dipolar cycloaddition of benzyl azide (1a) to ethy-
nylbenzene (2a) was examined (Table 1). All 1,3-dipolar cy-
cloaddition reactions were carried out under Ar atmosphere
by pretreating catalysts with the respective alkyne at 608C
for 30 min before the addition of an organic azide (other-
wise mentioned, see the Experimental Section).[11] Among
the solvents examined, non-polar toluene, p-xylene, and me-
sitylene were good solvents and gave quantitative yields of
1-benzyl-4-phenyl-1H-1,2,3-triazole (3a) for the 1,3-dipolar
cycloaddition of 1a to 2a (Table 1, entries 1–3). The reaction
in halogenated solvents such as 1,2-dichloroethane and
chloroform efficiently proceeded (Table 1, entries 4 and 5).
Acetonitrile also gave a quantitative yield of 3a (Table 1,
entry 6). In contrast, polar aprotic as well as protic solvents
such as dimethyl sulfoxide (DMSO), N,N-dimethylforma-
mide (DMF), 2-propanol, and water were poor likely be-
We have developed various heterogeneously catalyzed ef-
ficient functional group transformations by supported ruthe-
nium[9] and rhodium[10] hydroxide catalysts. The monomeri-
cally (or at least mainly if not wholly) dispersed metal hy-
droxide species on appropriate supports would possess both
Lewis acid and Brønsted base sites on the same metals, and
the various functional group transformations have been pro-
moted through the concerted activation by Lewis acid and
Brønsted base sites.[9,10] During the course of our investiga-
tions, we have very recently developed the copper hydroxide
on aluminum oxide (Cu(OH)x/Al2O3) for the 1,3-dipolar cy-
cloaddition.[6i] Herein, we report that the supported copper
hydroxide on titanium oxide (Cu(OH)x/TiO2) could act as
an efficient additive-free heterogeneous catalyst for the 1,3-
dipolar cycloaddition and showed much higher catalytic per-
formance than previously reported heterogeneous catalysts[6]
including Cu(OH)x/Al2O3.[6i] The observed catalysis was
truly heterogeneous and the Cu(OH)x/TiO2 catalyst could
be reused several times with keeping its high catalytic per-
formance. In addition, the applicability of the present
Cu(OH)x/TiO2-catalyzed system was wide and various com-
binations of structurally diverse organic azides and terminal
alkynes indicated in Figure 1 could selectively be converted
into the corresponding 1,4-disubstituted-1,2,3-triazole deriv-
atives in high yields. In this paper, the active species and
possible reaction mechanism for the present 1,3-dipolar cy-
cloaddition are also investigated in detail.
Table 1. Effect of solvents on the 1,3-dipolar cycloaddition of 1a to 2a.[a]
Entry
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
toluene
p-xylene
99
99
99
99
80
96
12
3
mesitylene
1,2-dichloroethane
chloroform
acetonitrile
DMSO
DMF
9
10
2-propanol
water
1
nd
[a] Reaction conditions: Cu(OH)x/TiO2 (Cu: 1.5 mol%), 1a (0.5 mmol),
2a (0.5 mmol), solvent (1.5 mL), 608C, 10 min, under Ar atmosphere. All
reactions were carried out by pretreating Cu(OH)x/TiO2 with 2a at 608C
for 30 min. nd=not detected. [b] GC yield.
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N. Mizuno et al.
cause of their strong coordination to the active copper
center (Table 1, entries 7–10). No leaching of copper species
was observed and the reactions were completely stopped by
the removal of the solid Cu(OH)x/TiO2 catalyst by hot filtra-
tion in the case of the 1,3-dipolar cycloaddition in non-polar
solvents such as toluene and p-xylene (for example, Figure
S1a, in the Supporting Information). Thus, all reactions
were hereafter carried out in toluene.
than that with previously reported Cu(OH)x/Al2O3 (Fig-
ure S4).[6i] The reaction hardly proceeded with Cu(OH)x/
SiO2 (Table 2, entry 4). The 1,3-dipolar cycloaddition did not
proceed in the presence of CuCl2 supported on TiO2 and
Al2O3 prepared without the base treatment (Table 2, en-
tries 5 and 7, see the Experimental Section for the prepara-
tion). The treatment of these catalysts with an aqueous
NaOH solution (0.01m) significantly increased the activity
(Table 2, entries 6 and 8), showing that the base treatment
of catalysts is very important to obtain the high catalytic
performance.
Next, the catalytic activities for the 1,3-dipolar cycloaddi-
tion of 1a to 2a in toluene were compared among various
catalysts (Table 2). Among supported copper hydroxide cat-
No reaction proceeded in the absence of catalysts, or in
the presence of supports or the catalyst precursor of CuCl2
(Table 2, entries 9 and 20–22). Although CuSO4·5H2O has
been reported to be active for the 1,3-dipolar cycloaddition
in the presence of reducing agents, such as sodium ascorbate
in a mixed solvent of tert-butyl alcohol and water,[3a] the cor-
responding triazole 3a was hardly produced without reduc-
ing agents (Table 2, entry 10). Also, other simple CuI and
Table 2. The 1,3-dipolar cycloaddition of 1a to 2a by various catalysts.[a]
Entry
Catalyst
t [min]
Yield [%][b]
1
2
3
4
5
6
Cu(OH)x/TiO2
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/SiO2
CuCl2/TiO2
CuCl2/TiO2 treated
with 0.01m aq. NaOH
CuCl2/Al2O3
10
10
60
60
60
10
99
28
>99
nd
nd
99
CuII salts and complexes such as Cu
(CH3CN)4]PF6, and CuI phenylacetylide ([CuI
ACTHNGUTERU(NNG C CPh)]n)
ACHTUNGRTEN(NGNU OTf)2, CuCl, [Cu-
ꢁ
A
were not effective for the 1,3-dipolar cycloaddition (Table 2,
entries 11–14). The 1,3-dipolar cycloaddition with bulk
copper oxides and hydroxide such as CuO, Cu2O, and
Cu(OH)2 hardly proceeded (Table 2, entries 15–17). The cat-
alytic activities of physical mixtures of Cu(OH)2 and sup-
ports were much lower than those of the corresponding sup-
ported copper hydroxide catalysts (Table 2, entries 18 and
19 vs. entries 1 and 3). Therefore, the highly dispersed
copper hydroxide species are effective for the 1,3-dipolar cy-
cloaddition.
7
8
60
60
nd
99
CuCl2/Al2O3 treated
with 0.01m aq. NaOH
CuCl2
9
10
11
12
13
14
15
16
60
60
60
60
60
60
60
60
60
60
60
60
60
60
nd
1
nd
2
CuSO4·5H2O
Cu
CuCl
[Cu(CH3CN)4]PF6
[CuI
A
A
1
ꢁ
G
E
nd
nd
nd
nd
4
CuO
Cu2O
17
Cu(OH)2
Cu(OH)2 +TiO2
Cu(OH)2 +Al2O3
TiO2
Al2O3
none
Heterogeneous nature and catalyst reuse: To examine
whether the observed catalysis is derived from the solid
Cu(OH)x/TiO2 catalyst or leached copper species, the 1,3-di-
polar cycloaddition reactions of 1a to 2a in various solvents
were carried out under the conditions described in Table 1
and the Cu(OH)x/TiO2 catalyst was removed from the reac-
tion mixture at 50–60% conversion of substrates by hot fil-
tration at the reaction temperature. Then, the reaction was
again carried out with the filtrate under the same conditions.
In polar solvents, the 1,3-dipolar cycloaddition reactions
were not completely stopped by the removal of the solid
Cu(OH)x/TiO2 catalyst by hot filtration (for example, Fig-
18[c]
19[c]
20[d]
21[d]
22
5
nd
nd
nd
[a] Reaction conditions: Catalyst (Cu: 1.5 mol%), 1a (0.5 mmol), 2a
(0.5 mmol), toluene (1.5 mL), 608C, under Ar atmosphere. All reactions
were carried out by pretreating catalysts with 2a at 608C for 30 min.
[b] GC yield. [c] A mixture of Cu(OH)2 (Cu: 1.5 mol%) and support
(50 mg). [d] 50 mg. nd=not detected.
alysts tested,[12] Cu(OH)x/TiO2 showed the highest catalytic
activity. The Cu(OH)x/TiO2-catalyzed 1,3-dipolar cycloaddi-
tion efficiently proceeded with an equimolar amount of 2a
with respect to 1a and a quantitative yield of 3a was ob-
tained within only 10 min (Table 2, entry 1). In this case,
only a small amount of 1,4-diphenyl-1,3-butadiyne (4a, 1%
yield based on 2a)[13] was formed as a by-product. Further,
AHCTUNGTREGuNNUN re S1b). It was confirmed by the inductively coupled
plasma atomic emission spectroscopy (ICP-AES) analysis
that copper species leached into the reaction solutions to
some extent (ꢂ10%, even in a weak Lewis base solvent of
acetonitrile).
In contrast, when the reaction was carried out in non-
polar solvents such as toluene and p-xylene, no further reac-
tions proceeded by the removal of the solid Cu(OH)x/TiO2
catalyst (for example, Figure S1a) and no copper species
was detected in the filtrate (below the detection limit of the
ICP-AES analysis). Furthermore, the catalyst retrieved after
the reaction could be reused at least three times with the re-
tention of its high catalytic performance; quantitative yields
1
it was confirmed by analysis of the H NMR spectra (Fig-
ACHTUNGTRENNUNG
ure S2a), difference NOE spectrum (Figure S2b),[14] and X-
ray crystallographic analysis (Figure S3) that the 1,4-disub-
stituted-1,2,3-triazole 3a was formed in a completely regio-
selective manner without formation of the 1,5-regioisomer.
The initial rate for the 1,3-dipolar cycloaddition with
Cu(OH)x/TiO2 was at least one order of magnitude larger
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An Efficient Reusable Heterogeneous Catalyst
FULL PAPER
of 3a were obtained from the first, second, and third recy-
cling experiments with the retrieved catalyst after the reac-
tion (Table 3, entries 2–4).[15] These facts can rule out any
action; the reaction rates for the 1,3-dipolar cycloaddition of
1a to 2-, 3-, and 4-methylethynylbenzenes (2c–2e) were
almost the same as one another, for example. In the case of
the deuterated alkyne 2a’, the corresponding triazole 3a
was also obtained in an excellent yield. In this case, the deu-
terium content at the 5-position of 3a was 27% (see the
later section). Also, aliphatic terminal alkynes (2h and 2i)
worked well as reaction partners of organic azides. Notably,
the present system could be applied to the double bond-con-
taining alkyne (2j).
Table 3. The Cu(OH)x/TiO2-catalyzed 1,3-dipolar cycloaddition.[a]
Entry
Azide
Alkyne
Triazole[b]
t [min]
Isolated yield [%]
89(99[c]
)
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1c
1c
1c
1d
2a
2a
2a
2a
2a’
2b
2c
2d
2e
2 f
2g
2h
2i
3a
3a
3a
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
5
5
5
5
5
5
5
5
5
5
5
10
10
10
5
5
5
5
30
80
2[d]
3[d]
4[d]
5
99[c]
99[c]
99[c]
95[e]
91
98
97
89
91
95
78
96
91
92
95
92
88
In addition, Cu(OH)x/TiO2 efficiently catalyzed the 1,3-di-
polar cycloaddition even at room temperature (258C) and
the corresponding triazole 3a was obtained in 99% yield for
40 min under the conditions described in Equation (1).
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
2j
2a
2e
2a
2g
2 f
2a
In this case, the TOF (based on the initial rate) reached
up to 60 hꢀ1 and this value was higher than those of the pre-
viously reported reactions with heterogeneous copper cata-
lysts at ambient temperature (below 308C); Cu0 nanocluster
(TOF=4.4 hꢀ1),[6a] Cu0/boehmite (2.6 hꢀ1),[6c] Cu0/Al2O3
(3.7 hꢀ1),[6d] CuII-ALG (0.3 hꢀ1),[6e] CuI-USY (0.6 hꢀ1),[6f,6 g]
CuII-HT (2.7 hꢀ1),[6 h] and Cu(OH)x/Al2O3 (27 hꢀ1).[6i] Fur-
thermore, the catalyst amount could be much reduced; in a
5 mmol-scale reaction of 1a to 2a using 0.12 mol% of
Cu(OH)x/TiO2, the TOF (based on the initial rate) was
505 hꢀ1 and the TON reached up to 800 [Eq. (2)].
98
98
[a] Reaction conditions: Cu(OH)x/TiO2 (Cu: 2.5 mol%), azide
(0.5 mmol), alkyne (0.5 mmol), toluene (1.5 mL), 608C, under Ar atmos-
phere. All reactions were carried out by pretreating Cu(OH)x/TiO2 with
the respective alkyne at 608C for 30 min. [b] The data of isolated tri-
ACHTUNGTRENNUNGazoles are shown in the Supporting Information. [c] GC yield. [d] Reuse
experiments; 1st reuse (entry 2), 2nd reuse (entry 3), and 3rd reuse
(entry 4). [e] The deuterium content at the 5-position was 27%.
contribution to the observed catalysis from copper species
that leached into the reaction solution and the observed cat-
alysis is intrinsically heterogeneous in toluene.[16]
Scope of the present Cu(OH)x/TiO2-catalyzed 1,3-dipolar cy-
cloaddition: The scope of the 1,3-dipolar cycloaddition of
various kinds of organic azides (including aromatic and ali-
phatic ones) and terminal alkynes (including aromatic, ali-
phatic, and double bond-containing ones) with the most
active Cu(OH)x/TiO2 catalyst was examined. Various combi-
nations of organic azides and terminal alkynes were effi-
ciently converted into the corresponding triazole derivatives
in excellent isolated yields (see the Experimental Section)
without any additives such as reducing agents, stabilizing li-
gands, and bases (Table 3). In all cases, 1,4-regioisomers
were exclusively obtained without the formation of 1,5-re-
gioisomers. Not only benzylic (1a and 1b), but also aliphatic
azides (1c and 1d) gave excellent yields of the correspond-
ing triazole derivatives. Aromatic terminal alkynes (2a–2g)
with electron-donating as well as electron-withdrawing sub-
stituents on the phenyl rings smoothly reacted with organic
azides to give the corresponding triazole derivatives. The
position of substituents on phenyl rings did not affect the re-
These values were the highest among those reported for
heterogeneous catalysts so far; Cu0 nanocluster (TOF=
4.4 hꢀ1, TON=80),[6a] Cu0/C + EtN3 (120 hꢀ1, 20),[6b] Cu0/
boehmite (6.3 hꢀ1, 19 at 608C; 2.6 hꢀ1, 31 at room temp.),[6c]
Cu0/Al2O3 (3.7 hꢀ1, 11),[6d] CuII-ALG (0.3 hꢀ1, 5),[6e] and CuI-
USY (1.7 hꢀ1, 9 at 1108C; 0.6 hꢀ1, 9 at room temp.),[6f,6 g]
CuII-HT (2.7 hꢀ1, 16),[6 h] and Cu(OH)x/Al2O3 (144 hꢀ1,
667).[6i]
Active species for the 1,3-dipolar cycloaddition: In the pres-
ence of Cu(OH)x/TiO2, the 1,3-dipolar cycloaddition of 1a
to internal alkynes such as diphenylacetylene and 2-octyne
did not proceed, suggesting that the copper species in
Cu(OH)x/TiO2 is likely terminally bound to an alkyne to
form the copper-acetylide species. Thus, the catalysts need
the ability to abstract an alkyne hydrogen (activation of an
alkyne).
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N. Mizuno et al.
To examine the ability to abstract an alkyne hydrogen,
the H/D exchange reactions of [D1]ethynylbenzene (2a’,
deuterium content at the terminal position: 98%) were car-
ried out with various catalysts. The treatment of
a
[D1]chloroform solution of 2a’ (0.48 mmol, 0.32m, 1.5 mL)
with Cu(OH)x/TiO2 (2.5 mol%) at 208C for 5 h resulted in a
decrease in the deuterium content (98%!57%, determined
1
by the H analysis).[17,18] Similarly, the deuterium content of
2a’ was decreased by the presence of Cu(OH)x/Al2O3
(98%!51%). In contrast, the H/d-exchange reaction
hardly proceeded with CuCl2/TiO2, CuCl2/Al2O3, TiO2, or
Al2O3 under the same conditions. Next, a chloroform solu-
tion of 2a’ (0.48 mmol, 0.32m, 1.5 mL) was treated with
Cu(OH)x/TiO2 (2.5 mol%) under the same conditions. After
the treatment, THF (1.5 mL), water (0.1 mL), and
[D6]benzene (10 mL, internal standard) were added to the
reaction mixture and stirred at 208C for 30 min. Then, the
Figure 2. Reaction profiles for the Cu(OH)x/Al2O3-catalyzed 1,3-dipolar
cycloaddition of 1a to 2a in toluene under Ar atmosphere catalyzed by
a) Cu(OH)x/Al2O3 without the alkyne pretreatment and b) Cu(OH)x/
Al2O3 pretreated with 2a for 30 min before the addition of 1a. Reaction
conditions: Cu(OH)x/Al2O3 (Cu: 1.5 mol%), 1a (0.5 mmol), 2a
(0.5 mmol), toluene (1.5 mL), 608C, under Ar atmosphere.
2
catalyst was removed by filtration and the H NMR spec-
trum of the filtrate was measured. As shown in Figure S5,
0.23 mmol of deuterium oxides (HDO and D2O, calculated
as HDO) and 0.21 mmol of 2a’ were detected in the filtrate.
In contrast, no formation of deuterium oxides were ob-
served by the treatment of 2a’ with CuCl2/TiO2 and TiO2.
Therefore, the H/D-exchange reaction easily proceeds on
the copper hydroxide species dispersed on TiO2 or Al2O3
and the following reaction likely occurs [Eq. (3)]. The role
of the copper hydroxide species is probably the abstraction
of an alkyne hydrogen to form the alkynyl species.
amount of 4a did not increase after the 1,3-dipolar cycload-
dition was initiated by the addition of 1a to the reaction
mixture.
The relationship between the amount of 4a produced and
the pretreatment period of the catalysts (Cu(OH)x/TiO2 and
Cu(OH)x/Al2O3) with 2a is shown in Figure 3. The condi-
On the other hand, no H/D-exchange reaction proceeded
in the presence of the copper hydroxide supported on acidic
SiO2 (Cu(OH)x/SiO2). In addition, the 1,3-dipolar cycloaddi-
tion did not proceed with Cu(OH)x/SiO2 (Table 2, entry 4).
Thus, the acidic nature of SiO2 support inhibits the abstrac-
tion of an acidic alkyne hydrogen and acidic supports are
not effective for the present 1,3-dipolar cycloaddition.[6f,g]
Next, the reaction profiles for the 1,3-dipolar cycloaddi-
tion of 1a to 2a in toluene at 608C under Ar atmosphere
were carefully monitored. First, we used the Cu(OH)x/Al2O3
catalyst instead of Cu(OH)x/TiO2 because the reaction rate
with Cu(OH)x/TiO2 was very large under the present condi-
tions and the profiles could not be accurately monitored (es-
pecially at the initial stage of the reactions, Figure S4). The
1,3-dipolar cycloaddition of 1a to 2a without the alkyne pre-
treatment showed an induction period of approximately 10–
20 min (Figure 2a). Upon the pretreatment of Cu(OH)x/
Al2O3 with 2a at 608C for 30 min before the addition of 1a
(the alkyne pretreatment), the induction period disappeared
as shown in Figure 2b. During the pretreatment, the diyne
4a was formed by the alkyne–alkyne homocoupling.[13] The
Figure 3. The relationship between the amount of 4a produced and the
pretreatment period of catalysts with 2a: a) Cu(OH)x/TiO2 and
b) Cu(OH)x/Al2O3. The amount of 4a produced (2a consumed) can be
regarded as the degree of reduction of CuII species in the catalysts to CuI
species and 50 mmol of 4a production (100 mmol of 2a consumption) cor-
responds to 100% reduction of the CuII species under the present condi-
tions. Reaction conditions: Catalyst (Cu: 100 mmol), 2a (5 mmol), toluene
(15 mL), 608C, under Ar atmosphere.
tions are shown in the Figure caption. As shown in Figure 3,
almost equimolar amounts of 2a with respect to the copper
species in the catalysts were converted into 4a, and then the
reaction stopped; 110ꢃ10 mmol of 2a was converted into 4a
using 100 mmol of Cu(OH)x/TiO2 for the 30 min-pretreat-
ment (Figure 3a). The Cu(OH)x/TiO2 catalyst was retrieved
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Chem. Eur. J. 2009, 15, 10464 – 10472

An Efficient Reusable Heterogeneous Catalyst
FULL PAPER
under an Ar atmosphere after the 30 min-pretreatment with
2a and the UV/Vis spectrum was measured. As shown in
Figure S6, the absorption band at l=730 nm assignable to
the d–d transition of the CuII species[19] was almost disap-
peared by the alkyne pretreatment.[20,21] All these results
suggest that the following reduction of CuII species to CuI
species by an alkyne takes place during the alkyne pretreat-
ment [Eq. (4)].[13] According to Equation (3), the abstraction
of an alkyne hydrogen to form the CuII-acetylide species can
occur on the Cu(OH)x/TiO2 and Cu(OH)x/Al2O3 catalysts.
an organic azide. During the pretreatment, all of the CuII
species in Cu(OH)x/TiO2 were reduced to the catalytically
active CuI species.[24] On the other hand, the degree of the
reduction of CuII species in Cu(OH)x/Al2O3 was ca. 10%
(estimated by the diyne formation) by the 30 min-pretreat-
ment.
A possible reaction mechanism: We here propose a possible
reaction mechanism for the present 1,3-dipolar cycloaddition
(Scheme 1). First, the alkyne-alkyne homocoupling proceeds
Upon the pretreatment of Cu(OH)x/TiO2 with 2a, the re-
duction of the CuII species was completed within 20 min as
shown in Figure 3a. The formation rate of 4a with Cu(OH)x/
TiO2 (based on the consumption of 2a) was 16.1ꢃ
1.6 mmhꢀ1 and more than twenty times larger than that with
Cu(OH)x/Al2O3 (0.684ꢃ0.075 mmhꢀ1).[22] This result shows
that the reduction of CuII species on TiO2 more easily pro-
ceeds than that on Al2O3 as has been reported.[23] The cata-
lytic reaction rate for the 1,3-dipolar cycloaddition of 1a to
2a with Cu(OH)x/TiO2 and Cu(OH)x/Al2O3 linearly in-
creased with an increase in the amount of in situ generated
CuI species (controlled by changing the length of the alkyne
pretreatment and estimated by the diyne formation) as
shown in Figure 4. This means that the in situ generated CuI
species are catalytically active species for the present 1,3-di-
polar cycloaddition. The present 1,3-dipolar cycloaddition
reactions were carried out by pretreating catalysts with the
respective alkyne at 608C for 30 min before the addition of
Scheme 1. A possible reaction mechanism for the present Cu(OH)x/TiO2-
catalyzed 1,3-dipolar cycloaddition. First, the alkyne-alkyne homocou-
pling proceeds on the CuII site to form the corresponding diyne and the
catalytically active CuI species. After the CuI species are generated, the
1,3-dipolar cycloaddition likely proceeds via the reaction mechanism pro-
posed by Sharpless and co-workers.[3a]
on the CuII sites to form the corresponding diyne and re-
duced CuI species according to Equations (3) and (4).[13,22]
This step corresponds to the induction period for the reac-
tion without the alkyne pretreatment. Upon the pretreat-
ment of catalysts with an alkyne, the induction period can
be eliminated. In the present Cu(OH)x/TiO2-catalyzed
system, an alkyne itself can act as an efficient reducing
agent to generate the catalytically active CuI species. There-
fore, no reducing agents, such as sodium ascorbate and as-
corbic acid, are necessary in the present system. After the
CuI species are generated by the alkyne-alkyne homocou-
pling, the 1,3-dipolar cycloaddition possibly proceeds as fol-
lows (Scheme 1):[3,5,6] The CuI-acetylide species is formed by
the reaction of the CuI species with an alkyne (Figure S6).[20]
The reaction of the acetylide species with an azide to form
Figure 4. The relationship between the catalytic reaction rate of the 1,3-
dipolar cycloaddition of 1a to 2a and the amount of CuI species formed
in the supported copper hydroxide catalysts. The amount of CuI species
was estimated by the amount of 4a production and was controlled by
changing the length of the alkyne pretreatment. Reaction conditions:
Catalyst (Cu(OH)x/TiO2 or Cu(OH)x/Al2O3, Cu: 100 mmol), 1a (5 mmol),
2a (5 mmol), toluene (15 mL), 608C, under Ar atmosphere. The triangle
(~) and square (&) symbols indicate the results with Cu(OH)x/TiO2 and
Cu(OH)x/Al2O3, respectively.
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10469

N. Mizuno et al.
the corresponding CuI-tryazolyl intermediate. Finally, the
ligand exchange between the tryazolyl intermediate and
proton or water to produce the corresponding triazole and
CuI species.[15]
v) reusability of the Cu(OH)x/TiO2 catalyst, and vi) use of an
easily prepared Cu(OH)x/TiO2 catalyst.
As above-mentioned, the 1,3-dipolar cycloaddition of 1a
to the deuterated 2a’ gave 3a in 99% yield (by GC) and the
deuterium content at the 5-position of 3a was 27%
[Eq. (5)].[25] When the 1,3-dipolar cycloaddition of 1a to the
non-deuterated 2a in the presence of Cu(OH)x/TiO2 pre-
treated with D2O (see the Experimental Section), the deute-
rium was introduced at the 5-position of 3a and the content
was 59% [Eq. (6)].[26] In the cycloaddition of 1a to 2a’ using
the catalyst pretreated with D2O, the 5-position of 3a was
deuterated in 86% [Eq. (7)]. Therefore, the hydrogen at the
5-position of 3a mainly comes from water (or proton) on
the catalyst. All these results for the deuterium-labeling ex-
periments are consistent with the above-mentioned possible
reaction mechanism involving the acetylide formation (via
Experimental Section
General: GC analyses were performed by using a Shimadzu GC-2014
with a FID detector equipped with a TC-1 or TC-5 capillary column. The
mass spectra were recorded by using a Shimadzu GCMS-QP2010 at an
ionization voltage of 70 eV. The liquid-state NMR spectra were recorded
by using a JEOL JNM-EX-270. The 1H and 13C NMR spectra were mea-
sured at 270 and 67.8 MHz, respectively, with TMS as an internal stan-
dard (d=0 ppm). The 2H NMR spectra were measured at 41.25 MHz
using [D6]benzene as an internal standard (d=7.2 ppm). The XRD pat-
terns were measured with Rigaku MultiFlex using CuKa radiation
(40 kV–50 mA). The XPS measurements were carried out by using a
JEOL JPS-90 using monochromated AlKa radiation (hn=1486.6 eV). The
X-ray anode was run at 200 W and the voltage was kept at 10 kV. The
pass energy was fixed at 10.0 eV to ensure sufficient resolution to deter-
mine peak positions accurately. The binding energies were calibrated by
using the Au 4f7/2 signal at 84.0 eV. The UV/Vis spectra were recorded on
Jasco V-570. The ICP-AES analyses were performed with Shimadzu
ICPS-8100.
ꢀ
cleavage of the terminal C H bond) and the ligand ex-
change between the tryazolyl intermediate and water (or
proton).
Reagents: TiO2 (anatase, ST-01, BET surface area: 316 m2 gꢀ1), Al2O3
(KHS-24, BET surface area: 174 m2 gꢀ1), and SiO2 (CARiACT Q-10, Lot
No. C-0502007, BET surface area: 273 m2 gꢀ1) were obtained from Ishi-
hara Sangyo Kaisya Ltd., Sumitomo Chemical Co. Ltd., and Fuji Silysia,
respectively. Copper salts were obtained from Wako Pure Chemical In-
dustries, Kanto Chemical, or TCI (reagent grade) and used as received.
Toluene and acetonitrile (Kanto Chemical) were purified by The Ulti-
mate Solvent System (GlassContour Company).[27] Other solvents and al-
kynes were obtained from TCI or Aldrich (reagent grade) and purified
prior to the use.[28] Organic azides (except for 1d) were prepared by the
nucleophilic substitution of the corresponding alkyl chloride (or iodide)
with sodium azide.[29] Compound 1d was obtained from Aldrich (reagent
grade).
Preparation of supported copper hydroxide catalysts: A typical proce-
dure for the preparation of the supported copper hydroxide catalysts is
as follows.[22] The aqueous solution (60 mL) of CuCl2·2H2O (0.085 g,
8.3 mm) containing the TiO2 powder (2.0 g) calcined at 5508C was vigo-
rously stirred at room temperature. After 15 min, the solution was quick-
ly adjusted to pH 12 by addition of an aqueous solution of NaOH (1.0m,
base treatment) and the resulting slurry was further stirred for 24 h. The
solid was then filtered off, washed with a large amount of water, and
dried in vacuo to afford 2.0 g of Cu(OH)x/TiO2 as a light blue powder.
The content of copper was 1.6 wt%. The content of water was ꢂ10 wt%.
The content of copper was controllable in the range of 0.5–2.0 wt% by
changing the concentration of the initial CuCl2 solution. The XRD pat-
tern of Cu(OH)x/TiO2 was the same as that of the parent TiO2 support;
no signals due to copper metal (clusters) and copper oxides were ob-
served. The XPS spectrum of Cu(OH)x/TiO2 showed the binding energies
of Cu 2p3/2 at 933.8 eV (full width at the half maximum: 3.7 eV) with the
shakeup satellite peak at 942.3 eV, suggesting that the oxidation state of
the copper species is +2.[30] No chlorine was detected in Cu(OH)x/TiO2
by the XPS measurement.
Conclusions
The supported copper hydroxide Cu(OH)x/TiO2 showed
high catalytic performance for the 1,3-dipolar cycloaddition
of organic azides to terminal alkynes under anaerobic condi-
tions. The reaction of various kinds of structurally diverse
substrates could be converted into the desired 1,4-disubsti-
tuted-1,2,3-triazoles in high to excellent yields. The observed
catalysis was truly heterogeneous and the catalyst retrieved
after the reaction could be reused with retention of its high
catalytic performance. The in situ generated CuI species
would be the catalytically active species for the present 1,3-
dipolar cycloaddition. The present systems have the follow-
ing significant advantages; i) applicability to various organic
azides and terminal alkynes, ii) higher catalytic activities
than those of the previously reported heterogeneous cata-
lysts,[6] iii) no use of additives such as reducing agents, stabi-
lizing ligands, and bases, iv) easy catalyst/product separation,
Preparation of CuCl2/TiO2 and CuCl2/Al2O3: The CuCl2/TiO2 catalyst
was prepared according to the following procedure. The acetone solution
(5 mL) of CuCl2·2H2O (0.027 g, 31.7 mm) containing the TiO2 powder
(1.0 g) was vigorously stirred at room temperature. After 3 h, acetone
was removed by evaporation to afford 1.0 g of CuCl2/TiO2 as a light blue
powder. The content of copper was 1.0 wt%. The CuCl2/Al2O3 (1.0 wt%)
catalyst was prepared by means of the same procedures.
Pretreatment of Cu(OH)x/TiO2 with D2O: All operations were carried
out under Ar atmosphere. The D2O solution (10 mL) of Na2CO3
(0.1 mm) containing the Cu(OH)x/TiO2 catalyst (0.5 g) was vigorously
stirred at room temperature for 24 h. The solid was then filtered off,
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Chem. Eur. J. 2009, 15, 10464 – 10472

An Efficient Reusable Heterogeneous Catalyst
FULL PAPER
washed with D2O (10 mL), and dried in vacuo. The above cycle was re-
peated three times.
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Procedure for the 1,3-dipolar cycloaddition: A typical procedure for the
1,3-dipolar cycloaddition of organic azides to terminal alkynes is as fol-
lows: Into a glass vial were successively placed Cu(OH)x/TiO2 (2.5 mol%
with respect to an alkyne), 2a (0.5 mmol), and toluene (1.5 mL). The so-
lution was stirred at 608C for 30 min under Ar atmosphere (pretreatment
of Cu(OH)x/TiO2). Then, 1a was added to the solution and the resulting
reaction mixture was stirred at 608C under Ar atmosphere. The yield was
periodically determined by the GC analysis. After the reaction was com-
pleted (5 min, 99% GC yield), Cu(OH)x/TiO2 was separated by filtration
and was further washed with toluene. The filtrate was evaporated in
vacuo, giving analytically pure 3a (89% isolated yield). The recovered
Cu(OH)x/TiO2 was further washed with toluene and dried in vacuo
before recycling. The products were confirmed by the comparison of
their GC retention times, mass spectra, 1H and 13C NMR spectra, and ele-
mental analyses with those of authentic data.[5k,6i,14] The data of isolated
triazoles are shown in the Supporting Information. Purities of isolated
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1
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Acknowledgements
This work was supported in part by the Core Research for Evolutional
Science and Technology (CREST) program of the Japan Science and
Technology Agency (JST), the Global COE Program (Chemistry Innova-
tion through Cooperation of Science and Engineering), and Grants-in-
Aid for Scientific Researches from Ministry of Education, Culture,
Sports, Science and Technology.
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under an air atmosphere gave 10% yield of 3a without the alkyne
treatment under the conditions described in Table 1.
[12] The preparation of the highly dispersed copper hydroxide supported
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the aqueous CuCl2 solution.
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treated catalyst resulted in a slight decrease in the deuterium con-
tent from 98% to 94% under the same conditions.
[18] It was confirmed that no H/D-exchange reaction proceeded in the
presence of an equimolar amount of water with respect to 2a’ with-
out Cu(OH)x/TiO2 or with TiO2.
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N. Mizuno et al.
[20] In addition to the disappearance of the d–d transition, a new broad
absorption band appeared around 400–500 nm by the pretreatment
of Cu(OH)x/TiO2 with 2a (Figure S6). In the UV/Vis spectrum of
ꢁ
[24] In the 1,3-dipolar cycloaddition of 1a to 2a, the TOF values (based
on copper species in the catalysts) did not change with the loadings
of copper species (0.5–2.0 wt%) because all of the CuII species were
reduced to the catalytically active CuI species during the alkyne pre-
treatment.
[25] Under the same conditions without 1a, the deuterium content at the
terminal position of 2a’ was decreased from 98% to 43% by the H/
d-exchange reaction in the presence of Cu(OH)x/TiO2.
[26] We confirmed that no H/D-exchange reaction of the hydrogen at
the 5-position of non-deuterated triazole 3a proceeded in the pres-
ence of Cu(OH)x/TiO2 pretreated with D2O under the present reac-
tion conditions.
[27] A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen, F. J.
Timmers, Organometallics 1996, 15, 1518.
[CuI
ACHTUNGTRENNUNG(C CPh)]n, a similar broad absorption band was observed
around 400–460 nm. Therefore, the CuI-acetylide species[21] is likely
formed by the pretreatment. Upon the treatment with 1a in toluene
at 608C (forty equivalents with respect to the copper species in
Cu(OH)x/TiO2), the absorption band due to the acetylide species
disappeared with the formation of 3a.
[21] It has been reported that the acetylide!CuI LMCT band was ob-
served at 374 nm for the CuI acetylide complex of [CuI
4ACTHNUTRGENUG(N m-
1
2
2+
ꢁ
dppm)4(m4-h ,h -C C)]
(dppm=bis(diphenylphosphino)methane):
V. W.-W. Yam, K. K.-W. Lo, W. K.-M. Fung, C.-R. Wang, Coord.
Chem. Rev. 1998, 171, 17.
[22] The catalytic alkyne–alkyne homocoupling efficiently proceeded
with Cu(OH)x/TiO2 at 1008C using molecular oxygen as a re-oxidant
of the CuI species (Table S1). In contrast, the homocoupling hardly
proceeded with Cu(OH)x/Al2O3: T. Oishi, T. Katayama, K. Yamagu-
chi, N. Mizuno, Chem. Eur. J. 2009, 15, 7539.
[28] Purification of Laboratory Chemicals, 3rd ed. (Eds.: D. D. Perrin,
W. L. F. Armarego), Pergamon Press, Oxford, 1988.
[29] E. Lieber, T. S. Chao, C. N. R. Rao, J. Org. Chem. 1957, 22, 238.
[30] a) D. Briggs, M. P. Seah, Practical Surface Analysis by Auger and X-
ray Photoelectron Spectroscopy, Wiley, New York, 1983; b) G. P. Wil-
liams in CRC Handbook of Chemistry and Physics, 82nd ed. (Ed.:
D. R. Lida), CRC Press, Washington, 2001, Section 10, pp. 200–205.
[23] The interaction between Cu species and TiO2 leads to a better re-
ducibility of CuII species. It has been reported that the oxo bond Ti
ꢀ
ꢀ
O Cu is likely involved the reductive step. See: a) H. Irie, S. Miura,
K. Kamiya, K. Hashimoto, Chem. Phys. Lett. 2008, 457, 202; b) G.
Li, N. M. Dimirijevic, L. Chen, T. Rajh, K. A. Gray, J. Phys. Chem.
C 2008, 112, 19040.
Received: May 29, 2009
Published online: August 28, 2009
10472
www.chemeurj.org
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 10464 – 10472