Hydroxyapatite-supported copper(II)-catalyzed azide-alkyne [3+2] cycloaddition with neither reducing agents nor bases in water

Article abstract of DOI:10.1016/j.tetlet.2011.10.060

Copper(II)-exchanged hydroxyapatite, prepared by ion-exchanging of Ca(II) in calcium hydroxyapatite [Ca₁₀(PO₄)₆(OH) ₂] with Cu(NO₃)₂ at 70 °C in water, functions as a reusable heterogeneous

Full text of DOI:10.1016/j.tetlet.2011.10.060

Tetrahedron Letters 52 (2011) 6916–6918
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Tetrahedron Letters
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Hydroxyapatite-supported copper(II)-catalyzed azide–alkyne [3+2]
cycloaddition with neither reducing agents nor bases in water
Yoshiro Masuyama a, , Kazuki Yoshikawa a, Noriyuki Suzuki a, Kenji Hara b, Atsushi Fukuoka b
⇑
a Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
b Catalysis Research Center, Hokkaido University, Sapporo 001-0021, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Copper(II)-exchanged hydroxyapatite, prepared by ion-exchanging of Ca(II) in calcium hydroxyapatite
[Ca10(PO4)6(OH)2] with Cu(NO3)2 at 70 °C in water, functions as a reusable heterogeneous catalyst with
neither reducing agents nor bases for azide–alkyne [3+2] cycloaddition at 50 °C in water under air.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 18 August 2011
Revised 6 October 2011
Accepted 11 October 2011
Available online 17 October 2011
Keywords:
Copper(II)-exchanged hydroxyapatite
Azide–alkyne [3+2] cycloaddition
Reusable heterogeneous catalyst
Environmentally-benign process
Cu(I)-catalyzed azide–alkyne [3+2] cycloaddition is one of the
most versatile reactions in click chemistry,1–3 and has been applied
to drug discovery4 and material sciences5 as a synthetic tool. It has
been proposed that Cu(I) catalysis is essential to the azide–alkyne
cycloaddition.6–8 Cu(II) species such as CuSO4 can also be reduced
in situ with reducing agents such as sodium ascorbate to be applied
to the azide–alkyne cycloaddition.3 Heterogeneous Cu(I)-supported
catalysts have been applied to the azide–alkyne cycloaddition in
repetitive uses. The Cu(I) species have been directly immobilized
onto inorganic supports9,10 or organic polymers,11 or have been gen-
species.16c Cu(I) species seem to be active catalysts in most of the
cycloadditions described above. No direct role of Cu(II) species in
the azide–alkyne cycloaddition has been recognized, whereas a
few Cu(II)-immobilized catalysts have been found to serve as the
cycloaddition reducing agents such as sodium ascorbate, in the
development of heterogeneous catalytic systems.17,18
The availability of hydroxyapatites (HAP) for supporting transi-
tion metals has been demonstrated; this must be attributed to their
cation-exchange ability and adsorption capability. Some HAP-sup-
ported transition metals, such as ruthenium, palladium, copper,
and silver, have been applied as heterogeneous catalysts to environ-
mentally benign organic syntheses. These have been prepared by
four kinds of methods: adsorption, incorporation, ion-exchange,
and nanoparticle formation.19 We have recently reported that an
ion-exchanged HAP-supported palladium(II) (PdHAP), easily pre-
pared from calcium hydroxyapatite [Ca10(PO4)6(OH)2] and Pd(NO3)2
in water, functions as a reusable catalyst for the allylic alkylation of
allyl methyl carbonate with carbon nucleophiles in water.20 An ion-
exchanged HAP-supported copper(II) (CuHAP), prepared from
calcium hydroxyapatite [Ca10(PO4)6(OH)2] and Cu(OAc)2 in water,
has been applied only as a heterogeneous catalyst to the three-com-
ponent coupling of aldehydes, amines, and alkynes in refluxing ace-
tonitrile.21 Thus, we planned to demonstrate the direct role of Cu(II)
species in the azide–alkyne [3+2] cycloaddition without any addi-
tives such as reducing agents or bases. We would use CuHAP, easily
prepared from [Ca10(PO4)6(OH)2] and Cu(NO3)2 in water similarly to
PdHAP. Thus we would establish a reusable process of CuHAP in
water under air with the aim of advancing ion-exchanged CuHAP
for environmentally benign catalysis.
erated in situ from Cu(0)12,13 or Cu(II)14 species.
c-Keggin silicotung-
state containing dicopper(II) core can be applied to the azide–alkyne
cycloaddition without any additives such as reducing agents or
nitrogen bases.15 It was postulated that its actual catalysts were
Cu(I) species to which copper(II) species in the c-Keggin silicotung-
state were reduced with terminal alkynes. At that time the alkynes
caused oxidative homocoupling to produce 1,4-disubstituted 1,3-
butadiynes. Using azides bearing Cu(II)-co-ordinate N-containing
groups such as 2-pyridyl or amino groups or multidentate nitrogen
ligands chelating to Cu(II), a homogeneous catalytic process with
Cu(OAc)2 was also realized without reducing agents.16 In the
Cu(OAc)2-catalyzed cycloaddition, it was speculated that the partial
reduction of Cu(II) species to Cu(I) species would take place under
either alcohol oxidation or alkyne oxidative homocoupling to
prepare a catalytically active Cu(II)/Cu(I) mixed valency dinuclear
⇑
Corresponding author. Tel.: +81 3 3238 3453; fax: +81 3 3238 3361.
E-mail address: y-masuya@sophia.ac.jp (Y. Masuyama).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.060

Y. Masuyama et al. / Tetrahedron Letters 52 (2011) 6916–6918
6917
N
R1
N
N
N
CuHAP
N
N
N
N
N
N
N
N
R1 N3
Ph
Ph
Ph
R2
+
ð1Þ
R2
C6H4p-Me
C6H4p-OMe
98%
(50 ºC, 8 h, H2O)
C6H13
1
2
3
98%
(50 ºC, 8 h, H2O)
55%
(70 ºC, 8 h, H2O)
A
calcium hydroxyapatite of Ca/P = 1.67 [Ca10(PO4)6(OH)2]
(HAP)22 (2 mmol) was added to a solution of Cu(NO3)2 (0.20 mmol)
in water (150 mL). The solution was stirred at 70 °C for 24 h. The
obtained slurry was filtered, washed with deionized water, and
dried overnight at 110 °C to afford a Cu(II)-exchanged hydroxyap-
atite (CuHAP, Cu content: 0.10 mmol g-1) as a blue powder. Induc-
tively coupled plasma (ICP) analysis revealed that Cu2+ was absent
in the filtrate and that in the filtrate there was a 1.4 molar quantity
of Ca2+ to that of Cu2+ employed. XRD showed that the isomorphic
substitution of Ca for Cu had occurred.23
N
N
N
N
N
N
N
N
N
Ph
Ph
Ph
OH
OH
OH
93%
83%
60%
(70 ºC, 8 h, EtOH)
(70 ºC, 8 h, EtOH)
(70 ºC, 8 h, EtOH)
N
N
N
N
N
The catalytic activity of the CuHAP was investigated for the
[3+2] cycloaddition of benzyl azide (1; R1 = PhCH2) and phenyl-
acetylene (2; R2 = Ph) (Eq. 1). The results are summarized in Table
1. The cycloaddition with CuHAP occurred at 50 °C for 8 h in water
under air to afford 1-benzyl-4-phenyl-1,2,3-triazole (3; R1 = PhCH2,
R2 = Ph) regioselectively in 97% yield (entry 1).24 The cycloaddition
with CuHAP needed neither reducing agents such as sodium ascor-
bate nor bases such as triethylamine,1,2 and smoothly proceeded
N
N
N
N
Ph
Ph
Ph
OH
OH
OMe
Ph
78%
O
74%
(50 ºC, 8 h, H2O)
86%
(50 ºC, 8 h, H2O)
(50 ºC, 8 h, H2O)
N
C8H17
N
N
N
N
C8H17
under air, in contrast to that with dicopper(II) substituted c-Keggin
C8H17
N
N
N
N
silicotungstate.15 Water (97%) as a solvent was superior to ethanol
(37%), dioxane (4%), or toluene (13%) (entries 1–4). Since the cyclo-
addition with either Cu(NO3)2 (0.02 mmol) or HAP (0.20 g) affor-
ded almost the same yield (13–14%) as that without CuHAP at
50 °C for 24 h in water (entries 5–7), neither Cu(NO3)2 nor HAP
would serve as a catalyst for the cycloaddition. Benzyl azide (1;
R1 = PhCH2) and octyl azide [1; R1 = CH3(CH2)7] can be applied to
the [3+2] cycloaddition with various alkynes in H2O, as shown in
Figure 1. Internal alkynes such as 1-phenylpropyne and 5-decyne
did not react with 1 (R1 = PhCH2) at all under the same reaction
conditions as those of the typical procedure.
OEt
C6H4p-OMe
68%
(70 ºC, 16 h, H2O)
Ph
O
73%
(70 ºC, 16 h, H2O)
88%
(70 ºC, 16 h, H2O)
Figure 1. CuHAP-catalyzed azide–alkyne [3+2] cycloaddition.
Table 2
Reusability of CuHAP for the azide–alkyne [3+2] cycloadditiona
Repetitive use
Yield (%)
1st
95
2nd
96
3rd
94
4th
95
5th
86
6th
78
7th
80
8th
80
The reusability of CuHAP for the [3+2] cycloaddition of 1
(R1 = PhCH2) and 2 (R2 = Ph) was demonstrated by maintaining
its catalytic activity in eight repetitive uses under almost the same
conditions as those of the typical procedure in H2O (Table 1, entry
1), as shown in Table 2. Although the ionic radius of Cu2+ is smaller
than that of Ca2+, the powder X-ray diffraction (XRD) peaks for ion-
exchanged CuHAP were the same as those of calcined HAP, and
then did not change even after eight repetitive uses. X-ray photo-
electron spectroscopy (XPS) confirmed no variation of binding en-
ergy and intensity of Cu 2p3/2 peaks between fresh CuHAP and
eight repetitively used CuHAP; a small peak of 934.3 eV that would
be assigned to Cu(II) was observed even after eight repetitive uses.
X-ray fluorescence (XRF) analyses revealed that most of the copper
had remained in the HAP matrix even after eight repetitive uses.
The [3+2] cycloaddition of 1 (R1 = PhCH2, 1.0 mmol) and 1-deu-
tero-2-phenylethyne (1.5 mmol) slowly proceeded at 50 °C in H2O
(1 mL) to produce only 41% yield of 21%-deuterated 4 at 5-position
a
The [3+2] cycloaddition of benzyl azide (1.0 mmol) and phenylacetylene
(1.5 mmol) was carried out with CuHAP (Cu 0.05 mmol) at 50 °C for 16 h in H2O
(1 mL).
even after 24 h (Eq. 2), while the [3+2] cycloaddition of
1
(R1 = PhCH2, 1.0 mmol) and 2 (R2 = Ph, 1.5 mmol) at 50 °C for 8 h
in D2O (1 mL) afforded 90%-deuterated 5 at 5-position in 96% yield
(Eq. 3).
N
CuHAP
N
N
Ph
+
PhCH2N3
D
Ph
ð2Þ
ð3Þ
H2O
50 ºC, 24 h
41%
D
Ph
4 (21% deuterated)
N
CuHAP
N
N
Ph
+
PhCH2N3
H
Ph
D2O
50 ºC, 8 h
96%
D
Ph
Table 1
[3+2] Cycloaddition of 1 (R1 = PhCH2) and 2 (R2 = Ph)a
5 (90% deuterated)
Entry
Catalyst
Cu (mmol)
Solvent
Time (h)
3, Yield (%)
On the basis of (1) the performance without either any reducing
agent or any base, (2) no detection of alkyne oxidative homocou-
pling products, namely 1,4-disubstituted 1,3-butadiynes, in the
reaction with excess alkynes under air, (3) the XPS assignment of
Cu(II) species in repeatedly used CuHAP, (4) the extremely slow
reaction of 1-deutero-2-phenylethyne in H2O, in contrast to the
reaction of 2 (R2 = Ph) in D2O (Eqs. 2 and 3), and (5) no availability
of internal alkynes, the direct participation of Cu(II) species and the
formation of Cu(II)-acetylide complex as a key and rate-determin-
1
2
3
4
5
6
7
CuHAP
CuHAP
CuHAP
CuHAP
Cu(NO3)2
HAP
0.02
0.02
0.02
0.02
0.02
0
H2O
8
8
8
97
37
4
13
13
14
14
Ethanol
Dioxane
Toluene
H2O
H2O
H2O
8
24
24
24
—
0
a
The [3+2] cycloaddition of benzyl azide (1.0 mmol) and phenylacetylene
(1.5 mmol) was carried out with CuHAP (Cu 0.02 mmol) at 50 °C in a solvent (1 mL).

6918
Y. Masuyama et al. / Tetrahedron Letters 52 (2011) 6916–6918
N
References and notes
N
N
R1
R2
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ing step was suggested.18 Part of deuterated phosphoric acids in
HAP, generated from 1-deutero-2-phenylethyne together with
the initial Cu(II)-acetylide intermediate, were probably maintained
until forming a final intermediate A6–8 as shown inFigure 2, similar
to the general 5-cuprated 1,2,3-triazole intermediates in Cu(I)-cat-
alyzed azide–alkyne cycloadditions. Thus, 21%-deuterated 4 would
be produced in dependence on the D–H exchange of deuterated
phosphoric acids with H2O.
In conclusion, at this point in time from the results of no detec-
tion of alkyne oxidative homocoupling products and XPS assign-
ment of Cu(II) species, we speculated that Cu(II) species on
CuHAP served as a reusable catalyst for the azide–alkyne [3+2]
cycloaddition without either any reducing agent or any base in
H2O under air. The phosphate group of HAP would serve efficiently
for the retention of Cu(II) species to HAP support. The smooth pro-
gress of the [3+2] cycloaddition in H2O seems to be attributable to
the locally high concentration of liquid substrates, namely both
azides and alkynes on the CuHAP surface, which probably bases
on the substrate-dispersing effect of H2O and the substrate-adsorb-
ing effect of CuHAP. Therefore the CuHAP-catalyzed azide–alkyne
[3+2] cycloaddition will be considered as one of the most environ-
mentally-benign processes.
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24. Typical procedure for CuHAP-catalyzed azide–alkyne [3+2] cycloaddition: To a
suspension of CuHAP (0.2 g, Cu 0.02 mmol) in water (1 mL) were added benzyl
azide (1; R1 = PhCH2, 0.13 g, 1 mmol) and phenylacetylene (2; R2 = Ph, 0.15 g,
1.5 mmol). After the suspension was shaken at 50 °C for 8 h under air in a
shaking aluminum block (Nissinrika Co., Block Shaker NX-70B, stroke: 10 mm,
speed: 220–230 rpm), ethyl acetate (8 mL) was added to the suspension. The
solution was separated from CuHAP by centrifugation followed by decantation.
The same operation with ethyl acetate (8 mL) was repeated five times. The
separated CuHAP was reused after being evacuated to dryness.
Dichloromethane (100 mL) was added to the residue after removing ethyl
acetate and water in the combined solution. The solution was dried over
anhydrous MgSO4. After evaporation of dichloromethane and purification by
column chromatography (silica gel, hexane/ethyl acetate = 3:1), 0.23 g (97%) of
1-benzyl-4-phenyl-1,2,3-triazole (3; R1 = PhCH2, R2 = Ph) was obtained as a
colorless solid. The structures of all products were confirmed by the
comparison of spectroscopic values (IR and NMR) with those of authentic
samples in the literature: see Supplementary data.
Acknowledgment
We thank the Cooperative Research Program of Catalysis Re-
search Center, Hokkaido University (Grant #2010-B-24).
Supplementary data
Supplementary data (XRD of HAP, fresh CuHAP and repetitively
reused CuHAP, XPS and XRF of fresh CuHAP and repetitively reused
CuHAP, and IR and NMR spectra of products) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.10.060.