Copper-catalyzed synthesis of internal alkynes via domino coupling between 1,1-dihalo-1-alkenes and arylboronic acids

Article abstract of DOI:10.1039/c2ra21577b

We have developed the practical copper-catalyzed formation of various internal alkynes via domino couplings between 1,1-dihalo-1-alkenes and arylboronic acids in the presence of low-cost 8-hydroxylquinoline as the ligand.

Full text of DOI:10.1039/c2ra21577b

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Copper-catalyzed synthesis of internal alkynes via
domino coupling between 1,1-dihalo-1-alkenes and
arylboronic acids3
Cite this: RSC Advances, 2013, 3, 377
Received 26th July 2012,
Accepted 11th November 2012
Hong Yan, Linhua Lu, Peng Sun, Yan Zhu, Hailong Yang, Defu Liu, Guangwei Rong
and Jincheng Mao*
DOI: 10.1039/c2ra21577b
www.rsc.org/advances
We have developed the practical copper-catalyzed formation of
various internal alkynes via domino couplings between 1,1-
dihalo-1-alkenes and arylboronic acids in the presence of low-
cost 8-hydroxylquinoline as the ligand.
internal alkynes via the Stille reaction of 1,1-dibromo-1-alkenes in
the presence of a Pd catalyst.9 Chelucci et al. disclosed a Pd-based
protocol for the one-pot synthesis of internal alkynes from the
Suzuki–Miyaura coupling of 1,1-dibromo-1-alkenes with arylboro-
nic acids or borate esters followed by dehydrobromination of the
intermediate coupled products.10 However, Schmidt and Rahimi
have just found that a cyclobutene-1,2-bis(imidazolium) salt is an
efficient catalyst precursor for the Pd-catalyzed tandem reaction of
1,1-dibromo-1-alkenes with arylboronic acids.11 Recently, Rao and
co-workers have found that 0.09 equiv of Pd(PPh3)4 could
successfully catalyze the domino couplings between 1,1-dibromo-
1-alkenes and triarylbismuths.12 Although great progress has been
made in the past few decades, toxic and high-cost Pd-catalysts will
undoubtedly limit their application at industrial scales. Herein,
from the cost perspective, we report a copper-catalyzed synthesis
of internal alkynes via the one-step domino couplings between 1,1-
dihalo-1-alkenes and various arylboronic acids.
We started our investigation by treating 1,1-dibromo-1-alkene
with 4-methoxyphenylboronic acid. The efficiency of a series of
readily available ligands was initially studied (L1–L8, Scheme 1),
including 1,4-diazabicyclo[2.2.2]octane (L1), rac-binol (L2), 1,10-
phenanthroline (L3), L-proline (L4), 8-hydroxylquinoline (L5),
triphenylphosphine (L6), N1,N2-dimethylethane-1,2-diamine (L7)
and ethyl 2-oxocyclohexanecarboxylate (L8). As shown in Fig. 1, it
was clear to see that L5 afforded a better yield of the desired
It is well known that structural motifs with carbon–carbon triple
bonds have prevailed in many bioactive compounds, natural
products, pharmaceuticals, and functional materials.1 Since the
late 20th century, the Sonogashira reaction has been proved to be
an effective approach for the synthesis of various alkynes.2 The
typical Sonogashira coupling is performed in the presence of
PdCl2(PPh3)2 or Pd(PPh3)4 together with CuI as the cocatalyst and
larger amount of amines as the solvents or cosolvents.3 In view of
the high-cost and toxicity of Pd catalysts, chemists have paid more
attention to the cheaper metals. In the past ten years, many
efficient protocols have been developed based on copper or iron
catalysts.4 Thus, Sonogashira couplings can potentially be applied
in industrial applications because of the reduced cost. Although
the question of a low-cost catalyst has been solved, easily available
resources of raw materials should also be considered. It is known
that various types of terminal alkynes are usually volatile liquids
with bad smells that are not easily prepared or stored. Thus, some
chemists5a–h and our group5i–j have found that stable alkynyl
carboxylic acids could be successfully employed as alternative
sources of alkynes for the decarboxylative coupling reaction with
aryl halides. However, these alkynyl carboxylic acids were not yet
readily available.
Recently, gem-dihaloolefins have been widely used in organic
syntheses owing to their utility as synthetic intermediates.6 They
can be easily prepared from corresponding aldehydes and ketones
using CBr4/PPh37 or the ylide CCl2PPh3.8 So far, it is easy to believe
that the internal alkynes could possibly be prepared by coupling
between gem-dihaloolefins and some nucleophiles. Shen and
Wang described the preparation of trisubstituted alkenes and
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
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/
3
Scheme 1 Various ligands evaluated in this study.
C2RA21577B
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Table 2 Copper-catalyzed domino couplings between various arylboronic acids
a
and 1,1-dibromo-2-phenylethene
Entry ArB(OH)2
1
Product
Yieldb (%)
61
2
3
4
52
42
20
Fig. 1 The relationship between ligand and the catalytic effect.
Table 1 Screening of the catalytic conditions in the domino coupling between
phenylboronic acid and 1,1-dibromo-2-phenylethenea
5
6
73
56
Entry Cu cat. (mol%) Solvent Base
T (uC)/t (h) Yieldb (%)
7
8
73
60
1
2
3
4
5
6
7
8
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
Cu (15)
CuO (15)
Cu(OAc)2 (15)
CuBr (15)
Cu2O (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (10)
CuI (10)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
CuI (15)
–
DMF
PEG400 K2CO3
H2O K2CO3
toluene K2CO3
DMSO K2CO3
CH3CN K2CO3
K2CO3
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
53
28
NR
–
38
–
50
12
9
13
NR
NR
46
39
–
36
27
42
29
37
43
26
38
48
34
58
trace
10
58
42
28
NR
61
52
DMAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
K2CO3
tBuOK
K3PO4
KOH
Et3N
Na2CO3 110/18
Cs2CO3 110/18
9
10
11
12
63
46
51
34
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25e
26f
27f,g
28f,h
29f,i
30f,j
31f,k
32f
33f
34f
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
110/18
110/18
110/18
110/18
110/18
90/18
100/18
120/18
130/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/18
110/48
110/24
110/48
13
17
a
Reaction conditions: 1,1-dibromo-2-phenylethene (0.3 mmol),
arylboronic acid (0.6 mmol), CuI (15 mol%), L5 (30 mol%), K2CO3 (2
equiv), DMF (2 mL), 110 uC, 24 h, in Ar. Isolated yield based on
1,1-dibromo-2-phenylethene (average of two runs).
b
CuI (15)
CuI (15)
product, giving a result of 53% (Table 1, entry 1). Then, after a
series of solvents was tested using this readily available ligand, it
was found that DMF is superior to other solvents for the formation
of the expected product, though DMAc was also a solvent
candidate, giving a result of 50% (Table 1, entry 7). At the same
time, TLC detection showed that the use of either a common weak
organic base (such as triethylamine) or strong inorganic bases
a
Catalytic conditions: 1,1-dibromo-2-phenylethene (0.3 mmol),
phenylboronic acid (0.4 mmol), catalyst (15 mol%), ligand (30
mol%), additive (30 mol%), base (2 equiv), solvent (2 mL), 110 uC,
b
c
18h, in Ar. Isolated yield based on 1,1-dibromo-1-alkene. L5 (10
d
e
mol%). L5 (20 mol%). 1,1-Dibromo-1-alkene (0.4 mmol),
phenylboronic acid (0.3 mmol). 1,1-Dibromo-1-alkene (0.3 mmol),
phenylboronic acid (0.6 mmol). Iodine as the additive. NaI as the
additive. TBAB as the additive. LiCl as the additive. Ligand-free.
f
g
h
i
j
k
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catalyst, especially CuI, which exhibited higher a efficiency than
any other Cu(I) salts. As we all know, copper-catalyzed Suzuki
reactions usually need higher reaction temperatures.13 In this
study, 110 uC was favorable for the catalytic reaction after
screening different temperatures (Table 1, entries 19–22). The
effect of the amount of copper salt and the ligand was also tested.
It was indicated that the catalyst system containing 15 mol% of
CuI and 30 mol% of ligand was optimal (58% yield) (Table 1, entry
26). In order to improve the yield, some additives were employed,
such as iodine, TBAB, NaI and LiCl. However, we never acheieved
better results (Table 1, entries 27–30). In addition, the control
experiment in the absence of ligand showed low catalytic
efficiency, only giving a result of 28% (Table 1, entry 31). As
expected, in the absence of CuI, no product was achieved (Table 1,
entry 32). Then, the reaction times were screened (Table 1, entries
33–34) and 24 h was the optimal. Based on the above results, the
optimal reaction conditions proved to be with L5 as the ligand,
CuI as the copper source, and DMF as the solvent at 110 uC for 24
h.
With the optimized protocol in hand, we then set out to
investigate the scope and limitations of this domino coupling
reaction. The results are shown in Table 2. Various arylboronic
acids were tested under our standard conditions, and most of the
substrates could achieve moderate yields. We found that the
reactions of 1,1-dibromo-1-alkenes with 4-, 3- and 2-methoxyphe-
nylboronic acids gave the cross-coupling products in decreased
yields from 61% to 42% (Table 2, entries 1–3). The coupling of
phenylboronic acid and a-naphthylboronic acid afforded the
corresponding products in low yield (20% and 34%, respectively)
(Table 2, entries 4 and 12). Other substituted phenylboronic acids
can proceed smoothly to give the desired coupling products in
moderate to good yields (Table 2, entries 5–11). To our
disappointment, 3-pyridylbronic acid was not a suitable substrate
for the copper-catalyzed domino coupling reaction (17%, Table 2,
entry 13).
Table 3 Copper-catalyzed domino couplings between various 1,1-dihalo-1-
alkenes and 4-methylphenylboronic acida
Entry 1,1-Dihalo-1-alkene Product
1
Yieldb (%)
73
33
82
2
3
4
43
5
6
53
64
7
59
8
9
60
82
We next applied our methodology to the domino coupling
between 4-methyl phenylboronic acid and various 1,1-dihalo-1-
alkenes (Table 3). We can see that 1,1-dibromo-1-alkenes bearing
either electron-donating or electron-withdrawing groups reacted
well with 4-methylphenylboronic acid to provide the desired
products in yields ranging from 33% to 82% (Table 3, entries 1–9).
We were delighted to observe that heteroaryl gem-dibromoalkene
was suitable for the domino coupling reaction under the standard
conditions (Table 3, entry 10), as we know that C–Br bond cleavage
usually takes place in preference to C–Cl bond cleavage. The
corresponding product of 1,1-dichloro-1-alkene was obtained in
poor yield (Table 3, entry 11). Interestingly, an excellent catalytic
10
65
11c
12
13
80
a
Reaction conditions: 1,1-dibromo-1-alkene (0.3 mmol),
4-methylphenylboronic acid (0.6 mmol), CuI (15 mol%), L5 (30
mol%), K2CO3 (2 equiv), DMF (2 mL), 110 uC, 24 h, in Ar. Isolated
yield based on 1,1-dibromo-1-alkene (average of two runs). 48 h.
b
c
t
(such as BuOK and KOH) were unfavorable for the reaction
(Table 1, entries 8, 10–11). Another interesting aspect of the
reaction is the source of copper. The use of copper powder and
Cu(OAc)2 both lead to lower catalytic efficiency. When CuO was
employed in the reaction, no desired product was detected
(Table 1, entry 15). It can be seen that the Cu(I) salt was the ideal
Scheme 2 Synthesis of trans-1-phenyl-4-tolyl-but-3-ene-1-yne.
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scope. It is noteworthy that our protocol avoided the use of high-
cost and toxic palladium catalysts or any organoreagents, which is
of benefit when considering possible large-scale synthesis or
industrial application. It can be seen that this is a practical
approach for preparing various substituted diarylalkynes. Efforts
are underway to extend this methodology to other types of 1,1-
dihalo-1-alkenes and aryl reagents.
Scheme 3 Copper-catalyzed couplings between 4-cyano-1,1-dibromo-1-alkene
and various phenylboronic acid derivatives.
Acknowledgements
performance was observed with the cyano-substituted gem-
dichloroalkene (Table 3, entry 12).
We are grateful to the grants from the International S&T
Cooperation Program of Jiangsu Province (BZ2010048), the
Scientific Research Foundation for the Returned Overseas
Chinese Scholars, the State Education Ministry, the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, and the Key Laboratory of Organic Synthesis of
Jiangsu Province.
Enynes have been proven to have versatile uses, they are not
only present in abundant natural products but are also
intermediates for the manufacture of potential pharmaceuticals
and chemicals.14 trans-1-Phenyl-4-tolyl-but-3-ene-1-yne can be
readily synthesized using our protocol (Scheme 2).
Meanwhile, a wide range of arylboronic reagents, including
potassium tetrafluoroborate, sodium tetraphenylborate and 2-phe-
nylbenzo[d][1,3,2]dioxaborole, have been successfully coupled with
4-cyano-1,1-dibromo-1-alkene under the optimized conditions, as
presented in Scheme 3.
A possible mechanism is proposed in Scheme 4.15 Initially,
copper iodide is coordinated with 8-hydroxylquinoline to form
tetracoordinated copper complex (L3CuI). Afterwards, the reaction
might go through two paths. On the one hand, L3CuI could react
directly with 1,1-dibromo-1-alkene via intermolecular oxidative
addition to afford intermediate b in Path A. Then, intermediate c
was easily generated in the presence of ArB(OH)2. Subsequently,
reductive elimination of intermediate c gave intermediate d and
liberated L3CuI to go on for another circle. Finally the coupling
product e was afforded by the elimination of d in the basic
condition. On the other hand, 1,1-dibromo-1-alkene might
undergo elimination in the presence of potassium carbonate to
create 1-bromo-2-phenylacetylene (a9) firstly. Then it goes through
Path B in a similar way to Path A to form the final product (e).
In summary, we have successfully accomplished the copper-
catalyzed synthesis of internal alkynes via the domino couplings
between various 1,1-dihalo-1-alkenes and arylboronic acids in a
single step. Our methodology is efficient for a wide substrate
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