Importance of bases on the copper-catalyzed oxidative homocoupling of terminal alkynes to 1,4-disubstituted 1,3-diynes

Article abstract of DOI:10.1016/j.tetlet.2012.08.050

Copper-catalyzed, solvent-free oxidative homocoupling of terminal alkynes can be performed to 1,3-diynes in good to excellent yields in the absence of any additives, using air as environmentally friendly oxidant and the occurrence of water as an exclusive byproduct in the whole process. It is shown that AcO ^- of copper (II) acetate catalyst may take the role of base and found that the homocoupling cannot occur using weakly basic copper salt catalysts such as CuBr, CuCl, or CuI. Thus, the bases are absolutely necessary in the process of the homocoupling of terminal alkynes. 2012 Elsevier Ltd. All rights reserved.

Full text of DOI:10.1016/j.tetlet.2012.08.050

Tetrahedron Letters 53 (2012) 5559–5561
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Importance of bases on the copper-catalyzed oxidative homocoupling
of terminal alkynes to 1,4-disubstituted 1,3-diynes
Xinjiang Niu a, Chunju Li a, Jian Li a, Xueshun Jia a,b,
⇑
a Department of Chemistry, Shanghai University, Shanghai 200444, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2012
Revised 19 July 2012
Accepted 10 August 2012
Available online 17 August 2012
Copper-catalyzed, solvent-free oxidative homocoupling of terminal alkynes can be performed to 1,3-diy-
nes in good to excellent yields in the absence of any additives, using air as environmentally friendly oxi-
dant and the occurrence of water as an exclusive byproduct in the whole process. It is shown that AcOÀ of
copper (II) acetate catalyst may take the role of base and found that the homocoupling cannot occur using
weakly basic copper salt catalysts such as CuBr, CuCl, or CuI. Thus, the bases are absolutely necessary in
the process of the homocoupling of terminal alkynes.
Keywords:
Base
Ó 2012 Elsevier Ltd. All rights reserved.
Homocoupling
Terminal alkyne
1,3-Diyne
Copper
The homocoupling of terminal alkynes to 1,3-diynes is an
important carbon–carbon bond-formation reaction.1 1,3-Diynes
are widespread in many natural products, pharmaceuticals, and
bioactive compounds with antiinflammatory, antifungal, anti-
HIV, antibacterial, or anticancer activities, etc.2 They have been
also isolated from various natural sources including bacteria, cor-
als, fungi, marine sponges, and plants. The 1,3-diynes play a signif-
icant role in the construction of macrocyclic annulenes,3,4 organic
conductors,5,6 supramolecular switches,7 and carbon-rich materi-
als.3,6 Accordingly, considerable efforts8 have been put toward
the development of new and effective approaches for the forma-
tion of 1,3-diynes since 1869.9 Palladium and copper salts are effi-
cient and mild catalytic system for the homocoupling of terminal
alkynes,10 however, palladium catalysts are expensive, and air-sen-
sitive and expensive phosphine ligands as well as amines were
usually required in this step of reaction. Therefore, from the view
of economic and environmental points, the development of more
efficient and straightforward methods is highly desirable. We have
reported previously the CuI-promoted alkyne homocoupling reac-
tion employing inorganic Na2CO3 instead of amine as the base,11
however, a stoichiometric amount of CuI and an expensive and
harmful oxidant iodine were needed. In succession, we also
achieved the homocoupling reaction of terminal alkynes using
the catalytic amount of CuI, but the stoichiometric amount of NaO-
Ac as base was required.12 It can be seen that the bases are abso-
lutely necessary among the all literatures reported for the
homocoupling of terminal alkynes. Recently, we demonstrated
the Cu(I)-, and Cu(II)-catalyzed oxidative alkyne homocoupling
using DMSO as solvent without ligands and bases.13 Nevertheless
some chemists think that DMSO may take the role of bases.
Whether DMSO takes the role of bases in the process of homocou-
pling of terminal alkynes or not, we decided to perform experi-
ments toward this end.
We reported herein our finding in the homocoupling of terminal
alkynes, which illustrated the effective example of achieving 1,3-
diynes using a simple and cheap copper salt as the catalyst without
any other additives (Scheme 1).
In our initial experiments, 1-(n-pentyl)-4-ethynylbenzene (1f)
was employed to optimize reaction conditions. As shown in
Table 1, a variety of catalysts were screened, and interestingly, cop-
per(II) acetate monohydrate alone gave the best result, in which
the yield of product 2f was up to 91% (Table 1, entry 9). While
among the Cu (I) salts, only CuOAc provided the desired product
2f in 83% yield (Table 1, entry 4), which showed lower catalyzing
efficiency than copper(II) acetate monohydrate, and the homocou-
pling cannot occur using weakly basic Cu(I) salts such as CuBr,
CuCl, or CuI (Table 1, entries 1–3), which indicated that DMSO do
Cu
2 R
CH
R
R
air, neat
⇑
Corresponding author. Tel./fax: +86 21 66132408.
E-mail address: xsjia@mail.shu.edu.cn (X. Jia).
Scheme 1. The homocoupling of terminal alkynes.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.050

5560
X. Niu et al. / Tetrahedron Letters 53 (2012) 5559–5561
Table 1
2 HOAc
+
Cu
Reaction parameters of the homocoupling of 1fa
air
Entry
Catalyst
Time (h)
Yieldb (%)
R
R
R
R
1
2
3
4
CuBr
CuCl
CuI
CuOAc
5
5
5
4
None
None
None
83
A
HOAc
Cu(OAc)2
R
5
6
7
8
CuBr2
5
5
5
6
4.5
4
8
6
10
32
40
30
34
CuCl2ÁH2O
CuSO4Á5H2O
Cu(NO3)2Á3H2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
Cu(OAc)2ÁH2O
NaOAc
Cu(OAc)2 + H2O
9
91
10
11
12
13
88c
70d
69e
Nonef
R
Scheme 2. Proposed mechanism for the formation of 1,3-diynes.
a
b
c
d
e
f
Reaction conditions: 3.0 mmol of 1f, 0.3 mmol of Cu(II) or Cu(I) salt.
Isolated yield.
Cu(OAc)2ÁH2O (0.6 mmol).
Cu(OAc)2ÁH2O (0.15 mmol).
At 90 C.
homocoupling of the aliphatic alkynes also carried out satisfacto-
rily (Table 2, entries 10–16), and amino, chloro, hydroxyl, car-
bon–carbon double bond did not affect the homocoupling
reactions (Table 2, entries 12–13, 15–16).
Why cannot the homocoupling of terminal alkynes conduct in
the absence of any additives including solvent DMSO? We consider
that AcOÀ of Cu(OAc)2 catalyst may take the role of base. Scheme 2
illustrates the proposed mechanism for the sp–sp homocoupling of
terminal alkynes in the presence of 10 mol % of Cu(OAc)2. The alky-
nylcopper intermediate A is formed from the reaction of terminal
alkyne and Cu(OAc)2, and then it undergoes smooth oxidative
dimerization with air to the sp–sp homocoupling product and
water. Cu(OAc)2 generated is recycled.
In conclusion, we have proved the homocoupling of terminal al-
kynes carried out well in the absence of any additives including
solvent DMSO.14 It is shown AcOÀ of Cu(OAc)2 catalyst may take
the role of base, and found that the homocoupling cannot occur
using weakly basic copper salt catalysts such as CuBr, CuCl, or
CuI, which indicated that DMSO do take the role of base in our pre-
vious work on CuCl-catalyzed homocoupling of terminal alkyne-
s.13a Thus, the bases are absolutely necessary in the process of
the homocoupling of terminal alkynes. Also, copper is very impor-
tant in this reaction because the homocoupling is unable to happen
using NaOAc as catalyst or promoter. At the same time, a copper-
catalyzed, green, and economical method for homocoupling of ter-
minal alkynes is developed. The reaction proved to be tolerant to
varied functional groups and no byproduct was observed. Hence,
the practical, economical, and attractive methodology is applicable
in organic synthetic chemistry and industrial preparation.
NaOAc (0.3 or 3.0 mmol).
take the role of base in our previous work on CuCl-catalyzed homo-
coupling of terminal alkynes.13a Other Cu (II) salts gave low yields
(Table 1, entries 5–8). The increase of Cu(OAc)2 H2O’s amount did
not obviously change the yield of product 2f (Table 1, entry 10).
On the other hand, the decrease of Cu(OAc)2 H2O’s amount resulted
.
.
in long reaction time and low yield of the product 2f (Table 1, entry
11). In addition, the decrease of the reaction temperature to 90 °C
led to long reaction time and low yield (Table 1, entry 12). We also
found that copper was very important in this reaction because the
homocoupling cannot occur using NaOAc as catalyst or promoter
(Table 1, entry 13).
The substrate scope toward this homocoupling of terminal al-
kynes was further investigated using the optimized reaction condi-
tions, and the results were summarized in Table 2. A variety of
terminal alkynes including aliphatic and aromatic acetylenes were
examined under the optimal conditions, and good to excellent
yields were obtained in producing the corresponding 1,3-diynes
(Table 2). The aromatic acetylenes, which bear substituted groups
such as methyl, ethyl, n-propyl, n-pentyl, bromo, all conducted
smoothly self-homocoupling reactions to afford the desired corre-
sponding products (Table 2, entries 1–8). For the heterocyclic
substituted terminal alkyne, the dimerization of 2-ethynylthioph-
ene conducted well (Table 2, entry 9). Furthermore, the
Table 2
Acknowledgments
Cu(OAc)2ÁH2O-catalyzed homocoupling of terminal alkynesa
We thank the National Natural Science Foundation of China
(21142012, 21002061, 20902057), the Key Laboratory of Synthetic
Chemistry of Natural Substances, Chinese Academy of Sciences,
Leading Academic Discipline Project of Shanghai Municipal Educa-
tion Commission (No: J50101), and the Graduate Innovation Fund
of Shanghai University for financial support. We also thank Dr.
Hongmei Deng (Laboratory for Microstructures, Shanghai Univer-
sity) for the NMR measurement.
Entry
Alkyne
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Phenylacetylene 1a
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-Bromo-4-ethynylbenzene 1h
2-Ethynylthiophene 1i
1-Heptyne 1j
1-Decyne 1k
2-Methyl-3-butyn-2-ol 1l
1-Ethynylcyclohex-1-ene 1m
1-Methoxy-4-(2-propynyloxy)benzene 1n
6-Chloro-1-hexyne 1o
7
7
8
6
6.5
4.5
7
9
6
6
6
5
7
7
7
7
85 (2a)
84 (2b)
78 (2c)c
84 (2d)
88 (2e)
91 (2f)
76 (2g)d
78 (2h)
86 (2i)
78 (2j)
81 (2k)
91 (2l)e
85 (2m)
81 (2n)
80 (2o)
78 (2p)
9
10
11
12
13
14
15
16
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
050.
1-Dimethylamino-2-propyne 1p
a
b
c
Reaction conditions: 3.0 mmol of 1, 0.3 mmol of Cu(OAc)2ÁH2O.
References and notes
Isolated yield.
At 160 °C.
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d
e
At 140 °C.
At 130 °C.

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14. General procedure for the homocoupling of terminal alkynes: alkyne (3.0 mmol)
and Cu(OAc)2ÁH2O (0.3 mmol) were added to a tube (100 mL) successively in
the open air. Then the tube was sealed, and the resulting mixture was allowed
to react at 110 °C. Progress of this reaction was monitored by TLC and the
reaction phenomena (The reactions passed through henna, gradually to black
from starting to end). After completion of the reaction, 30 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. Selected data of 1,4-bis(4-methylphenyl)-1,3-butadiyne: 1H NMR
(500 MHz, CDCl3): d = 7.43 (d, J = 8.0 Hz, 4H, ArH), 7.15 (d, J = 8.0 Hz, 4H,
ArH), 2.37 (s, 6H, CH3). 13C NMR(125 MHz, CDCl3): d = 139.6, 132.5, 129.3,
118.9, 81.6, 73.5, 21.7. EI-MS m/z 230 [M+].