Copper(i)-catalyzed synthesis of 1,3-enynes via coupling between vinyl halides and alkynes or domino coupling of vinyl halides

Article abstract of DOI:10.1039/c1ob06210g

1,3-Enynes were easily prepared from coupling between vinyl halides and alkynes or domino coupling of vinyl halides in the presence of copper iodide. It is noteworthy that the double-bond geometry of the vinyl halides was retained during the reaction. This ligand-free protocol is potentially useful and practical.

Full text of DOI:10.1039/c1ob06210g

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Copper(I)-catalyzed synthesis of 1,3-enynes via coupling between vinyl halides
and alkynes or domino coupling of vinyl halides†
Yan Zhu, Tingyi Li, Xiaoming Qu, Peng Sun, Hailong Yang and Jincheng Mao*
Received 20th July 2011, Accepted 31st August 2011
DOI: 10.1039/c1ob06210g
1,3-Enynes were easily prepared from coupling between vinyl
halides and alkynes or domino coupling of vinyl halides in the
presence of copper iodide. It is noteworthy that the double-
bond geometry of the vinyl halides was retained during the
reaction. This ligand-free protocol is potentially useful and
practical.
vinyl halide, which is certainly considered as the most straight-
forward way [eqn (1)].6 In the past several years, some modified
protocols have been developed using iron or copper catalysts.7
On the other hand, conjugated enynes could also be obtained
by metal-catalyzed couplings between a terminal alkyne and
an organometallic alkene (B, Sn, Te, Al, Cu, Zr) [eqn (2)].8
The alternative way is by coupling between an alkene and an
alkynylmetal (Mg, Cu, Zn, Si, Sb, Sn) [eqn (3)].9 However, these
organometallic reagents are not only toxic, but are also difficult
to prepare. In this paper, it is the first time that we report a new
approach to synthesizing symmetrical 1,3-enynes just by domino
coupling of vinyl halides in the presence of CuI under ligand-
free conditions [eqn (4)]. Furthermore, this methodology could be
applied to the coupling between terminal alkyne and vinyl halide
to prepare unsymmetrical 1,3-enynes.
The 1,3-enyne is a core structure of various natural products
or designed pharmaceutical molecules.1 Successful examples of
these include terbinafine (A) which is used in the treatment
of superficial fungal infections,2 oxamflatin (B) which is a
novel antitumor compound that inhibits mammalian histone
deacetylase,3 and 17-hydroxy-17-pentafluoroethylestra-4,9(10)-
dien-11-ethynylphenyl derivative (C) which is used as progesterone
receptor antagonists (Fig. 1).4 In addition, 1,3-enynes are im-
portant precursors to polysubstituted benzenes and conjugated
dienes.5
(1)
(2)
(3)
(4)
Initially, we examined the domino coupling of (E)-b-
bromostyrene as the model reaction to screen the reaction
conditions and the results are depicted in Table 1. It can be
seen that only 10 mol% of CuI could catalyze the coupling to
afford the desired (E)-1,4-diphenylbut-1-en-3-yne in 54% yield
(Table 1, entry 1). Under the same conditions, the control
experiment showed that the reaction could not occur without using
copper salt (Table 1, entry 2). Screening various bases including or-
ganic bases and inorganic bases (Table 2, entries 3–6), K3PO4 was
proved the best (Table 1, entry 5). DMSO showed higher efficiency
as the reaction medium than all other employed solvents, such as
DMF, PEG-400 and NMP (Table 1, entries 7–9). Other copper
sources gave inferior results (Table 1, entries 10–14). Varying the
amount of CuI did not afford higher yields of desired product
(Table 1, entries 15–16). When the temperature was increased to
135 ◦C, the corresponding 1,3-enyne was obtained in a yield of 82%
(Table 1, entry 17).
Fig. 1 Examples of compounds containing the 1,3-enyne moiety.
Traditionally, the 1,3-enynes were prepared via Pd/Cu-
catalyzed Sonogashira coupling between terminal alkyne and
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chem-
istry, Chemical Engineering and Materials Science, Soochow University,
Suzhou, 215123, P. R. China. E-mail: jcmao@suda.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c1ob06210g
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Table 1 Screening conditions for domino coupling of (E)-b-bromo-
Table 2 Domino coupling of various (E)-vinyl halides in the presence of
styrenea
CuIa
Entry
Cu cat. (mol%)
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
CuI (10)
—
Cs2CO3
Cs2CO3
K2CO3
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
54
Entry Vinyl halide
1
Product
Yield (%)b
82
NR
trace
trace
78
48
51
34
45
74
71
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuBr (10)
Cu2O (10)
CuCl (10)
Cu (10)
K3PO4
tBuOK
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
PEG-400
NMP
2
3
55
69
9
10
11
12
13
14
15
16
17c
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
77
<20
trace
42
75
82
Cu(OAc)2 (10)
CuI (5)
CuI (20)
CuI (10)
4
5
6
7
70
55
45
52
a Reaction conditions: (E)-b-bromostyrene (0.8 mmol), base (0.8 mmol),
solvent (2 mL), 110 ◦C, Ar, 24 h. b Isolated yield (based on (E)-b-
bromostyrene). c 135 ◦C.
In order to improve the results, various commonly-used lig-
ands (A–J) were investigated in the domino coupling of (E)-b-
bromostyrene. It can be seen from Fig. 2 that some N,N-ligands
(E, F, H) could give good results and other ligands afforded low
8
9
38
25
10
11
<5
36
a Reaction conditions: Vinyl halide (0.8 mmol), CuI (0.04 mmol), K3PO4
(0.8 mmol), DMSO (2 mL), 135 ◦C, Ar, 24 h. b Isolated yield based on half
of vinyl halide (average of two runs).
yields of desired product. Compared with the result from using
only CuI as the catalyst, we did not acquire a much better result.
Thus, in view of the cost of catalytic reaction, the best protocol
for the following experiments was determined to be ligand-free
conditions.
We next aimed to investigate the analogous sequence of
alternative (E)-vinyl halides10 and the domino coupling yields
are listed in Table 2. Using electron-rich or electron-deficient
Fig. 2 The relationship between ligands and catalytic effect: [Reaction
conditions: CuI (10 mol%), ligand (20 mol%), (E)-b-bromostyrene (0.8
mmol), K3PO4 (0.8 mmol), DMSO (2 mL), 110 ◦C, Ar, 24 h].
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Table 3 CuI-catalyzed coupling between (E)-vinyl halide and alkyne to
vinyl bromides, moderate yields of desired products were obtained
(55–82%) (Table 2, entries 1–5). Subsequently, (E)-b-iodostyrene
with higher activity was employed into the reaction. However, to
our surprise, the expected enyne product was acquired with 45%
yield (Table 2, entry 6). TLC indicated that a large amount of
byproduct was obtained from homocoupling of phenylacetylene.
Under the same conditions, a slightly higher yield was obtained
when electron-rich vinyl iodide was used (Table 2, entry 7). Using
(E)-b-chlorostyrene as the substrate, the desired enyne product
was not obtained, but the homocoupling product was produced
in 38% yield (Table 2, entry 8). In addition, (Z)-b-bromostyrene11
was also employed into the domino coupling reaction and the
corresponding product was obtained in low yield (Table 2, entry
9), which was possibly ascribed to the case that the more stable
(E)-isomer was more easily generated than the less stable (Z)-
isomer of the enyne product. Furthermore, coupling of 1-(2,2-
dibromovinyl)benzene afforded a low amount of homocoupling
product (Table 2, entry 10). The domino coupling of conjugated
vinyl bromide, 1-((1E,3E)-4-bromobuta-1,3-dienyl)benzene, was
examined using our methodology. The desired (1E,3E,7E)-1,8-
diphenylocta-1,3,7-trien-5-yne was obtained in 36% yield (Table
2, entry 11). It is noteworthy that the double-bond geometry of
the vinyl halides was retained during the reaction.
prepare unsymmetrical 1,3-enynesa
Entry
1
Vinyl halide
Alkyne
Yield (%)b
>99
2
81
3
4
68
41
5
67
Since symmetrical 1,3-enynes were obtained, the question was
raised: how can we get the unsymmetrical 1,3-enynes? As we
know, the direct synthesis was via coupling between vinyl halides
and alkynes.7 Actually, in the past several years, some efficient
catalytic systems have been developed for such coupling reactions.
For example, Bao and co-workers found that just 15 mol%
of CuI could catalyze the coupling of (E)-b-bromostyrene and
phenylacetylene with 88% yield in the presence of 30 mol% of
1,10-phenanthroline as the ligand;7b Li and Xie et al. reported a
convenient iron-catalyzed cross-coupling of terminal alkynes with
vinyl iodides with moderate yields using 1,10-phenanthroline as
the ligand. However, their protocol is not suitable for the reaction
of vinyl bromides.7c Thus, based on this research background, the
optimized protocol was applied to such couplings and the related
results are illustrated in Table 3. It was found that the coupling
of (E)-b-bromostyrene and phenylacetylene afforded the desired
product with quantitative yield (Table 3, entry 1). Subsequently,
various vinyl bromides with substituents were employed as the
substrates and moderate to good yields of corresponding products
were obtained (Table 3, entries 2–5). Generally, terminal alkynes
with an electron-donating group showed higher reactivity than
those with electron-withdrawing groups (Table 3, entries 6–9).
The couplings of aliphatic alkynes were also investigated and the
corresponding products were obtained with considerably lower
yields (Table 3, entries 10–11). In addition, the coupling of (Z)-
b-bromostyrene and phenylacetylene afforded the (Z)-isomer of
product in 27% yield (Table 3, entry 12). The coupling of vinyl
iodide with phenylacetylene resulted in 20% yield of desired
product (Table 3, entry 13). However, the corresponding product
was not observed when vinyl chloride was employed (Table 3,
entry 14). Perhaps it is attributed to the competing reaction that
vinyl halides could generate alkynes in situ. Another experiment
was carried out by cross-coupling of 1-((1E,3E)-4-bromobuta-
1,3-dienyl)benzene and phenylacetylene. It can be seen that
the corresponding (1E,3E)-1,6-diphenylhexa-1,3-dien-5-yne was
acquired in 42% yield (Table 3, entry 15). Thus, these fluorescent
6
7
8
99
76
76
9
62
42
10
11
trace
27
12
13c
14c
20
trace
15
42
a Reaction conditions: Vinyl halide (0.4 mmol), terminal alkyne (0.5
mmol), CuI (0.04 mmol), K3PO4 (0.8 mmol), DMSO (2 mL), 135 ◦C,
Ar, 24 h. b Isolated yield based on vinyl halide (average of two runs).
c Homocoupling of phenylacetylene was obtained.
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enynes may find some uses in the emerging field of functional
materials in the future.
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CuI-catalyzed decarboxylative coupling of (E)-b-bromostyrene
and phenylpropiolic acid12 was performed in the absence of any
ligand. The desired conjugated 1,3-enynes was obtained in 89%
yield, which is shown in Scheme 1. As far as we know, this is also
the first example of copper-catalyzed decarboxylative coupling of
(E)-b-bromostyrene and phenylpropiolic acid in the absence of
ligand.
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Scheme 1 CuI-catalyzed decarboxylative coupling between (E)-b-bromo-
styrene and phenylpropiolic acid.
In summary, we have developed an effective way to prepare
conjugated 1,3-enynes by copper-catalyzed domino coupling of
vinyl halides or coupling between various vinyl halides and
terminal alkynes and the corresponding target products were
obtained in moderate to good yields. It is noteworthy that the
double-bond geometry of the vinyl halides was retained during
the reaction. Thus, this ligand-free protocol is potentially useful
in the synthesis of some biologically active molecules. Further
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Acknowledgements
We are grateful to the grants from Natural Science Foundation
of China (20802046), International S&T Cooperation Program of
Jiangsu Province (BZ2010048) and the Key Laboratory of Organic
Synthesis of Jiangsu Province for financial support. This project
was also funded by the Priority Academic Program Development
of Jiangsu Higher Education Institutions. We thank Dr Marc
Creus from University of Basel, Switzerland for helpful discussion.
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