Sonogashira Coupling Reaction with Palladium Powder, Potassium Fluoride in Aqueous Media

Article abstract of DOI:10.1081/SCC-120025176

A Sonogashira coupling reaction of aromatic iodides and bromides with terminal alkynes in the presence of palladium powder, potassium fluoride, cuprous iodide, and triphenylphosphine in aqueous media was developed. The reaction generates the corresponding

Full text of DOI:10.1081/SCC-120025176

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Sonogashira Coupling Reaction with Palladium Powder,
Potassium Fluoride in Aqueous Media
Lei Wang a b & Pinhua Li a
a Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui, P.R. China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai, P.R. China
Published online: 16 Aug 2006.
To cite this article: Lei Wang & Pinhua Li (2003): Sonogashira Coupling Reaction with Palladium Powder, Potassium Fluoride in
Aqueous Media, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:21, 3679-3685
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 21, pp. 3679–3685, 2003
Sonogashira Coupling Reaction with Palladium
Powder, Potassium Fluoride in Aqueous Media
1
Lei Wang1,2, and Pinhua Li
*
1Department of Chemistry, Huaibei Coal Teachers
College, Huaibei, Anhui, P.R. China
2State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai, P.R. China
ABSTRACT
A Sonogashira coupling reaction of aromatic iodides and bromides
with terminal alkynes in the presence of palladium powder, potassium
fluoride, cuprous iodide, and triphenylphosphine in aqueous media
was developed. The reaction generates the corresponding coupling
products aryl alkynes in good to excellent yields.
The palladium catalyzed carbon-carbon cross-coupling of organo-
metallics with organoelectrophiles is an important synthetic reaction in
*Correspondence: Lei Wang, Department of Chemistry, Huaibei Coal Teachers
College, Huaibei, Anhui 235000, P.R. China; State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, P.R. China.
3679
DOI: 10.1081/SCC-120025176
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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3680
Wang and Li
organic synthesis.[1] Most organometallic compounds are sensitive to
air, moisture, or are toxic and often will not tolerate functional groups
which may be important in complex syntheses. The Sonogashira coupling
reaction of terminal alkynes and aryl or alkenyl halides is an efficient
route to aryl alkynes.[2–7] Numerous applications to natural product
syntheses have been reported by using Sonogashira coupling reaction,
including the construction of complex enediyne antibiotics.[8–13] The
classic Sonogashira reaction is generally carried out in organic solvent
such as amines, benzene, and DMF along with complex palladium
catalysts which are soluble in these solvents. These soluble palladium
reagents tend to be expensive and sometimes difficult to manipulate
and recover. The solvents also pose recyclability (waste handling) prob-
lems of their own. In addition, amine such as piperidine, diethylamine,
and triethylamine are required in most Sonogashira reaction and they
have a bad smell and add to the environmental burden. We recently
reported that an energy efficient modification of the Sonogashira reaction
by using palladium powder doped on the mixture of potassium fluoride
and alumina under solventless reaction conditions, but the reaction is
limited to aromatic iodides.[14]
Here, we wish to report a Sonogashira coupling reaction of aromatic
or alkenyl iodides and bromides with terminal alkynes in the presence of
palladium powder, potassium fluoride, cuprous iodide, and triphenylphos-
phine in aqueous media, which produces the corresponding coupling
products aryl alkynes in good to excellent yields.
Pd-CuI-PPh3-KF
R1
X = I, Br
+
R2
R2
X
H
R1
THF-H2O
Our initial attempt explored the reaction conditions for Sonogashira
coupling reaction of terminal alkynes with aromatic halides. The results
shown that the coupling reaction requires a base for the Sonogashira
coupling reaction in aqueous media. Among the inorganic bases we
tested, potassium fluoride was most effective. The palladium powder,
triphenylphosphine and cuprous iodide were found to be essential in this
reaction. The best reaction conditions for the Sonogashira coupling
were found to be Pd (10 mg, 0.094 mmol, 99.9þ% as a submicron
powder), CuI (10 mg, 0.053 mmol), PPh3 (100 mg, 0.379 mmol),
KF (236 mg, 4.00 mmol), terminal alkyne (1.00 mmol), aryl halide
(1.00 mmol), THF-H2O (3/1, v/v, 6 mL), reaction temperature (60ꢀC),
and reaction time (8 h).

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Sonogashira Coupling Reaction
3681
Table 1 summarizes the experimental results of Sonogashira coupling
reaction. A variety of aromatic iodides were successfully coupled with
aromatic terminal alkynes and aliphatic terminal alkynes to produce the
corresponding aryl alkynes in excellent yields. Meanwhile, heteroaromatic
iodide and vinyl iodide went smoothly to couple with terminal alkynes to
generate the desired coupling products. Aryl bromides also reacted with
terminal alkynes to form the coupling products in good yields. However,
aryl chloride and aryl fluoride did not react with terminal alkynes under
reaction conditions and the starting materials are recovered unchanged.
Substituent effects were investigated. The results indicated that the
electronic characteristics of a general electron-donating group (such as
CH3O, (CH3)2N, CH3) or a general electron-withdrawing group (such as
CH3CO, F) on the aromatic ring were relatively insensitive to the coupling
reaction. Very strong electron-withdrawing group (such as NO2) on the
aromatic ring also led to a good yield of coupling product. It is interesting
Table 1. Sonogashira coupling reaction of organic
halides with terminal alkynes.
Yielda
(%)
Entry
R1X
R2
a
b
c
C6H5I
C6H5Br
n-C8H17
n-C8H17
n-C6H13
C6H5
94
78
91
95
93
81
90
76
92
94
93
84
87
90
C6H5I
C6H5I
d
e
p-CH3C6H4I
p-CH3C6H4Br
p-CH3OC6H4I
p-CH3OC6H4Br
o-FC6H4I
n-C8H17
n-C8H17
n-C8H17
n-C8H17
n-C8H17
C6H5
f
g
h
i
j
p-FC6H4I
k
m
n
o
p-CH3COC6H4I
p-CH3COC6H4Br
p-NO2C6H4I
o-(CH3)2NC6H4I
C6H5
C6H5
C6H5
C6H5
p
C6H5
C6H5
86
I
S
I
Cl
q
90
aIsolated yields.

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Wang and Li
to note that a bulky group on the ortho-position of the aromatic ring did
not inhibit the reaction (Entry o).
It is important to note that the palladium powder can be recovered
and recycled by a simple decantation of the reaction solution. In one
series of experiments, we carried out six consecutive preparation of
1-phenyl-1-decyne with no significant loss in product yields.
In conclusion, a reliable and practical procedure for the synthesis of
arylacetylenes via a Sonogashira coupling reaction was developed which
involves the use of potassium fluoride, palladium powder, cuprous iodide,
and triphenylphosphine in aqueous media. The significant advantages
of the procedure are operational simplicity, mild reaction conditions,
excellent yields, and cleaner reaction media.
EXPERIMENTAL
Melting points were recorded on a WRS-1A melting point apparatus
1
and are uncorrected. All H NMR and 13C NMR spectra were recorded
on a 300 MHz Bruker AZ 300 spectrometer. Chemical shift are given as ꢀ
value with reference to tetramethylsilane (TMS) as internal standard.
GC/MS data were obtained by using a Hewlett-Packard 6890 series
GC equipped with a 5983 mass selective detector. The reagents were
received from commercial supply without purification prior to use.
Products were purified by flash column chromatography.
General Procedure for Sonogashira Reaction of Aryl or
Alkenyl Halides with Terminal Alkynes
Aryl or alkenyl iodide or bromide (1.00 mmol) and terminal alkyne
(1.00 mmol) were added to a mixture of KF (236 mg, 4.00 mmol),
palladium powder (10 mg, 0.094 mmol, 99.9þ% as a submicron
powder), cuprous iodide (10 mg, 0.053 mmol), and triphenylphosphine
(100 mg, 0.376 mmol) contained in a clean round-bottomed flask with
THF-H2O (3/1, v/v, 6 mL) solution. The mixture solution was stirred
at 60ꢀC for 8 h on an oil bath. After cooling, ether (10 mL) was added
to extract the products. After the organic layer was dried with anhydrous
sodium sulfate, the solvents were evaporated under reduced pressure. The
product was purified by flash chromatography to yield the desired aryl
alkyne.

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Sonogashira Coupling Reaction
3683
1-Phenyl-1-decyne. Oil.[15] 1H NMR (CDCl3): ꢀ 7.41–7.39 (m, 2H),
7.28–7.24 (m, 3H), 2.37 (t, J ¼ 6.99 Hz, 2H), 1.64–1.55 (m, 2H),
1.45–1.32 (m, 10H), 0.88 (t, J ¼ 6.44 Hz, 3H). 13C NMR (CDCl3):
ꢀ 131.4, 128.1, 127.4, 124.2, 90.2, 80.5, 31.8, 29.2, 29.1, 28.9, 28.8, 22.8,
19.3, 14.0. MS m/z (%): 214 (Mþ, 11), 171 (3), 157 (20), 143 (55), 129 (69),
115 (100), 91 (41).
1-Phenyl-1-octyne. Oil.[16] 1H NMR (CDCl3): ꢀ 7.42–7.38 (m, 2H),
7.29–7.25 (m, 3H), 2.38 (t, J ¼ 6.95 Hz, 2H), 1.68–1.59 (m, 2H),
1.51–1.36 (m, 6H), 0.89 (t, J ¼ 6.72 Hz, 3H). 13C NMR (CDCl3): ꢀ 131.6,
128.0, 127.4, 124.1, 90.3, 80.6, 31.6, 28.8, 22.7, 19.4, 14.1. MS m/z (%):
186 (Mþ, 23), 157 (18), 143 (59), 129 (60), 115 (100), 91 (35).
Diphenylacetylene. M.p.: 59–61ꢀC (Lit.[17] 60–62ꢀC). 1H NMR
(CDCl3): ꢀ 7.56–7.53 (m, 4H), 7.34–7.30 (m, 6H). 13C NMR (CDCl3): ꢀ
131.5, 128.2, 128.1, 123.2, 89.2. MS m/z (%): 178 (Mþ, 100), 152 (20), 126
(9), 89 (15).
1-(4-Methylphenyl)-1-decyne. Oil.[17] 1H NMR (CDCl3): ꢀ 7.30 (d,
J ¼ 7.95 Hz, 2H), 7.10 (d, J ¼ 7.55 Hz, 2H), 2.36 (t, J ¼ 7.69 Hz, 2H),
2.30 (s, 3H), 1.62–1.57 (m, 2H), 1.43–1.29 (m, 10H), 0.89 (t, J ¼ 6.47 Hz,
3H). 13C NMR (CDCl3): ꢀ 137.1, 131.5, 128.7, 121.0, 89.4, 80.5, 31.9, 29.2,
29.1, 28.9, 28.8, 22.9, 21.3, 19.4, 14.1. MS m/z (%): 228 (Mþ, 19), 185 (4),
171 (10), 157 (32), 143 (35), 131 (100), 115 (20), 91 (14).
1-(4-Methoxylphenyl)-1-decyne. Oil.[17] 1H NMR (CDCl3): ꢀ 7.31
(d, J ¼ 8.74 Hz, 2H), 6.90 (d, J ¼ 8.75 Hz, 2H), 3.76 (s, 3H), 2.34
(t, J ¼ 7.05 Hz, 2H), 1.65–1.57 (m, 2H), 1.45–1.27 (m, 10H), 0.88 (t, J ¼
6.08 Hz, 3H). 13C NMR (CDCl3): ꢀ 159.1, 132.9, 116.4, 113.9, 88.8, 80.2,
55.2, 31.8, 29.2, 29.1, 28.9, 22.2, 19.4, 14.1. MS m/z (%): 244 (Mþ, 19), 201
(5), 188 (24), 173 (30), 159 (31), 147 (100), 121 (35), 115 (20), 91 (14).
1-(2-Fluorophenyl)-1-decyne. Oil.[17] 1H NMR (CDCl3): ꢀ 7.41–7.36
(m, 1H), 7.28–7.19 (m, 1H), 7.04–6.98 (m, 2H), 2.45 (t, J ¼ 6.87 Hz,
2H), 1.65–1.57 (m, 2H), 1.48–1.32 (m, 10H), 0.88 (t, J ¼ 6.38 Hz, 3H).
13C NMR (CDCl3): ꢀ 162.5 (d, J ¼ 248.2 Hz), 133.5, 129.0 (d, J ¼ 7.5 Hz),
123.7 (d, J ¼ 3.5 Hz), 115.3 (d, J ¼ 21.7 Hz), 112.6 (d, J ¼ 15.5 Hz), 95.9
(d, J ¼ 3.1 Hz), 74.0, 31.9, 29.2, 29.1, 28.9, 28.6, 22.7, 19.5, 14.0. MS m/z
(%): 232 (Mþ, 50), 175 (34), 161 (75), 147 (66), 133 (100), 109 (58).
1-(4-Fluorophenyl)phenylacetylene. M.p.: 108–109ꢀC (Lit.[17] 108–
110ꢀC). 1H NMR (CDCl3): ꢀ 7.54–7.48 (m, 4H), 7.38–7.35 (m, 3H),
7.09–7.01 (m, 2H). 13C NMR (CDCl3): ꢀ 162.4 (d, J ¼ 248.0 Hz), 133.5
(d, J ¼ 8.8 Hz), 131.5, 128.4, 123.1, 119.3 (d, J ¼ 5.8 Hz), 115.7
(d, J ¼ 22.5 Hz), 89.1, 88.3. MS m/z (%): 196 (Mþ, 100), 175 (11), 144
(7), 98 (16).
1-(4-Acetylphenyl)phenylacetylene. M.p.: 95–97ꢀC (Lit.[17] 95–96ꢀC).
1H NMR (CDCl3): ꢀ 7.92 (d, J ¼ 8.44 Hz, 2H), 7.60 (d, J ¼ 8.41 Hz, 2H),

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Wang and Li
7.54–7.52 (m, 2H), 7.37–7.35 (m, 3H), 2.60 (s, 3H). 13C NMR (CDCl3): ꢀ
197.1, 136.0, 131.7, 131.6, 128.6, 128.4, 128.2, 128.1, 122.7, 92.6, 88.7, 26.5.
MS m/z (%): 220 (Mþ, 62), 205 (100), 176 (51), 151 (21), 102 (11), 88 (22).
1-(4-Nitrophenyl)phenylacetylene. M.p.: 120–121ꢀC (Lit.[17] 120–
122ꢀC). 1H NMR (CDCl3): ꢀ 8.22 (d, J ¼ 8.84 Hz , 2H), 7.65 (d,
J ¼ 8.71 Hz, 2H), 7.56–7.52 (m, 2H), 7.38–7.36 (m, 3H), 2.58 (s, 3H).
13C NMR (CDCl3): ꢀ 146.8, 132.2, 131.7, 130.2, 129.2, 128.4, 123.6,
122.0, 94.7, 87.5. MS m/z (%): 223 (Mþ, 100), 193 (42), 176 (80), 165
(31), 151 (44), 139 (10), 126 (15).
N,N-Dimethyl-2-(phenylethynyl)benzeneamine. M.p.: 46–48ꢀC (Lit.[17]
46–47ꢀC). H NMR (CDCl3): ꢀ 7.56–7.48 (m, 3H), 7.36–7.20 (m, 4H),
1
6.91–6.86 (m, 2H), 2.98 (s, 6H). 13C NMR (CDCl3): ꢀ 154.5, 134.2,
131.2, 129.1, 128.2, 127.9, 123.7, 120.2, 116.8, 114.8, 94.5, 89.0, 43.3.
MS m/z (%): 220 (Mþ, 100), 204 (23), 178 (20), 144 (70).
2-Phenylethynylthiophene. M.p.: 51–53ꢀC (Lit.[17] 51–53ꢀC). 1H NMR
(CDCl3): ꢀ 7.52–7.48 (m, 2H), 7.32–7.24 (m, 5H), 6.99–6.96 (m, 1H).
13C NMR (CDCl3): ꢀ 131.9, 131.5, 128.3, 127.1, 127.0, 123.4, 122.9,
93.1, 82.6. MS m/z (%): 184 (Mþ, 100), 152 (20), 139 (20), 92 (10).
7-Chloro-1-phenyl-3-hepten-1-yne. Oil.[17] 1H NMR (CDCl3): ꢀ 7.45–
7.43 (m, 2H), 7.32–7.29 (m, 3H), 6.24–6.13 (m, 1H), 5.74 (d, J ¼ 16.92 Hz,
1H), 3.51 (t, J ¼ 6.82 Hz, 2H), 2.36–2.28 (m, 2H), 1.93–1.84 (m, 2H);
13C NMR (CDCl3): ꢀ 142.5, 131.5, 128.1, 128.0, 123.3, 111.0, 88.5,
87.8, 44.1, 31.5, 30.1. MS m/z (%): 206, 204 (Mþ, 16, 50), 155 (60), 141
(100), 128 (24), 115 (76), 91 (20).
ACKNOWLEDGMENT
We wish to thank the National Natural Science Foundation of China
(No. 20172018), the Excellent Scientist Foundation of Anhui Province
(No. 2001040), the Natural Science Foundation of the Education
Department of Anhui Province (No. 2002kj254ZD), the Scientific
Research Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry (No. 2002247), and the Excellent Young Teachers
Program of MOE (No. 2024), China for support of this research.
REFERENCES
1. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
2. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467.

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Sonogashira Coupling Reaction
3685
3. Thorand, S.; Krause, N. J. Org. Chem. 1998, 61, 8551.
4. Ma, S.; Shi, Z.; Yu, Z. Tetrahedron 1999, 55, 12137.
5. Jones, G.B.; Wright, J.M.; Ploured, H.G.W.; Hynd, G.; Huber, R.S.;
Mathews, J.E. J. Am. Chem. Soc. 2000, 122, 1937.
6. Liu, S.-X.; Michel, C. Org. Lett. 2000, 2, 3959.
7. Shen, W.; Thomas, S.A. Org. Lett. 2000, 2, 2857.
8. Sonogashira, K. In Comprehensive Organic Synthesis; Trost, B.M.,
Fleming, I., Eds.; Pergamon Presss: New York, 1991; Vol. 3, 521 pp.
9. Nicolaou, K.C.; Dai, W.-M. Angew. Chem. Int. Ed. Eng. 1991,
30, 1387.
10. Grissom, J.M.; Gunawardena, G.U.; Klingberg, D.; Huang, D.
Tetrahedron 1996, 52, 6453.
11. De Kort, M.; Correa, V.; Valentijin, A.R.P.M.; Van der Marel,
G.A.; Potter, B.V.L.; Taylor, C.W.; Van Boom, J.H. J. Med.
Chem. 2000, 43, 3295.
12. Nazare, M.; Waldmann, H. Tetrahedron Lett. 2000, 41, 625.
13. Lang, P.; Magnin, G.; Mathis, G.; Burger, A.; Biellmann, J.-F.
J. Org. Chem. 2000, 65, 7825.
14. Kabalka, G.W.; Wang, L.; Namboodiri, V.; Pagni, R.M.
Tetrahedron Lett. 2000, 41, 5151.
15. Sato, H.; Isono, N.; Miyoshi, I.; Mori, M. Tetrahedron 1996,
52, 8143.
16. Masuda, Y.; Hoshi, M.; Arase, A. Chem. Lett. 1980, 413.
17. Kabalka, G.W.; Wang, L.; Pagni, R.M. Tetrahedron 2001, 57, 8017.
Received in the UK October 4, 2002

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