A novel silver iodide catalyzed sonogashira coupling reaction

Article abstract of DOI:10.1055/s-2006-949640

A novel and efficient Ag-catalyzed Sonogashira coupling reaction has been developed. Terminal alkynes couple with aryl iodides and aryl bromides in the presence of silver iodide, tri-phenylphosphine and potassium carbonate to afford the corresponding cross-coupling products in high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949640

LETTER
2261
A Novel Silver Iodide Catalyzed Sonogashira Coupling Reaction
A
N
ovel Silve
i
r
Iodide
n
Catalyzed
S
h
onogashira
C
u
oupling Re
a
a
ction Li,a Lei Wang*a,b
a
Department of Chemistry, Huaibei Coal Teachers College, Huaibei, Anhui 235000, P. R. of China
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
Fax +86(561)3090518; E-mail: leiwang@hbcnc.edu.cn
Received 10 February 2006
free/microwave irradiation system17 were demonstrated.
Nevertheless, the development of new, practical, econom-
ic and efficient catalyst systems is still an important topic
in this area. Recently, He developed a Ag-catalyzed
intramolecular amidation of saturated C–H bonds and Li
explored a silver-catalyzed three-component coupling of
aldehyde, alkyne and amine.18 The latter showed that the
exclusive aldehyde–alkyne–amine coupling product was
observed in the absence of phosphine, whereas in the pres-
ence of a phosphine ligand, exclusive aldehyde–alkyne
coupling product was obtained. Although Pale et al. inves-
tigated extensively the Sonogashira coupling reactions of
terminal alkynes or 1-trimethylsilyl acetylenes with vinyl
triflates or aryl iodides in the presence of a catalytic
amount of Pd(PPh3)4 and AgI or AgCl, and Mori devel-
oped a Pd/Ag-assisted Sonogashira reaction,11q–t,12f–i,19 to
the best of our knowledge, there is no report on the
Sonogashira reaction catalyzed by silver alone. Some
similar properties of silver with palladium and its cheap
availability, it prompted us to try a silver-catalyzed Sono-
gashira reaction.
Abstract: A novel and efficient Ag-catalyzed Sonogashira cou-
pling reaction has been developed. Terminal alkynes couple with
aryl iodides and aryl bromides in the presence of silver iodide, tri-
phenylphosphine and potassium carbonate to afford the correspond-
ing cross-coupling products in high yields.
Key words: silver iodide, Sonogashira coupling reactions, terminal
alkynes, aryl iodides, aryl bromides
In 1963, Stephens and Castro first discovered that diaryl-
acetylenes were prepared by treating aryl iodides with
cuprous acetylides in refluxing pyridine under a nitrogen
atmosphere.1 Later, Cassar observed that acetylene or
monosubstituted acetylenes were converted into aryl- and
vinyl-substituted acetylene derivatives by reaction with
aryl and vinyl halides in the presence of a nickel or palla-
dium triarylphosphine complex along with a base in 1975.
With the palladium triphenylphosphine complexes, the
conversion could be carried out catalytically under mild
conditions.2 Subsequently, Sonogashira et al. combined
these two procedures into a cross-coupling reaction of
terminal alkynes with aryl and alkenyl halides catalyzed
by the palladium complexes in the presence of a catalytic
amount of CuI and an amine (as solvent or in large excess)
bearing his name in 1978.3 Since then, the Sonogashira
reactions have become one of the most powerful and
straightforward methods for the formation of sp2–sp
carbon–carbon bonds in organic synthesis.4 They have
been widely used for the syntheses of natural products,5
biologically active molecules,6 non-linear optical materi-
als and molecular electronics,7 dendrimeric and polymeric
materials,8 macrocycles with acetylene links,9 and poly-
alkynylated molecules.10 However, a number of modifica-
tions for palladium catalyst systems, including copper-
free,11 amine- and copper-free,12 ligand-free,13 ligand-,
copper- and amine-free,14 have been used to solve the
problems (homocoupling products of terminal alkynes
along with the cross-coupling reaction owing to the addi-
tion of CuI, more expensive palladium complex catalyst,
and a bad smell of amine used in the reaction) encountered
in the traditional Sonogashira reaction conditions. Most
recently, new catalytic systems without palladium, such
as nickel system,15 CuI system,16 and transition-metal-
In this paper, we report a Sonogashira protocol in the pres-
ence of silver iodide (10 mol%), triphenylphosphine and
potassium carbonate, which generates the corresponding
cross-coupling products in good to excellent yields
(Scheme 1).
AgI, PPh3, K2CO3
X +
R
H
R
DMF
R1
R1
R = aryl, alkyl
X = I, Br
Scheme 1
Our initial investigation was directed towards exploring
the reaction conditions for the cross-coupling of p-iodo-
toluene with phenylacetylene catalyzed by silver.
We examined several different bases for the Sonogashira
coupling reactions catalyzed by silver iodide. Potassium
carbonate was found to be the most effective base. Other
bases, such as potassium hydroxide, sodium hydroxide,
caesium carbonate, potassium fluoride, sodium carbonate
and potassium phosphate were substantially less effective,
and triethylamine, diethylamine and piperidine were no
longer the effective bases in this catalytic system, due to
the strong coordination of organic bases containing nitro-
gen with silver(I) (Table 1, entries 1–10).
SYNLETT 2006, No. 14, pp 2261–2265
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Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949640; Art ID: W02606ST
© Georg Thieme Verlag Stuttgart · New York

2262
P. Li, L. Wang
LETTER
A significant effect of solvent was found in the coupling Table 2 Effect of Solvent on the Sonogashira Coupling Reactiona
reaction. When the reactions were conducted in ethanol,
AgI, PPh3
+
OMe
H
MeO
I
isopropanol, N,N-dimethylformamide or N,N-dimethyl-
acetamide, good yields (88%, 89%, 92% and 91%, respec-
tively) of products were obtained. Use of dioxane,
methanol, acetonitrile, and tetrahydrofuran as solvents led
to slower reactions, and no desired cross-coupling product
was observed while reaction was performed in ethylene
glycol (Table 2, entries 1–9). This solvent effect may re-
sult from the difference of the solubility of silver iodide,
triphenylphosphine, potassium carbonate and starting
materials in the above-mentioned solvents at the reaction
temperature indicated in Table 2.
K2CO3,
Solvent
Entry
Solvent
MeOH
i-PrOH
THF
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
68
80
70
89
55
73
67
88
92
91
0
70
Dioxane
MeCN
EtOH
80
70
Table 1 Effect of Base on the Sonogashira Coupling Reactiona
80
AgI, PPh3
DMF
100
100
100
+
OMe
H
MeO
I
Base, DMF
DMA
Entry
Base
Yield (%)b
(CH2OH)2
1
2
K2CO3
Cs2CO3
Na2CO3
K3PO4
KOH
92
86
56
34
88
87
82
<5
<5
<5
a Reagents and conditions: Phenylacetylene (102 mg, 1.00 mmol), p-
iodotoluene (218 mg, 1.00 mmol), AgI (Aldrich, 99.999%, 23.5 mg,
0.10 mmol), PPh3 (78.6 mg, 0.30 mmol), and K2CO3 (276 mg, 2.00
mmol) in solvent (4.00 mL) at the temperature indicated in Table 2 for
8 h.
3
4
b Isolated yield.
5
Table 3 Effect of Ligand on the Sonogashira Coupling Reactiona
6
NaOH
KF
AgI, Ligand
OMe
H
MeO
I
+
7
K2CO3, DMF
8
Et3N
Entry
Ligand
Yield (%)b
9
Et2NH
1
2
3
4
5
6
7
PPh3
92
81
70
0
10
Piperidine
Dppf
a Reagents and conditions: Phenylacetylene (102 mg, 1.00 mmol),
p-iodotoluene (218 mg, 1.00 mmol), AgI (Aldrich, 99.999%, 23.5 mg,
0.10 mmol), PPh3 (78.6 mg, 0.30 mmol), and base (2.00 mmol) in
DMF (4.00 mL) at 100 °C for 8 h.
P(OMe)3
N,N-Dimethylglycine
L-Proline
b Isolated yield.
0
a,a-Bipyridine
0
We then turned our attention to ligand and silver salt
effects. The silver salt and ligand are all essential to the
reaction. No reaction occurs in the absence of silver salt or
ligand. Among the ligands tested, triphenylphosphine
proved to be the best choice (high yields of products and
easy availability), while dppf and P(OMe)3 were inferior.
When other ligand, such as N,N-dimethylglycine, L-pro-
line, a,a-bipyridine or 1,10-phenanthroline, was em-
ployed instead of triphenylphosphine for the above-
mentioned reaction, no cross-coupling product was de-
tected (Table 3, entries 1–7).
1,10-Phenanthroline
0
a Reagents and conditions: Phenylacetylene (102 mg, 1.00 mmol), p-
iodotoluene (218 mg, 1.00 mmol), AgI (Aldrich, 99.999%, 23.5 mg,
0.10 mmol), ligand (0.30 mmol), and K2CO3 (276 mg, 2.00 mmol) in
DMF (4.00 mL) at 100 °C for 8 h.
b Isolated yield.
During the course of our further optimization of the reac-
tion conditions, when using a 10 mol% loading of silver
iodide, the reactions were generally complete in a matter
of hours, but the time, as expected, was inversely propor-
tional to the temperature. A reaction temperature of 100
°C was found to be optimal. Thus, the optimized reaction
conditions for this Sonogashira reaction are silver iodide
(10 mol%), triphenylphosphine (30 mol%), potassium
carbonate (2 equiv) in N,N-dimethylformamide at 100 °C
for eight hours.
Meanwhile, the catalytic reactivity of silver salts decreas-
es in order for the Sonogashira reaction: AgI ≈ AgOTf >
AgBr > AgCl ≈ Ag2O ≈ AgNO3 (Table 4, entries 1–6).
AgI was chosen as catalyst in the following investigation
for its high efficiency, and easy commercial availability
(Aldrich, AgI, 99.999%, $24.10/1 g; AgCF3SO3, 99.95%,
$38.30/1 g).
Synlett 2006, No. 14, 2261–2265 © Thieme Stuttgart · New York

LETTER
A Novel Silver Iodide Catalyzed Sonogashira Coupling Reaction
2263
Table 5 AgI-Catalyzed Sonogashira Coupling Reactiona
Table 4 Effect of Silver Salt on the Sonogashira Coupling
Reactiona
Entry Terminal alkyne
Organic halide
p-MeOC6H4I
p-MeC6H4I
PhI
Yield (%)b
92
Ag salt, PPh3
OMe
H
MeO
I
+
1
2
PhC≡CH
K2CO3, DMF
Entry
Silver Salt
AgI
Yield (%)b
PhC≡CH
93
3
PhC≡CH
95
1
2
3
4
5
6
92
75
78
89
77
91
4
PhC≡CH
p-O2NC6H4I
p-MeCOC6H4I
p-CF3C6H4I
m-O2NC6H4I
o-CF3C6H4I
m-CNC6H4I
PhI
99
AgNO3
AgCl
5
PhC≡CH
94
6
PhC≡CH
99
AgBr
7
PhC≡CH
80
Ag2O
8
PhC≡CH
73
AgOTf
a Reagents and conditions: Phenylacetylene (102 mg, 1.00 mmol), p-
iodotoluene (218 mg, 1.00 mmol), Ag salt (0.10 mmol), PPh3 (78.6
mg, 0.30 mmol), and K2CO3 (276 mg, 2.00 mmol) in DMF (4.00 mL)
at 100 °C for 8 h.
9
PhC≡CH
91
10
11
12
13
14
15
16
17
18
p-CH3C6H4C≡CH
p-C6H5C6H4C≡CH
p-FC6H4C≡CH
p-BrC6H4C≡CH
n-C8H17C≡CH
n-C6H13C≡CH
PhC≡CH
96
PhI
94
b Isolated yield.
PhI
98
PhI
95
To survey the generality of this Sonogashira-type reac-
tion, we investigated the reactions using a variety of aryl
iodides and bromides, and a wide range of terminal
alkynes as the substrates under the present reaction condi-
tions. The results are shown in Table 5. As can be seen
from Table 5, electron-neutral, electron-rich and electron-
poor aryl iodides reacted with phenylacetylene very well
to generate the corresponding cross-coupling products in
good to excellent yields under the standard reaction con-
PhI
80
PhI
83
2-Bromopyridine
p-CNC6H4Br
p-O2NC6H4Br
p-MeCOC6H4Br
p-MeC6H4Br
99
PhC≡CH
92
PhC≡CH
95
ditions (Table 5, entries 1–9). For an ortho-substituted 19
PhC≡CH
85
aryl iodide, a relatively lower yield was isolated under the
present reaction conditions (Table 5, entry 8). Regardless
20
PhC≡CH
62c
of their electronic characters, both of the aromatic termi- a Reagents and conditions: Terminal alkyne (1.00 mmol), organic
halide (1.00 mmol), AgI (Aldrich, 99.999%, 23.5 mg, 0.10 mmol),
PPh3 (78.6 mg, 0.30 mmol ), K2CO3 (276 mg, 2.00 mmol) in DMF
nal alkynes and aliphatic terminal alkynes component
coupled smoothly with iodobenzene to produce the de-
(4.00 mL) at 100 °C for 8 h.
sired products in good to excellent yields (Table 5, entries
3 and 10–15). Activated aryl bromides also reacted with
phenylacetylene to provide the products in excellent
yields (Table 5, entries 16–19). However, for an electron-
rich aryl bromide, only a moderate yield (62%) was ob-
tained even if the reaction was performed for 12 hours
(Table 5, entry 20). It is worth noting that the regioselec-
tive Sonogashira cross-coupling products were formed for
substituted aryl halides, such as p-CH3COC6H4I, p-
CH3COC6H4Br, m-CNC6H4I, and p-CNC6H4Br (Table 5,
entries 5, 9, 17, 19).20
b Isolated yield.
c Reaction for 12 h.
responsible for the generation of the biaryl rather than, as
previously suggested, an alternative non-palladium-medi-
ated pathway.22 Inspired by their results, we therefore in-
vestigated how much palladium is present in potassium
carbonate, N,N-dimethylformamide, triphenylphosphine
and silver iodide in our Sonogashira reaction system in or-
der to establish whether this process is only catalyzed by
Ag and not by a microamount palladium or a Ag/Pd mix-
ture. We analyzed the N,N-dimethylformamide, potassi-
um carbonate, triphenylphosphine and silver iodide used
In 2003, Leadbeater reported the transition-metal-free
Suzuki coupling reaction21 and Sonogashira-type cou-
pling (under microwave irradiation conditions).17 Two in the reaction by ICP–MS and found that the palladium
years later, after delicate analysis of the microamount pal- level is 0.32, 9.15, 5.32, and 2.64 ppb, respectively, which
ladium in the reaction mixtures, including ultrapure water we believe to be too low to be catalytically active. The or-
and commercially available sodium carbonate by ICP– ganic reagents used in the reactions were all purified prior
MS, Leadbeater found that, although the reaction can be to use and we believe them to be palladium free. There-
fore, we expected that this reaction was catalyzed by Ag
alone. Although the investigation of mechanism of Ag/Pd
catalysis showed that the corresponding alkynyl silver
run without the need for addition of a transition-metal cat-
alyst, palladium contaminants down to a level of 50 ppb
found in commercially available sodium carbonate are
Synlett 2006, No. 14, 2261–2265 © Thieme Stuttgart · New York

2264
P. Li, L. Wang
LETTER
was formed after mixing the alkyne and silver salt,23 the
Ag-catalyzed Sonogashira coupling reaction mechanism
in the absence of any palladium is not fully clear and a fur-
ther investigation is currently underway in our laboratory.
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We gratefully acknowledge financial support from the National
Natural Science Foundation of China (No. 20372024), the Excellent
Scientist Foundation of Anhui Province, China (No. 04046080), the
Scientific Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry, China (No. 2002247), the
Excellent Young Teachers Program of MOE, China (No. 2024), and
the Key Project of Science and Technology of State Education
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LETTER
A Novel Silver Iodide Catalyzed Sonogashira Coupling Reaction
2265
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108.5–109.5 °C). 1H NMR (300 MHz, CDCl3): d = 7.59–
7.66 (m, 4 H), 7.53–7.57 (m, 2 H), 7.36–7.40 (m, 3 H). 13
C
NMR (75 MHz, CDCl3): d = 132.0 (2 × C), 131.8, 129.1,
128.5, 128.2, 122.2, 118.5, 111.4, 93.7, 87.7. MS: (relative
intensity, %): m/z = 203 (100) [M+], 176 (8), 151 (5), 75 (5).
(3-Cyanophenyl)phenylacetylene: mp 69–71 °C (Lit.25 70–
71 °C). 1H NMR (300 MHz, CDCl3): d = 7.79 (t, J = 1.50 Hz,
1 H), 7.73 (dt, J = 1.50, 7.80 Hz, 1 H), 7.59 (dt, J = 1.50, 7.80
Hz, 1 H), 7.52–7.55 (m, 2 H), 7.45 (t, J = 7.80 Hz, 1 H),
7.35–7.39 (m, 3 H). 13C NMR (75 MHz, CDCl3): d = 135.6,
134.8, 131.7, 131.3, 129.2, 128.9, 128.4, 124.8, 122.2,
118.0, 112.8, 91.7, 86.8. MS (relative intensity, %): m/z =
203 (100) [M+], 176 (7), 151 (5), 75 (5).
(21) (a) Leadbeater, N. E.; Marco, M. Angew. Chem. Int. Ed.
2003, 42, 1407. (b) Leadbeater, N. E.; Marco, M. J. Org.
Chem. 2003, 68, 5660.
(20) The unique Sonogashira coupling products were
characterized by mp, 1H NMR and 13C NMR, and MS.
(4-Acetylphenyl)phenylacetylene: mp 95-96 °C (Lit.24 94–
96 °C). 1H NMR (250 MHz, CDCl3): d = 7.91 (d, J = 8.41
Hz, 2 H), 7.58 (d, J = 8.41 Hz, 2 H), 7.52-7.54 (m, 2 H), 7.33-
7.36 (m, 3 H), 2.57 (s, 3 H). 13C NMR (62.5 MHz, CDCl3):
d = 197.1, 136.1, 131.7, 131.6, 128.7, 128.4, 128.2, 128.1,
122.6, 92.6, 88.6, 26.5. MS (relative intensity, %): m/z = 220
(60) [M+], 205 (100), 176 (48), 151 (18), 102 (10), 88 (19).
(4-Cyanophenyl)phenylacetylene: mp 109–110 °C (Lit.25
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V. A.; Granados, P.; Singer, R. D. J. Org. Chem. 2005, 70,
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Reson. Chem. 2004, 42, 831.
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2005, 70, 9185. (b) Létinois-Halbes, U.; Pale, P.; Berger, S.
Magn. Reson. Chem. 2004, 42, 831.
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Synlett 2006, No. 14, 2261–2265 © Thieme Stuttgart · New York