Ligand-free copper-catalyzed cross-coupling reaction of alkynes with aryl iodides and vinyl halides

Article abstract of DOI:10.1055/s-0033-1340461

A copper-catalyzed cross-coupling reaction of alkynes with aryl iodides is described. The system tolerates a broad range of functional groups and enables the sterically demanding substrates presented during the catalysis with only 5-10 mol% of Cu₂O as the catalyst. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340461

LETTER
▌443
letter
Ligand-Free Copper-Catalyzed Cross-Coupling Reaction of Alkynes with
Aryl Iodides and Vinyl Halides
Cross-Coupling Reaction of Alkynes with Aryl Iodides and Vinyl Halides
Wan-Ting Tsai, Yun-Yung Lin, Yi-An Chen, Chin-Fa Lee*
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, R. O. C.
Fax +886(4)22862547; E-mail: cfalee@dragon.nchu.edu.tw
Received: 12.08.2013; Accepted after revision: 17.11.2013
portantly, the purity of reagents and copper sources have
also been examined by ICP-MS technique in this report
(with 4 ppb of palladium).20 Very recently, Mao and co-
workers have also reported that [Cu(acac)2]–H2O is an ac-
tive catalyst for the same propose. All reagents including
[Cu(acac)2]–H2O, aryl halides, alkynes, K2CO3, and
DMSO have been measured by ICP-MS, and no palladi-
um was detected.20 These results strongly suggest that
copper can serve as the sole metal for the coupling of al-
kynes with aryl halides without palladium. Notably, the li-
gand is important in Bolm and Mao’s systems.20,21 Thus,
it is desirable to develop a simpler system which employs
copper as a catalyst in the absence of ligand. As part of our
ongoing interests in this area,22 herein we report that com-
mercially available Cu2O can be utilized as a catalyst for
the copper-catalyzed cross-coupling reaction of aryl io-
dides and vinyl halides with alkynes in the absence of ad-
ditional ligand. This system shows good functional-group
compatibility with unprotected amines, bromo, chloro,
and heterocyclic groups. Moreover, di-ortho-substituted
aryl iodides with sterically demanding groups also work
with alkynes, giving the corresponding internal alkynes in
good yields.
Abstract: A copper-catalyzed cross-coupling reaction of alkynes
with aryl iodides is described. The system tolerates a broad range of
functional groups and enables the sterically demanding substrates
presented during the catalysis with only 5–10 mol% of Cu2O as the
catalyst.
Key words: copper, cross-coupling, Sonogashira reaction, ligand-
free, aryl iodide, vinyl halide
Functional alkynes and enynes are important compounds
in organic synthesis1,2 and organic materials.3 The Sono-
gashira cross-coupling reaction employs a catalytic com-
bination of palladium and copper salts as the most popular
method for preparing such internal alkynes by reaction of
aryl and vinyl halides with terminal alkynes.1–4 Recently,
copper has been used as a sole metal source in combina-
tion with appropriate ligands for the Sonogashira-type re-
action owing to the low cost of the copper salts.5–14
Ligands such as Ph3P,5–7 N,N-dimethylglycine,8 ethylene-
diamine,9 1,4-diazabicyclo[2.2.2]octane,10 pyrimidine,11
1,3-diphenylpropane-1,3-dione,12 N,N-dimethylethylene-
diamine,13 and others14 have been reported. Some ligands,
however, are expensive and require time-consuming syn-
theses. Mao reported the ligand-free iron–copper co-cata-
lyzed coupling reaction of terminal alkynes with aryl
iodides,15 however, the scope of this system is limited to
aryl alkynes. Furthermore, this catalytic system requires
30 mol% of Fe(acac)3 and 10 mol% of CuI. Rothenberg et
al. revealed that the copper clusters are active species for
promoting the Sonogashira-type reaction, however, only
phenylacetylene was involved in their system.16 Biffis re-
ported that CuO on alumina could be used as a catalyst for
the same purpose, however, low yields were observed for
alkyl alkynes.17 Recently, Yuan et al. reported that CuO
nanoparticles can also catalyze the coupling of alkynes
with aryl iodides; however, the reactions were carried out
at 160 °C, and only one alkyl alkyne was explored in this
protocol.18 Although in 2010, Novák and coworkers re-
ported that trace amount of palladium is a key for the cop-
per-catalyzed Sonogashira reaction.19 Bolm et al. have
demonstrated that the [Cu(DMEDA)2]Cl2–H2O complex
can serve as a catalyst in combination of Cs2CO3 as a base
in dioxane in this area. They have proposed the mecha-
nism for the copper-catalyzed Sonogashira reaction. Im-
Initially, phenylacetylene (1a) and iodobenzene (2a) were
chosen as the substrates to determine the optimal reaction
conditions. The results are summarized in Table 1. To our
delight, a 94% isolated yield was obtained when the reac-
tion was carried out by using 5 mol% of Cu2O as a
catalyst23 and Cs2CO3 as a base in DMF under ligand-free
conditions (Table 1, entry 1). A lower yield was observed
when the catalyst was decreased to 1.5 mol% (Table 1, en-
try 2). The control experiment showed that no product was
formed when the reaction was performed without catalyst
(Table 1, entry 3). Copper salts including CuI, CuO,
CuCl2, CuBr, and Cu(OAc)2 (Table 1, entries 4–8, respec-
tively) were tested, but Cu2O was the best choice. Other
bases (Table 1, entries 9–12) such as Na2CO3, K2CO3,
K3PO4, and KOt-Bu could not provide satisfying results.
The study of solvent effect (Table 1, entries 13–17) re-
vealed that NMP is also suitable for this transformation;
other solvents did not show good results. It was recog-
nized that no product was obtained when the reactions
were conducted under shorter reaction times (Table 1, en-
try 18) and lower temperatures (Table 1, entry 19).
We then explored the scope of this catalytic system to a
variety of aryl alkynes and aryl iodides. As demonstrated
in Table 2,24 aryl alkynes bearing heterocyclic groups or
unprotected amine and trifluoromethyl groups were cou-
SYNLETT 2014, 25, 0443–0447
Advanced online publication: 19.12.2013
DOI: 10.1055/s-0033-1340461; Art ID: ST-2013-W0769-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

444
W.-T. Tsai et al.
LETTER
Table 1 Optimization of Copper-Catalyzed Coupling of Phenylacet-
Table 2 Cu2O-Catalyzed Cross-Coupling Reaction of Aryl Alkynes
ylene with Iodobenzenea
with Aryl Iodidesa
Cu2O (5 mol%)
Cu2O (5 mol%)
Ar1
H
Ar2
I
Ar1
Ar2
Ph
H
Ph
2a
I
Ph
Ph
+
+
base, solvent
135 °C, 24 h
Cs2CO3, DMF
135 °C, 24 h
1a
3a
1
2
3
Entry
[Cu]
Base
Solvent
Yield (%)
Entry Ar1
Ar2
Product 3 Yield (%)
1
2
Cu2O
Cu2O
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO
dioxane
DME
DEF
94
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4I
4-H2NC6H4I
4-MeOC6H4I
2-MeOC6H4I
2-BrC6H4I
3b
3c
3d
3e
3f
94
86
88
64
81
92
93
93
82
85
71
59
70
75
80b
c
3
–
3
4
CuI
80
31
72
84
73
58
45
67
–
4
5
CuO
CuCl2
CuBr
5
6
6
2-MeC6H4I
2-Et-6-MeC6H3I
4-ClC6H4I
3g
3h
3i
7
7
8
Cu(OAc)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
8
9
9
4-BrC6H4I
3j
10
11
12
13
14
15
16
17
18
19
10
11
12
13
14
(2,4,6-trimethyl)C6H2I 3k
K3PO4
3-thiophene PhI
3l
KOt-Bu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
3-H2NC6H4
4-F3CC6H4
Ph
PhI
3m
3n
3o
83
81
38
70
92
PhI
3-iodopyridine
a Reaction conditions unless otherwise stated: Cu2O (0.05 mmol,
5 mol%), aryl alkyne (1.5 mmol), aryl iodide (1.0 mmol), Cs2CO3
(2.0 mmol) in DMF (0.5 mL).
Table 3 Cu2O-Catalyzed Cross-Coupling Reaction of Alkyl Al-
d
kynes with Aryl Iodidesa
DMF
DMF
–
e
Cu2O (10 mol%)
–
R
H
Ar
I
R
Ar
+
Cs2CO3, DMF
135 °C, 24 h
a Reaction conditions unless otherwise stated: Cu2O (0.05 mmol, 5.0
mol%), phenylacetylene (1.5 mmol), iodobenzene (1.0 mmol), base
(2.0 mmol) in solvent (0.5 mL).
4
2
5
Entry
R
Ar
Product 5 Yield (%)
b Cu2O: 1.5 mol%.
c No catalyst.
1
2
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C8H17
n-C8H17
n-C8H17
PhI
5a
5b
5c
5d
5e
5f
74
d Reaction time: 12 h.
e Reaction temperature: 120 °C.
4-MeOC6H4I
4-BrC6H4I
4-MeC6H4I
2-iodopyridine
2-MeC6H4I
4-ClC6H4I
PhI
56
3
67
pled smoothly with many aryl iodides, giving the internal
alkynes in good to excellent yields. Notably, functional
groups including unprotected amine (Table 2, entries 2
and 12), bromo (Table 2, entries 5 and 9), chloro (Table 2,
entry 8), thiophene (Table 2, entry 11), and pyridine moi-
ety (Table 2, entry 14) are tolerated under the reaction
conditions employed. Moreover, the sterically demanding
di-ortho-substituted aryl iodide, for example, 2-ethyl-6-
methyliodobenzene was smoothly coupled with phenyl-
acetylene to give 3h in 93% yield (Table 2, entry 7).
4
63
5
43b
65c
48b
52
6
7
5g
5h
5i
8
9
4-MeOC6H4I
2-MeC6H4I
47b
83b
10
5j
A low product yield was obtained when the above reac-
tion conditions (5.0 mol% of catalyst) were applied to al-
kyl alkynes. However, satisfactory results can be achieved
when the catalyst loading was increased from 5–10 mol%.
The results are listed in Table 3: Alkyl alkynes 4 reacted
a Conditions unless otherwise stated: Cu2O (0.10 mmol, 10 mol%), al-
kyl alkyne (1.5 mmol), aryl iodide (1.0 mmol), Cs2CO3 (2.0 mmol) in
DMF (0.5 mL).
b Reaction time: 48 h.
c Reaction time: 30 h.
Synlett 2014, 25, 443–447
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reaction of Alkynes with Aryl Iodides and Vinyl Halides
445
with a variety of aryl iodides to afford the corresponding of 5–10 mol% of Cu2O (Table 4, entries 1–11). Interest-
alkynes in moderate to good yields.
ingly, phenylacetylene was worked with bromostyrene to
obtain the product 7m in 67% yield (Table 4, entry 13).
However, the alkyl vinyl bromide did not couple with al-
kyl and aryl alkynes in the present system.
This catalytic system is also applicable to the synthesis of
enynes, and the results are summarized in Table 4. Alkyl
vinyl iodides were reacted with alkyl and aryl alkynes to
provide enynes in good to excellent yields in the presence
Table 4 Cu2O-Catalyzed Cross-Coupling Reaction of Alkynes with Vinyl Iodides and Bromidea
.
R2
X
Cu2O (5–10 mol%)
R2
R1
+
Cs2CO3, DMF
R1
135 °C, 12–24 h
1
6
7
Entry
1
6
Product 7
Yield (%)
I
t-Bu
n-C4H9
1
n-C4H9C≡CH
n-C8H17C≡CH
63
t-Bu
7a
6a
6a
t-Bu
n-C8H17
2
3
64
85
7b
t-Bu
t-Bu
6a
6a
7c
4
51
Me
Me
7d
F3C
F3C
t-Bu
5
6
6a
6a
88
53
7e
S
t-Bu
S
7f
NH2
NH2
t-Bu
7
8
6a
6a
58
7g
t-Bu
t-Bu
t-Bu
81
7h
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 443–447

446
W.-T. Tsai et al.
LETTER
Table 4 Cu2O-Catalyzed Cross-Coupling Reaction of Alkynes with Vinyl Iodides and Bromidea (continued)
.
R2
X
Cu2O (5–10 mol%)
R2
R1
+
Cs2CO3, DMF
R1
135 °C, 12–24 h
1
6
7
Entry
1
6
Product 7
Yield (%)
I
Ph
Ph
9
80
Ph
7i
6b
6b
n-C4H9
10
11
12
n-C4H9C≡CH
50b
71
7j
I
7k
6c
n-C4H9
n-C4H9C≡CH
6c
42b
7l
Br
13
67b,c
7m
6d
a Reaction conditions unless otherwise stated: Cu2O (0.025 mmol, 5 mol%), alkyne (0.75 mmol), vinyl halide (0.5 mmol), Cs2CO3 (1.0 mmol)
in DMF (0.5 mL).
b Cu2O (0.05 mmol, 10 mol%), 24 h.
c The starting 1-(2-bromovinyl)benzene (6d) contains ratio of E/Z = 10:1 (the ratio of E/Z was determined by GC–MS and 1H NMR techniques).
Only E-form product 7m was detected.
(NCHU) for sharing his GC–MS instruments. C.F.L. is a Golden-
Jade Fellow of Kenda Foundation, Taiwan.
In conclusion, we report that the commercially available
Cu2O is an active catalyst for the coupling of terminal al-
kynes with aryl iodides, vinyl iodides, and bromide with-
out the necessity of additional ligand. A variety of
functional groups such as unprotected amines, chloro,
bromo, and heterocycles were tolerated by the reaction
conditions. Moreover, highly sterically demanding sub-
strates, for example, 2-ethyl-6-methyliodobenzene could
be coupled with alkyne to provide the corresponding
alkyne in good yield.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
References and Notes
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Acknowledgement
The National Science Council, Taiwan (NSC 101-2113-M-005-
008-MY3), the National Chung Hsing University and the Center of
Nanoscience and Nanotechnology (NCHU) are gratefully acknow-
ledged for financial support. We also thank Prof. Fung-E Hong
Synlett 2014, 25, 443–447
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cross-Coupling Reaction of Alkynes with Aryl Iodides and Vinyl Halides
447
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(24) General Procedure for the Synthesis of Compounds 3a–e
A sealable vial equipped with a magnetic stir bar was
charged with Cs2CO3 (652 mg, 2.0 mmol) and Cu2O (7.0 mg,
0.05 mmol) under a nitrogen atmosphere. The aperture of the
vial was then covered with a rubber septum. Under a
nitrogen atmosphere, aryl alkyne 1 (1.5 mmol), aryl iodide 2
(1.0 mmol), and DMF (0.5 mL) were added by syringe. The
septum was then replaced by a screw cap containing a
Teflon-coated septum, and the reaction vessel was placed at
135 °C. After stirring at this temperature for 24 h, the
heterogeneous mixture was cooled to r.t. and diluted with
EtOAc (20 mL). The resulting solution was filtered through
a pad of silica gel, then washed with EtOAc (20 mL), and
concentrated to give the crude material which was then
purified by column chromatography on silica gel to yield
alkyne 3.
(6) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett.
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(11) Xie, Y.-X.; Deng, C.-L.; Pi, S.-F.; Li, J.-H.; Yin, D.-L. Chin.
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Data for Five Representative Examples
Diphenylacetylene (3a)25
Following the general procedure, using Cs2CO3 (652 mg, 2.0
mmol) and Cu2O (7.0 mg, 0.05 mmol) in DMF (0.5 mL),
then purified by column chromatography (SiO2, hexane) to
provide 3a as a white solid (168 mg, 94% yield); mp 58–59
°C (lit.25 60–61 °C). 1H NMR (400 MHz, CDCl3): δ = 7.26–
7.41 (m, 6 H), 7.56–7.60 (m, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 89.4, 123.2, 128.2, 128.3, 131.6 ppm.
Phenyl-p-tolylacetylene (3b)25
(12) Monnier, F.; Turtaut, F.; Duroure, L.; Taillefer, M. Org. Lett.
2008, 10, 3203.
(13) Zuidema, E.; Bolm, C. Chem. Eur. J. 2010, 16, 4181.
(14) For more selected examples, see: (a) Hosseinzadeh, R.;
Mohadjerani, M.; Tavakoli, R. Synth. Commun. 2010, 40,
282. (b) Thakur, K. G.; Jaseer, E. A.; Naidu, A. B.; Sekar, G.
Tetrahedron Lett. 2009, 50, 2865. (c) Guan, J. T.; Yu, G.-A.;
Chen, L.; Weng, T. Q.; Yuan, J. J.; Liu, S. H. Appl.
Organomet. Chem. 2009, 23, 75. (d) Mao, J.; Guo, J.; Ji, S.-
J. J. Mol. Catal. A: Chem. 2008, 284, 85. (e) Tang, B.-X.;
Wang, F.; Li, J.-H.; Xie, Y.-X.; Zhang, M.-B. J. Org. Chem.
2007, 72, 6294. (f) Colacino, E.; Daïch, L.; Martinez, J.;
Lamaty, F. Synlett 2007, 1279. (g) Thathagar, M. B.;
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Li, Y. Z. Adv. Synth. Catal. 2009, 351, 1263. (j) Wu, M.;
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K.; Furuune, M.; Miura, M.; Nomura, M. Tetrahedron Lett.
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Following the general procedure, using phenylacetylene
(0.0167 mL, 1.5 mmol) and 4-iodotoluene (218 mg, 1.0
mmol), then purified by column chromatography (SiO2,
hexane) to provide 3b as a white solid (181 mg, 94% yield);
mp 69–70 °C (lit.25 71–72.5 °C). 1H NMR (400 MHz,
CDCl3): δ = 2.17 (s, 3 H), 6.96–6.97 (m, 1 H), 6.14–6.16 (m,
2 H), 7.28–7.38 (m, 2 H), 7.37–7.39 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 21.5, 88.7, 89.5, 120.1, 123.4, 128.0,
128.3, 129.1, 131.5, 131.5, 138.4 ppm.
4-(Phenylethynyl)aniline (3c)19c
Following the general procedure, using phenylacetylene
(0.167 mL, 1.5 mmol) and 4-iodoaniline (218 mg, 1.0
mmol), then purified by column chromatography (SiO2,
hexane–EtOAc = 9:1) provide 3c as a brown solid (166 mg,
86% yield); mp 123–124 °C (lit.19c 126–127 °C). 1H NMR
(400 MHz, CDCl3): δ = 3.75 (br s, 2 H), 6.57 (d, J = 8.0 Hz,
2 H), 7.28–7.33 (m, 5 H), 7.48–7.50 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 87.3, 90.1, 112.5, 114.7, 123.8,
127.6, 128.2, 131.3, 132.9, 146.6 ppm.
(4-Methoxyphenyl)phenylacetylene (3d)25
(15) Mao, J.; Xie, G.; Wu, M.; Guo, J.; Jia, S. Adv. Synth. Catal.
2008, 350, 2477.
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2004, 6, 215.
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Tetrahedron Lett. 2007, 48, 8761.
(18) Yuan, Y.; Zhu, H.; Zhao, D.; Zhang, L. Synthesis 2011,
1792.
Following the general procedure, using phenylacetylene
(0.083 mL, 0.75 mmol) and 4-iodoanisole (120 mg, 0.5
mmol), then purified by column chromatography (SiO2,
hexane–EtOAc = 10:1) to provide 3d as a white solid (92
mg, 88% yield); mp 55–57 °C (lit.25 58–60 °C). 1H NMR
(400 MHz, CDCl3): δ = 3.75 (s, 3 H), 6.83–6.85 (m, 2 H),
7.28–7.31 (m, 3 H), 7.44–7.52 (m, 4 H) ppm. 13C NMR (100
MHz, CDCl3): δ = 55.1, 88.0, 89.4, 113.9, 115.3, 123.5,
127.9, 128.2, 131.4, 133.0, 159.6 ppm.
(19) Gonda, Z.; Tolnai, G. L.; Novák, Z. Chem. Eur. J. 2010, 16,
11822.
2-(Phenylethynyl)anisole (3e)19c
(20) Zou, L.-H.; Johansson, A. J.; Zuidema, E.; Bolm, C. Chem.
Eur. J. 2013, 19, 8144.
Following the general procedure, using phenylacetylene
(0.167 mL, 1.5 mmol) and 2-iodoanisole (0.130 mL, 1.0
mmol), then purified by column chromatography (SiO2,
hexane–EtOAc = 9:1) to provide 3e as a yellow oil (132 mg,
64% yield). 1H NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H),
6.84–6.93 (m, 2 H), 7.24–7.33 (m, 4 H), 7.48–7.50 (m, 1 H),
7.54–7.57 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 55.7, 85.7, 93.3, 110.6, 112.3, 120.4, 123.5, 128.0,
128.2, 129.7, 131.5, 133.5, 159.9 ppm.
(21) Li, T.; Qu, X.; Xie, G.; Mao, J. Chem. Asian J. 2011, 6, 1325.
(22) (a) Tsai, W.-T.; Lin, Y.-Y.; Wang, Y.-J.; Lee, C.-F.
Synthesis 2012, 44, 1507. (b) Lin, Y.-Y.; Wang, Y.-J.;
Cheng, J.-H.; Lee, C.-F. Synlett 2012, 23, 930. (c) Lin,
C.-H.; Wang, Y.-J.; Lee, C.-F. Eur. J. Org. Chem. 2010,
4368.
(23) ICP-MS analysis showed 2 ppb of palladium in Cu2O; no
palladium has been detected in Cs2CO3 and phenylacetylene.
(25) Li, P.; Wang, L.; Li, H. Tetrahedron 2005, 61, 8633.
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Synlett 2014, 25, 443–447

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