Cu/HP20-catalyzed solvent-free huisgen cycloaddition at ordinary temperatures

Article abstract of DOI:10.3987/COM-13-S(S)6

We have developed an environmentally friendly and highly efficient solvent-free Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using a polymer-supported copper catalyst (Cu/HP20). Substrates poorly soluble in common organic solvents are also

Full text of DOI:10.3987/COM-13-S(S)6

HETEROCYCLES, Vol. 88, No. 1, 2014
233
HETEROCYCLES, Vol. 88, No. 1, 2014, pp. 233 - 243. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 15th April, 2013, Accepted, 29th May, 2013, Published online, 31st May, 2013
DOI: 10.3987/COM-13-S(S)6
Cu/HP20-CATALYZED SOLVENT-FREE HUISGEN CYCLOADDITION
AT ORDINARY TEMPERATURES
Yoshiaki Kitamura,1 Kazumi Taniguchi,2 Tomohiro Maegawa,2,§ Yasunari
Monguchi,2 Yukio Kitade,1,3 and Hironao Sajiki2,*
1
Department of Chemistry and Biomolecular Science, Faculty of Engineering,
Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
2
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4
Daigaku-nishi, Gifu 501-1196, Japan, E-mail address: sajiki@gifu-pu.ac.jp
3
United Graduate School of Drug Discovery and Medical Information Sciences,
Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
This paper is dedicated to Professor Dr. Victor Snieckus on the occasion of his
77th birthday.
Abstract – We have developed an environmentally friendly and highly efficient
solvent-free Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction using
a polymer-supported copper catalyst (Cu/HP20). Substrates poorly soluble in
common organic solvents are also applicable to the present cycloaddition reaction
without any solvents and provide the corresponding 1,4-triazole in high yields.
INTRODUCTION
In recent years, environmentally-friendly reaction processes have been vigorously studied on the basis of
green chemistry. One of the major environmental impacts of organic synthesis is the solvent use, and the
reaction systems without a solvent have attracted much attention. The use of heterogeneous catalysts
instead of stoichiometric amounts of reagents or homogeneous catalysts in a solvent-free reaction is also
highly recommended since only the appropriate and small amount of solvent(s) to dissolve the organic
products and residual reagents is required to separate the catalyst from the reaction mixture. We have
recently reported the solvent-free and heterogeneous Pd/C-catalyzed hydrogenation and Suzuki-Miyaura
coupling reaction.1
The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC), independently developed by Sharpless2 and
Meldal,3 has become the most remarkable example of click chemistry and has been widely applied in

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HETEROCYCLES, Vol. 88, No. 1, 2014
organic syntheses as well as the medicinal and process chemistry fields.4 Although a number of CuAAC
methods using homogeneous catalysts have been developed to date,5 most of the procedures have some
drawbacks, such as the use of a significant amount of expensive and/or difficult-to-prepare catalysts,
and/or organic solvents, etc. Likewise, numerous heterogeneous (supported) copper catalysts have been
applied to the CuAAC methods,6 and Kiser7 and Fokin8 independently developed transition-metal-free
azide-alkyne cycloadditions, while the use of organic solvents is required for these reactions. A few
solvent-free and heterogeneous CuAACs were recently reported, but these methods required elevated
temperature conditions9 and special equipment, such as a microwave10 and a ball-mill.11 However, the
Amberlyst A21-supported copper (I) catalyst12 is an exception to this requirement.
We have recently reported a newly-developed solvent-free CuAAC using a copper catalyst (Cu/CR11)
supported on a polystyrene-divinylbenzene-based chelate resin possessing iminodiacetic acid moieties as
a tridentate ligand, DIAION CR11 (Mitsubishi Chemical Corporation).13 Although Cu/CR11 is a highly
dispersed heterogeneous catalyst, the application of heat (70 ºC) was required for the efficient reaction
progress due to the tight chelation of copper to the resin. On the other hand, we have also previously
developed a polystyrene-divinylbenzene-based polymer, DIAION HP20 (Mitsubishi Chemical
Corporation)-supported copper catalyst (1% Cu/HP20) and used it as a catalyst for CuAAC under mild
conditions with an organic solvent, such as toluene, at room temperature.6v In addition, we have disclosed
the preparation of the HP20-supported palladium catalyst (10% Pd/HP20)14 and demonstrated the
application
to
the
ligand-free
cross-coupling
reaction.15
Since
HP20
is
a
polystyrene-divinylbenzene-based polymer possessing a high-specific surface area (ca. 590 m2/g) without
chelating functionalities within the molecule, it is anticipated to have a high catalyst activity even under
solvent-free conditions due to the loose interaction between the Cu species and HP20. Therefore, we
explored the application of Cu/HP20 to the solvent-free CuAAC.
RESULTS AND DISCUSSION
We investigated the CuAAC using 4-fluorobenzylazide (1a) and 3-methyl-1-butyn-3-ol (2a) as substrates
under solvent-free conditions. In the presence of 1% Cu/HP20 (2.0 mol% versus 1a) and Et3N (1.1 equiv
versus 1a),16 the cycloaddition was completed within 4 h at room temperature (Table 1, Entry 1). The use
of Cu/HP20 and Et3N was then optimized because the reduction of catalysts and reagents is an important
issue for an industrial application. The use of 1% Cu/HP20 could be reduced to 1.0 mol% without
significant reduction of the reactivity (Table 1, Entries 1 and 2). A further reduction of Cu/HP20 (0.5
mol% and 0.1 mol%) obviously suppressed the reaction progress, and the conversion yields of the
Huisgen adduct (3a) decreased with the lower use of Cu/HP20 [83% (0.5 mol%) and 25% (0.1 mol%),
respectively] (Entries 3 and 4). The reaction efficiency did not decrease with the reduced use of Et3N

HETEROCYCLES, Vol. 88, No. 1, 2014
235
down to 0.22 equiv, although the reaction was incomplete with 0.11 equiv of Et3N even after 24 h
(Entries 2 and 6–9). The addition of both Cu/HP20 and Et3N was indispensable for the reaction progress,
since no cycloaddition took place without Cu/HP20 or Et3N (Entries 5 and 10).16 We then confirmed the
substrate applicability of the present solvent-free cycloaddition of alkynes with azides in the presence of
1% Cu/HP20 (1.0 mol%) and 0.22 equiv of Et3N.
Table 1. Optimization of amounts of Cu/HP20 and Et3N for the Huisgen cycloaddition under solvent-free
conditions
Et3N (equiv)
Entry
1% Cu/HP20 (mol%)
Ratio 1a/3aa
0:100
1
2
3
4
5
2.0
1.0
0.5
0.1
0
1.1
1.1
1.1
1.1
1.1
0:100
17:83
75:25
100:0
6
7
8
9
1.0
1.0
1.0
1.0
1.0
0.55
0.33
0.22
0.11
0
0:100
0:100
0:100
27:73b
100:0
10
a Ratio was determined by 1H NMR. b The reaction was continuously performed for 24 h.
As shown in Table 2, a wide range of azides (1a–g) efficiently reacted with 3-methyl-1-butyn-3-ol (2a)
even though the reaction was performed at room temperature to give the corresponding Huisgen adducts
(3a–g) in nearly quantitative isolated yields (Entries 2–7). It is noteworthy that the cycloaddition of
3,5-dinitrobenzylazide (1c) with 2a also smoothly occurred at room temperature under solvent-free
conditions, although the reaction in toluene as a solvent never proceeded at room temperature and could
be completed by heating at 60 ºC (Entry 3).6v
Various terminal mono-substituted alkynes (2a–f) were also found to react with 4-fluorobenzylazide (1a)
to generate the corresponding 1,4-disubstituted triazoles (3) in moderate to quantitative yields (Table 3).
When 3-methyl-1-butyn-3-ol (2a) and 2-ethynylpyridine (2e) were used as substrates, the cyclization
proceeded in a very efficient way, since heteroatoms (O and N, respectively) adjacent to the alkynes
would presumably facilitate the approach to the Cu species of their C–C triple bonds (Entries 1 and 5).
On the other hand, conjugated terminal alkynes of ethynylbenzene (2c) and 1-ethynylcyclohexane (2d)

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HETEROCYCLES, Vol. 88, No. 1, 2014
Table 2. Cu/HP20-catalyzed solvent-free Huisgen cycloaddition between various azides (1a–g) and
3-methyl-1-butyn-3-ol (2a)
Entry
1
Azide
Time (h)
4
Product
Yield (%)a
100
2
3
6
92
89
24
24
24
24
(0c, 100d)b
4
5
6
100
100
100
7
24
100
b
c
d
a Isolated yield. Toluene (1 mL) was used as the solvent. No reaction was observed at rt. The
reaction was carried out at 60 °C.

HETEROCYCLES, Vol. 88, No. 1, 2014
237
without the neighboring-group participation indicated lower reactivities (Entries 3 and 4).
Table 3. Cu/HP20-catalyzed solvent-free Huisgen cycloaddition between 4-fluorobenzylazide (1a) and
various alkynes (2a–f)
Entry
1
Alkyne
Time (h)
4
Product
Yield (%) a
100
2
3
24
24
78
47
4
5
24
47
3
96
77
6
24
a Isolated yield.

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Next, the reuse test of 1% Cu/HP20 using 4-fluorobenzylazide (1a) and 3-methyl-1-butyn-3-ol (2a) as
substrates was examined. The reaction efficiency significantly decreased with the number of reuses
(Table 4). To confirm the reason for the degradation of the catalyst activity, the leaching of the copper
species from Cu/HP20 was then measured using inductively coupled plasma atomic emission
spectrometry (ICP-AES).17 The amount of leached copper was approximately 19%, thus the leaching of
copper species might be the cause of the difficult reuse of Cu/HP20.
Table 4. Investigation of the catalyst reuse of Cu/HP20
Run
Catalyst
Yield (%)a
1
2
3
4
Cu/HP20
100
88
34
recycled Cu/HP20 (1st)
recycled Cu/HP20 (2nd)
recycled Cu/HP20 (3rd)
27
a Isolated yield.
CONCLUSIONS
We have developed a solvent-free 1% Cu/HP20-catalyzed Huisgen cycloaddition reaction at room
temperature. The cycloaddition between azides (1) and terminal alkynes (2) in the presence of 1 mol% of
1% Cu/HP20 and only 0.22 equiv (versus azides) of Et3N has been regioselectively achieved under totally
solvent-free and mild conditions to give the corresponding 1,4-disubstituted thiazoles (3). It is particularly
worth noting that the reaction could be easily achieved at room temperature. Although significant
amounts of copper species were leached from Cu/HP20, it possesses a significantly strong catalyst
activity due to the weak interaction with HP20 as a support compared to the Cu catalyst supported on a
chelate resin (Cu/CR1114). The present methodology will find many applications for the synthesis of
heat-labile triazole-containing molecules.
EXPERIMENTAL
General
All reactions were carried out under argon. The deionized water was purchased from Wako Pure
Chemical Industries, Ltd. HP20 was a gift from the Mitsubishi Chemical Co. The azides were prepared
according to the known procedure.10 The terminal alkynes were purchased from Tokyo Chemical Industry

HETEROCYCLES, Vol. 88, No. 1, 2014
239
Co., Ltd. Et3N and the solvents were purchased from Nacalai Tasque, Inc. or Wako Pure Chemical
Industries, Ltd. The commercial reagents and solvents were used without further purification. Flash
column chromatography was performed using Kanto Chemical Co., Inc. silica gel 60N, spherical neutral
(63–210 µm).
General Procedure for 1% Cu/HP20-catalyzed CuAAC under solvent-free conditions
A mixture of the azide (1.0 mmol), the terminal alkyne (1.1 mmol), Et3N (30.4 μL, 220 μmol), and 1%
Cu/HP20 (63.5 mg, 10 μmol) in a test tube was stirred at room temperature. After a given period, the
mixture was diluted with H2O (2 mL) and EtOAc (2 mL), and passed through a filter paper. The filtrate
was separated into two layers, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica gel to give the corresponding
1,4-triazole, the structure of which was confirmed by comparison to the literature structure.
1
2-[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]propan-2-ol (3a)6v: Pale brown solid; H NMR (CDCl3) δ
7.34 (s, 1H), 7.27 (dd, J = 8.7 Hz, 5.3 Hz, 2H), 7.07 (t, J = 8.7 Hz, 2H), 5.47 (s, 2H), 1.61 (s, 6H); 13C
NMR (CDCl3) δ 162.5 (d, J = 247.0 Hz), 156.1, 130.4 (d, J = 3.3 Hz), 129.7 (d, J = 8.2 Hz), 119.2, 115.7
(d, J = 21.4 Hz), 68.1, 52.9, 30.2; MS (EI) C12H15N3OF (M+) 236.
1
2-(1-Benzyl-1H-1,2,3-triazol-4-yl)propan-2-ol (3b)18: Colorless solid; H NMR δ 7.40–7.34 (m, 4H),
7.29–7.26 (m, 2H), 5.50 (s, 2H), 1.61 (s, 6H); 13C NMR δ 156.0, 134.6, 129.0, 128.6, 128.0, 119.1, 68.4,
54.0, 30.3; MS (EI) C12H15N3O (M+) 217.
2-[1-(3,5-Dinitrobenzyl)-1H-1,2,3-triazol-4-yl]propan-2-ol (3c)6v: Pale yellow solid; 1H NMR
(DMSO-d6) δ 8.79 (s, 1H), 8.65 (s, 2H), 8.09 (s, 1H), 5.87 (s, 2H), 5.13 (s, 1H), 1.44 (s, 6H); 13C NMR
(DMSO-d6) δ 156.4, 148.2, 140.1, 128.8, 121.2, 118.4, 67.0, 50.9, 30.6; MS (EI) C12H13N5O5 (M+) 307.
1
2-[1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl]propan-2-ol (3d)6v: Yellow solid; H NMR (CDCl3) δ
7.37 (s, 1H), 7.21 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.39 (s, 2H), 3.78 (s, 3H), 1.58 (s, 6H); 13C
NMR (CDCl3) δ 159.6, 129.5, 126.5, 126.5, 118.9, 114.2, 68.2, 55.1, 53.4, 30.3; MS (EI) C13H17N3O2
(M+) 247.
1
2-(1-Phenyl-1H-1,2,3-triazol-4-yl)propan-2-ol (3e)6v: Yellow solid; H NMR (CDCl3) δ 8.04 (s, 1H),
7.67 (d, J = 8.1 Hz, 2H), 7.46–7.42 (m, 3H), 1.71 (s, 6H); 13C NMR (CDCl3) δ 156.5, 136.8, 129.4, 128.4,
120.2, 117.8, 68.3, 30.3; MS (EI) C11H13N3O (M+) 203.
2-[1-(3-Phenylpropyl)-1H-1,2,3-triazol-4-yl]propan-2-ol (3f)6v: Yellow oil; 1H NMR (CDCl3) δ 7.45 (s,
1H), 7.28 (t, J = 7.2 Hz, 2H), 7.21–7.14 (m, 3H), 4.29 (t, J = 7.2 Hz, 2H), 2.64 (t, J = 7.2 Hz, 2H), 2.21
(quint, J = 7.2 Hz, 2H), 1.63 (s, 6H); 13C NMR (CDCl3) δ 140.0, 128.4, 128.2, 126.1, 119.2, 68.2, 49.3,
32.4, 31.4, 30.3; MS (EI) C14H19N3O (M+) 245.

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HETEROCYCLES, Vol. 88, No. 1, 2014
{4-[4-(2-Hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl]phenyl}phenylmethanone (3g)6v: Pale brown
solid; 1H NMR (CDCl3) δ 8.05 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 7.3
Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H), 1.73 (s, 6H); 13C NMR (CDCl3) δ 195.2, 139.7,
137.3, 137.0, 132.8, 131.7, 129.9, 128.5, 119.8, 68.7, 30.5; MS (EI) C18H17N3O2 (M+) 307.
1
3-[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]propan-1-ol (3h)6v: Pale yellow solid; H NMR (CDCl3) δ
7.41 (s, 1H), 7.25 (dd, J = 8.7 Hz, 5.3 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 5.43 (s, 2H), 3.97 (s, 1H), 3.85 (t,
J = 6.3 Hz, 1H), 2.89 (t, J = 6.3 Hz, 1H); 13C NMR (CDCl3) δ 162.6 (d, J = 248.8 Hz), 145.7, 130.5 (d, J =
3.3 Hz), 129.7 (d, J = 8.2 Hz), 121.6, 115.7 (d, J = 22.0 Hz), 61.0, 53.0, 28.6; MS (EI) C11H12N3OF (M+)
221.
1
1-(4-Fluorobenzyl)-4-phenyl-1H-1,2,3-triazole (3i)6v: Colorless solid; H NMR (CDCl3) δ 7.79 (d, J =
7.2 Hz, 2H), 7.69 (s, 1H), 7.37 (t, J = 7.2 Hz, 2H), 7.31–7.24 (m, 3H), 7.02 (t, J = 8.6 Hz, 2H), 5.48 (s,
2H); 13C NMR (CDCl3) δ 162.1 (d, J = 246.2 Hz), 148.1, 130.5 (d, J = 3.1 Hz), 130.3, 129.8 (d, J = 8.2
Hz), 128.7, 128.1, 125.5, 119.4, 115.9 (d, J = 22.0 Hz), 53.2; MS (EI) C15H12N3F (M+) 253.
4-Cyclohexenyl-1-(4-fluorobenzyl)-1H-1,2,3-triazole (3j)6v: Colorless solid; 1H NMR (CDCl3) δ 7.32 (s,
1H), 7.25 (dd, J = 8.5 Hz, 5.4 Hz, 2H), 7.05 (t, J = 8.5 Hz, 2H), 6.50–6.48 (m, 1H), 5.47 (s, 2H),
2.37–2.32 (m, 2H), 2.20–2.15 (m, 2H), 1.76–1.71 (m, 2H), 1.67–1.61 (m, 2H); 13C NMR (CDCl3) δ 162.7
(d, J = 247.0 Hz), 150.0, 130.8 (d, J = 3.3 Hz), 129.7 (d, J = 8.2 Hz), 127.1, 125.1, 118.0, 115.9 (d, J =
21.6 Hz), 53.1, 26.2, 25.1, 22.3, 22.1; MS (EI) C15H16N3F (M+) 257.
2-[1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl]pyridine (3k)6v: Pale brown solid; 1H NMR (CDCl3) δ 8.53
(d, J = 4.8 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 8.08 (s, 1H), 7.74 (dd, J = 7.8 Hz, 6.4 Hz, 1H), 7.33–7.29 (m,
2H), 7.19 (dd, J = 6.4 Hz, 4.8 Hz, 1H), 7.04 (t, J = 8.6 Hz, 2H), 5.54 (s, 2H); 13C NMR (CDCl3) δ 162.7 (d,
J = 247.0 Hz), 150.0, 149.2, 148.6, 136.7, 130.2 (d, J = 3.3 Hz), 130.0 (d, J = 8.2 Hz), 122.7, 121.7, 120.0,
115.9 (d, J = 21.6 Hz), 53.3; MS (EI) C14H11N4F (M+) 254.
1
1-(4-Fluorobenzyl)-4-trimethylsilyl-1H-1,2,3-triazole (3l)6v: Pale yellow solid; H NMR (CDCl3) δ
13
7.47 (s, 1H), 7.27 (dd, J = 8.8 Hz, 5.2 Hz, 2H), 7.04 (t, J = 8.8 Hz, 2H), 5.53 (s, 2H), 0.30 (s, 9H); C
NMR (CDCl3) δ 162.6 (d, J = 248.6 Hz), 147.1, 130.8 (d, J = 3.3 Hz), 129.8 (d, J = 8.1 Hz), 128.6, 115.8
(d, J = 22.2 Hz), 52.5, -1.3; MS (EI) C12H16N3FSi (M+) 249.
Recycling of 1% Cu/HP20
A mixture of 4-fluorobenzylazide (756 mg, 5.0 mmol), 3-methyl-1-butyn-3-ol (538 μL, 5.5 mmol), Et3N
(152 μL, 1.1 mmol), and 1% Cu/HP20 (318 mg, 50 μmol) in a test tube was stirred at room temperature.
After 5 h, the mixture was diluted with H2O (10 mL) and EtOAc (10 mL), passed through a filter paper
and the catalyst was washed with H2O (2 × 5 mL) and EtOAc (2 × 5 mL). The filtrate was separated into
two layers, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers

HETEROCYCLES, Vol. 88, No. 1, 2014
241
were washed with brine (10 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (CHCl3/MeOH, 100:0~10:1) to give
2-[1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl]propan-2-ol (1.17 g, 100%). The recovered the Cu/HP20,
which was dried in a desiccator under vacuum for more than 12 h, was used for the 2nd run. The reuse
tests were carried out in line with the amount of the recovered catalyst, e.g., for the 2nd run, recovered
1% Cu/HP20 (299 mg, 47 μmol), 4-fluorobenzylazide (710 mg, 4.7 mmol), 3-methyl-1-butyn-3-ol (506
μL, 5.17 mmol), and Et3N (143 μL, 1.03 mmol) were used. The reuse tests were repeated until the 4th
run.
Assay of Residual Copper in the Reaction Mixture
A mixture of 4-fluorobenzylazide (756 mg, 5.0 mmol), 3-methyl-1-butyn-3-ol (538 μL, 5.5 mmol), Et3N
(152 μL, 1.1 mmol), and 1% Cu/HP20 (318 mg, 50 μmol) in a test tube was stirred at room temperature.
After 5 h, the mixture was diluted with H2O (10 mL) and EtOAc (10 mL), passed through a filter paper
and the catalyst was wash with H2O (2 × 5 mL) and EtOAc (2 × 5 mL). The filtrate was separated into
two layers, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers
were concentrated in vacuo and the residue was diluted with EtOH to 50 mL of total volume. The
aqueous layer was diluted with H2O to 50 mL of total volume. The residual copper involved in each
solution was then assayed using a Shimadzu ICP8000 (Shimadzu, Kyoto, Japan). The concentration of
leached copper was 12 ppm (organic layer) and <1 ppm (aqueous layer).
ACKNOWLEDGEMENTS
We thank the Mitsubishi Chemical Corporation for the gift of Diaion HP20. We also thank the N.E.
Chemcat Corporation for the ICP-AES measurements.
REFERENCES AND NOTES
§
Current address: Laboratory of Medicinal Chemistry, School of Pharmaceutical Sciences, Kinki
University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan
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