CuCl-catalyzed green oxidative alkyne homocoupling without palladium, ligands and bases

Article abstract of DOI:10.1039/c0gc00413h

CuCl-catalyzed green oxidative homocoupling of terminal alkynes produces symmetrical 1,4-disubstituted 1,3-diynes in good to excellent yields, using air as an environmentally friendly oxidant and the occurrence of water as exclusive byproduct in the whole process, and eliminating the need for ligands, bases, oxidants and expensive palladium catalysts. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00413h

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COMMUNICATION
CuCl-catalyzed green oxidative alkyne homocoupling without palladium,
ligands and bases†
a
a
a
a,b
Kun Yin, Chunju Li, Jian Li and Xueshun Jia*
Received 8th August 2010, Accepted 14th January 2011
DOI: 10.1039/c0gc00413h
CuCl-catalyzed green oxidative homocoupling of terminal
alkynes produces symmetrical 1,4-disubstituted 1,3-diynes
in good to excellent yields, using air as an environmentally
friendly oxidant and the occurrence of water as exclusive
byproduct in the whole process, and eliminating the need for
ligands, bases, oxidants and expensive palladium catalysts.
continues to be of great importance and interest. Previously, we
have described the CuI-mediated alkyne homocoupling reaction
10
employing inorganic Na
however, a stoichiometric amount of CuI, 200 mol% base and
00 mol% iodine (as the oxidant) were required. To the best
2
CO
3
instead of amine as the base,
1
of our knowledge, no studies have so far been carried out to
evaluate whether or not Cu(I)-catalyzed alkyne homocoupling
reaction can be performed in the absence of any other additives.
Recently, we also focused on searching for more “green” or
1
,3-Diynes occur widely in numerous natural products, phar-
maceuticals and bioactive compounds with antiinflammatory,
antifungal, anti-HIV, antibacterial or anticancer activities,
11a–b
environmentally friendly chemical processes.
As a continua-
1
a–h
etc.
For example, diplyne D, isolated from the Philippine
tion of our interest in the homocoupling of terminal alkynes
and green chemistry, herein, we describe our recent finding
that in the absence of any additives, only 5.0 mol% of CuCl
could efficiently catalyze the homocoupling of various terminal
alkynes. The dimethylsulfoxide (DMSO) solution of terminal
sponge Diplastrella, has been shown to exhibit potent anti-HIV
1a
activity. falcarindiol, isolated from Panax ginseng, shows anti-
1b
staphylococcal activity, and thiarubrine A possesses effective
1c
antiviral and antibacterial activities. In addition, conjugated
diynes play an important role in the construction of macrocyclic
◦
alkyne and 5 mol% CuCl was heated at 90 C in the open air, and
2
,3a–b
4,5
6
annulenes,
organic conductors, supramolecular switches
1,3-diynes were obtained in good to excellent yields. This is the
first example of Cu(I)-catalyzed alkyne homocoupling without
any other additives.
2,5
7a–q
and carbon-rich materials. Therefore, much attention
has
been devoted to the development of new and efficient methods
8
for the synthesis of diynes since 1869. Catalytic systems medi-
Our initial studies of this process focused on the development
of an optimum of reaction conditions for the homocoupling
reaction of 1-(n-propyl)-4-ethynylbenzene (1e) using CuCl as
the catalyst and air as the oxidant. Some preliminary studies re-
vealed that the best result was obtained when the homocoupling
ated by a combination of palladium (Pd) and copper salts are the
most attractive routes for the homocoupling of terminal alkynes
9
a–k
due to their efficiency and mildness,
however, palladium
reagents are expensive, and they often require air-sensitive and
expensive phosphine ligands as well as foul-smelling amine
reagents. Recently, the CuCl-catalyzed homocoupling reaction
◦
was run with 5.0 mol% CuCl and DMSO as solvent at 90 C
(Table 1, entry 7). The results employing various solvents are
listed in Table 1. These results clearly show that high polarity
solvents, N,N-dimethyl formamide (DMF) and DMSO (Table 1,
entries 6–7), exhibited significant superiorities over low polarity
solvents. For example, the employment of 1,4-dioxane led to very
low yield (15%, Table 1, entry 1), whereas no reaction occurred
when toluene was used as solvent or under the solvent-free con-
ditions (Table 1, entries 4, 10). On the other hand, the product
conversion was susceptible to temperature changes (Table 1,
7c
of terminal alkynes has been reported, however, this protocol
requires TMEDA or DBEDA as a ligand (other ligands are
unsuccessful such as salen, DCU and 1,5-cis-diazadecalin) and
the sterically hindered amine (DBU or DABCO) as a base (other
bases are unsuccessful such as K
,5-naphthyridine) as well as long reaction time.
Although the homocoupling of terminal alkynes has been
2
CO
3
, Cs
2
CO , TEA, DIPA,
3
1
investigated for more than 140 years, from the view of economic
and environmental points, the development of new approaches
◦
entries 7–9). The decrease of reaction temperature to 25 C led
to long reaction time and low yields (Table 1, entry 8–9).
The counteranion for the Cu(I) catalyst was found to play
a significant role on the effectiveness of the transformation.
As can be seen from Table 2 (entries 1–5), the efficiency of
CuCl, CuBr and CuI was very high since excellent yields (93%–
a
Shanghai University, 99 Shangda Road, Shanghai, 200444, P. R. China.
E-mail: xsjia@mail.shu.edu.cn; Fax: +86-21-66132408
b
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
3
9
(
7%) were obtained. While in the presence of other Cu(I) salts
Table 2, entries 6–8), the reaction proceeded slowly in low
45 Lingling Road, Shanghai, 200032, P. R. China
Electronic supplementary information (ESI) available: See DOI:
0.1039/c0gc00413h
†
1
yields. Furthermore, the effect of catalyst concentrations was
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a
Table 1 Solvent and temperature screening for the homocoupling of
Table 3 CuCl-catalyzed homocoupling of terminal alkynes
a
1
e
◦
b
Entry
Solvent
Temp. ( C)
Time (h)
Yield (%)
CuCl
(mol%) (h)
Time Yield
b
Entry Alkyne
(%)
1
2
3
4
5
6
7
8
9
1,4-Dioxane
90
Reflux
90
90
90
90
90
60
25
24
24
24
24
4.0
4.5
2.5
12
48
24
15
38
25
CH
3
CN
PhCN
Toluene
NMP
1
2
3
4
5
6
7
8
Phenylacetylene 1a
5
5
5
5
5
5
5
5
20
50
5
5
10
5
10
5
10
5
10
5
5
7
4
5
7
96 (2a)
96 (2b)
93 (2c)
91 (2d)
97 (2e)
99 (2f)
98 (2g)
72 (2h)
75 (2h)
86 (2h)
90 (2i)
65 (2j)
83 (2j)
74 (2k)
82 (2k)
78 (2l)
83 (2l)
77 (2m)
84 (2m)
75 (2n)
79 (2o)
c
3-Ethynyltoluene 1b
4-Ethynyltoluene 1c
1-Ethyl-4-ethynylbenzene 1d
1-Ethynyl-4-propylbenzene 1e
1-Ethynyl-4-pentylbenzene 1f
4-Ethynylanisole 1g
1-Ethynyl-4-fluorobenzene 1h
1h
—
82
95
97
86
12
DMF
DMSO
DMSO
DMSO
Neat
2.5
3
10
20
3
2.5
2.5
20
8
24
2
24
2
2
2
2.5
13
c
1
0
90
—
9
10
11
a
b
c
Reaction conditions: 1.0 mmol of 1e. Isolated yield. No reaction
1h
occurred.
2-Ethynylthiophene 1i
3-Ethynylpyridine 1j
1j
1
1
2
3
a
Table 2 Catalyst screening for the homocoupling of 1e
14
1-Heptyne 1k
15
16
17
18
19
20
21
1k
1-Octyne 1l
1l
Ethynylcyclopropane 1m
1m
b
Entry
Catalyst
Time (h)
Yield (%)
1-Ethynylcyclohex-1-ene 1n
((But-3-ynyloxy)methyl)benzene 1o
1
2
3
4
5
6
7
8
CuCl, 2 mol (%)
CuCl, 5 mol (%)
CuCl, 10 mol (%)
CuBr, 5 mol (%)
CuI, 5 mol (%)
CuOAc, 5 mol (%)
CuCN, 5 mol (%)
45
93
97
97
94
94
50
65
20
a
b
2.5
2.0
4.5
4.0
12
20
24
Reaction conditions: 1.0 mmol of 1, 1.0 mL of DMSO. Isolated yield.
which could be attributed to the electron-donating nature of
the thiophene group on 1i and the electron-withdrawing nature
of the pyridine group on 1j. (Table 3, entries 11–13). On the other
hand, the reaction was a little sluggish in the case of aliphatic
alkynes. Similarly, the increase of CuCl (5%→10%) facilitates
the transformation, allowing shorter reaction time and better
yield (Table 3, entries 14–19).
Cu
2
O, 5 mol (%)
a
b
Reaction conditions: 1.0 mmol of 1e, 1.0 mL of DMSO. Isolated
yield.
also studied. The reaction can be carried out in 93% yield in
the presence of 2 mol% CuCl (Table 2, entry 1). However, the
reaction proceeded very slowly (45 h). Increasing the amount
of CuCl from 2 mol% to 5 mol% results in significant decrease
of reaction time from 45 to 2.5 h (Table 2, entries 1–2). While
the increase of amount of CuCl to 10 mol% does not obviously
improve the transformation (Table 2, entries 2–3). On the other
hand, since CuCl is much cheaper than CuBr and CuI, all of
the following experiments are performed using 5 mol% CuCl as
catalyst.
In conclusion, we have developed a facile and green method
for the CuCl-catalyzed homocoupling reaction of terminal
12
alkynes. The reaction proved to be tolerant to a variety
of functional groups. The great attractiveness of the current
method lies in the simple experimental procedure, avoidance
of palladium, base and ligand, use of air as environmentally
friendly oxidant as well as the occurrence of water as an exclusive
byproduct in the whole process. These features make this
methodology economical and attractive for use in combinatorial
chemistry and industrial preparation.
We then focused on our attention to substrate generality using
the optimized reaction conditions. Various terminal alkynes
including aliphatic and aromatic acetylenes were examined
under the optimal conditions and the results were summarized
in Table 3. For the aromatic acetylenes, the homocoupling
processes were affected dramatically by the substituents on the
aromatic ring. Electron-donating substituents such as alkyl and
methoxy groups facilitate the reaction, allowing better yields
and shorter reaction times (Table 3, entries 1–7). While electron-
withdrawing fluoro group (1h) decreases the transformation
rate very much, needing the amount of CuCl increased to
Acknowledgements
The authors thank the National Natural Science Foundation of
China (No: 20872087 and 20902057), the Key Laboratory of
Synthetic Chemistry of Natural Substances, Chinese Academy
of Sciences, Leading Academic Discipline Project of Shanghai
Municipal Education Commission (No: J50101) and the Inno-
vation Fund of Shanghai University for financial support.
Notes and references
5
0 mol% (Table 3, entries 8–10). For the heterocyclic substituted
1
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92 | Green Chem., 2011, 13, 591–593
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12 General procedure: To a stirred solution of alkyne (1.0 mmol) in
DMSO (1.0 mL), CuCl (5 mol%), (see Table 3) was added in
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90 C in air. Process of this reaction was monitored by TLC and
the reaction phenomena. (The reactions passed through yellowness,
cyan to black from starting to end). After completion of the
reaction, 10 mL of ethyl acetate was added. The mixture was filtered
through a pad of diatomite under reduced pressure, and the filtration
residue was washed with ethyl acetate. Ethyl acetate was removed
under reduced pressure. The residue was then purified by column
chromatography on silica gel using petroleum ether as eluent to
afford the corresponding 1,3-diynes. All of the products are known
and were characterized by comparison of their spectral data with
those of authentic samples.
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Green Chem., 2011, 13, 591–593 | 593