Solvent-free Huisgen cyclization using heterogeneous copper catalysts supported on chelate resins

Article abstract of DOI:10.1039/c2gc36584g

Copper catalysts supported on chelate resins bearing iminodiacetate moieties (DIAION CR11) or polyamine moieties (DIAION CR20) as chelating functional groups (12% Cu/CR11 and 7% Cu/CR20, respectively) were developed. 12% Cu/CR11 effectively catalyzed the

Full text of DOI:10.1039/c2gc36584g

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Solvent-free Huisgen cyclization using heterogeneous
copper catalysts supported on chelate resins†
Cite this: Green Chem., 2013, 15, 490
Yasunari Monguchi,*a Kei Nozaki,a Toshihide Maejima,a Yutaka Shimoda,a
Yoshinari Sawama,a Yoshiaki Kitamura,b Yukio Kitadeb,c and Hironao Sajiki*a
Copper catalysts supported on chelate resins bearing iminodiacetate moieties (DIAION CR11) or poly-
amine moieties (DIAION CR20) as chelating functional groups (12% Cu/CR11 and 7% Cu/CR20, respecti-
vely) were developed. 12% Cu/CR11 effectively catalyzed the Huisgen cycloaddition of mono-substituted
alkynes to azides in the presence of triethylamine under totally solvent-free conditions to afford the cor-
responding 1,4-disubstituted 1,2,3-triazoles in excellent yields and in a completely regioselective manner.
Furthermore, the Huisgen cycloaddition was found to effectively proceed without addition of triethyl-
amine by the use of 7% Pd/CR20 as a catalyst.
Received 9th October 2012,
Accepted 3rd December 2012
DOI: 10.1039/c2gc36584g
www.rsc.org/greenchem
the metal particles are embedded on the supports.5 The elimi-
nation of solvents from the reaction mixture is also an impor-
Introduction
The Huisgen 1,3-dipolar cycloaddition of azides to alkynes has tant issue, leading to the significant reduction of solvent
been recognized as one of the most attractive synthetic tools wastes and the size of the synthetic equipment and/or manu-
due to the convenient and reliable construction of 1,2,3-tri- facturing plants.6 During the course of our study to establish
azole derivatives, whose subunits are often found as a key environmentally and economically responsible methods
nucleus of biologically active molecules.1 The utility of the in organic chemistry, the solvent-free hydrogenation and the
reaction has explosively increased since Sharpless and Meldal Suzuki–Miyaura reaction catalyzed by palladium on carbon as
independently developed the regioselective synthetic method a heterogeneous catalyst have recently been reported.7
for the preparation of 1,4-disubstituted 1,2,3-triazoles using
Application of copper catalysts immobilized on supports for
mono-substituted (terminal) alkynes and azides by the the Huisgen cyclization of azides to alkynes has been demon-
addition of a copper salt.2,3 The copper-catalyzed Huisgen strated.8 The supports employed to date are activated carbon,9
cyclization is currently recognized as a representative of ‘click inorganic materials, such as zeolites,10 amine-bound silica,11
chemistry,’ the concept of which was established by Sharpless superparamagnetic mesoporous silica,12 AlO(OH),13 metal
et al. for reliable reactions to efficiently produce functional oxide,14 and hydrotalcite,15 an ionic liquid,16 a ligand-bound
materials.4
organic polymer,17 a polysaccharide,18 and an ion exchange
The development of the environmentally benign and cost- resin, such as Amberlyst A2119 and Dowex.20 The catalysts
efficient protocols has been demanded from the view points supported on these materials require multiple steps to
of green sustainable chemistry. The use of heterogeneous prepare, in most cases, and centrifugation or decantation to
transition metal catalysts is expected for possible reuse, since separate them from the reaction mixture in some cases.
Copper oxide on acetylene carbon black9d and copper on
Amberlyst A2119b were only employed for the solvent-free
aLaboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4
Daigaku-nishi, Gifu 501-1196, Japan. E-mail: sajiki@gifu-pu.ac.jp,
monguchi@gifu-pu.ac.jp; Fax: +81 58 230 8109; Tel: +81 58 230 8109
bLaboratory of Molecular Science, Faculty of Engineering, Gifu University,
Huisgen cyclizations. The former catalyst could be reused for
at least five cycles, but microwave conditions were adopted and
centrifugation is required for the separation from the reaction
mixture. The reuse is not even mentioned in the latter case.
A non-supported copper metal organic framework also cata-
lyzed the solvent-free Huisgen cyclization, but excess amounts
of catalyst (10 mol%) and acetylene (12 equiv.) were used.8c
We recently developed a copper catalyst supported on a
commercial synthetic adsorbent, DIAION HP20 (Mitsubishi
Chemical Corporation),21,22 which is a polystyrene-divinyl-
benzene-based polymer with a relatively large pore size (radius
1-1 Yanagido, Gifu 501-1193, Japan
cUnited Graduate School of Drug Discovery and Medicinal Information Sciences,
Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
†Electronic supplementary information (ESI) available: Scanning transmission
electron microscopy (STEM) images, electron probe microanalysis (EPMA) data,
and X-ray photoelectron spectroscopy (XPS) spectra of 12% Cu/CR11 and 7% Cu/
CR20, detailed procedure and results of reuse test of catalysts, spectral data
of products, and 1H and 13C NMR spectra of new products. See DOI:
10.1039/c2gc36584g
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approximately 260 Å) and area (approximately 590 m2 g−1),
with an expectation of its stable supply and strong activity.
Although only one weight% of copper ions was embedded on
the catalyst, the Huisgen cycloaddition of azides to alkynes
heterogeneously proceeded in toluene at room temperature.23
Chelate resins, DIAION CR11 and DIAION CR20 (Mitsubishi
Chemical Corporation), polystyrene-divinylbenzene-based poly-
mers possessing iminodiacetic acid moieties and polyamine
moieties as the ligands, respectively, can capture various metal
ions by their chelating abilities, and have been used to remove
heavy metal ions from water.24 These resins should also be
guaranteed as industrial products in quality and properties
due to the advanced product control under the strict regu-
lations. Therefore, we expected that highly loaded copper cata-
lysts supported on DIAION CR11 and CR20 with reliable
quality could be readily produced by the rigid complexation.
Table 1 Solvent effect on the 12% Cu/CR11-catalyzed cycloaddition of benzyl-
azide with ethynylbenzene
12% Cu/CR11
Entry (mol%)
Temp
Solvent (°C)
Time
(h)
Ratioa
1 : 2 : 3
1
2
3
4
5
6
7
8
9
0
0.5
1
3
1
1
1
1
1
H2O
H2O
H2O
H2O
MeOH
Toluene 70
Neat
Neat
Neat
Neat
70
70
70
70
70
10
10
10
10
10
10
4
24
24
4
55 : 28 : 17
7 : 86 : 7
3 : 97 : 0
0 : 100 : 0
21 : 79 : 0
65 : 35 : 0
0 : 100 : 0
20 : 80 : 0
0 : 100 : 0
0 : 100 : 0
70
rt
50
80
10
1
a Determined by 1H NMR.
Results and discussion
Preparation of 12% Cu/CR11 and 7% Cu/CR20
Table 2 Effect of catalytic amounts of additives on the 12% Cu/CR11-cata-
Copper ion was immobilized by immersing DIAION CR11 in
an aqueous solution of Cu(NO3)2·3H2O at room temperature
for 4 h. The resulting light blue solids were collected by fil-
tration, washed with water and MeOH, then dried under
reduced pressure to give copper on DIAION CR11 (Cu/CR11)
(Scheme 1). The inductively coupled plasma-atomic emission
spectrometry (ICP-AES) of the Cu/CR11 showed that 12 wt%
copper species were embedded on the DIAION CR11. DIAION
CR20 was treated with an aqueous solution of Cu(NO3)2·3H2O
in accordance with the procedure for the preparation of 12%
Cu/CR11 to afford 7% Cu/CR20.25
lyzed cycloaddition of benzylamine with ethynylbenzene
Ratioa
1 : 2 : 3
Entry
Additive
Equiv.
1
2
3
4
5
6
7
8
None
Et3N
Tri-n-butylamine
Diethyl amine
Ethylenediamine
Pyridine
Aniline
1,10-Phenanthroline
Na2CO3
NaHCO3
Cs2CO3
—
67 : 19 : 14
0 : 100 (98)b : 0
15 : 83 : 2
0 : 100 : 0
74 : 16 : 10
77 : 15 : 8
78 : 15 : 7
81 : 10 : 9
71 : 18 : 11
0 : 100 (95)b : 0
73 : 16 : 11
79 : 10 : 11
45 : 55 : 0
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.22
0.11
0.55
12% Cu/CR11-catalyzed Huisgen cyclization
The 12% Cu/CR11-catalyzed Huisgen cyclization of benzylazide
with ethynylbenzene (1.1 equiv.) in the presence of Et3N
(0.22 equiv.) was examined in heated H2O (70 °C). The reaction
efficiency and regioselectivity were remarkably enhanced with
the escalating use of 12% Cu/CR11 (Table 1, entries 1–4),
and complete regioselectivity was achieved using more than
1 mol% of 12% Cu/CR11 to give 1,4-disubstituted 1,2,3-triazole
as the sole product after a 10 h reaction (entries 3 and 4).
Although 12% Cu/CR11 (1 mol%) poorly catalyzed the reaction
in MeOH or toluene (entries 5 and 6), it was completed within
4 h even without solvents contrary to our expectation (entry 7).
The application of heat is effective for the reaction progress
(entries 7–10), but the effect was virtually the same at higher
than 70 °C (entries 7 and 10).
9
10
11
12
13
14
15
Ascorbic acid
Sodium ascorbate
Et3N
42 : 58 : 0
0 : 100 : 0
Et3N
a Determined by 1H NMR. b Isolated yield.
absence of Et3N (Table 2, entry 1). The addition of Et3N,
n-Bu3N, Et2NH, or NaHCO3 was found to accelerate the reac-
tion progress (entries 2, 3, 4, and 10), while other nitrogen-con-
taining bases and inorganic bases showed no positive effects
on both the conversion and regioselectivity (entries 5–9 and
11). The addition of ascorbic acid or its sodium salt as a redu-
cing agent of CuII to CuI poorly promoted the reaction (entries
12 and 13).3 As a result, Et3N was selected as the optimal addi-
tive due to the lower nucleophilicity compared to Et2NH and
NaHCO3, which achieved a 100% conversion to the 1,4-disub-
stituted triazole (2). The reaction smoothly proceeded using
The solvent-free 1,3-dipolar cycloaddition of ethynyl-
benzene with benzylazide was markedly impeded in the
Scheme 1 Preparation of 12% Cu/CR11.
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Table 3 12% Cu/CR11-catalyzed solvent-free Huisgen cyclization between
Table 4 12% Cu/CR11-catalyzed solvent-free Huisgen cyclization between
various azides and phenylacetylene
various alkynes and benzyl azide
12% Cu/CR11
(mol%)
Time
(h)
Yielda Entry
(%)
1
R
12% Cu/CR11 (mol%) Time (h) Yielda (%)
Entry
R
1
5
4
2
92
84
1
2
Bn
1
1
4
4
98
b
—
2
3
4
3
5
3
4
88
91
3
4
5
6
7
8
9
n-Pr
n-Bu
n-Pentyl
n-Hexyl
EtO2C
EtO2C
EtO2C
5
5
5
5
1
1
1
8
8
8
8
4
2
3
99
88
88
94
b
—
94c
95d
5
6
Ph
5
5
3
3
89
85
a Isolated yield. b Complex mixture. c Obtained as
a
mixture of
regioisomers (1,4-/1,5-substituted triazoles = 86 : 14) without base.
d NaHCO3 was used instead of Et3N, and the 1,4-disubstituted triazole
was obtained as the sole product.
7
8
5
5
4
4
79
81
(entry 7),26 and a mixture of 1,4-disubstituted and 1,5-disubsti-
tuted triazoles was obtained in the ratio of 86 : 14 without Et3N
(entry 8). The poor regioselectivity was completely overcome by
the use of NaHCO3 as a base (entry 9), as is the case of the
cycloaddition of ethynylbenzene with benzyl azide (Table 2,
entry 10). The 12% Cu/CR11-catalyzed Huisgen cycloaddition
was therefore established as a general method for the prep-
aration of the 1,4-disubstituted 1,2,3-triazole under solvent-
free conditions.
9
1
1
5
4
86
87
10
Me(CH2)5
a Isolated yield.b A mixture of the starting azide, 1,4-disubstituted
triazole, and 1,5-disubstituted triazole was obtained in the ratio of
33 : 57 : 6, respectively (1H NMR spectrum of the crude materials).
7% Cu/CR20-catalyzed Huisgen cyclization
only 0.22 equiv. of Et3N, and 2 was regioselectively obtained in
a quantitative conversion yield (entries 2 vs. 14 and 15).
Since the 7% Cu/CR20 possesses chelating polyamino moieties
The results of the 12% Cu/CR11-catalyzed solvent-free within DIAION CR20 as the support, the reaction was expected
Huisgen cyclization of ethynylbenzene (1.1 equiv.) with a to proceed without the addition of Et3N. As expected, the reac-
variety of azides in the presence of Et3N (0.22 equiv.) are tion of benzylazide and ethynylbenzene was smoothly com-
shown in Table 3. When the reaction did not effectively pleted at 70 °C together with a complete regioselectivity in a
proceed with 1 mol% of 12% Cu/CR11, the reaction efficiency solvent-free manner in the absence of Et3N (Table 5, entries 1
was improved by the escalating use of the catalyst up to 5 mol% and 2). Further optimization of the reaction conditions
(entries 3–8). While the reaction of 4-fluorobenzylazide revealed that 1 mol% of 7% Cu/CR20 loading and 70 °C of
using 1 mol% of 12% Cu/CR11 afforded a mixture of the heat were necessary for the smooth reaction (entries 3–6).
unreacted azide, the desired 1,4-substituted triazole, and the
A variety of 1,4-disubstituted 1,2,3-triazoles was synthesized
undesired 1,5-disubstituted triazole (entry 2), the reaction using 7% Cu/CR20 at 70 °C under neat conditions (Table 6).
efficiency was significantly improved with an increase in the Although linear alkyl substituted azides and alkynes were
use of 12% Cu/CR11 to 3 mol%, and the 1,4-disubstituted tri- slightly less reactive as substrates, the reaction efficiencies
azole was obtained in 88% yield as the sole product (entry 3). were improved by the increase of the catalyst usage and pro-
Arylmethylazides (entries 1, 3, and 4), arylazides (entries 5–8), longed reaction time (entries 6, 9, and 10).
and alkylazides (entries 9 and 10) could react with ethynylben-
Reuse test of 12% Cu/CR11 and 7% Cu/CR20
zene in a solvent-free fashion to produce the corresponding
1,4-disubstituted triazoles in excellent yields.
The reuse test of 12% Cu/CR11 was next examined (Table 7).
The catalyst was effectively recovered from the reaction mixture
until the 4th run. The recovered amounts of the catalyst sig-
nificantly decreased after the 5th run due to the difficulty of
the catalyst removal from the filtering paper because of the
Both aryl- (Table 4, entries 1 and 2) and alkylalkynes
(entries 3–6) were good substrates for the solvent-free cyclo-
addition with benzyl azide. However, the reaction of ethyl
2-propynoate with benzyl azide afforded a complex mixture
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Table 5 Optimization for the solvent-free 7% Cu/CR20-catalyzed cycloaddition
Table 7 Reuse test of 12% Cu/CR11
of benzylazide with ethynylbenzene
Run
Recovered catalyst (%)
Yield of triazolea (%)
Ratioa
Entry
7% Cu/CR20 (mol%)
Temp (°C)
1 : 2 : 3
1
2
3
4
5
100
96
94
94
88
97
98
98
1b
2
1.0
1.0
0.50
1.0
1.0
1.0
70
70
70
rt
60
80
0 : 100 : 0
0 : 100 : 0
22 : 74 : 4
73 : 27 : 0
1 : 99 : 0
99
74 (21b)
3
4c
5
a Isolated yield. b Recovered starting azide.
6
0 : 100 : 0
a Determined by 1H NMR. b Et3N was added as the additive. c The
reaction was carried out for 24 h.
Table 8 Reuse test of 7% Cu/CR20
Table 6 7% Cu/CR20-catalyzed solvent-free Huisgen cyclization between
various alkynes and azides
Run
Recovered catalyst (%)
Yield of triazolea (%)
1
2
3
4
5
100
100
96
98
92
100
99
100
100
100
7% Cu/
CR20
(mol%)
Time
(h)
Yielda
(%)
Entry R1
R2
a Isolated yield.
1
2
Bn
Ph
Ph
1
1
4
4
93
96
mixture to remove the catalyst by filtration, and approximately
3.0% of copper species was leached out from the 12%
Cu/CR11.
The reuse test of 7% Cu/CR20 was also conducted using the
cycloaddition of benzylazide with ethynylbenzene (Table 8). No
decrease in the catalytic activity was observed until at least the
5th run, and the desired triazole was quantitatively obtained at
each run.
3
4
5
Ph
Ph
5
7
1
4
4
90
87
95
Ph
Ph
10
6
7
Me(CH2)5
Bn
7
1
12
3
98
86
Conclusions
8
Bn
1
4
92
In summary, we developed novel copper catalysts, 12%
Cu/CR11 and 7% Cu/CR20, supported on commercially avail-
able chelate resins possessing iminodiacetic acid moieties and
polyamine moieties, respectively, as the chelating functional-
ities. The preparation method of 12% Cu/CR11 and 7%
Cu/CR20 only requires soaking the chelate resins in a stirring
aqueous solution of Cu(NO3)2·3H2O. 12% Cu/CR11 effectively
catalyzed the Huisgen cyclization of azides to alkynes in the
presence of a catalytic amount of Et3N under the solvent-free
conditions, and a variety of 1,4-disubstituted 1,2,3-triazoles
were obtained in excellent yields. The solvent- and Et3N-free
Huisgen cyclization was also established by the use of 7%
Cu/CR20 as a catalyst. 12% Cu/CR11 and 7% Cu/CR20 could be
reused several times without any significant reduction of the
9
10
Bn
Bn
n-Bu
n-Hexyl
7
7
12
10
72
68
a Isolated yield.
reduction of the catalyst particle size by the mechanical
damage during stirring. The catalyst could be used until the
4th run without any significant catalyst activity loss, while it
decreased in the 5th run presumably due to the physical
destruction of the catalyst and leaching of copper species from
the catalyst into the solvents used for washing during the
work-up process. The concentration of the copper species was
then measured after the addition of solvent to the reaction
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catalyst activity. A further study is currently underway in our Typical procedure of 7% Cu/CR20-catalyzed, solvent-free
laboratory to expand the utility of the 12% Cu/CR11 and 7% Huisgen cyclization
Cu/CR11 as the heterogeneous catalysts used for reactions
other than Huisgen reaction.
A mixture of the azide (500 μmol), the alkyne (550 μmol), and
7% Cu/CR20 (4.5 mg, 5.00 μmol) in a test tube was stirred at
70 °C for the specified time. CH2Cl2 (10 mL) was added, and
the mixture was then filtered. To the filtrate was added H2O
Experimental
General
(10 mL), and the layers were separated. The aqueous layer was
extracted with CH2Cl2 (10 mL × 2), and the combined organic
layers were washed with brine (10 mL × 2), dried over MgSO4,
filtered, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel to give the corres-
ponding 1,4-disubstituted 1,2,3-triazole.
All reagents and solvents were obtained from commercial
sources and used without further purification. The DIAION
CR11 and CR20 were obtained from Mitsubishi Chemical
Corporation (Japan). Flash column chromatography was
performed using silica gel 60N [spherical neutral (63–210 μm)]
from Kanto Chemical Co., Inc. The 1H and 13C NMR spectra
were recorded by a JEOL JNM AL-400 (400 MHz for 1H NMR
and 100 MHz for 13C NMR). Chemical shifts (δ) are expressed
in parts per million and internally referenced [0.00 ppm for
Acknowledgements
We sincerely thank the Mitsubishi Chemical Corporation
for the gift of DIAION CR11. We also thank the N.E. Chemcat
Corporation for the SEM, EPMA, and ICP-AES measurements.
1
tetramethylsilane (TMS)/CDCl3 for H NMR and 77.0 ppm for
CDCl3 for 13C NMR]. The mass spectra were taken by JEOL JMS
Q1000GC Mk II Quad GC/MS for EI and JEOL JMS-T100TD for
ESI. All products were characterized by their H and 13C NMR
1
Notes and references
and mass spectra (and high resolution mass spectra for two
new compounds). The spectral data for all known compounds
were identical to those in the literature, see ESI.†
1 (a) R. Huisgen, G. Szeimies and L. Moebius, Chem. Ber.,
1967, 100, 2494–2507; (b) R. Huisgen, in 1,3-Dipolar Cyclo-
addition Chemistry, ed. A. Padowa, Wiley, New York, 1984,
pp. 1–176.
Preparation of 12% Cu/CR11
2 (a) C. W. Tornøe, C. Christensen and M. Meldal, J. Org.
Chem., 2002, 67, 3057–3064; (b) V. V. Rostovtsev,
L. G. Green, V. V. Fokin and K. B. Sharpless, Angew. Chem.,
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2596–2599).
3 For reviews: (a) V. D. Bock, H. Hiemstra and J. H. van Maar-
seveen, Eur. J. Org. Chem., 2006, 51–68; (b) M. Meldal and
C. W. Tornøe, Chem. Rev., 2008, 108, 2952–3015.
4 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew.
Chem., 2001, 113, 2056–2075, (Angew. Chem., Int. Ed., 2001,
40, 2004–2021); (b) H. C. Kolb and K. B. Sharpless, Drug
Discovery Today, 2003, 8, 1128–1137.
DIAION CR11 (100 g) was added to an aqueous solution
(400 mL) of Cu(NO3)2·3H2O (24.2 g, 100 mmol), and the
mixture was gently stirred at room temperature for 4 h. The
resulting blue solid was collected on a Kiriyama funnel
(Kiriyama Glass Co., Ltd, Tokyo, Japan), washed with H2O
(200 mL) and MeOH (200 mL), and dried under reduced
pressure for 12 h to produce the Cu/CR11 (54.5 g). The induc-
tively coupled plasma-atomic emission spectrometry (ICP-AES)
revealed that copper ions were immobilized at 12 wt% con-
centration on CR11.
Preparation of 7% Cu/CR20
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(b) M. J. Climent, A. Corma and S. Iborra, Chem. Rev., 2011,
111, 1072–1133.
Cu/CR20 was similarly prepared from DIAION CR20 and
Cu(NO3)2·3H2O, and the concentration of copper ions of
Cu/CR20 was determined as 7 wt% by ICP-AES.
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Typical procedure of 12% Cu/CR11-catalyzed, solvent-free
Huisgen cyclization
A mixture of the azide (500 μmol), the alkyne (550 μmol), Et3N
(15.4 μL, 220 μmol), and 12% Cu/CR11 (2.6 mg, 5.00 μmol) in
a test tube was stirred at 70 °C for the specified time. CH2Cl2
(10 mL) was added, and the mixture was then filtered. To the
filtrate was added H2O (10 mL), and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (10 mL × 2), and
the combined organic layers were washed with brine (10 mL ×
2), dried over MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
to give the corresponding 1,4-disubstituted 1,2,3-triazole.
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R. Ito, K. Nozaki, T. Maegawa and H. Sajiki, Tetrahedron,
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