Copper-catalyzed coupling of aryl halides with terminal alkynes in the presence of KF/Al2O3

Article abstract of DOI:10.1080/00397910902964882

A convenient catalyst system consisting of copper iodide, L-proline, and potassium fluoride/Al₂O₃ was effective for the coupling reaction of aryl iodides and bromides with terminal alkynes. In contrast to the conventional Sonogashira

Full text of DOI:10.1080/00397910902964882

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Copper-Catalyzed Coupling of Aryl
Halides with Terminal Alkynes in the
Presence of KF/Al2O3
Rahman Hosseinzadeh a , Maryam Mohadjerani b , Rahmatollah
Tavakoli a & Mohammad Alikarami a
a Department of Organic Chemistry, Faculty of Chemistry,
Mazandaran University, Babolsar, Iran
b Department of Biology, Faculty of Science, Mazandaran University,
Babolsar, Iran
Available online: 29 Dec 2009
To cite this article: Rahman Hosseinzadeh, Maryam Mohadjerani, Rahmatollah Tavakoli & Mohammad
Alikarami (2009): Copper-Catalyzed Coupling of Aryl Halides with Terminal Alkynes in the Presence of
KF/Al2O3 , Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:2, 282-288
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Synthetic Communications1, 40: 282–288, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902964882
COPPER-CATALYZED COUPLING OF ARYL
HALIDES WITH TERMINAL ALKYNES IN THE
PRESENCE OF KF/Al2O3
Rahman Hosseinzadeh,1 Maryam Mohadjerani,2
Rahmatollah Tavakoli,1 and Mohammad Alikarami1
1Department of Organic Chemistry, Faculty of Chemistry,
Mazandaran University, Babolsar, Iran
2Department of Biology, Faculty of Science, Mazandaran University,
Babolsar, Iran
A convenient catalyst system consisting of copper iodide, L-proline, and potassium fluoride/
Al2O3 was effective for the coupling reaction of aryl iodides and bromides with terminal
alkynes. In contrast to the conventional Sonogashira reactions, the new procedure is free
of palladium and phosphines. Different functionalized aryl halides were coupled with
terminal alkynes using this system in good to excellent yields.
Keywords: Aryl halides; copper iodide; coupling reaction; KF=Al2O3; Sonogashira reaction; terminal
alkynes
INTRODUCTION
The Sonogashira reaction of terminal alkynes with aryl or vinyl halides has
received great attention in organic synthesis because molecules containing a carbon–
carbon triple-bond moiety are widely used for various functional organic materials,
biologically important molecules, and their intermediates.[1,2] The most commonly
used catalytic system for this transformation is a palladium complex combined with
a phosphine ligand and copper iodide (CuI).[3,4] However, many phosphine ligands
are expensive and air-sensitive, which hampered the applications of the palladium-
based catalytic system for industrial use.[5,6] In view of the high prices of palladium
complexes, chemists aimed to use of copper(I) alone as the catalyst for the coupling
of aryl halides and terminal alkynes.[7,8] In this way, the low cost of copper-based
catalytic systems makes them particularly attractive for potential large-scale indus-
trial applications. However, the application of potassium fluoride (KF)=Al2O3 to
organic synthesis has provided new methods for a wide array of organic reactions,
many of which are staples of synthetic organic chemistry.[9] Its benefits include its
strongly basic character, which has led to it replacing organic bases in a number
Received March 16, 2009.
Address correspondence to Rahman Hosseinzadeh, Department of Organic Chemistry, Faculty of
Chemistry, Mazandaran University, Babolsar, Iran. E-mail: r.hosseinzadeh@umz.ac.ir
282

COUPLING REACTION OF ARYL HALIDES AND ALKYNES
283
Scheme 1. Copper-catalyzed coupling reaction of aryl halides with terminal alkynes.
of reactions.[10] In many cases, the use of this base provides milder conditions and
simpler procedures than previously reported methods. KF=Al2O3 as a base in the
presence of CuI was chosen because we recently used this system for C–N[11] and
C–O[12] bond formation. Very recently, simple amino acids have been used as ligand
for Cu-catalyzed cross-coupling reactions between aryl halides and diverse nucleo-
philes.[7b,13] The amino acid–mediated coupling reactions are advantageous because
they are cheap and safe to use as ligand and easily removable after the reaction, as
they are very soluble in water. We joined the copper iodide and KF=Al2O3 with
L-proline as an efficient and simple catalyst system to obtain good to excellent yield
of the alkynes from the reaction of aryl iodides and bromides with terminal alkynes
(Scheme 1).
To find the optimum conditions, we used the cross-coupling reaction of
4-iodoanisole and phenylacetylene in the presence of various ligands, CuI, and
KF=Al2O3 as a model reaction. Variation of solvent, temperature, and molar ratio
of the substrates revealed that a molar ratio of 1:1.2,4-iodoanisole to phenylacetylene
and CuI (10 mol%), ligand (30 mol%), and KF=Al2O3 (5 equivalents) in dimethylfor-
mamide (DMF) at 110ꢀC gives the greatest yield of the 1-(4-methoxylphenyl)
phenylacetylene. Of the ligands tested (L-proline, glycine, thriphenylphosphine,
ethylene glycol, and 1,10-phenanthroline), L-proline proved to be the best ligand.
In addition, when we carried out this coupling reaction under optimum conditions
in the presence of KF as base instead of KF=Al2O3, the coupling of 4-iodoanisole
with phenylacetylene had a much lower yield. To show the generality of this method,
we subjected a series of aryl iodides and bromides to these reaction conditions, and
the results are summarized in Table 1.
As can be seen in Table 1, either electron-deficient or electron-rich aryl iodides
reacted with phenyl acetylene to give the corresponding cross-coupling products in
74–88% yields (entries 1–6). Similarly 1-iodonaphthalene and 2-iodothiophene with
phenyl acetylene gave the desired products in good yields (entries 7 and 8). More
important, we were pleased to observe that aryl bromides also worked well for this
reaction, although greater catalyst loading (15 mol% CuI and 45 mol% L-proline)
was required to obtain satisfactory yields (entries 9–12). Substituent effects indicate
that the reaction is relatively insensitive to the electronic characteristics of a substitu-
ent as well as its location. Aliphatic alkynes were also suitable substrates for this
reaction besides aryl alkynes. For examples, 1-hexyne coupled with aryl iodides in
good yields to provide aliphatic alkynes (entries 13–16).
In conclusion, we have developed an operationally simple and efficient method
for the Cu-catalyzed coupling of a variety of aryl halides with terminal alkynes using
KF=Al2O3 as a base, CuI as the catalyst, and L-proline as the ligand. The reaction is
an inexpensive alternative to the palladium-catalyzed process and results in good
yields of the desired products.

284
R. HOSSEINZADEH ET AL.
Table 1. Copper-catalyzed coupling of aryl halides with terminal alkynesa
Time Yield
(%)b
Entry
1
Aryl halide
Alkyne
Product
(h)
10
82
2
3
4
5
6
10
10
10
10
6
80
74
87
85
88
7
10
78
8
9
8
24
24
90
55
62
10
11
12
24
24
60
65
(Continued )

COUPLING REACTION OF ARYL HALIDES AND ALKYNES
285
Table 1. Continued
Time Yield
(%)b
Entry
13
Aryl halide
Alkyne
Product
(h)
15
76
14
15
16
15
15
15
72
70
74
aReaction conditions: Aryl iodide (1 mmol), alkyne (1.2 mmol), CuI (0.1 mmol), L-proline (0.3 mmol),
KF=Al2O3 (5 mmol) in 5 mL of DMF, 110ꢀC; or aryl bromide (1 mmol), alkyne (1.2 mmol), CuI
(0.15 mmol), L-proline (0.45 mmol), KF=Al2O3 (5 mmol) in 5 mL of DMF, 110ꢀC.
bIsolated yield; products were characterized by 1H NMR and mp.
EXPERIMENTAL
Melting points were recorded on an electrothermal melting-point apparatus
and are uncorrected. The NMR spectra were recorded in CDCl3 with tetramethylsi-
lane (TMS) as an internal standard on Bruker Advance DPX 500-MHz (GmbH,
Germany) and Bruker DRX 300-MHz NMR spectrometers. Purity determination
of the products was accomplished by thin-layer chromatography (TLC) on silica-gel
polygram SIL G=UV 254 plates. Products were identified by the comparison of their
1
melting points and H NMR spectra with those reported for authentic samples.
General Procedure for the Reaction
A mixture of aryl halide (1 mmol), alkyne (1.2 mmol), CuI (10 mol% for aryl
iodides and 15 mol% for aryl bromides), L-proline (30 mol% for aryl iodides and
45 mol% for aryl bromides), KF=Al2O3 (5 equivalents), and DMF (5 ml) was stirred
at 110ꢀC for the desired time. The progress of the reaction was monitored by TLC.
After completion of the reaction, diethyl ether was poured into the mixture and
filtered off. The filtrate washed with water, the organic phase was dried with anhy-
drous MgSO4 and evaporated under vacuum, and the residue was purified by column
chromatography on silica gel using hexane as eluent to afford the pure product.
Selected Data for Products
Diphenylacetylene. Mp 58–60ꢀC (lit.[14] 60–62ꢀC); 1H NMR (300 MHz,
CDCl3): d 7.56–7.51 (m, 4H), 7.35–7.32 (m, 6H).

286
R. HOSSEINZADEH ET AL.
1
1-(4-Methoxylphenyl)phenylacetylene. Mp 56–57ꢀC (lit.[7b] 58–60ꢀC); H
NMR (500 MHz, CDCl3): d 7.57–7.51 (m, 4H), 7.40–7.30 (m, 3H), 6.93–6.92 (m,
2H), 3.88 (s, 3H).
1-(2-Methoxylphenyl)phenylacetylene. Oil;[7b] 1H NMR (300 MHz,
CDCl3): d 7.59–7.53 (m, 3H), 7.35–7.31 (m, 4H), 7.00–6.91 (m, 2H), 3.93 (s, 3H).
1-(4-Methylphenyl)phenylacetylene. Mp 73–74ꢀC (lit.[14] 71–73ꢀC); 1H
NMR (300 MHz, CDCl3): d 7.56–7.49 (m, 2H), 7.47 (d, J ¼ 8.4 Hz, 2H), 7.38–7.35
(m, 3H), 7.19 (d, J ¼ 8.4 Hz, 2H), 2.38 (s, 3H).
1-(2-Methylphenyl)phenylacetylene. Oil;[8b] 1H NMR (500 MHz, CDCl3):
d 7.61–7.60 (m, 2H), 7.57 (d, J ¼ 7.5 Hz, 1H), 7.44–7.38 (m, 3H), 7.30 (d, J ¼ 3.9 Hz,
2H), 7.25–7.22 (m, 1H), 2.59 (s, 3H).
1-(4-Chlorophenyl)phenylacetylene. Mp 78–80ꢀC (lit.[7a] 81–82ꢀC); 1H
NMR (500 MHz, CDCl3): d 7.59–7.57 (m, 2H), 7.52–7.50 (m, 2H), 7.42–7.37 (m, 5H).
1-(Phenylethynyl)naphthalene. Oil;[7a] 1H NMR (300 MHz, CDCl3): d 8.46
(d, J ¼ 8.2 Hz, 1H), 7.87 (t, J ¼ 7.5 Hz, 2H), 7.78 (d, J ¼ 7.1 Hz, 1H), 7.68–7.40
(m, 8H).
2-(Phenylethynyl)thiophene. Mp 50–52ꢀC (lit.[14] 52–54ꢀC); 1H NMR
(500 MHz, CDCl3): d 7.54–7.50 (m, 2H), 7.33–7.24 (m, 5H), 7.09–7.07 (m, 1H).
1-(4-Acetylphenyl)phenylacetylene. Mp 94–95ꢀC (lit.[14] 95–96ꢀC); 1H
NMR (300 MHz, CDCl3): d 7.92 (d, J ¼ 8.4 Hz, 2H), 7.59 (d, J ¼ 8.4 Hz, 2H),
7.55–7.52 (m, 2H), 7.37–7.34 (m, 3H), 2.58 (s, 3H).
1-Phenyl-1-hexyne. Oil;[15] 1H NMR (500 MHz, CDCl3): d 7.45–7.43 (m,
2H), 7.33–7.30 (m, 3H), 2.46 (t, J ¼ 7.1 Hz, 2H), 1.66–1.62 (m, 2H), 1.56–1.51 (m,
2H), 1.00 (t, J ¼ 7.3 Hz, 3H).
1-(4-Methoxylphenyl)-1-hexyne. Oil;[15] 1H NMR (300 MHz, CDCl3): d
7.34 (d, J ¼ 9.0 Hz, 2H), 6.81 (d, J ¼ 9.0 Hz, 2H), 3.80 (s, 3H), 2.40 (t, J ¼ 6.9 Hz,
2H), 1.62–1.45 (m, 4H), 0.96 (t, J ¼ 7.2 Hz, 3H).
1-(2-Methoxylphenyl)-1-hexyne. Oil;[16] 1H NMR (300 MHz, CDCl3): d
7.38 (d, J ¼ 7.4 Hz, 1H), 7.25 (t, J ¼ 8.0 Hz, 1H), 6.91–6.84 (m, 2H), 3.88 (s, 3H),
2.49 (t, J ¼ 6.9 Hz, 2H), 1.67–1.44 (m, 4H), 0.96 (t, J ¼ 7.1 Hz, 3H).
1-(4-Methylphenyl)-1-hexyne. Oil;[15] 1H NMR (500 MHz, CDCl3): d 7.33
(d, J ¼ 7.2 Hz, 2H), 7.12 (d, J ¼ 7.8 Hz, 2H), 2.44 (t, J ¼ 7.1 Hz, 2H), 2.37 (s, 3H),
1.65–1.60 (m, 2H), 1.56–1.52 (m, 2H), 0.99 (t, J ¼ 7.3 Hz, 3H).
ACKNOWLEDGMENT
Financial support of this work from the Research Council of Mazandaran
University is gratefully acknowledged.

COUPLING REACTION OF ARYL HALIDES AND ALKYNES
287
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