Sustainable click reaction catalyzed by supported ionic liquid catalyst (Cu-SILC)

Article abstract of DOI:10.1055/s-0028-1087926

Cuprous bromide was immobilized as a copper-supported ionic liquid catalyst (Cu-SILC) in the pores of amorphous mercaptopropyl silica gel with the aid of an ionic liquid, [bmim]PF₆. The heterogeneous Cu-SILC effectively and regioselectively cat

Full text of DOI:10.1055/s-0028-1087926

LETTER
643
Sustainable Click Reaction Catalyzed by Supported Ionic Liquid Catalyst
(Cu-SILC)
Sustainable Click
i
sn
ahiro Hagiwara,*a Hirokazu Sasaki,a Takashi Hoshi,b Toshio Suzukib
a
Graduate School of Science and Technology, Niigata University, 8050 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Fax +81(25)2627368; E-mail: hagiwara@gs.niigata-u.ac.jp
b
Faculty of Engineering, Niigata University, 8050 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
Received 18 November 2008
which each of them has their own characteristic advan-
tage.
Abstract: Cuprous bromide was immobilized as a copper-support-
ed ionic liquid catalyst (Cu-SILC) in the pores of amorphous mer-
captopropyl silica gel with the aid of an ionic liquid, [bmim]PF6.
The heterogeneous Cu-SILC effectively and regioselectively cata-
lyzed Huisgen [3+2] cycloadditions at room temperature in aqueous
ethanol, and was used up to six times after simple decantation.
In the present study, copper(I) in ionic liquid as a support-
ing liquid layer was immobilized in the pores of an inor-
ganic support. The heterogeneous catalyst thus prepared
(Cu-SILC: copper-supported ionic liquid catalyst) exhib-
ited higher catalytic activity and a recyclable nature in
Huisgen [3+2] cycloadditions (Figure 1).
Key words: heterogeneous catalysis, ionic liquids, click reaction,
copper, supported catalysis
Cu-SILC was prepared according to the same procedure
used for Pd-SILC preparation.11 A suspension of amor-
phous silica in a solution of copper salts and an ionic liq-
uid in acetonitrile was stirred until the color of the solution
became transparent. Poor solubility of copper(I) salts in
organic solvents or water was an issue for immobilization
as a SILC, which was solved by employing acetonitrile.
After acetonitrile evaporation, the Cu-SILC was rinsed
with anhydrous diethyl ether to give dry powder. The free
flowing nature of Cu-SILC suggests that an ionic liquid
layer exists in the pores of amorphous silica in the same
manner as Pd-SILC (Figure 1).11a
Click chemistry is presently emerging in synthetic organic
chemistry owing to its usefulness in facile and reliable
connection of two molecules by covalent bonds. Huisgen
[3+2] cycloaddition1 is a perfect example of click reac-
tions,2 in which azides 1 and acetylenes 2 are connected in
the presence of a copper(I) catalyst and a base to afford
1,4-disubstituted 1,2,3-triazoles 3 (Scheme 1). Since the
reaction quickly and securely fastens two fragments via a
stable triazole ring without producing wastes, the reaction
currently attracts much attention in various areas of syn-
thetic organic chemistry such as polymer synthesis,3 drug
discovery,4 and others.5
+
N
–
N
R1
N
R1
1
+
N
Cu(I), base
solvent
N
N
R2
R2
2
3
Scheme 1 Huisgen [3+2] cycloaddition
In view of the usefulness of Huisgen [3+2] cycloaddi-
tions, more efficient and environmentally more benign
protocols are anticipated involving immobilization and
recycle use of the copper(I) catalyst. To the best of our
knowledge, a solid catalyst for recycle use is not yet
known except for the copper(I)–tren complex.6 A limited
number of liquid supports are reported for immobilization
of homogeneous copper salts such as a soluble polymer7a
or ionic liquid.7b On the other hand, solid supports were
utilized in several instances such as Amberlyst in aceto-
nitrile,8 Zeolite in toluene,9 and charcoal in dioxane,10 in
Figure 1 Cu-SILC and click reaction
Employing the click reaction of benzylazide 1 (R1 = Bn)
and 2-methylbut-3-yn-2-ol [2, R2 = C(Me)2OH] as a
benchmark reaction to tune reaction parameters
(Figure 1), an optimum solid support for the cuprous bro-
mide–dimethylsulfide complex was initially evaluated.
As shown in Table 1 (entry 1), the Cu-SILC immobilized
on mercaptopropyl silica gave the best yield. This is partly
because the mercapto group has better affinity toward
copper than the amino group to interact with copper(I).12
Because the amount of Cu in the ether rinse was 0.6 ppm
as determined by inductively coupled plasma atomic
emission spectroscopy (ICP-AES) analysis, more than
99.9% of Cu was immobilized as Cu-SILC.
SYNLETT 2009, No. 4, pp 0643–0647
x
x.
x
x.
2
0
0
9
Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087926; Art ID: U12108ST
© Georg Thieme Verlag Stuttgart · New York

644
H. Hagiwara et al.
LETTER
Table 1 Investigation of Optimum Solid Support for Immobiliza-
tion of Copper(I) Salt
Table 3 Investigation for Optimum Copper Salt
Entrya
Copper salt
CuBr·SMe2
CuI
Time (h)
Yield (%)b
Entrya
Support material
Time
1
Yield (%)b
1
2
3
2
2
1
94
1
2
3
mercaptopropyl SiO2
N,N-diethylaminopropyl SiO2
polyimino SiO2
100
89
–
52
2.5
6
Cu(NO3)2·3H2Oc
100
a Reaction was carried out at r.t. in 50% aq EtOH with 0.05 equiv of
Cu-SILC, in which copper salts (Cu loading: 0.18 mmol/g) were im-
mobilized on mercaptopropyl SiO2 with the aid of [bmim]PF6.
b Isolated pure product based on benzylazide (1).
a Reaction was carried out at r.t. in 50% aq EtOH with 0.05 equiv of
Cu-SILC, in which the CuBr·SMe2 (Cu loading: 0.18 mmol/g) was
immobilized with the aid of [bmim]NTf2.
b Isolated pure product based on benzylazide 1.
c Reduced with sodium ascorbate prior to reaction.
Among the bases investigated, both triethylamine10 and
potassium carbonate were effective, while N,N-diethyl-
aminopropyl silica (NDEAP) showed no effect as a recy-
clable base. Without a base, the reaction did not take
place.
Table 4 Effect of Loading of Cu in SILC for Recycle Use in Click
Reaction of Benzylazide (1) and 2-Methylbut-3-yn-2-ol (2)
I) Cu loading: 0.18 mmol/g
II) Cu loading: 0.09 mmol/g
Time (h) Yield (%)b
Cyclea Time (h) Yield (%)b Cyclea
1
2
3
1
100
84
1
2
3
4
5
6
1
96
100
95
The effect of a solvent was investigated to determine more
efficient and environmentally benign solvents, in which
50% aqueous ethanol11c provided the best result (Table 2,
entry 2).
1.5
4
1.5
1.5
3
92
90
Table 2 Optimization of the Solvent for the Cycloaddition of Ben-
zylazide (1) and 2-Methylbut-3-yn-2-ol (2)
6
94
Entrya
Solvent
Time (h)
Yield (%)b
23
85
a Reaction was carried out at r.t. in 50% aq EtOH with 0.05 equiv of
Cu-SILC, in which the CuBr·SMe2 was immobilized on mercaptopro-
pyl SiO2 with the aid of [bmim]NTf2.
1
2
3
4
5
6
7
EtOH
2.5
2.5
4
19
89
84
33
42
70
63
H2O–EtOH (1:1)
H2O–EtOH (3:1)
H2O
b Isolated pure product based on benzylazide (1).
5
simple decantation. However, the reaction in the sixth
cycle became very sluggish, as shown in Table 4 (II).
H2O–t-BuOH (1:1)
toluene
3
Partial deterioration of Cu-SILC during recycle use was
solved by exchange of ionic liquid from [bmim]NTf2 to
the less lipophilic [bmim]PF6,13 which became more dura-
ble, as shown in Table 5 (I, cycle 6).
4
C5H9OMe
4
a Reaction was carried out at r.t. with 0.05 equiv of Cu-SILC, in which
the CuBr·SMe2 (Cu loading: 0.18 mmol/g) was immobilized on
NDEAP silica with the aid of [bmim]NTf2.
Table 5 Catalytic Performance of Cu-SILC Immobilized with
[bmim]PF6 in Click Reaction of Benzylazide (1) and 2-Methylbut-3-
yn-2-ol (2)
b Isolated pure product based on benzylazide (1).
Cyclea
Time (h)
Yield (%)b
The result of the investigation for the optimum copper(I)
salt is shown in Table 3. Among the copper salts investi-
gated, Cu-SILC derived from the cuprous bromide–dime-
thylsulfide complex was selected for further experiments
(Table 3, entry 1) owing to the low level of leaching of
copper(I) (0.13%, vide infra), as determined by ICP-AES
analysis; on the other hand, the level of leaching of Cu-
SILC prepared from cupric nitrate was 9%.
1
2
3
4
5
6
2
91
99
98
96
91
80
1.5
1.5
3
3
The amount of copper(I) salt on SILC could be adjusted
as needed, in which lower loading was superior in the re-
cycle experiments because the Cu-SILC became less reac-
tive in the third cycle when compared with cycle 3 both in
Table 4 (I and II). The Cu-SILC could be recycled after
4
a Reaction was carried out at r.t. with 0.07–0.08 equiv of Cu-SILC, in
which the CuBr·SMe2 was immobilized on mercaptopropyl SiO2 with
the aid of [bmim]PF6.
b Isolated pure product based on benzylazide (1).
Synlett 2009, No. 4, 643–647 © Thieme Stuttgart · New York

LETTER
Sustainable Click Reaction
645
The cuprous bromide–dimethylsulfide complex could plays an important role in maintaining the catalytic activ-
also be immobilized in mercaptopropyl silica without ion- ity of copper(I) species.
ic liquid, although its catalytic activity decreased substan-
tially in four cycles. This result indicates that ionic liquid
0.67 ppm (0.13%) as determined by ICP-AES analysis in
The level of leaching of copper from the Cu-SILC was
Table 6 Catalytic Performance of Cu-SILC20
Entrya
Azide 1
Acetylene 2
Product 3
Time (h) Yield (%)b
N
N
N
N
N
OH
OH
1
2
94
98
98
N3
2a
1a
1a
3a15
N
N
2
3
1.5
1.5
HO
HO
2b
2c
3b16
3c18
N
N
C5H11
C5H11
1a
1a
1a
N
N
N
4
5
2
100
OH
OH
3d22
2d
N
R
R
N
N
1.5
98
3e9 R = H
2e R = H
2f R = OMe
6
7
1a
1a
3f17 R = OMe
3g17 R = NO2
1.5
2
73
85
2g R = NO2
8
9
2a
23
100
98
N
OH
N3
N
N
1b
3h23
N
N
N
MeO
MeO
N3
2a
2a
3
2
OH
1c
3i19
N
N3
TBSO
O
N
N
TBSO
O
10
11
100
85
O
O
OH
1d
3j24
N
N3
AcO
N
N
AcO
O
O
2a
2a
2
O
O
OH
N
1e
3k25
N
N
12
1.5
99
N3
OH
1f
3l26
a Reaction was carried out at r.t. in 50% aq EtOH with 0.05–0.08 equiv of Cu-SILC, which was prepared from the CuBr·SMe2.
b Isolated pure product based on azide 1.
Synlett 2009, No. 4, 643–647 © Thieme Stuttgart · New York

646
H. Hagiwara et al.
LETTER
(4) (a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today
the reaction of benzylazide (1) and 2-methylbut-3-yn-2-ol
(2) when 0.05 equivalents of the Cu-SILC was employed.
Based on the analysis, the reaction was attempted again
using 0.13% of the cuprous bromide–dimethylsulfide
complex at room temperature for two hours in 50% aque-
ous ethanol; however, the reaction did not take place at all.
This result suggests that the reaction proceeded inside the
Cu-SILC, in which substrates were partitioned into the
ionic liquid layer in the pores of amorphous silica and cat-
alyzed by copper(I), as illustrated in Figure 1. A turnover
number (TON) of the Cu-SILC was evaluated to be 139 in
the reaction of benzylazide (1) and 2-methylbut-3-yn-2-ol
(2), while at 60 °C6 the TON was improved to 1,940 with-
out the formation of 1,5-adduct.
2003, 8, 1128. (b) Loaiza, P. R.; Löber, S.; Hübner, H.;
Gmeiner, P. J. Comb. Chem. 2006, 8, 252.
(5) Wolfbeis, O. S. Angew. Chem. Int. Ed. 2007, 46, 2980.
(6) Candelon, N.; Lastécouères, D.; Diallo, A. K.; Aranzaes,
J. R.; Astruc, D.; Vincent, J.-M. Chem. Commun. 2008, 741.
(7) (a) Bergbreiter, D. E.; Hamilton, P. N.; Koshti, N. M. J. Am.
Chem. Soc. 2007, 129, 10666. (b) Zhao, Y.-B.; Yan, Z.-Y.;
Liang, Y.-Y. Tetrahedron Lett. 2006, 47, 1545.
(8) Girard, C.; Önen, E.; Aufort, M.; Beauvière, S.; Samson, E.;
Herscovici, J. Org. Lett. 2006, 8, 1689.
(9) Chassaing, S.; Kumarraja, M.; Sido, A. S. S.; Pale, P.;
Sommer, J. Org. Lett. 2007, 9, 883.
(10) Lipshutz, B. H.; Taft, B. R. Angew. Chem. Int. Ed. 2006, 45,
8235.
(11) (a) Hagiwara, H.; Sugawara, Y.; Isobe, K.; Hoshi, T.;
Suzuki, T. Org. Lett. 2004, 6, 2325. (b) Hagiwara, H.;
Sugawara, Y.; Hoshi, T.; Suzuki, T. Chem. Commun. 2005,
2942. (c) Hagiwara, H.; Ko, K. H.; Hoshi, T.; Suzuki, T.
Chem. Commun. 2007, 2838. (d) Hagiwara, H.; Okunaka,
N.; Hoshi, T.; Suzuki, T. Synlett 2008, 1813.
(12) Ho, T.-L. Hard and Soft Acids and Bases Principle in
Organic Chemistry; Academic Press: New York, 1977.
(13) Observed octanol–water partition coefficients (KOWs) are
0.0220 for [bmim]PF6 and 0.11 for [bmim]NTf2. See: Ropel,
L.; Belvèze, L. S.; Aki, S. N. V. K.; Stadtherr, M. A.;
Brennecke, J. F. Green Chem. 2005, 7, 83.
The present protocol was applicable in general to a com-
bination of various azides and terminal acetylenes to af-
ford 1,4-disubstituted 1,2,3-triazoles, as shown in
Table 6. Electron-donating or electron-withdrawing sub-
stituents on aryl rings of acetylenes or azides showed no
effect on the reactivity of the reaction.
The slightly low yields in entries 5 and 6 are due to the low
solubility of the products during workup. Less reactive ali-
phatic alkyne (entry 3) or sterically hindered azide (entry
7) provided triazoles without any problem.
(14) Recent advances on SILC: (a) Mehnert, C. P.; Mozeleski,
E. J.; Cook, R. A. Chem. Commun. 2002, 3010.
In summary, cuprous bromide or cupric nitrate was immo-
bilized as Cu-SILC14 in the pores of mercaptopropyl silica
gel with the aid of the ionic liquid [bmim]PF6. Immobili-
zation was simple and cost effective, because there was no
need to synthesize a polymer or to employ a large amount
of ionic liquid as a liquid support. The Cu-SILC exhibited
higher and regioselective catalytic activity toward a vari-
ety of substrates in aqueous ethanol without a ligand at
room temperature and could be recycled after simple de-
cantation up to 6 times in 95% average yield. Because
leaching of copper(I) was less than pharmaceutical stan-
dards,16 the present protocol is suitable for application to
derivatization of enzymes, living cells, or drug syntheses,
which are sensitive to contamination of copper(I) ion.
(b) Riisager, A.; Wasserscheid, P.; van Hal, R.; Fehrmann,
R. J. Catal. 2003, 219, 452. (c) Huang, J.; Jiang, T.; Gao,
H.; Han, B.; Liu, Z.; Wu, W.; Chang, Y.; Zhao, G. Angew.
Chem. Int. Ed. 2004, 43, 1397. (d) Breitenlechner, S.;
Fleck, M.; Müller, T. E.; Suppan, A. J. Mol. Catal. A: Chem.
2004, 214, 175. (e) Riisager, A.; Fehrmann, R.; Flicker, S.;
van Hal, R.; Hanmann, M.; Wasserscheid, P. Angew. Chem.
Int. Ed. 2005, 44, 815. (f) Mehnert, C. P. Chem. Eur. J.
2005, 11, 50. (g) Lou, L.-L.; Yu, K.; Ding, F.; Thou, W.;
Peng, X.; Liu, S. Tetrahedron Lett. 2006, 47, 6513.
(15) Moulin, F. Helv. Chim. Acta 1952, 35, 167.
(16) Macdonald, J. E.; Kelly, J. A.; Veinot, J. G. C. Langmuir
2007, 23, 9543.
(17) Luvino, D.; Amalric, C.; Smietana, M.; Vasseur, J.-J. Synlett
2007, 3037.
(18) Hanelt, S.; Liebscher, J. Synlett 2008, 1058.
(19) Park, I. S.; Kwon, M. S.; Kim, Y.; Lee, J. S.; Park, J. Org.
Lett. 2008, 10, 497.
Acknowledgment
(20) Preparation of Cu-SILC
Mercaptopropyl silica gel (powder for column
This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas (20031011 for H.H.) from the Ministry
of Education, Culture, Sports, Science and Technology (MEXT).
Thanks are also due to Fuji Silysia Chemical LTD., for generous
supply of mercaptopropyl silica.
chromatography supplied by Fuji Silysia Chemical LTD.,
2.068 g) and CuBr·Me2S (62 mg, 0.302 mmol) were added
to a solution of [bmim]PF6 (200 mg, 10 wt%) in MeCN.
Resulting slurry was stirred at r.t. for 4 h, when the brown
color of MeCN solution was transparent. After evaporation
of MeCN in vacuo, the powder was rinsed with anhyd Et2O
(5×). Evacuation of in vacuo provided Cu-SILC (2.301 g,
0.15 mmol/g SiO2) as white powder.
References and Notes
(1) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984.
(2) Some representative reviews: (a) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem. Int. Ed. 2001, 40, 2004.
(b) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. Eur. J.
Org. Chem. 2006, 51. (c) Meldal, M.; Tornøe, C. W. Chem.
Rev. 2008, 108, 2952.
(3) (a) Lutz, J.-F. Angew. Chem. Int. Ed. 2007, 46, 1018.
(b) Malkoch, M.; Schleicher, K.; Drockenmuller, E.;
Hawker, C. J.; Russell, Y. P.; Wu, P.; Fokin, V. V.
Macromolecules 2005, 38, 3663.
(21) Click Reaction of Benzylazide and 2-Methylbut-3-yn-2-ol
A suspension of benzylazide (65 mg, 0.49 mmol), 2-methyl-
but-3-yn-2-ol (51 mg, 0.61 mmol), and Cu-SILC (299 mg,
0.035 mmol CuBr) in 50% aq EtOH (2 mL) was stirred at r.t.
for 2 h. The organic layer was separated by filtration and the
flask was rinsed with Et2O. The combined organic layer was
evaporated to dryness in vacuo. The residue was purified by
column chromatography (eluent: n-hexane–EtOAc = 3:1 to
1:5) to afford 2-[1-benzyl-1,2,3-triazol-4-yl]propan-2-ol
(3a, 96 mg, 91%). Recovered Cu-SILC was used intact for
further recycle experiments.
Synlett 2009, No. 4, 643–647 © Thieme Stuttgart · New York

LETTER
Sustainable Click Reaction
647
(22) Compound 3d: 1H NMR (270 MHz, CDCl3): d = 2.11–2.22
(m, 2 H), 2.38 (br s, 1 H), 2.67–2.88 (m, 2 H), 4.88 (br s, 1
H), 5.51 (s, 2 H), 7.14–7.40 (m, 11 H). 13C NMR (67.5 MHz,
CDCl3): d = 151.5, 141.4, 134.4, 129.0, 128.7, 128.4, 128.3,
128.0, 125.8, 120.1, 66.4, 54.2, 38.9, 31.7. IR: 3409, 3011,
1496, 1456, 1224, 1049 cm–1. HRMS: m/z [M]+ calcd for
C18H19N3O: 293.1528; found: 293.1524.
2110, 1463, 1383, 1255, 1089, 838 cm–1. HRMS: m/z [M]+
calcd for C18H35N3O4Si: 385.2397; found: 385.2392.
(25) Compound 3k: 1H NMR (270 MHz, CDCl3): d = 1.30 (s, 3
H), 1.41 (s, 3 H), 1.64 (s, 3 H), 1.65 (s, 3 H), 2.12 (s, 3 H),
2.53 (br s, 1 H), 3.88–3.94 (m, 1 H), 4.12–4.25 (m, 3 H), 4.54
(dd, J = 14.4, 5.1 Hz, 1 H), 4.63 (dd, J = 14.4, 3.6 Hz, 1 H),
7.61 (s, 1 H). 13C NMR (67.5 MHz, CDCl3): d = 170.4,
155.6, 120.8, 110.3, 76.1, 75.5, 68.2, 63.2, 50.9, 30.4, 30.3,
26.9, 26.8, 20.7. IR: 3470, 2989, 1742, 1374, 1226, 1167,
1046 cm–1. HRMS: m/z [M]+ calcd for C14H23N3O5:
313.1637; found: 313.1638.
(23) Compound 3h: 1H NMR (270 MHz, CDCl3): d = 1.64 (s, 6
H), 1.79 (s, 6 H), 2.24 (s, 10 H), 7.50 (s, 1 H). 13C NMR (67.5
MHz, CDCl3): d = 154.2, 115.2, 68.6, 59.5, 43.0, 36.0, 30.6,
30.5, 29.5. IR: 3398, 2981, 2857, 1454, 1360, 1310, 1167,
1057, 1026, 954, 854 cm–1. HRMS: m/z [M]+ calcd for
C15H23N3O: 261.1841; found: 261.1838.
(26) Compound 3l: 1H NMR (270 MHz, CDCl3): d = 0.97 (d,
J = 6.6 Hz, 3 H), 1.19–1.52 (m, 3 H), 1.59 (s, 3 H), 1.64 (s,
6 H), 1.68 (s, 3 H), 1.73–1.78 (m, 1 H), 1.88–2.00 (m, 3 H),
2.52 (br s, 1 H), 4.32–4.38 (m, 2 H), 5.04–5.09 (m, 1 H), 7.42
(s, 1 H). 13C NMR (67.5 MHz, CDCl3): d = 155.4, 131.2,
123.9, 118.8, 68.1, 48.2, 37.1, 36.5, 30.3, 29.8, 25.5, 25.1,
19.0, 17.5. IR: 3408, 2976, 2929, 1460, 1380, 1168, 1052,
955, 853 cm–1. HRMS: m/z [M]+ calcd for C15H27N3O:
265.2154; found: 265.2158.
(24) Compound 3j: 1H NMR (270 MHz, CDCl3): d = 0.03 (s, 6
H), 0.85 (s, 9 H), 1.23 (s, 3 H), 1.31 (s, 3 H), 1.57 (s, 3 H),
1.59 (s, 3 H), 3.61–3.79 (m, 3 H), 4.17–4.23 (m, 1 H), 4.41
(dd, J = 14.3, 5.9 Hz, 1 H), 4.63 (dd, J = 14.3, 3.2 Hz, 1 H),
7.57 (s, 1 H). 13C NMR (67.5 MHz, CDCl3): d = 155.3,
120.6, 109.7, 77.3, 77.1, 68.2, 62.9, 51.6, 30.4, 30.3, 26.9,
26.9, 25.9, 18.3, –5.4, –5.5. IR: 3450, 2988, 2956, 2931,
Synlett 2009, No. 4, 643–647 © Thieme Stuttgart · New York

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