Microwave-assisted copper-catalyzed cross-coupling reaction of alkynes with aryl iodides and vinyl halides

Article abstract of DOI:10.1055/s-0031-1290813

The microwave-assisted, copper-catalyzed coupling of terminal alkynes with aryl iodides and vinyl halides is reported. In general, the reactions are completed in 10-30 min using 2-5 mol% [CuI(xantphos)] as a catalyst to provide the corresponding alkynes and enynes in good to excellent yields. A broad spectrum of aryl iodides, vinyl iodides, and bromides are coupled with aryl- and alkyl alkynes.

Full text of DOI:10.1055/s-0031-1290813

SPECIAL TOPIC
▌1507
special topic
Microwave-Assisted Copper-Catalyzed Cross-Coupling Reaction of Alkynes
with Aryl Iodides and Vinyl Halides
Microwave-Assisted Copper-Catalyzed Cross-Coupling
Wen-Ting Tsai, Yun-Yung Lin, Yu-Jen Wang, Chin-Fa Lee*
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, ROC
Fax +886(4)22862547; E-mail: cfalee@dragon.nchu.edu.tw
Received: 20.02.2012; Accepted: 05.03.2012
Here, we report a general procedure for the microwave-
Abstract: The microwave-assisted, copper-catalyzed coupling of
assisted, copper-catalyzed coupling of alkynes with aryl
terminal alkynes with aryl iodides and vinyl halides is reported. In
iodides. Aryl and alkyl substrates both reacted smoothly
to provide the corresponding alkynes in good to excellent
general, the reactions are completed in 10–30 min using 2–5 mol%
[CuI(xantphos)] as a catalyst to provide the corresponding alkynes
and enynes in good to excellent yields. A broad spectrum of aryl yields.
iodides, vinyl iodides, and bromides are coupled with aryl- and
alkyl alkynes.
Initially, iodobenzene and phenylacetylene were selected
as model substrates to screen for optimal reaction condi-
tions; the results are summarized in Table 1. A 22% prod-
uct yield resulted when the reaction was carried out using
our previously developed conditions for the coupling of
aryl iodides with alkynes under oil bath heating (Table 1,
entry 1).4a,b In general, polar solvents have been shown to
enhance the efficiency of microwave irradiation.7–10 To
our delight, a 95% yield was afforded when the solvent
was changed to dimethyl sulfoxide (DMSO; Table 1, en-
Key words: microwaves, copper, cross-coupling, alkynes, aryl
iodide
Functional alkynes and enynes are important molecules in
organic synthesis and materials science;1 as such, many
methods have been developed for the synthesis of these
compounds.2–4 Pioneering work reported by Sonogashira
employed palladium and a copper cocatalyst for the cou-
pling of alkynes with aryl halides1b and, since this discov-
ery, transition-metal-catalyzed coupling of terminal
alkynes with aryl halides and vinyl halides has become an
important method for the preparation of alkynes and
enynes.3,4 More recently, the exclusive use of copper as a
catalyst has gained significant attention in the Sonogashira-
type reaction owing to the low cost of the copper salts.4
Table 1 Optimization of Microwave-Assisted Copper-Catalyzed
Coupling of Iodobenzene with Phenylacetylenea
CuI(xantphos)
(2 mol%)
I
Ph
Ph
Ph
+ Ph
2a
base, solvent, 135 °C
MW, 10 min
3a
1a
Entry
Base
Solvent
Yield (%)
Microwave irradiation has been widely applied in organic
synthesis5,6 due to the high efficiency of this technique.
While microwave-promoted Sonogashira-type reactions
are known,7–9 such protocols are typically found using
Pd/Cu7 or Pd8 as the catalysts for the coupling of alkynes
with aryl halides. Using exclusively copper in the micro-
wave-assisted, copper-catalyzed coupling reaction is
known,9,10 however, there are some limitations. First,
ortho-substituted aryl halides are not involved in these
systems.9a Second, the substrates used in these procedures
are mainly aryl alkynes.9 Recently, Xie and Wan reported
the microwave-assisted coupling of aryl- and alkyl al-
kynes with aryl iodides.10 However, some drawbacks re-
main in these systems. First, high levels of catalyst and
ancillary ligand (10 mol% CuI and 20 mol% PPh3) were
required. Second, these systems needed excess phase-
transfer reagents. Third, 2.4–3.0 equivalents of alkynes
are necessary for these couplings.
1
2
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
K3PO4
dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
22
95
b
3
–
4
43
34
71
–
5
6
K2CO3
7
KOt-Bu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8
98
63
trace
85
96
9
H2O
11
12
13
14
THF
MeCN
NMP
Recently, we reported the copper-catalyzed coupling re-
action of alkynes with aryl iodides4a and vinyl halides.4b
86c
DMF
a Reaction conditions: [CuI(xantphos)] (0.01 mmol, 2 mol%), phenyl-
acetylene (0.75 mmol), iodobenzene (0.5 mmol), base (1.0 mmol),
solvent (0.5 mL).
SYNTHESIS 2012, 44, 1507–1510
Advanced online publication: 02.04.2012
DOI: 10.1055/s-0031-1290813; Art ID: SS-2012-C0169-ST
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
b No catalyst.
c [CuI(xantphos)] (0.005 mmol, 1.0 mol%)

1508
W.-T. Tsai et al.
SPECIAL TOPIC
try 2). No product was observed when the reaction was loadings resulted in diminished yield of the desired target
carried out in the absence of catalyst (Table 1, entry 3). (Table 1, entry 14).
We then studied the effect of base on the reaction (Table
In order to explore the scope of the system, a variety of
1, entries 4–7), and the results showed that Cs2CO3 was
aryl alkynes were reacted with aryl iodides (Table 2, en-
optimal for this transformation. Other solvents were ex-
tries 1–12). Functional groups such as free amines (Table
amined (Table 1, entries 8–13) and N,N-dimethylform-
2, entries 2 and 11), chloro (Table 2, entries 4 and 12),
bromo (Table 2, entry 5), and sulfur-containing heterocy-
amide (DMF) was found to be superior, giving the product
in 98% isolated yield (Table 1, entry 8). Lower catalyst
cles (Table 2, entries 6 and 7) were all tolerated under the
Table 2 Microwave-Assisted Copper-Catalyzed Coupling of Alkynes with Aryl Iodidesa
CuI(xantphos) (2–5 mol%)
Cs2CO3, DMF
R
Ar
Ar
+
I
R
135 °C, MW, 10–30 min
1
2
3
Yield (%)b
99
Entry
R
2
Product
1
2
Ph
4-MeC6H4I
4-H2NC6H4I
4-MeOC6H4I
4-ClC6H4I
4-BrC6H4I
2-iodothiophene
3-iodopyridine
PhI
3b
3c
3d
3e
3f
99c
70
82
87
Ph
3
Ph
4
Ph
5
Ph
53d
97
6
Ph
3g
3h
3i
7
Ph
87c
67
8
4-MeC6H4
4-MeOC6H4
4-F3CC6H4
3-H2NC6H4
3-ClC6H4
n-Bu
9
PhI
3j
99c
76
99
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
PhI
3k
3l
PhI
PhI
3m
3n
3o
3p
3q
3r
3s
75c
75
99
PhI
n-Bu
4-MeOC6H4I
4-H2NC6H4I
2-Et-6-MeC6H3I
4-MeC6H4I
3-iodopyridine
2-MeC6H4I
4-BrC6H4I
PhI
n-Bu
34c
76
74
63c
78
90
80
87
n-Bu
n-Bu
n-Bu
n-Bu
3t
n-Bu
3u
3v
3w
3x
3y
n-C8H17
n-C8H17
n-C8H17
n-C8H17
4-MeOC6H4I
4-MeC6H4I
2-MeC6H4I
42c
a Reaction conditions: [CuI(xantphos)] (0.01 mmol, 2 mol% for entries 1–12; 0.025 mmol, 5 mol% for entries 13–24), alkyne (0.75 mmol), aryl
iodide (0.5 mmol), base (1.0 mmol), DMF (0.5 mL), 10 min.
b Isolated yield.
c 30 min.
d [CuI(xantphos)] (0.025 mmol, 5 mol%), 10 min.
Synthesis 2012, 44, 1507–1510
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Microwave-Assisted Copper-Catalyzed Cross-Coupling
1509
reaction conditions. In general, alkyl alkynes were more
problematic than aryl alkynes for the copper-catalyzed
Sonogashira-type reaction.4a Good yields were obtained
when the reactions were carried out using 5 mol% catalyst
(Table 2, entries 13–24). Functional group tolerance was
evident in cases in which the substrate contained an un-
protected amine (Table 2, entry 2), a bromine (Table 2,
entry 5), or when nitrogen-containing heterocycles were
used. More importantly, the sterically demanding 2-iodo-
toluene could also be used as a coupling partner to provide
the products in moderate yields (Table 2, entries 19 and
24), and a 34% isolated yield was obtained when the reac-
tion was carried out with 2-ethyl-6-methyliodobenzene
(Table 2, entry 16).
Table 3 Microwave-Assisted Copper-Catalyzed Coupling of
Alkynes with Vinyl Halidesa
CuI(xantphos)
R2
(2 mol%)
X
Cs2CO3, DMF
R1
R2
+
R1
135 °C
MW, 30 min to 1 h
5
4
2
Entry
1
X
Product
Yield
(%)
I
I
5a
5b
57
t-Bu
t-Bu
We then turned our attention to the coupling of vinyl ha-
lides with alkynes, as illustrated in Table 3. A variety of
vinyl iodides reacted with alkynes, giving the correspond-
ing enynes in good to excellent yield. Interestingly, 1-(2-
bromovinyl)benzene could also be used as a substrate for
this system, giving the enynes in good yields (Table 3, en-
tries 11 and 12).
61b
2
OMe
3
4
I
I
5c
43
53
t-Bu
t-Bu
S
In summary, we have demonstrated that [CuI(xantphos)]
is an active catalyst for the microwave-assisted coupling
reaction of alkynes with aryl iodides, vinyl iodides and
bromides, giving the corresponding internal alkynes and
enynes in good to excellent yields.
5d
C8H17
5
6
7
I
I
I
5e
5f
80
All products are known compounds, with spectral data agreeing
with literature values. See the Supporting Information for details.
48b
67
n-Bu
Microwave-Assisted Copper-Catalyzed Coupling of Iodoben-
zene with Phenylacetylene; General Procedure for Table 1
A sealable vial equipped with a magnetic stir bar was charged with
base (1.0 mmol) and [CuI(xantphos)] (7.7 mg, 0.01 mmol) under a
nitrogen atmosphere. The aperture of the vial was then covered with
a rubber septum. Under a nitrogen atmosphere, phenylacetylene
(1a; 0.083 mL, 0.75 mmol), iodobenzene (2a; 0.056 mL, 0.5 mmol)
and solvent (0.5 mL) were added by using a syringe. The septum
was then replaced by a screw-cap containing a Teflon-coated sep-
tum, and the reaction vessel was placed under microwave irradia-
tion at 135 °C. After stirring at this temperature for 10 min, 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
(SiO2, hexane) to yield 3a.
5g
Ph
Ph
56b
40b
8
9
I
5h
5i
n-Bu
Br
36b
10
Br
5j
Microwave-Assisted Copper-Catalyzed Coupling of Alkynes
with Aryl Iodides; General Procedure for Table 2
n-Bu
A sealable vial equipped with a magnetic stir bar was charged with
Cs2CO3 (325 mg, 1.0 mmol) and [CuI(xantphos)] (7.69 mg, 0.01
mmol for aryl alkyne; 19.23 mg, 0.025 mmol for alkyl alkyne) un-
der a nitrogen atmosphere. The aperture of the vial was then covered
with a rubber septum. Under a nitrogen atmosphere, aryl or alkyl al-
kyne (1; 0.75 mmol), aryl iodide (2; 0.5 mmol) and DMF (0.5 mL)
were added by using a syringe. The septum was then replaced by a
screw-cap containing a Teflon-coated septum, and the reaction ves-
sel was placed under microwave irradiation at 135 °C. After stirring
at this temperature for 10–30 min, the heterogeneous mixture was
cooled to r.t. and diluted with EtOAc (20 mL). The resulting solu-
tion 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 (SiO2, hexane or hexane–
EtOAc) to yield alkyne 3.
a Reaction conditions: [CuI(xantphos)] (0.01 mmol, 2 mol% for aryl
alkyne; 0.025 mmol, 5 mol% for alkyl alkyne), alkyne (0.75 mmol),
vinyl iodide or bromide (0.5 mmol), Cs2CO3 (1.0 mmol), DMF (0.5
mL), 30 min.
b Reaction time: 1 h.
Microwave-Assisted Copper-Catalyzed Coupling of Alkynes
with Vinyl Halides; General Procedure for Table 3
A 4-mL sealable vial equipped with a magnetic stir bar was charged
with Cs2CO3 (325 mg, 1 mmol) and [CuI(xantphos)] (7.69 mg, 0.01
mmol for aryl alkyne; 19.23 mg, 0.025 mmol for alkyl alkyne) un-
der a nitrogen atmosphere. The aperture of the vial was then covered
with a rubber septum. Under a nitrogen atmosphere, alkenyl halide
(4; 0.5 mmol), aryl or alkyl alkyne (2; 0.75 mmol), and DMF (0.5
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1507–1510

1510
W.-T. Tsai et al.
SPECIAL TOPIC
mL) were added by using a syringe. The septum was then replaced
by a screw-cap containing a Teflon-coated septum, and the reaction
vessel was placed under microwave irradiation at 135 °C. After stir-
ring at this temperature for 30–60 min, the heterogeneous mixture
was cooled to r.t. 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 chroma-
tography (SiO2, hexane) to yield 5.
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Acknowledgment
Financial support by the National Science Council, Taiwan
(NSC99-2113-M-005-004-MY2) and the National Chung Hsing
University are gratefully acknowledged. We thank Prof. Fung-E
Hong for generously sharing his GC-MS instruments. C.F.L. is a
Golden-Jade Fellow of Kenda Foundation, Taiwan.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinIfatgnonmSorti
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npfurotIangSiuptor
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© Georg Thieme Verlag Stuttgart · New York