Ionic liquid-promoted Copper(II)-Catalyzed homocoupling of terminal alkynes in aqueous phase or under solvent-limited conditions

Article abstract of DOI:10.1246/bcsj.20160081

A reusable ionic liquid 1-butyl-3-methylimidazolium bromide/Cu(II) system was proven to be a reusable catalyst for the homocoupling of terminal alkynes at mild temperature using air as oxidant in aqueous phase or under solvent-limited conditions. In most cases, good to excellent yields can be achieved, either aromatic alkynes or aliphatic alkynes were used as substrates. The homocoupling products 1,3-diynes were separated by extraction from the reaction system. And the activity of residue showed it could be reused for 3 and 6 cycles respectively under the aqueous phase conditions and solventlimited conditions. Furthermore, this reaction can be easily scaled up to gram level.

Full text of DOI:10.1246/bcsj.20160081

Ionic Liquid-Promoted Copper(II)-Catalyzed Homocoupling of Terminal
Alkynes in Aqueous Phase or under Solvent-Limited Conditions
Shiguang Li, Xi Chen, Jinping Chen, and Hang Gong*
The Key Laboratory of Environmentally Friendly Chemistry and Application of the Ministry of Education,
College of Chemistry, Xiangtan University, Xiangtan 411105, P. R. China
E-mail: hgong@xtu.edu.cn
Received: March 15, 2016; Accepted: April 18, 2016; Web Released: April 26, 2016
Hang Gong
Hang Gong is an associate professor at Xiangtan University. He received his Ph.D. degree from the College
of Chemistry, Xiangtan University in 2011. He was awarded a research fellowship of the National Nature
Science Foundation of China (NSFC) for Young Scientists from 2015 to 2017. He was awarded the Québec-
China Postdoctoral scholarships and worked at McGill University in Chaojun Li’s group from 2013–2015. His
research interest is organic synthetic methodology.
Part A:
Abstract
NiCl2 or CuCl2, H2O, 200 oC
A reusable ionic liquid 1-butyl-3-methylimidazolium bro-
mide/Cu(II) system was proven to be a reusable catalyst for
the homocoupling of terminal alkynes at mild temperature
using air as oxidant in aqueous phase or under solvent-limited
conditions. In most cases, good to excellent yields can be
achieved, either aromatic alkynes or aliphatic alkynes were
used as substrates. The homocoupling products 1,3-diynes were
separated by extraction from the reaction system. And the
activity of residue showed it could be reused for 3 and 6 cycles
respectively under the aqueous phase conditions and solvent-
limited conditions. Furthermore, this reaction can be easily
scaled up to gram level.
R
R
R
R
R
R
[Pd]-[Cu]/ligand, base, I2, H2O, r.t.
or CuSO4/ligand, base, I2, H2O, 120 oC
Pd(OAc)2/Agarose, base, H2O, 90 oC
R
R
R
or [Pd]-[Cu], H2O, 140 oC, M.W.
Part B: Solvent-free reactions (Chen, Mack, Cui)
CuCl2, Et3N
R
R
R
R
R
R
R
R
R
60 oC, air
Pd(PPh3)4, K2CO3
Ball milling
CuI, benzylamine
r.t., O2
1. Introduction
This work:
H2O, 50 oC
Relative to development of efficient, selective, and high-
yielding transformations, green chemistry has received increas-
ing attention because of environmental pressures.1 Green
chemistry aims to minimize waste and provide mild reaction
conditions.1a The purpose of green chemistry is to utilize
nontoxic solvent or solvent-limited conditions, low reaction
temperature, and reusable materials. In the present work, a
green approach toward the synthesis of 1,3-diynes is described.
Glaser coupling is considered the most convenient method
for obtaining 1,3-diynes,2 which are important building blocks
for synthesizing natural products,3 pharmaceuticals,4 organic/
inorganic composites,5 and polymers.6 Current methods for the
transition-metal-catalyzed Glaser coupling reaction are usually
conducted in harmful organic solvents, such as CH3CN, DMF,
toluene, etc., although reactions can be also conducted in ionic
liquids7 and supercritical CO2.8 The use of organic solvents is
harmful to the environment, whereas ionic liquids and super-
R
R
R
R
[Cu]/Ionic liquid
air
R
solvent-limited, r.t.
Scheme 1. Glaser coupling reaction in aqueous phase or
under solvent-free/limited conditions.
critical CO2 are expensive. Relative to the reaction mediums
mentioned above, aqueous phase and solvent-free/limited reac-
tions still have strong attractions. The aqueous phase reaction
and solvent-free/limited reactions are low-cost, non-toxic, safe,
and can possibility allow recovery of the transition metal
catalysts used.9
Several references on Glaser coupling reaction carried out in
aqueous phase are available (Scheme 1, part A).10 However,
these references require the use of high temperature, expensive
palladium catalyst, or I2 as oxidant. Glaser coupling reaction
794 | Bull. Chem. Soc. Jpn. 2016, 89, 794–797 | doi:10.1246/bcsj.20160081
© 2016 The Chemical Society of Japan

under solvent-limited conditions were reported in a few papers
(Scheme 1, part B).11 However, these protocols required the
use of expensive palladium catalyst, smelly organic base, or
slightly heated condition.
To achieve reactions that are aligned with the aims of green
chemistry, more environmentally friendly and economic meth-
odologies for Glaser coupling reaction are desired. Thus, in this
paper, ionic liquid promoted copper-catalyzed homocoupling
of terminal alkynes using air as oxidant in water at 50 °C or
under solvent-limited conditions at room temperature are de-
scribed. Both of the strategies are environmentally benign,
economic, efficient, and simple.
7, 11, and 12). In this reaction, the base and ionic liquid
were pre-reacted with Cu-salt in THF for 3 h at 50 °C (see
Section 3.3), where the NHC (N-heterocyclic carbene)-Cu
compound might be formed. Failure to conduct the above
procedure would reduce the yield to 30%. Thus, the said
procedure is necessary. For base and ionic liquid, 0.4 and 1.2
equiv were the most suitable amounts, respectively (Entry 7).
Lower yields were obtained if the base and ionic liquid ratios
change; the lower yield may be caused by the accumulation of
the base and ionic liquid adducts in the reaction mixture, which
have a synergy effect to the reaction.12 Finally, the control
experiments revealed that both the Cu(II) and [BMIm][Br] were
essential for this reaction (Entries 13 and 14).
The optimized reaction conditions for the aqueous phase and
solvent-limited reactions are as follows: For the aqueous phase
reaction, 20 mol % Cu(CF3COO)2¢H2O/60 mol % [BMIm][Br]
were used as catalyst at 50 °C under air in water for 24 h; Fot
the solvent-limited reaction, 20 mol % Cu(CF3COO)2¢H2O/1.2
equiv [BMIm][Br] was used as catalyst and 0.4 equiv t-BuOK
as base at room temperature under air for 24 h. The generality
of these two methods was then explored.
Various terminal alkynes, including aromatic and aliphatic
acetylenes, were tested under the optimized conditions. The
results showed that both strategies tolerate a variety of func-
tional groups. As shown in Table 3, the homocoupling of
phenylacetylenes 1a-1i, which contain electron-donating
groups, as well as electron-withdrawing groups, proceeded
readily to afford the corresponding conjugate 1,3-diynes with
good to excellent yields (Entries 1-8). However, the desired
product of m-aminophenylacetylene 1i was isolated in 44%
(aqueous phase) and 52% (solvent-limited) yields, respectively;
this result may be caused by the partial oxidation of the substrate
(Entry 9). The reaction of the heteroaromatic alkyne 1j also
proceeded efficiently and produced the desired 1,3-diyne 2j in
83% (aqueous phase) and 72% (solvent-limited) yields, respec-
2. Results and Discussion
Our investigation commenced with the homocoupling reac-
tion of p-tolylacetylene using various Cu(II) (20 mol %) and 1-
butyl-3-methylimidazolium bromide ([BMIm][Br]) (60 mol %)
as catalysts, under air in water at 50 °C for 24 h (Table 1,
Entries 1-5). Among the catalysts, Cu(CF3COO)2¢H2O was
the most effective, which afforded 75% yield of the isolated
conjugate 1,3-diyne (Entry 5). Then, the reaction temperature
was examined (Entries 5-7). Increasing or decreasing the reac-
tion temperature were not beneficial to the coupling reaction.
The control experiments revealed that both copper and ionic
liquid [BMIm][Br] were essential for reaction (Entries 8 and 9).
The ionic liquid might work as the phase-transfer catalyst or as
the reagent to increase the solubility of reagent to increase the
solubility of arylacetylenes in water.
Investigation on homocoupling reaction of terminal alkynes
under solvent-limited conditions was carried out (Table 2). The
investigation was conducted similar to the previous optimiza-
tion experiments, but phenylacetylene was used as the model
substrate instead. First, various Cu(II) salts were examined
under air at room temperature for 24 h, using 20 mol % Cu(II)
and 1.2 equiv [BMIm][Br] as catalyst, and 0.4 equiv t-BuOK as
base (Entries 1-7). Among the catalysts, Cu(CF3COO)2¢H2O
was the most effective, which afforded 99% yield of the
isolated conjugate 1,3-diyne (Entry 7). Then, the amount of
t-BuOK (Entries 7-10) and [BMIm][Br] was evaluated (Entries
Table 2. Screening the reaction parameters under solvent-
limited conditionsa)
20 mmol% Cu(II) salt/[BMIm][Br]
t-BuOK, Air, r.t., 24 h
1b
2b
Table 1. Optimization of the reaction conditions in aqueous
phasea)
t-BuOK [BMIm][Br] Yield
Entry Cu
/equiv
/equiv
/%b)
20 mol% Cu
60 mol% [BMIm][Br]
Me
Me
Me
1
2
3
Cu(CH3COO)2¢H2O
CuSO4¢5H2O
CuCl2¢H2O
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.6
0.2
0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2
52
77
71
69
33
48
99
58
77
68
82
56
18
0
Air, H2O, 24 h
1a
2a
Entry
Cu(II) salt
T/°C
Yield/%b)
4
CuBr2
1
2
3
4
5
6
7
Cu(CH3COO)2¢H2O
CuSO4¢5H2O
CuCl2¢H2O
50
50
50
50
50
30
80
50
50
19
38
13
10
75
14
42
0
5
Cu(CF3SO3)2
6
CuF2
7
8
9
10
11
12
13
14
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
none
CuBr2
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
Cu(CF3COO)2¢H2O
none
0.4
0.4
0.4
0.4
8
9c)
4
0
1.2
Cu(CF3COO)2¢H2O
6
a) The reactions were carried out using 1a (0.5 mmol) in the
presence of catalyst (0.1 mmol) and [BMIm][Br] (0.3 mmol)
in 2 mL of H2O under air for 24 h. b) Isolated yields. c) No
[BMIm][Br].
a) The reactions were carried out using 1b (0.5 mmol) in the
presence of catalyst (0.1 mmol) under air for 24 h at room
temperature. b) Isolated yields.
Bull. Chem. Soc. Jpn. 2016, 89, 794–797 | doi:10.1246/bcsj.20160081
© 2016 The Chemical Society of Japan | 795

Table 3. Homocoupling of terminal aryl alkynes in water or under solvent-limited conditionsa)
[Cu]/Ionic liquid, H2O, 50 oC, air or
R
R
R
[Cu]/Ionic liquid, solvent-limited, r.t., air
1
2
Yield Yield
Yield Yield
Entry
1
Product
Entry
Product
/%b)
/%c)
/%b)
/%c)
S
2a
75
88
10
2j
83
72
S
N
99
89e)
99
64e)
2d)
3
2b
2c
11
12
2k
35
64
85
63
N
n-C8H17
n-C8H17
68
84
82
60
83
81
2l
MeO
OMe
Cl(H2C)2H2C
CH2(CH2)2Cl
4
5
2d
13
14
2m
2n
72
58
78
67
npen
npen 2e
Cl
6
2f
96
82
15
2o
50
69
Cl
7
8
2g
2h
81
73
88
78
16
17
2p
2q
94
99
65
63
F
F
OH
F3C
CF3
HO
H2N
OH
9
2i
44
52
18
2r
93
67
HO
NH2
a) Reaction conditions: 1 (0.5 mmol), Cu(CF3COO)2¢H2O (20 mol %), [BMIm][Br] (0.6 equiv), H2O (2 mL) at 50 °C under air for 24 h
(aqueous phase reaction); 1 (0.5 mmol), Cu(CF3COO)2¢H2O (20 mol %), [BMIm][Br] (1.2 equiv), and t-BuOK (0.2 mmol) at room
temperature under air for 24 h (solvent-limited reaction). b) Isolated yields for aqueous phase reactions. c) Isolated yields for solvent-
limited reactions. d) 5 mol % [Cu] was used. e) Gram-scale reaction.
tively (Entry 10). The homocoupling of 2-ethynylpyridine 1k
also proceeded well in solvent-limited conditions. A total of
85% isolated yield was obtained, whereas a low yield of 35%
was obtained when the reaction was carried out in water
(Entry 11).
Table 4. Reuse studies of Cu(CF3COOH)2¢H2O/[BMIm]-
[Br] catalyzed homocoupling of phenylacetylene 1ba)
Yield/%b)
Entry
1st
2nd
3rd
4th
5th
6th
cycle
cycle
cycle
cycle
cycle
cycle
Various aliphatic acetylenes, including linear alkyne
(Entry 12), halogen-containing linear alkyne (Entry 13), small
ring-containing alkyne (Entry 14), medium ring-containing
alkyne (Entry 15), and conjugated enyne (Entry 16), were also
investigated. Moderate to good isolated yields (50-94%) were
obtained in most cases. When alkynes based on propargylic
alcohols were used as substrates in aqueous phase conditions,
excellent yields were achieved (Entries 17 and 18). This result
may be caused by the presence of hydroxy, which played some
role with water, thus benefitting the oxidative homocoupling
reactions. On one hand, only moderate yields were obtained
under the solvent-limited conditions using the propargylic
alcohols as substrates (Entries 17 and 18). The transformation
carried out in water with a longer reaction time (50 h) was
successful for gram-scale preparation, which produced 89%
yield. On the other hand, the gram-scale reaction conducted on
the solvent-limited conditions gave only moderate yields after
72 h (Entry 2).
1c)
2d)
99
99
91
93
81
96
68
94
82
86
a) The optimized reaction conditions were used. b) Isolated
yields. c) Aqueous phase reactions. d) Solvent-limited
reactions.
Finally, catalyst recycling was examined (Table 4). The
catalyst can be separated with other organics by extraction and
can be reused directly. Unfortunately, the catalyst activity in
the aqueous phase system was reduced after three cycles
(Entry 1). The catalyst in the solvent-limited conditions could
be used for six cycles with only a slight activity decrease and a
good isolated yield of 86% (Entry 2).
3. Experimental
3.1 General. Deionized water was used as solvent. Other
reagents from commercial suppliers were used without further
796 | Bull. Chem. Soc. Jpn. 2016, 89, 794–797 | doi:10.1246/bcsj.20160081
© 2016 The Chemical Society of Japan

Ghaderi, M. Gholinejad, S. Rahimi, S. Jokar, RSC Adv. 2014, 4,
27674.
purifications. Flash column chromatography was performed
using silica gel (200-300 mesh). Analytical thin-layer chro-
matography was performed using glass plates pre-coated with
400-500 mesh silica gel impregnated with a fluorescent indi-
cator (254 nm).
2
a) J. R. Suárez, D. Collado-Sanz, D. J. Cárdenas, J. L.
Chiara, J. Org. Chem. 2015, 80, 1098. b) H. Peng, Y. Xi, N.
Ronaghi, B. Dong, N. G. Akhmedov, X. Shi, J. Am. Chem. Soc.
2014, 136, 13174. c) P. Siemsen, R. C. Livingston, F. Diederich,
Angew. Chem., Int. Ed. 2000, 39, 2632.
3.2 Typical Experimental Procedure for the Homocou-
pling Reaction in Aqueous Phase.
Phenylacetylene (0.5
3
a) J. S. Lampkowski, J. K. Villa, T. S. Young, D. D. Young,
mmol) was added to a mixture of Cu(CF3COO)2¢H2O (0.1
mmol), [BMIm][Br] (0.3 mmol), and H2O (2 mL). The mixture
was stirred under air at 50 °C for 24 h.
Angew. Chem., Int. Ed. 2015, 54, 9343. b) H. Yun, T.-C. Chou, H.
Dong, Y. Tian, Y. Li, S. J. Danishefsky, J. Org. Chem. 2005, 70,
10375. c) H. Yun, S. J. Danishefsky, J. Org. Chem. 2003, 68, 4519.
d) A. S. Ratnayake, T. Hemscheidt, Org. Lett. 2002, 4, 4667.
e) S. F. Mayer, A. Steinreiber, R. V. A. Orru, K. Faber, J. Org.
Chem. 2002, 67, 9115.
3.3 Typical Experimental Procedure for the Homocou-
pling Reaction under Solvent-Limited Conditions. t-BuOK
(0.2 mmol) was added to a mixture of Cu(CF3COO)2¢H2O (0.1
mmol), [BMIm][Br] (0.6 mmol), and THF (4 mL). The mixture
was reacted at 50 °C for 3 h. Then, the solvent was evaporated
under reduced pressure, and phenylacetylene (0.5 mmol) was
added. The mixture was stirred under air at room temperature
for 24 h.
4
a) M. Ladika, T. E. Fisk, W. W. Wu, S. D. Jons, J. Am.
Chem. Soc. 1994, 116, 12093. b) H. Yun, S. J. Danishefsky, J. Org.
Chem. 2003, 68, 4519. c) A. Stütz, Angew. Chem., Int. Ed. Engl.
1987, 26, 320. d) A. Stuetz, G. Petranyi, J. Med. Chem. 1984, 27,
1539.
3.4 Purification of Crude Product and Recycle Experi-
ment. After cooling to room temperature, the mixture was
extracted with diethyl ether. The remaining aqueous solution
(for aqueous phase reaction) or the residue (for solvent-limited
reaction) was recharged with 1b for the next cycle. Simulta-
neously, the combined extracts were concentrated under re-
duced pressure, and the residues were purified by silica gel
chromatography (petroleum ether as eluent) to yield the pure 2b.
5
a) Y. Lu, Y. Yang, A. Sellinger, M. Lu, J. Huang, H. Fan, R.
Haddad, G. Lopez, A. R. Burn, D. Y. Sasaki, J. Shelnutt, C. J.
Brinker, Nature 2001, 410, 913. b) Y. Yang, Y. Lu, M. Lu, J.
Huang, R. Haddad, G. Xomeritakis, N. Liu, A. P. Malanoski, D.
Sturmayr, H. Fan, D. Y. Sasaki, R. A. Assink, J. A. Shelnutt, F.
van Swol, G. P. Lopez, A. R. Burns, C. J. Brinker, J. Am. Chem.
Soc. 2003, 125, 1269. c) V. S.-Y. Lin, D. R. Radu, M.-K. Han, W.
Deng, S. Kuroki, B. H. Shanks, M. Pruski, J. Am. Chem. Soc.
2002, 124, 9040.
6
a) R. E. Martin, F. Diederich, Angew. Chem., Int. Ed. 1999,
4. Conclusion
38, 1350. b) J. M. Tour, Chem. Rev. 1996, 96, 537. c) F. Diederich,
Y. Rubin, Angew. Chem., Int. Ed. Engl. 1992, 31, 1101. d) F.
Babudri, D. Colangiuli, P. A. Di Lorenzo, G. M. Farinola, O. H.
Omar, F. Naso, Chem. Commun. 2003, 130.
In conclusion, an ionic liquid-promoted copper-catalyzed
homocoupling of terminal alkynes using air as oxidant in
aqueous phase or solvent-limited conditions was developed.
These strategies are environmentally benign, economical, effi-
cient, operationally simple, insensitive to air, and compatible
with water. Various conjugate 1,3-diynes can be achieved
with good to excellent yields in most cases using these two
methods. Additionally, the homocoupling reaction can be
easily increased to reach the gram-scale level with a longer
reaction time (50 h for aqueous phase reaction; 72 h for solvent-
limited conditions) under optimized conditions. Furthermore,
the reaction can be recycled easily six times under solvent-
limited conditions; thus, these methods have a potential for
industrial applications.
7
a) Y. Ren, M. Li, J. Yang, J. Peng, Y. Gu, Adv. Synth. Catal.
2011, 353, 3473. b) C. Ye, J.-C. Xiao, B. Twamley, A. D.
LaLonde, M. G. Norton, J. M. Shreeve, Eur. J. Org. Chem. 2007,
5095. c) J. S. Yadav, B. V. S. Reddy, K. Bhaskar Reddy, K. Uma
Gayathri, A. R. Prasad, Tetrahedron Lett. 2003, 44, 6493.
8
a) F.-W. Li, Q.-L. Suo, H.-L. Hong, N. Zhu, Y.-Q. Wang,
L.-L. Guo, L.-M. Han, J. Supercrit. Fluids 2014, 92, 70. b) H.-F.
Jiang, J.-Y. Tang, A.-Z. Wang, G.-H. Deng, S.-R. Yang, Synthesis
2006, 1155. c) J. Li, H. Jiang, Chem. Commun. 1999, 2369.
9
a) K. H. Shaughnessy, Chem. Rev. 2009, 109, 643. b) I. T.
Horváth, Green Chem. 2008, 10, 1024. c) R. A. Sheldon, Green
Chem. 2005, 7, 267.
10 a) W. Susanto, C.-Y. Chu, W. J. Ang, T.-C. Chou, L.-C. Lo,
Y. Lam, J. Org. Chem. 2012, 77, 2729. b) H. Firouzabadi, N.
Iranpoor, F. Kazemi, J. Mol. Catal. A: Chem. 2011, 348, 94.
c) T.-M. Wu, S.-H. Huang, F.-Y. Tsai, Appl. Organomet. Chem.
2011, 25, 395. d) S.-N. Chen, W.-Y. Wu, F.-Y. Tsai, Green Chem.
2009, 11, 269. e) P.-H. Li, J.-C. Yan, M. Wang, L. Wang, Chin. J.
Chem. 2004, 22, 219. f) P. H. Li, L. Wang, M. Wang, J. C. Yan,
Chin. Chem. Lett. 2004, 15, 1295. g) A. Ghaderi, M. Gholinejad,
H. Firouzabadi, Curr. Org. Chem. 2016, 20, 327.
11 a) L. Chen, B. E. Lemma, J. S. Rich, J. Mack, Green Chem.
2014, 16, 1101. b) G. Cheng, H. Zhang, X. Cui, RSC Adv. 2014, 4,
1849. c) D. Wang, J. Li, N. Li, T. Gao, S. Hou, B. Chen, Green
Chem. 2010, 12, 45.
We are grateful to the project sponsored by the Project of the
National Science Foundation of P. R. China (Nos. 21402168
and 21305118) and Scientific Research Foundation of Hunan
Provincial Education Department (No. 15B232).
Supporting Information
General procedure and NMR spectra of all products were
provided. This material is available on http://dx.doi.org/
10.1246/bcsj.20160081.
References
1
a) J. M. DeSimone, Science 2002, 297, 799. b) S.-J. Jeon,
H. Li, P. J. Walsh, J. Am. Chem. Soc. 2005, 127, 16416. c) M.
Poliakoff, P. Anastas, Nature 2001, 413, 257. d) R. A. Gross, B.
Kalra, Science 2002, 297, 803. e) H. Firouzabadi, N. Iranpoor, A.
12 H. Firouzabadi, N. Iranpoor, A. Ghaderi, J. Mol. Catal. A:
Chem. 2011, 347, 38.
Bull. Chem. Soc. Jpn. 2016, 89, 794–797 | doi:10.1246/bcsj.20160081
© 2016 The Chemical Society of Japan | 797