Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in supercritical carbon dioxide

Article abstract of DOI:10.1016/j.tet.2018.02.060

An efficient protocol for the synthesis of unsymmetrical 1,3-diynes was developed using supercritical carbon dioxide (ScCO₂) as the solvent. The direct coupling of two different terminal alkynes is catalysed by a bimetallic catalyst, CuCl₂·2H₂O/Pd(NH₃)₄Cl₂·H₂O, in the presence of the base tetramethylethylenediamine (TMEDA) and O₂. In pure ScCO₂, our bimetallic catalytic system maintains high activity over a wide substrate scope to provide unsymmetrical 1,3-diynes in good to excellent yields. In the proposed reaction mechanism, the synergistic cooperation between copper(II) and palladium(II) centres is responsible for the superior selectivity of the cross-coupling.

Full text of DOI:10.1016/j.tet.2018.02.060

Tetrahedron xxx (2018) 1e8
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Tetrahedron
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Copper(II)/Palladium(II) catalysed highly selective cross-coupling of
terminal alkynes in supercritical carbon dioxide
Yunlong Wang, Quanling Suo, Limin Han, Linlin Guo, Yaqi Wang*, Fawang Li
Chemical Engineering College, Inner Mongolia University of Technology, Hohhot, 010051, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the synthesis of unsymmetrical 1,3-diynes was developed using supercritical
carbon dioxide (ScCO2) as the solvent. The direct coupling of two different terminal alkynes is catalysed
by a bimetallic catalyst, CuCl2$2H2O/Pd(NH3)4Cl2$H2O, in the presence of the base tetramethylethyle-
nediamine (TMEDA) and O2. In pure ScCO2, our bimetallic catalytic system maintains high activity over a
wide substrate scope to provide unsymmetrical 1,3-diynes in good to excellent yields. In the proposed
reaction mechanism, the synergistic cooperation between copper(II) and palladium(II) centres is
responsible for the superior selectivity of the cross-coupling.
Received 31 December 2017
Received in revised form
13 February 2018
Accepted 23 February 2018
Available online xxx
Keywords:
Supercritical CO2
© 2018 Elsevier Ltd. All rights reserved.
Unsymmetrical diyne
Terminal alkyne
Bimetallic catalytic system
Cross-coupling reaction
1. Introduction
this cross-coupling has become a critical and challenging issue in
the synthesis of unsymmetrical diynes when terminal alkynes are
Conjugated alkynes are fundamental structural motifs in a va-
riety of natural products and bioactive compounds.1 Symmetrical
and unsymmetrical 1,3-diyne scaffolds are also important building
blocks for constructing functional materials with unique optical
and conductive properties, such as functional polymers, liquid
crystals, non-linear materials, molecular wires and supramolecular
materials.2e5 Therefore, the efficient and concise syntheses of 1,3-
diynes have attracted considerable attention from chemists for
decades.
Glaser-Hay coupling is a classic method used in the synthesis of
1,3-diynes and is extensively used to create symmetrical 1,3-diynes
through the Cu-catalysed oxidative homocoupling of terminal al-
kynes in the presence of a base and an oxidant.6 Along with the
increased demand for unsymmetrical 1,3-diynes, the cross-
coupling of alkynes has also been a focus in research. When two
different terminal alkynes were coupled using the Glaser-Hay
conditions, the yield suffered from an undesirable, competitive
homocoupling reaction and, as a result, yielded a mixture of three
coupling products (a heterodimer and two homodimers), which
were difficult to separate.7e10 Therefore, the improved selectivity of
used as starting materials. A pioneering solution to this problem is
the Cu(I)-catalysed cross-coupling between a 1-haloalkyne and a
terminal alkyne published by Cadiot and Chodkiewicz.11 In addition
to the Cadiot-Chodkiewicz coupling, which is currently the most
commonly used method, a number of alternative approaches have
been developed, and the reaction partners of the haloalkyne have
been expanded to metalated alkynes and other related substrates,
such as magnesium acetylides, lithium acetylides, alkynylzincs,
alkynylstannanes, alkynylborates and alkynylsilanes.6,12 These
precursors promoted the selective formation of unsymmetrical 1,3-
diynes. However, because of the labour-intensive pre-functionali-
zation of the alkyne, as well as the toxicity and low stability of 1-
haloalkynes and organometallic reagents, direct oxidative
coupling of two different terminal alkynes is widely believed to be
the most straightforward and economic route for synthesizing
unsymmetrical 1,3-diyne molecules. For years, considerable
research has been performed to improve the efficiency of this direct
synthetic methodology, such as modifying the catalytic systems
(Cu, Pd, Ni),7,13 bases,14 oxidants8 and other factors15e18 based on
the original Glaser-Hay conditions. Recently, significant progress
has been made in the Au19 or Cu-catalysed18,20 highly selective
cross-coupling of terminal alkynes. Despite these important ad-
vances, the competitive homocoupling reaction and the use of
environmentally harmful organic solvents remain great challenges.
* Corresponding author.
E-mail address: w.yaqi@yeah.net (Y. Wang).
https://doi.org/10.1016/j.tet.2018.02.060
0040-4020/© 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
supercritical carbon dioxide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.02.060

2
Y. Wang et al. / Tetrahedron xxx (2018) 1e8
Because of the increasing focus on applying green chemistry in
(Table 1, entries 1e9), CuCl2$2H2O with DBU as a base additive gave
the highest yield (3a yield: 56%). Interestingly, the yield of 3a
dropped dramatically to 18% when anhydrous CuCl2 was used as a
catalyst, which suggested that the crystal water of CuCl2$2H2O
should be advantageous for the catalytic process (Table 1, entries 3
and 4). Because single-metal catalysts provided only moderate ef-
ficiency, we employed CuCl2$2H2O based bimetallic catalysts to
enhance the performance of the reaction (Table 1, entries 11e13).
When CuCl2$2H2O was combined with PdCl2, NiCl2$6H2O or
Pd(NH3)4Cl2$H2O, the yields of 3a were noticeably raised to 66%,
74% and 86%, respectively. The reaction without CuCl2$2H2O only
yielded 22% of the heterocoupled diyne 3a (Table 1, entry 10),
which demonstrated the crucial role of the CuCl2$2H2O catalyst in
the formation of the heterocoupled diyne. The bimetallic catalyst
CuCl2$2H2O/Pd(NH3)4Cl2$H2O was more effective than either
CuCl2$2H2O or Pd(NH3)4Cl2$H2O as the sole catalyst, which indi-
cated that CuCl2$2H2O and Pd(NH3)4Cl2$H2O synergistically pro-
moted the reaction. The catalytic activity of Pd(NH3)4Cl2$H2O was
superior to PdCl2 in the Cu/Pd bimetallic catalyst system, which
suggested that the ammonia ligands and crystal water of
Pd(NH3)4Cl2$H2O might be helpful for the reaction. Notably, the
amount and stoichiometric ratio of CuCl2$2H2O and
Pd(NH3)4Cl2$H2O in the combined catalyst also influenced the
catalytic activity (Table 1, entries 13e17). An equimolar mixture of
CuCl2$2H2O and Pd(NH3)4Cl2$H2O (10:10, mol%) produced 3a in a
satisfactory yield and was therefore selected as a promising
bimetallic catalyst for the cross-coupling of terminal alkynes in
ScCO2.
We attempted to further improve the yield of 3a by changing
both the bases and the ratios of the terminal alkynes. As shown in
Table 2, the cross-coupling reaction could not occur in the absence
of base (Table 2, entry 1). Although inorganic bases NaOAc and
K2CO3 were effective for the reaction, the heterocoupled product
was obtained in moderate yield (Table 2, entries 2 and 3). The use of
other organic bases, including NEt3, pyridine, TBD and TMEDA, also
resulted in good yields (Table 2, entries 6e9), and TMEDA was the
optimum base, producing 3a in 91% yield with excellent hetero-/
homoselectivity (3a vs 4a, 3a/4a ¼ 91%/2%, entry 9). The variance in
the yield might be attributed to the better solubility of organic
bases in ScCO2.24,25 Incrementally increasing the amount of TMEDA
from 100 mol% to 200 mol% (Table 2, entries 9e13) showed that
120 mol% produced the highest yield and selectivity. The cross-
coupling reaction also strongly depended on the ratio of two ter-
minal alkynes (Table 2, entries 13e17). An equimolar mixture of
two alkynes gave a moderate yield of 3a (65%, entry 15). Increasing
the ratio of 1a to 2a from 1:1 to 1:2 significantly increased the yield
of 3a from 65% to 92% (Table 2, entry 14). When 2a was increased
further to a three-fold excess with respect to 1a, a comparable yield
for 3a (92%) was observed (Table 2, entry 13). In contrast, the yields
decreased when the ratio of 1a to 2a was inverted (2:1, 76%; 3:1,
84%; entries 16 and 17) because the redundant 1a is more easily
homocoupled. Thus, a two-fold excess of 2a was employed in the
following experiments. This bimetallic catalyst was also tested for
the homocoupling of 1a and the homocoupling of 2a, and the
corresponding homocoupled products were produced in relatively
low yields (4a: 53%, 5a: 40%; Table 2, entries 18 and 19), which
indicated that our catalytic system in ScCO2 was more efficient for
cross-coupling.
organic synthesis, applicable methods are required to be not only
high-yielding but also environmentally friendly.21 Consequently,
beyond developing highly selective catalysts, another frontier of
the modern Glaser-Hay-type reaction is the introduction of “green”
reaction media.22 Several environmentally benign reaction media,
such as supercritical carbon dioxide (ScCO2),23e25 ionic liquids,26
water,27 polyethylene glycol (PEG)28 and even solvent-free condi-
tions,29 have been applied to both Glaser-Hay homocoupling and
Cadiot-Chodkiewicz coupling, but the application of green media in
the cross-coupling of two terminal alkynes is still underexplored.
Therefore, it is essential to develop highly selective and environ-
mentally friendly methods for preparing unsymmetrical 1,3-diynes
via a Glaser-Hay-type heterocoupling pathway.
Supercritical carbon dioxide (ScCO2) is an inexpensive and
nontoxic solvent with notable properties, such as tunable solubility,
an easily accessible critical point, and chemical and thermal sta-
bility.30,31 To the best of our knowledge, there is no report in the
literature regarding the cross-coupling of terminal alkynes using
ScCO2 as the reaction medium. In our previous work, a DBU-
triggered and CuCl-catalysed oxidative homocoupling of terminal
alkynes was performed to produce symmetrical 1,3-diynes with co-
solvent free ScCO2 as the environmentally friendly medium.32
Encouraged by these results, we hypothesized that the cross-
coupling of terminal alkynes might also be performed in ScCO2.
In general, to achieve the direct cross-coupling of two alkynes,
the selective formation of a specific metal acetylide is crucial. In
other words, the two different alkynes must be “differentiated” by
the active metal centres of the catalyst.19,20 A synergistic activation
using two metal centres with distinct properties is often required to
achieve high selectivity.33e35 We can expect that a cooperative
bimetallic catalyst might be more suitable for the cross-coupling of
two terminal alkynes. Cu(I) salts are the most commonly used
catalysts, and they play a key role in the coupling of alkynes. Cu(II)
salts also work well if the oxidants are present in order to build the
Cu(I)/Cu(II) catalytic cycle.22 Palladium catalysts, including Pd(0)
complexes and Pd(II) salts in the presence of phosphines, are the
other suitable catalysts for the coupling of alkynes. In these sys-
tems, an alkynylpalladium(II) intermediate and Pd(0)/Pd(II) cata-
lytic cycle are the key steps for the coupling reactions to occur.36
With the above analyses in mind, we focused on using a commer-
cial Cu(II) salt and Pd(II) compound with crystal water to develop a
highly selective Cu(II)/Pd(II) bimetallic catalytic system for the
cross-coupling of terminal alkynes, and ScCO2 was selected as a
green reaction solvent.
In this paper, we report an efficient protocol towards unsym-
metrical 1,3-diynes through the CuCl2$2H2O/Pd(NH3)4Cl2$H2O
catalysed cross-couplings of terminal alkynes in green ScCO2. We
also describe
mechanism.
a proposed bimetallic catalytic cross-coupling
2. Results and discussion
2.1. Optimization of the cross-coupling conditions
Initially, the cross-coupling reaction of phenylacetylene (1a)
with 1-ethynyl-4-methoxybenzene (2a) was conducted as a model
using our homocoupling conditions (catalyst, CuCl; base, DBU;
oxidant, O2; solvent, ScCO2).32 All three of the possible coupled
products 3a, 4a, and 5a were obtained, and the heterocoupled
product, 3a, was given in 41% yield (Table 1, entry 1). Next, we
screened reaction conditions to further enhance the yield of het-
erocoupled product. The results are summarized in Tables 1e3.
The study of various catalysts was included in Table 1. When
copper, palladium and nickel salts were used as the sole catalyst
The effect of other reaction conditions, such as temperature, O2,
CO2 pressure and time, were also investigated (Table 3). The reac-
tion proceeded smoothly when the temperature ranged from
40 ꢀCe60 ꢀC and provided the best result at 50 ꢀC (Table 3, entries
1e3). O2 was necessary for the cross-coupling to occur, and 1 MPa
O2 pressure was sufficient to support the reaction (Table 3, entries
4e7). When air was used in place of O2, the yield of 3a decreased
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
supercritical carbon dioxide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.02.060

Y. Wang et al. / Tetrahedron xxx (2018) 1e8
3
Table 1
Performance of catalysts on cross-coupling reactiona.
Entry
Catalyst (mol%)
Yieldb (%)
3a
41
50
56
18
21
34
36
44
13
22
66
74
86
77
68
Hetero/Homo
4a
9
17
11
8
5a
63
64
58
46
53
59
61
63
28
59
74
55
15
26
31
36
27
e
3a/4a
4.6
2.9
5.1
2.3
3.5
3.4
2.6
7.3
0.9
1.4
2.6
19
7.2
9.6
17
3.2
4.9
e
1
2
3
4
5
6
7
8
CuCl (10)
CuI (10)
CuCl2$2H2O (10)
CuCl2 (10)
Cu(OAc)2$H2O (10)
PdCl2 (10)
Pd(PPh3)2Cl2 (10)
NiCl2$6H2O (10)
Pd(NH3)4Cl2$H2O (10)
Pd(NH3)4Cl2$H2O:NiCl2$6H2O (10:10)
CuCl2$2H2O: PdCl2 (10:10)
CuCl2$2H2O: NiCl2$6H2O (10:10)
CuCl2$2H2O: Pd(NH3)4Cl2$H2O (10:10)
CuCl2$2H2O: Pd(NH3)4Cl2$H2O (8:8)
CuCl2$2H2O: Pd(NH3)4Cl2$H2O (12:12)
CuCl2$2H2O: Pd(NH3)4Cl2$H2O (10:5)
CuCl2$2H2O: Pd(NH3)4Cl2$H2O (5:10)
None
6
10
14
6
15
16
25
4
12
8
4
9
10
11
12
13
14
15
16
17
18
51
69
16
14
e
e
a
Reaction conditions: phenylacetylene, 1a (0.5 mmol), 1-ethynyl-4-methoxybenzene, 2a (1.5 mmol), DBU (150 mol%), O2 (2 MPa), CO2 (9 MPa), 50 ꢀC, 5 h.
Isolated yields of 3a and 4a from 1a, and isolated yield of 5a from 2a.
b
Table 2
Effects of base and ratio of two terminal alkynes on cross-coupling reactiona.
Entry
Base (mol%)
Ratio 1a:2a
Yieldb (%)
3a
Hetero/Homo
3a/4a
4a
5a
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
None
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:3
1:2
1:1
3:1
2:1
1:0
0:1
e
e
4
2
2
12
6
6
2
2
6
e
e
NaOAc (150)
K2CO3 (150)
Cs2CO3 (150)
DBU (150)
NEt3 (150)
Pyridine (150)
TBD (150)
TMEDA (150)
TMEDA (100)
TMEDA (180)
TMEDA (200)
TMEDA (120)
TMEDA (120)
TMEDA (120)
TMEDA (120)
TMEDA (120)
TMEDA (120)
TMEDA (120)
67
72
2
8
17
36
1
11
44
15
8
5
14
4
19
11
14
16
12
42
2
86
82
76
82
91
90
91
88
92
92
65
84
76
e
7.2
14
13
41
46
15
46
22
46
46
16
42d
15d
e
2
4
2
2
4
69
66
53
e
5
e
e
40
e
a
Reaction conditions: CuCl2$2H2O/Pd(NH3)4Cl2$H2O (0.05/0.05 mmol, 10 mol%), O2 (2 MPa), CO2 (9 MPa), 50 ꢀC, 5 h.
Isolated yields of 3a and 4a from 1a; isolated yield of 5a from 2a.
Reaction time: 10 h.
Hetero/Homo ¼ 3a/5a.
b
c
d
slightly from 92% to 88% (Table 3, entry 8). Varying the pressure of
shown in Table 3, the cross-coupling could be accomplished effi-
ciently within a wide range of temperatures and CO2 pressure,
which indicates that our reaction system is highly adaptable.
Finally, the optimized reaction conditions were determined as
follows: ratio of two alkynes, 1:2; catalyst, CuCl2$2H2O/
Pd(NH3)4Cl2$H2O (10/10, mol%); CO2 pressure, 8 MPa; O2 pressure,
1 MPa; reaction temperature, 40 ꢀC; reaction time, 4 h. Moreover,
the optimized model reaction also afforded 3a in 82% yield with
good selectivity (3a/4a ¼ 21) in CHCl3 (Table 3, entry 16), which
CO2 from 8 MPa to 10 MPa had no significant effect on the hetero-
coupled product, 3a (Table 3, entries 5, 11 and 12). However, when
the pressure of CO2 was decreased to 5 MPa (below its critical point
pressure), no coupling products were detected (Table 3, entry 9).
The yields increased with reaction time and later became steady.
Prolonging the reaction time from 4 to 6 h was not beneficial for the
formation of product (Table 3, entries 11, 13e15) because the re-
action had reached equilibrium after 4 h (Table 3, entry 14). As
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
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Y. Wang et al. / Tetrahedron xxx (2018) 1e8
Table 3
Effect of reaction conditions on the cross-coupling reactiona.
Entry
O2 (MPa)
CO2(MPa)
T (ꢀC)
Timeb (h)
Yieldb (%)
Hetero/Homo
3a/4a
3a
4a
5a
1
2
3
4
5
6
7
8
2
2
2
0
1
2
3
Air
1
1
1
1
1
1
1
O2
9
9
9
9
9
9
9
9
5
7
8
10
8
8
8
40
50
60
50
50
50
50
50
50
50
50
50
50
50
50
50
5
5
5
5
5
5
5
5
5
5
5
5
3
4
6
5
90
92
87
Trace
92
92
92
88
e
6
2
8
16
18
19
Trace
29
18
52
25
e
15
46
11
e
Trace
2
2
2
2
46
46
46
44
e
9
e
10
11
12
13
14
15
16c
75
92
92
85
92
92
82
8
2
4
8
6
6
4
23
17
27
30
24
30
33
9.4
46
23
11
15
15
21
CHCl3
Entry 14 in Table 3 is the optimal condition.
a
Reaction conditions: phenylacetylene, 1a (0.5 mmol), 1-ethynyl-4-methoxybenzene, 2a (1 mmol), CuCl2$2H2O/Pd(NH3)4Cl2$H2O (10/10, mol%), TMEDA (120 mol%).
Isolated yields of 3a and 4a from 1a; isolated yield of 5a from 2a.
The reaction was carried out under an oxygen-filled balloon.
b
c
demonstrated that our Cu/Pd bimetallic catalyst was also amenable
to a traditional organic solvent.
provided the corresponding functionalized diynes 3p, 3q and 3r in
good yields (75%e85%, Table 4, entries 16e18).
In ScCO2, our bimetallic catalytic system generally performed
well for the cross-couplings of a variety of terminal alkynes, and the
limitations of certain of these alkynes might be related to their
special properties, such as the alkalinity of 3-pyridylacetylene and
the poor solubility of ethynylcyclopropane in ScCO2.
2.2. Scope and limitation of substrates
The optimized reaction conditions were applied to a diverse set
of terminal alkynes in order to assess the substrate scope of this
protocol, and the results are shown in Table 4.
Cross-coupling 2a with
a
set of para-substituted phenyl-
2.3. Proposed cross-coupling mechanism
acetylenes in ScCO2 gave the corresponding unsymmetrical 1,3-
diynes in good to excellent yields (Table 4, entries 1e7). The reac-
tion between 2a and halogenated phenylacetylenes (F, Cl, and Br)
afforded the desired products in 80%e91% yield (Table 4, entries
3e5). The relatively high yield of 3c may be attributed to the good
solubility of fluorophenylacetylene in ScCO2.24 Phenylacetylenes
with either electron-donating methyl or electron-withdrawing
trifluoromethyl groups were all suitable substrates, and produced
the target products 3b and 3f in comparable yields (Table 4, entries
2 and 6). Cross-coupling 4-fluorophenylacetylene with phenyl-
At the present time, the mechanism for CuCl2$2H2O/
Pd(NH3)4Cl2$H2O catalysed cross-coupling of terminal alkynes in
ScCO2 is not entirely clear. A preliminary investigation of the
mechanism was undertaken in order to study the function of the
bimetallic catalyst, CuCl2$2H2O/Pd(NH3)4Cl2$H2O. The conclusions
of this study are as follows: (1) Adding a radical inhibitor 2,2,6,6-
tetramethyl-piperidyl-1-oxyl (TEMPO) to the model reaction has
no effect on the yield of target product, which suggests that the
cross-coupling is not operated by a radical pathway in ScCO2 (see
supplementary material). (2) The model reactions in CDCl3 were
acetylene,
4-methylphenylacetylene
and
4-
trifluoromethylphenylacetylene, respectively provided the corre-
sponding products 3h-3j in the similarly high yields (81%e87%)
(Table 4, entries 8e10). These results implied that the electronic
nature of the substrates had little influence on the yield of the
desired product. Steric hindrance from the para-substituent on
phenylacetylene had a minor effect on the reaction, which was
supported by the reactions of 4-tert-butylphenylacetylene (Table 4,
entry 1 vs 7 and entry 11 vs 8).
Although an extended reaction time was required, the hetero-
aromatic 2-ethynylthiophene was also cross-coupled with 2a and
was successfully converted to diyne 3l in 74% yield (Table 4, entry
12). However, when 3-pyridylacetylene was used as a substrate, no
cross-coupled product was generated (Table 4, entry 13). This cat-
alytic system was also applied to aliphatic terminal alkynes. The
cross-coupling of heptyne with 2a showed somewhat lower reac-
tivity compared to aromatic alkynes and afforded the correspond-
ing product 3o in 69% yield (Table 4, entry 15). The cross-coupling
of ethynylcyclopropane with 2a generated no desired product, even
after the reaction time prolonged to 12 h (Table 4, entry 14). In
addition, terminal alkynes with a metallocene unit, unprotected
alcohol or silane could tolerate the reaction conditions and
monitored by IR and NMR, and the signals from the
p-coordinated
C^C bonds and -complexed C^C-M bonds were captured
s
throughout the reaction process (see supplementary material). (3)
The presence of catalyst, oxygen and base were essential for our
reaction system, and the ScCO2 primarily serves as the reaction
medium. In combination, these results show that the most plau-
sible pathway might involve the formation of metal-alkyne
complexes and metal acetylide intermediates, and that oxygen and
base are required to complete the catalytic cycle.
p-
Based on the experimental results and the general mechanism
of
copper
and
palladium
mediated
coupling
reactions,2,6,19,20,22,25,33,37e39 we consider that the good hetero-
selectivity is related to the synergistic effect between the copper
and palladium centres in the catalytic process.
A proposed mechanism for CuCl2$2H2O/Pd(NH3)4Cl2$H2O cata-
lysed cross-coupling of two terminal alkynes is shown in Scheme 1.
First, a
p-coordinated Cu(II) complex I′ is formed by the coordi-
nation of alkyne R1-C^CH with CuCl2$2H2O. Next, an acetylide
anion (formed from the deprotonation of R1-C^CH by the base
TMEDA) replaces one chlorine in I′ to generate a Cu(II)-acetylide
complex
I (Scheme 1, equation 1). At the same time, the
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Y. Wang et al. / Tetrahedron xxx (2018) 1e8
5
Table 4
Substrate Scopea.
Entry
1
Product
Time
(h)
Yield (%)b
3
92
Hetero/Homo
3/4
15
4
6
5
24
(3a)
(3b)
(3c)
(3d)
(3e)
(3f)
4
4
4
4
4
4
2
3
4
5
6
82
87
82
80
84
16
13
11
16
16
13
25
26
36
19
5.1
6.7
7.5
5.0
5.3
7
(3g)
(3h)
(3i)
(3j)
4
4
4
4
93
81
83
87
6
31
18
14
40
16
14
8
6
9
16
12
5.2
7.3
10
11
12
13
14
(3k)
(3l)
4
79
74
e
10
4
11
13
8
7.9
19
e
8
(3m)
(3n)
12
12
e
e
e
11
e
15
16
(3o)
(3p)
8
8
69
75
7
26
30
9.9
4.7
16
17
(3q)
(3r)
8
8
81
85
11
3
20
25
7.4
28
18
a
Reaction conditions: 1 (0.5 mmol), 2 (1 mmol), CuCl2$2H2O/Pd(NH3)4Cl2$H2O (10/10, mol%), TMEDA (120 mol%), O2 (1 MPa), CO2 (8 MPa), 50 ꢀC.
Isolated yields of 3 and 4 from 1; isolated yield of 5 from 2.
b
coordination of R2-C^CH with Pd(NH3)4Cl2$H2O, followed by the
Second, the complex I reacts with the complex II to generate the
bimetallic complex III with the help of TMEDA. Third, the bimetallic
complex III undergoes a reductive elimination to form the desired
heterocoupled product, P, and the homocoupled products, P′ and
P00, and the Cu(0) and Pd(0) intermediates are released. Finally, in
the present of TMEDA, the Cu(0) and Pd(0) intermediates are
oxidized by oxygen and coordinated to the acetylide anions and
ligand displacement of an acetylide anion, affords a Pd(II) complex
II (Scheme 1, equation 2). During the formation of the metal-
acetylide complexes I and II, the two alkynes could be differenti-
ated by the Cu(II) centre and Pd(II) centre because of their differing
Lewis acidities. The deprotonation of the base additive, TMEDA, in
the formation of the acetylide anion is indicated in equation 3.
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
supercritical carbon dioxide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.02.060

6
Y. Wang et al. / Tetrahedron xxx (2018) 1e8
Scheme 1. Proposed mechanism of cross-coupling.
chloride ions, which regenerates the complex I and complex II for
the next catalytic cycle. In this proposed mechanism, the high
heteroselectivity is caused by the synergistic cooperative effect
between the Cu(II) centre and Pd(II) centre and the easier reductive
elimination reaction between the ortho-alkynes in the bimetallic
complex III.
reaction system in pure ScCO2 a viable new methodology in the
field of unsymmetrical 1,3-diyne synthesis.
4. Experimental section
4.1. Materials
All alkynes, tetramethylethylenediamine (TMEDA), 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo[4.4.0]
dec-5-ene (TBD), triethylamine (NEt3), with a purity of >97%, and
Pd(NH3)4Cl2$H2O (Pd ꢁ 43.0%), were purchased from Shanghai
Macklin Biochemical Co. Ltd. All inorganic bases, copper salts,
NiCl2$6H2O and PdCl2, with a purity of >97%, were purchased from
Aladdin. All reagents were used as received without further puri-
fication. CO2 (99.99% purity) was purchased from Hohhot Huayuan
Gas Co. Ltd. All solvents were supplied in their analytically pure
form by Tianjin Fengchuan Chemical Reagent Co. Ltd. and used as
received. Silica gel (200e300 mesh) used for column chromatog-
raphy and silica gel plates (GF254) used for thin-layer chromatog-
raphy (TLC) were purchased from Qingdao Haiyang Chemical Co.
Ltd.
3. Conclusions
The combination of CuCl2$2H2O and Pd(NH3)4Cl2$H2O is an
efficient bimetallic catalyst for the selective, aerobic cross-coupling
of terminal alkynes in the green solvent, ScCO2. This methodology
is applicable to a broad range of unsymmetrical 1,3-diynes with
good to excellent yields. This method is straightforward, efficient
and environmentally benign and avoids the pre-preparation of any
sensitive or specialized coupling partners and the use of organic co-
solvents. In addition, our catalytic system performs the cross-
coupling of terminal alkynes more efficiently in ScCO2 than in
organic solvent. Altering the CO2 pressure and temperature within
a certain range has little impact on the reaction efficiency. We as-
sume a synergistic catalytic reaction mechanism involving Cu(II)
and Pd(II) metal centres, in which the formation of the bimetallic
complex III might be a key step in determining the hetero-
selectivity of the coupling reactions. The wide substrate scope, high
yields, and excellent adaptability make our bimetallic catalytic
4.2. General procedure for characterization
Melting points were measured with an SGCX-4 microscopic
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
supercritical carbon dioxide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.02.060

Y. Wang et al. / Tetrahedron xxx (2018) 1e8
7
melting point meter and were uncorrected. Gas chromatography-
mass spectrometry (GC-MS) was performed on a Thermo Fisher
Polaris Q GC-MS instrument. The 1H and 13C NMR spectra were
recorded on an Agilent 500 MHz DD2 spectrometer and chemical
72.52, 55.36; MS (EI, m/z): 266.0 (Mþ) (calcd. for C17H11ClO, 266.1);
FT-IR (KBr disk, cmꢂ1): 2999, 2835, 2213, 2138, 1601, 1485, 820.
4.3.5. 1-Bromo-4-((4-methoxyphenyl)buta-1,3-diyn-1-yl)benzene
(3e)21
shifts were reported in
d parts per million (ppm) with TMS as a
White solid; m.p. 173e174 ꢀC; 1H NMR (500 MHz, CDCl3):
reference. FT-IR spectra were recorded on a Nicolet FT-IR spec-
trometer using KBr discs. LR-EI-MS spectra were determined using
a Thermo Fisher Polaris Q MS instrument. HR-ESI-MS data were
measured on an Agilent 7200 Q-TOF GC-MS spectrometer and an
AB SCIEX Triple TOF 4600 LC-MS spectrometer.
d
7.49e7.45 (m, 4H), 7.38e7.35 (m, 2H), 6.87e6.85 (m, 2H), 3.83(s,
3H); 13C NMR (125 MHz, CDCl3):
d
160.49, 134.16, 133.75, 131.73,
123.42, 121.00, 114.19, 113.48, 82.49, 79.84, 75.34, 72.54, 55.36; MS
(EI, m/z): 310.2 (Mþ) (calcd. for C17H11BrO, 310.0); FT-IR (KBr disk,
cmꢂ1): 3076, 2960, 2831, 2206, 2135, 1601, 1479, 818.
4.3. Typical procedure for cross-coupling in ScCO2
4.3.6. 1-Methoxy-4-((4-(trifluoromethyl)phenyl)buta-1,3-diyn-1-
yl)benzene (3f)
A 15-mL autoclave equipped with a magnetic stirrer was
charged
methoxyphenylacetylene (130
(13 mg, 0.05 mmol), CuCl2$2H2O (10 mg, 0.05 mmol), TMEDA (54
with
phenylacetylene
L, 1 mmol), Pd(NH3)4Cl2$H2O
l,
(55
m
L,
0.5 mmol),
4-
White solid; m.p. 128e130 ꢀC; 1H NMR (500 MHz, CDCl3):
m
d
7.63e7.58 (m, 4H), 7.50e7.47 (m, 2H), 6.88e6.86 (m, 2H), 3.83 (s,
m
3H); 13C NMR (125 MHz, CDCl3):
d
160.64, 134.26, 132.81, 132.61,
0.6 mmol). Oxygen gas was transferred into the autoclave to a
pressure of 1 MPa and was later pressurized at room temperature
with CO2 to 9 MPa. The reaction mixture was stirred at 50 ꢀC for 4 h.
The agitation rate was fixed at 600 rpm. After the reaction was
complete, the system was allowed to cool to room temperature, and
CO2 was vented carefully. The residues were dissolved in
dichloromethane, then the solution was washed with water. The
organic phase was dried over anhydrous MgSO4, and the solvent
was removed under vacuum. The crude products were purified via
chromatography on a silica gel column (eluting with a petroleum
ether/ethyl acetate mixture, 50/1, v/v) and recrystallized in solution
(a mixture of hexane and dichloromethane).
130.67, 130.41, 125.96, 125.94, 125.47, 125.44, 125.39, 125.33, 125.30,
124.87, 122.70, 114.24, 113.24, 83.21, 79.33, 76.57, 72.32, 55.38;
HRMS (ESI, m/z): 300.0766 (Mþ) (calcd. for C18H11F3O, 300.0762);
FT-IR (KBr disk, cmꢂ1): 2943, 2840, 2209, 2135, 1601, 1505, 830.
4.3.7. 1-(Tert-butyl)-4-((4-methoxyphenyl)buta-1,3-diyn-1-yl)
benzene (3g)42
White solid; m.p. 143e145 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.48e7.44 (m, 4H), 7.36e7.34 (m, 2H), 6.87e6.84 (m, 2H), 3.82 (s,
3H), 1.31 (s, 9H); 13C NMR (125 MHz, CDCl3):
d
160.28, 152.47,
134.07, 132.21, 125.45, 118.90, 114.14, 113.86, 81.41, 81.33, 73.51,
72.92, 55.34, 34.90, 31.11; MS (EI, m/z): 288.0 (Mþ) (calcd. for
4.3.1. 1-Methoxy-4-(phenylbuta-1,3-diyn-1-yl)benzene (3a)40
White solid; m.p. 92e93 ꢀC; 1H NMR (500 MHz, CDCl3):
C
21H20O, 288.2); FT-IR (KBr disk, cmꢂ1): 3032, 2950, 2864, 2138,
2038, 1595, 1495, 832.
d
7.53e7.51 (m, 2H), 7.48e7.46 (m, 2H), 7.35e7.33 (m, 3H),
6.87e6.85 (m, 2H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3):
160.37, 134.12, 132.43, 129.01, 128.40, 122.02, 114.16, 113.71, 81.81,
81.02, 74.16, 72.73, 55.35; MS (EI, m/z): 232.0 (Mþ) (calcd. for
17H12O, 232.1); FT-IR (KBr disk, cmꢂ1): 3054, 2987, 2835, 2213,
4.3.8. 1-Fluoro-4-(phenylbuta-1,3-diyn-1-yl)benzene (3h)18
White solid; m.p. 118e120 ꢀC; 1H NMR (500 MHz, CDCl3):
d
d
7.54e7.49 (m, 4H), 7.40e7.32 (m, 2H), 7.06e7.01 (m, 3H); 13C NMR
C
(125 MHz, CDCl3):
d 164.06, 164.01, 162.05, 162.02, 134.57, 134.55,
2142, 1594, 1500, 1482, 832.
134.50, 134.48, 132.50, 129.27, 129.20, 128.45, 128.44, 121.69, 117.94,
117.91, 117.83, 117.80, 116.00, 115.98, 115.82, 115.80, 81.54, 80.43,
73.73, 73.70, 73.69, 73.53; MS (EI, m/z): 220.2 (Mþ) (calcd. for
4.3.2. 1-Methoxy-4-(p-tolylbuta-1,3-diyn-1-yl)benzene (3b)13
White solid; m.p. 137e139 ꢀC; 1H NMR (500 MHz, CDCl3):
C
16H9F, 220.1); FT-IR (KBr disk, cmꢂ1): 3047, 2150, 2038, 1588, 1495,
d
7.48e7.45 (m, 2H), 7.42e7.40 (m, 2H), 7.14 (d, 2H, J ¼ 8.0 Hz),
6.87e6.84 (m, 2H), 3.82 (s, 3H), 2.36 (s, 3H); 13C NMR (125 MHz,
CDCl3): 160.29, 139.39, 134.07, 132.34, 129.19, 118.88, 114.14,
828.
d
4.3.9. 1-Fluoro-4-(p-tolylbuta-1,3-diyn-1-yl)benzene (3i)43
113.85, 81.46, 81.31, 73.54, 72.86, 55.34, 21.61; MS (EI, m/z): 246.1
(Mþ) (calcd. for C18H14O, 246.1); FT-IR (KBr disk, cmꢂ1): 3002, 2970,
2835, 2132, 1597, 1496, 1457, 818.
White solid; m.p. 187e189 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.53e7.48 (m, 2H), 7.43e7.41 (m, 2H), 7.15e7.13 (m, 2H), 7.06e7.00
(m, 2H), 2.37e2.36 (d, 3H); 13C NMR (125 MHz, CDCl3):
d
164.05,
163.96, 162.05, 161.69,139.69, 139.48,134.56,134.50,134.43,132.42,
132.38, 129.24, 129.21, 118.79, 118.55, 118.06, 118.03, 117.83, 117.80,
116.00, 115.94, 115.82, 115.77, 81.87, 81.54, 80.43, 80.11, 73.86, 73.84,
73.54, 73.44, 73.14, 21.62; MS (EI, m/z): 234.3 (Mþ) (calcd. for
4.3.3. 1-Fluoro-4-((4-methoxyphenyl)buta-1,3-diyn-1-yl)benzene
(3c)40
White solid; m.p. 135e136 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.52e7.45 (m, 4H), 7.05e7.01 (m, 2H), 6.87e6.84 (m, 2H), 3.83(s,
C
17H11F, 234.1); FT-IR (KBr disk, cmꢂ1): 3032, 2924, 2209, 2138,
3H); 13C NMR (125 MHz, CDCl3)
d
164.05, 163.91, 162.05, 161.91,
1593, 1497, 836.
160.42, 134.57, 134.50, 134.46, 134.39, 134.13, 118.16, 118.13, 116.00,
115.92, 115.82, 115.75, 114.18, 113.60, 81.81, 79.90, 73.96, 72.57,
55.35; MS (EI, m/z): 250.0 (Mþ) (calcd. for C17H11FO, 250.1); FT-IR
(KBr disk, cmꢂ1): 3072, 2963, 2842, 2210, 2136, 1597, 1504, 1461,
828.
4.3.10. 1-Fluoro-4-((4-(trifluoromethyl)phenyl)buta-1,3-diyn-1-yl)
benzene (3j)44
White solid; m.p. 94e97 ꢀC; 1H NMR (500 MHz, CDCl3):
d
d
7.65e7.50(m, 6H), 7.07e7.02 (m, 2H); 13C NMR (125 MHz, CDCl3):
164.22, 164.06, 162.22, 162.05, 134.69, 134.62, 134.56, 134.50,
4.3.4. 1-Chloro-4-((4-methoxyphenyl)buta-1,3-diyn-1-yl)benzene
(3d)41
132.80, 132.70, 125.47, 125.44, 125.41, 125.38, 125.35, 117.83, 117.80,
117.51, 117.48, 116.08, 116.00, 115.90, 115.82, 81.71, 80.42, 79.77,
76.05, 75.62, 73.53, 73.22; MS (EI, m/z): 288.3 (Mþ) (calcd. for
Yellow solid; m.p. 177e178 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.48e7.43 (m, 4H), 7.33e7.29 (m, 2H), 6.88e6.84 (m, 2H), 3.83(s,
3H); 13C NMR (125 MHz, CDCl3):
160.48, 135.15, 134.16, 133.69,
133.59, 128.89, 128.82, 120.54, 114.19, 113.50, 82.41, 79.78, 75.17,
d
C
17H8F4, 288.1); FT-IR (KBr disk, cmꢂ1): 3073, 2217, 2139, 1594,1501,
830.
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
supercritical carbon dioxide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.02.060

8
Y. Wang et al. / Tetrahedron xxx (2018) 1e8
4.3.11. 1-(Tert-butyl)-4-(phenylbuta-1,3-diyn-1-yl)benzene (3k)45
White solid; m.p. 167e169 ꢀC; 1H NMR (500 MHz, CDCl3):
Acknowledgments
d
7.54e7.52 (m, 2H), 7.46 (d, 2H, J ¼ 8.5 Hz), 7.39e7.32 (m, 5H),
This work was supported by the Natural Science Foundation of
China (NSFC 21266019) and Natural Science Foundation of Inner
Mongolia Autonomous Region of China (2015MS0204).
1.31(s, 9H); 13C NMR (125 MHz, CDCl3):
d
152.56, 132.49, 132.24,
129.20, 128.43, 125.46, 121.79, 118.82, 81.55, 81.50, 73.90, 73.46,
34.91, 31.10; MS (EI, m/z): 258.0 (Mþ) (calcd. for C20H18, 258.1); FT-
IR (KBr disk, cmꢂ1): 3040, 2954, 2868, 2220, 2150, 1599, 1461, 834.
Appendix A. Supplementary data
4.3.12. 2-((4-Methoxyphenyl)buta-1,3-diyn-1-yl)thiophene (3l)45
White solid; m.p. 135e136 ꢀC; 1H NMR (500 M Hz, CDCl3):
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.02.060.
d
7.48e7.45 (m, 2H), 7.32 (d, 1H, J ¼ 3.5 Hz), 7.30 (d, 1H, J ¼ 5.5 Hz),
7.00e6.98 (dd, 1H, J1 ¼3.5 Hz, J2 ¼ 5.5 Hz), 6.87e6.84 (m, 2H),
3.83(s, 3H); 13C NMR (125 MHz, CDCl3):
160.45, 134.12, 134.00,
128.43, 127.12, 122.32, 114.18, 113.57, 83.89, 78.21, 74.00, 72.57,
55.36; MS (EI, m/z): 237.9 (Mþ) (calcd. for C15H10OS, 238.0); FT-IR
(KBr disk, cmꢂ1): 3103, 3006, 2936, 2840, 2198, 2135, 1594, 1497,
830.
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d
7.40e7.37 (m, 2H), 6.89e6.86 (m, 2H), 3.80 (s, 3H), 2.35 (t, 2H,
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J ¼ 7.5 Hz); 13C NMR (125 MHz, CD3OD):
d 160.31, 133.55, 113.81,
113.79, 83.13, 74.08, 72.46, 64.72, 54.43, 30.75, 27.81, 21.81, 18.62,
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(KBr disk, cmꢂ1): 3015, 2961, 2926, 2848, 2109, 1603, 1509, 1455,
828.
4.3.14. 1-Methoxy-4-(ferrocenylbuta-1,3-diyn-1-yl)benzene (3p)45
Red solid; m.p. 109e110 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.46 (d,
2H, J ¼ 7.5 Hz), 6.85 (d, 2H, J ¼ 7.5 Hz), 4.54 (s, 2H), 4.28 (s, 7H), 3.82
(s, 3H); 13C NMR (125 MHz, CDCl3):
160.21, 160.10, 134.02, 133.94,
d
114.12, 113.92, 81.36, 81.22, 79.05, 73.49, 72.95, 72.24, 70.35, 70.30,
69.44, 63.53, 55.32; MS (EI, m/z): 340.0 (Mþ) (calcd. for C21H16FeO,
340.1); FT-IR (KBr disk, cmꢂ1): 3094, 2958, 2965, 2835, 2209, 2140,
1594, 1500, 1454, 1106, 1036, 818.
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d 4.48 (t,
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(125 MHz, CDCl3):
d 83.94, 79.17, 72.22, 70.15, 69.33, 67.81, 65.82,
62.81, 53.42, 31.16; HRMS (ESI, m/z): 292.0548 (Mþ) (calcd. for
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White solid; m.p. 83e85 ꢀC; 1H NMR (500 MHz, CDCl3):
d
7.47e7.45 (m, 2H), 7.35e7.27 (m, 3H), 0.23e0.21 (m, 9H); 13C NMR
(125 MHz, CDCl3):
d 132.61, 129.29, 128.40, 121.33, 90.53, 87.93,
76.73, 74.23, ꢂ0.40; MS (EI, m/z): 197.9 (Mþ) (calcd. for C13H14Si,
198.1); FT-IR (KBr disk, cmꢂ1): 3058, 2961, 2902, 2206, 2105, 1596,
1442, 842.
Please cite this article in press as: Wang Y, et al., Copper(II)/Palladium(II) catalysed highly selective cross-coupling of terminal alkynes in
supercritical carbon dioxide, Tetrahedron (2018), https://doi.org/10.1016/j.tet.2018.02.060