Efficient copper-catalyzed cross-coupling reaction of alkynes with aryl iodides

Article abstract of DOI:10.1002/ejoc.201000653

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 use of sterically demanding substrates with only 1.0-2.5 mol-% of Cu ₂O and 1.0-2.5 mol-% of xantphos as the catalyst.

Full text of DOI:10.1002/ejoc.201000653

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000653
Efficient Copper-Catalyzed Cross-Coupling Reaction of Alkynes with Aryl
Iodides
Che-Hung Lin,[a] Yu-Jen Wang,[a] and Chin-Fa Lee*[a]
Keywords: Cross-coupling / Copper / Alkynes / Phosphane ligands
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 use of sterically de-
manding substrates with only 1.0–2.5 mol-% of Cu2O and
1.0–2.5 mol-% of xantphos as the catalyst.
sisting of Cu2O (1.0–2.5 mol-%) and xantphos (L1, 1.0–
2.5 mol-%), which serves as a powerful catalytic system for
coupling terminal alkynes with aryl iodides.
Introduction
Alkynes are important structural motifs utilized in phar-
maceutical chemistry,[1] organic synthesis,[2] and materials
science.[3] The transition-metal-catalyzed cross-coupling re-
action of terminal alkynes with aryl halides represents as a
powerful strategy for preparing functionalized alkynes.[4]
The Sonogashira reaction employs a Pd/Cu catalyst and is
probably the most well-known method for the synthesis of
alkynes.[1–4] However, the high cost of palladium may limit
its practical applications; thus, it is desirable to search for
alternative catalytic systems. The copper-catalyzed cross-
coupling reaction of alkynes with aryl halides has gained
much attention owing to the low-cost of copper cata-
lysts.[5–12] However, there are still some drawbacks to this
approach. First, the combination of 10 mol-% copper salt
is generally required[5–12] along with a variety of ligands in-
cluding PPh3 (10 mol-%),[5–7] N,N-dimethylglycine (30 mol-
%),[8] ethylene diamine (15 mol-%),[9] 1,4-diazabicyclo-
[2.2.2]octane (20 mol-%),[10] pyrimidine (20 mol-%),[11] 1,3-
diphenylpropane-1,3-dione (30 mol-%),[12] and others.[13]
Recently, less than 1.0 mol-% of copper salt along with 30%
of N,N-dimethylethylenediamine was reported by Bolm et
al.[14] Second, alkyl alkynes are typically less reactive than
aryl alkynes and some of the methods mentioned above
only work with aryl alkynes.[6,7] Third, although the reac-
tion of alkynes with mono-ortho-substituted aryl iodides is
known,[5–11] to the best of our knowledge, there is no exam-
ple that employs di-ortho-substituted aryl iodides as a cou-
pling partner, as these coupling products are widely utilized
in organic synthesis.[1–4] As a result of these limitations, it
is desirable to develop an efficient system to overcome such
difficulties. Herein we report a catalyst combination con-
Results and Discussion
To determine the optimal reaction conditions, we used
phenylacetylene and iodobenzene as substrates. As shown
in Table 1, we examined a series of ligands L1–L6 (Figure 1)
and discovered that xantphos (L1) was the best choice, af-
fording the desired product nearly quantitatively (Table 1,
Entry 1). Interestingly, the electron-rich and sterically hin-
dered ligand L2 (xantphos-type) shows no activity (Table 1,
Entry 2). Likewise, L3 and L6 were not effective for this
transformation. Ligands L4 and L5 showed good activity,
yielding the target in 90 and 82% yield, respectively
(Table 1, Entries 4 and 5). Among the solvents screened
(Table 1, Entries 7–10), dioxane turned out to be the most
effective. DMSO and DMF were also suitable for the reac-
tion, resulting in the desired product in 91 and 95% yield,
respectively (Table 1, Entries 7 and 9). We studied the effect
of base and found that Cs2CO3 was the best; other bases
such as K2CO3, K3PO4, and KOtBu (Table 1, Entries 13–
15) were found to be unsatisfactory. Furthermore, it was
observed that lower catalyst loadings (Table 1, Entry 12),
shorter reaction times (Table 1, Entry 19), and lower tem-
peratures (Table 1, Entry 20) diminished the yield of the
product. We next investigated the copper sources and found
that Cu2O was superior to CuI, CuO, and CuCl2. The 2:1
ratio of copper to L1 is better in this system: compare En-
try 1 (2:1) with Entries 11 (1:1) and 12 (1:0.5). Assuming
that a Cu–xantphos complex is formed,[15] 1 equiv. of Cu is
unligated. This situation is not understood at the moment.
A low yield of 3a and the dimerization of phenylacetylene
were observed when the reaction was carried out without
ligand (Table 1, Entry 21). No desired product was detected
in the absence of a catalyst (Table 1, Entry 22). No product
was formed when iodobenzene was replaced by bromoben-
zene (not shown).
[a] Department of Chemistry, National Chung Hsing University
Taichung, Taiwan 402, ROC
Fax: +886-4-2286-2547
E-mail: cfalee@dragon.nchu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000653.
4368
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4368–4371

Copper-Catalyzed Cross-Coupling Reaction of Alkynes with Aryl Iodides
Table 1. Optimization of copper-catalyzed coupling of phenyl-
acetylene with iodobenzene.[a]
Table 2. Cu2O-catalyzed cross-coupling reaction of aryl alkynes
with aryl iodides.[a]
Entry
[Cu]
Ligand
Base
Solvent
Yield [%]
Entry
Ar1
Ar2
Yield [%]
1
2
3
4
5
6
7
8
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
NMP
99
–
8
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4I
2-H2NC6H4I
4-MeOC6H4I
2-MeOC6H4I
4-CH3COC6H4I
2-MeC6H4I
4-EtO2CC6H4I
4-O2NC6H4I
4-ClC6H4I
98 (3b)
97 (3c)
96 (3d)
95 (3e)
99 (3f)
97 (3g)
89 (3h)
99 (3i)
85 (3j)
93 (3k)
95 (3l)
99 (3m)
86 (3n)
97 (3o)
89 (3p)
90 (3q)
90 (3b)
93 (3d)
91 (3r)
82 (3s)
2[b]
3[b]
4[c]
5
90
82
12
91
65
95
88
44
65
23
34
19
85
27
93
76
47
10
–
6
7
8
9
9
DMF
DME
10
11[b]
12[c]
13
14
15
16[d]
17[d]
18[d]
19[e]
20[f]
21
22
10
4-BrC6H4I
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
11[b]
12
4-H2NC6H4I
3-CH3COC6H4I
PhI
3-iodopyridine
2-iodopyridine
2-iodothiophene
PhI
13[d]
14
3-H2NC6H4
Ph
Ph
Ph
15
16
CuO
17[b,d]
18[b,d]
19
4-MeC6H4
4-MeOC6H4
Ph
CuCl2
Cu2O
Cu2O
Cu2O
–
PhI
2-Et-6-MeC6H3I
3-MeO2CC6H4I
20
Ph
–
[a] Reaction conditions unless otherwise stated: Cu2O (0.01 mmol,
1.0 mol-%), L1 (0.01 mmol, 1.0 mol-%), aryl alkyne (1.5 mmol),
aryl iodide (1.0 mmol), Cs2CO3 (2.0 mmol) in dioxane (0.5 mL).
[b] 12 h. [c] 20 h. [d] Aryl alkyne (1.0 mmol), aryl iodide
(1.5 mmol).
[a] Reaction conditions unless otherwise stated: Cu2O (0.01 mmol,
1.0 mol-%), ligand (0.01 mmol, 1.0 mol-%), phenylacetylene
(1.5 mmol), iodobenzene (1.0 mmol), base (2.0 mmol) in solvent
(0.5 mL). [b] Cu2O (0.5 mol-%). [c] Cu2O (0.5 mol-%), ligand
(0.5 mol-%). [d] Copper salt (2.0 mol-%). [e] 6 h. [f] 110 °C.
We turned our attention towards alkyl alkynes, as illus-
trated in Table 3. When the reaction was carried out by
using the conditions for aryl alkynes, 5a was obtained in
only 64% yield. However, a 91% yield of 5a can be ob-
Table 3. Cu2O-catalyzed cross-coupling reaction of alkyl alkynes
with aryl iodides.[a]
Figure 1. Structures of the ligands L1–L6.
Entry
R
Ar2
Time [h]
Yield [%]
To explore the scope of this novel system, a series of aryl
iodides bearing electron-rich and electron-deficient moieties
were tested with aryl alkynes. The functional groups, in-
cluding enolizable ketones (Table 2, Entries 5 and 12), esters
(Table 2, Entries 7 and 20), nitro (Table 2, Entry 8), unpro-
tected amines (Table 2, Entries 2, 11, and 13), chloride
(Table 2, Entry 9), bromide (Table 2, Entry 10), and hetero-
cycles (Table 2, Entries 14–16), all tolerated the reaction
conditions. Compound 3d was obtained in 96% when 4-
iodoanisole was employed with phenylacetylene. Moreover,
it is worthy to note that the sterically demanding di-ortho
substituted aryl iodide was also suitable as the substrate, as
demonstrated in the formation of 3r in 91% yield through
the coupling of 2-ethyl-6-methyliodobenzene with phenyl-
acetylene (Table 2, Entry 19).
1
2
3
4
nC8H17
nC8H17
nC4H9
nC4H9
nC8H17
nC8H17
nC4H9
nC4H9
nC8H17
nC4H9
nC4H9
nC4H9
PhI
4-MeC6H4I
PhI
24
24
12
20
24
24
18
24
24
24
24
24
91:64[b] (5a)
90 (5b)
99 (5c)
91 (5d)
98 (5e)
93 (5f)
80 (5g)
77 (5h)
88 (5i)
4-MeOC6H4I
2-MeC6H4I
4-MeOC6H4I
4-MeC6H4I
4-H2NC6H4I
2-Et-6-MeC6H3I
2-Et-6-MeC6H3I
2-MeC6H4I
3-iodopyridine
5
6
7[c]
8
9
10
11
12
93 (5j)
97 (5k)
85 (5l)
[a] Conditions unless otherwise stated: Cu2O (0.025 mmol, 2.5 mol-
%), L1 (0.025 mmol, 2.5 mol-%), alkyl alkyne (1.5 mmol), aryl io-
dide (1.0 mmol), Cs2CO3 (2.0 mmol) in DMF (0.5 mL). [b] Cu2O
(1.0 mol-%), L1 (1.0 mol-%). [c] 1-Hexyne (1.0 mmol), 4-iodotol-
uene (1.5 mmol).
Eur. J. Org. Chem. 2010, 4368–4371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4369

C.-H. Lin, Y.-J. Wang, C.-F. Lee
SHORT COMMUNICATION
reaction vessel was placed in an oil bath at 135 °C. After stirring
at this temperature for 8 h, the heterogeneous mixture was cooled
to room temperature and diluted with ethyl acetate (20 mL). The
resulting solution was filtered through a pad of silica gel then
washed with ethyl acetate (20 mL) and concentrated to give the
crude material, which was then purified by column chromatog-
raphy (SiO2, hexane) to yield 3a.
tained when the reaction was performed under the catalyst
combination of Cu2O (2.5 mol-%)/L1 (2.5 mol-%) in DMF
(Table 3, Entry 1). A variety of aryl iodides were coupled
smoothly with alkyl alkynes to give products 5a–l in good
to excellent yields based on this catalytic system. 4-Iodoani-
sole was coupled smoothly to afford 5d and 5f in excellent
yields (Table 3, Entries 4 and 6). Free amine (Table 3, En-
try 8) and pyridine moieties (Table 3, Entry 12) were also
tolerated during the catalysis. Furthermore, sterically de-
manding substrates did not hamper the efficiency of the
reaction, as seen for products 5i and 5j, which were ob-
tained in 88 and 93% yield, respectively (Table 3, Entries 9
and 10).
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, characterization data, and copies of the
1H and 13C NMR spectra of the new compounds.
Acknowledgments
When the reaction was carried out with 1a and 2b, prod-
uct 6 was obtained in 85% yield [Equation (1)].[10,16] Prod-
ucts 7a and 7b can be selectively synthesized in excellent
yields through 5-exo-dig cyclization[17] in one pot [Equa-
tion (2)].
Financial support by the National Science Council, Taiwan
(NSC97-2113-M-005-006-MY2) and the National Chung Hsing
University are gratefully acknowledged. We thank Prof. Fung-E
Hong for generously sharing his GC–MS instrument.
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Conclusions
In conclusion, we have demonstrated that the combina-
tion of Cu2O (1.0–2.5 mol-%) with xantphos (1.0–2.5 mol-
%) serves as a powerful catalytic system for the cross-cou-
pling reaction of terminal alkynes with aryl iodides. A vari-
ety of functional groups such as enolizable ketones, esters,
nitro groups, unprotected amines, chlorides, bromides, and
heterocycles were all tolerated by the reaction conditions
explored. Moreover, the highly sterically demanding sub-
strate di-ortho-substituted aryl iodide was also shown to be
a good coupling partner to give the alkynes in good to ex-
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Experimental Section
Representative Procedure: A sealable vial equipped with a magnetic
stir bar was charged with Cs2CO3 (652 mg, 2.0 mmol), Cu2O
(1.43 mg, 0.01 mmol), and L1 (5.79 mg, 0.01 mmol) under a nitro-
gen atmosphere. The aperture of the vial was then covered with a
rubber septum. Under a nitrogen atmosphere, phenylacetylene (1a;
0.167 mL, 1.5 mmol), iodobenzene (2a; 0.11 mL, 1.0 mmol), and
dioxane (0.5 mL) were added by syringe. The septum was then re-
placed by a screw cap containing a Teflon-coated septum, and the
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Copper-Catalyzed Cross-Coupling Reaction of Alkynes with Aryl Iodides
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Received: May 8, 2010
Published Online: July 7, 2010
Eur. J. Org. Chem. 2010, 4368–4371
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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