Copper-catalyzed cross-coupling of aryl iodides and aryl acetylenes using microwave heating

Article abstract of DOI:10.1016/j.tetlet.2004.02.124

An efficient copper-catalyzed cross-coupling of aryl iodides with aryl acetylenes under microwave irradiation is described. The reaction proceeds under microwave heating with 10mol% CuI and 2equiv Cs₂CO₃ in 43-87% yields.

Full text of DOI:10.1016/j.tetlet.2004.02.124

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3237–3239
Copper-catalyzed cross-coupling of aryl iodides and aryl acetylenes
using microwave heating
*
Huan He and Yong-Jin Wu
Department of Neuroscience Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA
Received 13 February 2004; accepted 25 February 2004
Abstract—An efficient copper-catalyzed cross-coupling of aryl iodides with aryl acetylenes under microwave irradiation is described.
The reaction proceeds under microwave heating with 10 mol % CuI and 2 equiv Cs CO in 43–87% yields.
2 3
Ó 2004 Elsevier Ltd. All rights reserved.
Biaryl alkynes moieties exist in a variety of natural and
unnatural products of biological and pharmaceutical
other metals normally require a stoichiometric amount
of the metal, thus producing concerns of cost efficiency
and toxicity. These concerns have been obviated in the
1
importance. These compounds include AGN-194310
Fig. 1), a RAR antagonist for the treatment of muco-
6
(
copper-free protocol using (allyl PdCl) , but there is
2
cutaneous toxicity currently in Phase III clinical trials,
as well as other compounds with potential as immuno-
modulators, antifungal, antipsoriatic, and antiar-
2
thritic agents.
still a pressing need for the development of methods for
catalytic coupling reactions using transition metals other
than palladium. Thus, Okuro et al. developed a CuI-
catalyzed coupling reaction of aryl and vinyl halides
2
3
1
7
with terminal alkynes. However, this reaction required
the addition of triphenylphosphine and extended reac-
The most widely used method for constructing biaryl
alkynes involves cross-coupling of aryl halides with
7
tion time (80–120 °C, 10–40 h). Recently, Wang et al.
reported a microwave-assisted version of this reaction.
4
8
terminal aryl acetylenes. Sonogashira et al. first
reported the palladium/copper-catalyzed cross-coupling
of aryl halides with terminal acetylenes. Recent
advances of Sonogashira reaction include development
of conditions with metals other than copper and a
6
copper-free protocol. Unfortunately, procedures with
Herein, we wish to report an efficient microwave-
assisted copper-catalyzed cross-coupling reaction of aryl
iodides with terminal alkynes that, unlike the Wang
procedure, does not require addition of any ligands.
5
A typical procedure involves irradiation of a mixture of
aryl iodide (1), aryl acetylene (2), catalytic CuI
(
10 mol %), and 2 equiv of Cs CO in N-methylpyrro-
2 3
O
O
lidinone (NMP) under microwave at 195 °C for 2–6 h
followed by purification of the crude products by silica
gel flash chromatography (Table 1). The isolated yields
of coupling products 3a–o ranged from 43% to 87%.
9
10
For example, the coupling reaction of 1-tert-butyl-4-
iodo-benzene with 1-ethnyl-2-fluorobenzene (Table 1,
entry h) provided an 87% yield of product under
microwave conditions. When the same reaction was
carried out using a preheated oil bath under otherwise
identical conditions (10 mol % CuI, 2 equiv Cs CO ,
S
AGN-194310
Figure 1.
2
3
1
95 °C, 2.5 h), a lower yield (71%) was obtained.
Keywords: Microwave; Aryl acetylenes; Cross-coupling; Aryl iodide.
*
Corresponding author. Tel.: +1-203-677-6605; fax: +1-203-677-7884;
e-mail: huan.he@bms.com
Without CuI catalysis, no reaction occurred under
microwave irradiation. In the absence of Cs CO , only
2
3
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.124

3238
H. He, Y.-J. Wu / Tetrahedron Letters 45 (2004) 3237–3239
Table 1. Cross-coupling of aryl iodides with aryl acetylenes
Table 1 (continued)
Entry Ar–I (1)
Alkynes (2)
Reac- Yield %
cat. CuI
Cs CO3
NMP
microwave
heating
tion
time
(h)
(3a–o)
2
R
R
Ar
I
1
2
3a-o
Ar
t-Bu
m
2
6
72
79
Entry Ar–I (1)
Alkynes (2)
Reac- Yield %
I
I
tion
time
(3a–o)
t-Bu
N
(
h)
n
t-Bu
a
4
2
76
71
t-Bu
N
I
o
4
79
OMe
I
NC
b
I
OMe
OMe
OMe
OMe
5
% conversion was observed as indicated by HPLC
analysis of the reaction mixture. Thus, the CuI catalyst
and Cs CO play critical roles in this coupling reaction.
2
3
c
3
2
2
68
54
43
For the aryl iodide component, a variety of functional
groups were tolerated, although lower yields were
obtained with ester and ketone derivatives (entries d and
e), presumably due to degradation of the starting
materials under the basic reaction conditions. For the
aryl acetylenes, electron-withdrawing and electron-neu-
tral groups generally provided slightly higher yields than
those with electron-donating groups (entries f, g, h, and
k vs a and l). This may be ascribed to the reduced acidity
of aryl acetylenes with electron-donating substituents.
Fluoro-, chloro-, and bromo-phenylacetylenes were well
tolerated (entries h–j) under these microwave condi-
tions, thus providing coupling products suitable for
further functionalization. Decreasing isolated yields
(entries h>i>j) were observed with increasing sizes of
ortho-halogens (F<Cl<Br). Of particular interest is
the finding that coupling of 4-ethynyl-phenylamine with
1
of the desired product 3l along with 10% yield of
di-arylamine 4 due to further N-arylation of 3l (Scheme 1).
Thus, the coupling of aryl iodides appears to be selective
with phenylacetylenes over the N-arylation of phenyl-
amines. When 1-ethynyl-4-nitrobenzene was treated
with 1-tert-butyl-4-iodo-benzene for 2 h, we observed
MeO
I
EtO C
2
d
I
O
e
I
t-Bu
f
2.5
85
83
87
I
t-Bu
-tert-butyl-4-iodo-benzene (entry l) furnished 78% yield
g
4
F
I
I
t-Bu
h
2.5
F
8
0% starting material along with 20% of the reduced
product. Thus, nitro group does not seem to be tolerated
under these conditions. In addition to phenyl acetylenes,
we also investigated pyridyl acetylenes (entries n and
o). Both 2- and 3-ethynyl-pyridines worked well but
required longer reaction time (4–6 h) to go to comple-
tion.
t-Bu
i
2.5
2.5
2
72
63
81
78
Cl
Br
I
I
I
I
t-Bu
j
Other variations of this reaction were briefly investi-
gated. Alkyl alkynes may not be suitable as no reaction
was observed with aryl iodides and benzylacetylene or
trimethyl-prop-2-ynyl-silane. In addition, sluggish reac-
tions were observed with aryl bromides. For example,
only 5% conversion was observed after 4 h microwave
heating with 1-bromo-4-tert-butyl-benzene and 1-eth-
nyl-2-fluorobenzene compared with the 87% yield
obtained with the aryl iodide (entry h). Use of NaOt-Bu
instead of Cs CO increased the conversion to 20% after
t-Bu
k
F3C
t-Bu
l
2
NH2
2
3

H. He, Y.-J. Wu / Tetrahedron Letters 45 (2004) 3237–3239
3239
CuI
2
CS CO3
NH2
3l (78%)
NMP
Microwave
I
NH2
+
1
95 °C
2
h
N
H
4
(10%)
Scheme 1. Synthesis of 3l.
4 h, but also increased the extent of the oligomerization
of 1-ethnyl-2-fluorobenzene.
1566–1568; (c) Negishi, E.; Anastasia, L. Chem. Rev. 2003,
03, 1979–2017.
. Soheili, A.; Albaneze-Walker, J.; Murry, J.; Dormer, P.;
Hughes, D. Org. Lett. 2003, 5, 4191–4194.
. Okuro, K.; Furuune, M.; Miura, M.; Nomura, M.
Tetrahedron Lett. 1992, 33, 5363–5364.
. Wang, J.; Liu, Z.; Hu, Y.; Wei, B.; Kang, L. Synth.
Commun. 2002, 32, 1937–1945.
11
1
6
7
8
9
In summary, we have developed an operationally simple
and efficient methodology for the copper-catalyzed
cross-coupling reactions of aryl iodides with aryl acet-
ylenes using microwave heating.
. Representative procedure: To a solution of 1-tert-butyl-4-
iodo-benzene (130 mg, 0.5 mmol) and 1-ethnyl-2-fluoro-
benzene (63 mg, 0.53 mmol) in N-methylpyrrolidinone
(
0.67 mL) in a microwave vial were added cesium carbon-
ate (325 mg, 1.0 mmol), and copper(I) iodide (9 mg,
.05 mmol). The vial was sealed and heated in a Smith
Acknowledgement
0
We thank Dr. Joanne Bronson for critical reading of the
manuscript.
Creator at 195 °C for 2.5 h. The temperature of the
contents of the vessel was monitored using a calibrated
infrared temperature control mounted under the reaction
vessel. The reaction mixture was cooled down to room
temperature and purified by silica gel flash chromato-
References and notes
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1
crystalline material (107 mg, 87% yield). H NMR (CDCl
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,
1
2
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data in agreement with the indicated structure.
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