Copper-free Sonogashira coupling in amine-water solvent mixtures

Article abstract of DOI:10.1016/j.tetlet.2008.10.037

Extensive study of different amine-water solvent mixtures was carried out for copper free Sonogashira coupling of aryl iodides. The influence of the palladium sources, ligands, amine-water ratio and further additives was also evaluated. Application of sec-butylamine-water mixture proved to be an excellent medium for rapid and efficient coupling of aryl-iodides at ambient temperature in the presence of PdCl₂(PPh₃)₂ as catalyst.

Full text of DOI:10.1016/j.tetlet.2008.10.037

Tetrahedron Letters 49 (2008) 7294–7298
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Tetrahedron Letters
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Copper-free Sonogashira coupling in amine–water solvent mixtures
*
Anna Komáromi, Gergely László Tolnai, Zoltán Novák
Department of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University, Pázmány Péter stny. 1/a, Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2008
Revised 30 September 2008
Accepted 8 October 2008
Available online 14 October 2008
Extensive study of different amine–water solvent mixtures was carried out for copper free Sonogashira
coupling of aryl iodides. The influence of the palladium sources, ligands, amine–water ratio and further
additives was also evaluated. Application of sec-butylamine–water mixture proved to be an excellent
medium for rapid and efficient coupling of aryl-iodides at ambient temperature in the presence of
PdCl2(PPh3)2 as catalyst.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Acetylenes
Sonogashira reaction
Palladium
The palladium-catalyzed Sonogashira cross-coupling reaction1
between aryl-halides and terminal acetylenes serves as a powerful
method for the preparation of internal acetylenes,2 heterocycles3
and natural products.4 Since its discovery by Sonogashira5 in
1975, several modifications have been reported including variation
of the ligands, palladium sources, solvents and bases in order to
perform the coupling reactions more efficiently with aryl iodides,6
bromides7 and chlorides.8 The presence of the copper co-catalyst
facilitates the coupling reaction by the in situ generation of copper
acetylide, but it can also induce a Glaser-type oxidative homocou-
pling9 of the terminal acetylene to yield a diyne. Focusing on the
suppression of the formation of this undesired side product, sev-
eral copper-free versions of the palladium-catalyzed Sonogashira
coupling have been developed.10
polarity and hydrogen bonding ability, but would also serve as
an environment friendly solvent for the reaction.13 Our extensive
studies also deal with the choice of palladium source and the
ligands for this key transformation.
Initially, several amines as solvent were tested for the Sono-
gashira coupling of phenyl iodide and phenylacetylene under
aqueous and copper-free conditions. We chose the stable and eas-
ily accessible PdCl2(PPh3)2 complex as catalyst.
While, acyclic tertiary amines (Table 1, entries 1–5) showed no
activity at all, the application of DABCO (entry 6) showed increased
activity. Although DABCO is a weaker base, compared to other ter-
tiary amines, its less bulky character could be responsible for its
higher activity. Among the secondary dialkyl amines, diisopropyl-
amine (DIPA, entry 13) proved to be an excellent base as full con-
version was observed after 90 min at 25 °C in DIPA–water 1:1
mixture. In dialkyl amines such as Et2NH and Pr2NH (entries 7
and 8), the reaction was slower compared to DIPA. The presence
Mechanistic studies11 of the copper-free version of the Sono-
gashira coupling have shown that the polarity and hydrogen bond-
ing ability of the solvents are important in accelerating the reaction
by stabilizing the ionic intermediates of the catalytic cycle,
whereas steric bulk decreases the stabilizing ability of the sol-
vent.12 Another important factor is the strength of the base, which
plays an important role in the deprotonation of the terminal acet-
ylene during the process.
Considering the aforementioned facts, we envisaged that the
use of amines as solvent and base under aqueous conditions would
influence the efficiency of the copper-free coupling. We examined
the applicability of different types of amine–water mixtures for the
copper-free Sonogashira coupling of aryl iodides with terminal
acetylenes at ambient temperature. We envisaged that water as
co-solvent would not only accelerate the reaction due to its high
i
of amines bearing larger alkyl groups (Bu2NH, Bu2NH, Hex2NH
and Cy2NH) resulted in dramatic changes in the catalytic activity
(entries 9–12), and no significant coupling was observed with
these bases. Whilst the reaction is facilitated in the presence of
cyclic secondary amines such as pyrrolidine, N-methylpiperazine
and 2,2,6,6-tetramethylpiperidine (entries 14–16), morpholine
and 1-methylimidazole (entries 17 and 18) were not applicable
at all.
Although the application of primary amines is not common in
Sonogashira cross-coupling reactions, we continued our examina-
tion with these bases. We have found that the coupling reaction
takes place very rapidly in the presence of primary amines (entries
20–25). After 90 min reaction time, all of the iodobenzene was con-
sumed at 25 °C, and the desired diphenylacetylene was formed as
the only product. Surprisingly, isopropylamine (entry 19) had a
* Corresponding author. Tel.: +36 1 209 0555x1610; fax: +36 1 372 2909.
E-mail address: novakz@elte.hu (Z. Novák).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.037

A. Komáromi et al. / Tetrahedron Letters 49 (2008) 7294–7298
7295
Table 1
Examination of different amine–water 1:1 solvent mixtures for the copper-free Sonogashira coupling of PhI and phenylacetylenea
2% PdCl2(PPh3)2
I
Amine/H2O 1:1,
25 oC
Entry
Amine
Conversion after 30 minb (%)
Entry
Amine
Conversion after 30 minb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
DIPEA
TEA
Cy2NMe
Bu3N
0
6
0
0
0
34
9
30
0
0
0
7
14
15
16
17
18
19
20
21
22
23
24
25
Pyrrolidine
N-Methylpiperazine
2,2,6,6-Tetramethylpiperidine
Morpholine
1-Methylimidazole
iPrNH2
33
47
36
0
0
4
75 (86)
65
72 (99)
54
62 (93)
64 (96)
Pr3N
DABCO
Et2NH
Pr2NH
Bu2NH
iBu2NH
Hex2NH
Cy2NH
DIPA
PrNH2
BuNH2
sBuNH2
iBuNH2
tBuNH2
CyNH2
63 (84)
a
0.5 mmol aryl iodide, 0.75 mmol acetylene, 2% PdCl2(PPh3)2, 250
GC conversions after 30 min, isolated yields after 90 min in parentheses.
l
L amine, 250
lL water, 25 °C.
b
deleterious effect on the conversion, in comparison to the other
primary amines and DIPA.
consequence of fast ligand dissociation and ligand exchange with
the primary amine.
We have also ran some reactions on preparative scale. As sec-
butylamine–water 1:1 mixture gave the highest isolated yield (Ta-
ble 1, entry 22), we chose this medium for further examinations.
It is well known that the electronic and steric properties of the
applied ligands have a strong effect on the reactivity of catalytic
systems, we therefore studied the influence of ligands and palla-
dium sources on the Sonogashira coupling.
Ligand screening was achieved in the presence of PdCl2. With-
out any ligand, we were not able to detect any coupling product
in the reaction mixture after 45 min (Table 2, entry 1). Addition
of a bulky ortho-biphenyl type ligand or tricyclohexylphosphine
(entries 2 and 3) did not result in significant conversions. Low
conversions were also observed with other sterically demanding
ligands such as tri-1-naphthyl-, tri-(o-tolyl) and tris(2,4,6-trimeth-
ylphenyl)phosphine (entries 5, 6 and 8). Probably, these ligands are
not able to coordinate to the palladium in the presence of excess
amine due to steric hindrance. Application of the preformed chloro
complexes of tricyclohexylphosphine and tri(o-tolyl)phosphine
was also not effective (entries 4 and 7), which could be the
In the presence of tri(2-furyl)phosphine, the reaction was al-
most complete in 90 min (entry 9), and triaryl phosphines bearing
both electron-withdrawing and electron-donating groups at the
para position showed similar activity (entries 10 and 11). Although
the electronic properties of the para substituted phosphines did
not affect the catalytic activity significantly, more electron defi-
cient phosphines such as tris-(3,5-bis-trifluoromethyl)-phosphine
led to the coupling reaction occurring at a lower rate, which is sup-
posedly due to the decreased coordinating ability of the ligand. The
highest conversions were observed by adding triphenylphosphine
either separate from PdCl2 or in complexed form (PdCl2(PPh3)2)
(entries 13 and 14). Although reducing the catalyst loading to
1 mol % and 0.5 mol % gave lower reaction rates, the reactions were
complete in 2 and 4 h, respectively (entries 15 and 16). The reac-
tion also takes place with almost the same efficiency under aerobic
conditions with the same palladium complex (entry 17).
Bidentate ligands with PdCl2 have also showed appreciable
activities (entries 18–22); however, the conversions were lower
compared to those with triaryl phoshines.
Table 2
Ligand screening experimentsa
2% PdCl2, 2—4% Ligand
I
sBuNH2/H2O 1:1,
25 oC
Entry
Palladium cat.
Ligand
Conversionb (%)
Entry
Palladium cat.
Ligand
Conversionb (%)
1
2
3
4
5
6
7
8
9
PdCl2
PdCl2
PdCl2
PdCl2(PCy3)2
PdCl2
PdCl2
PdCl2(o-Me-PPh3)2
PdCl2
PdCl2
PdCl2
—
0
0
0
0
0
0
0
0
75
68
65
20
13
14
15
16
17
18
19
20
21
22
23
24
PdCl2
PPh3
—
—
—
—
79
86
62
tBu-XPhos
Cy3P
PdCl2(PPh3)2
1 mol % PdCl2(PPh3)2
0.5 mol % PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
—
32
(1-Naphthyl)3P
(o-Tolyl)3P
—
(Mesityl)3P
(2-Furyl)3P
(4-Fluorophenyl)3P
(4-Methoxyphenyl)3P
(3,5-Bis-trifluoromethyl)3P
71 (94)c
2
BINAPd
Xanthphosd
dpped
dpppd
dppbd
PPh3
PPh3
12
15
23
22
70
3
10
11
12
PdCl2
PdCl2
Pd(OAc)2
Pd2(dba)3
a
0.5 mmol aryl iodide, 0.75 mmol acetylene, 4 mol % palladium, 4 mol % ligand, 250
GC conversions after 45 min.
Reaction was performed in the presence of air, isolated yield in parentheses.
2 mol % of ligand was used.
lL
sBuNH2, 250
lL water, 25 °C
b
c
d

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A. Komáromi et al. / Tetrahedron Letters 49 (2008) 7294–7298
Figure 1. Conversions of the coupling of iodobenzene with phenylacetylene as a function of the amount of water in 250 lL of sec-butylamine.
The coupling reaction with Pd(OAc)2 as an alternative palla-
dium(II) source under the same conditions also took place and pro-
vided a comparable conversion to PdCl2 (entry 23). Surprisingly,
Pd2(dba)3 showed much lower activity than the Pd(II) salts (entry
24).
After finding PdCl2(PPh3)2 as a suitable catalyst for the coupling,
the influence of the amount of added water on the catalytic activity
was studied. First, we ran the Sonogashira coupling of iodobenzene
with phenylacetylene in freshly distilled sec-butylamine, then the
conversions in different amine–water mixtures (250 lL sec-butyl-
amine and 2% PdCl2(PPh3)2 were present in all the reactions) were
compared (see Fig. 1).
After 15 min only 13% conversion was obtained in the absence
of water. Even the presence of very small amounts of water caused
significantly higher reaction rates. In 10:250 v/v water/amine mix-
ture, 49% conversion was obtained within the same period of time.
Increasing the water content to 30:250 and 50:250, the conver-
sions were found to be even higher. Further addition of water to
the system resulted in smaller effects on the conversion, and the
optimal ratio was found to be between 125:250 and 250:250.
We also applied a strong inorganic base besides the amines, dis-
solved in the aqueous phase. In the presence of 1.5 equiv of KOH
the reaction took place rapidly, and full conversion was obtained
within 30 min at 25 °C.
s
After these optimization studies, we applied BuNH2/water 1:1
mixture and PdCl2(PPh3)2 for the copper-free coupling of various
aryl iodides and terminal acetylenes to assess the scope of the
developed reaction conditions. First, phenylacetylene (2a) was re-
acted with aryl iodides bearing either electron-withdrawing or
electron-donating functional groups, to afford the corresponding
acetylenes 3a–g in good isolated yields (Table 3, entries 1–7).
Among these substrates, the coupling reaction worked efficiently
even in the case of bulky 2-iPr-iodobenzene (1d) (entry 4).
Heteroaromatic systems such as 2-iodopyridine (1i), 3-iodopyr-
idine (1 h) and 2-iodothiophene (1j) were also coupled successfully
with phenylacetylene under the developed conditions (entries 8–
10). Coupling of 3-ethynyltoluene (2b) as an aromatic acetylene
with an electron-donating group yielded the appropriate internal
Table 3
PdCl2(PPh3)2 catalyzed Sonogashira coupling of aryl iodides with terminal acetylenes in sBuNH2/water 1:1 mixturea
2% PdCl2(PPh3)2
I
R'
R'
sBuNH2/H2O 1:1,
R
R
3
1
2
25 oC, 90 min
Entry
1
Aryl Iodide
Alkyne
Product
Yieldb (%)
99
I
1a
3a
2a
I
2
3
4
2a
90
94
93
3b
1b
I
2a
2a
1c
1d
3c
iPr
I
iPr
3d
H3CO
I
H3CO
5
2a
84
3e
1e

A. Komáromi et al. / Tetrahedron Letters 49 (2008) 7294–7298
7297
Table 3 (continued)
Entry
Aryl Iodide
Alkyne
Product
Yieldb (%)
87
O
O
6
7
2a
I
3f
1f
I
2a
96
3g
1g
F
F
I
8
9
2a
2a
94
92
3h
3i
N
N
1h
1i
I
N
N
I
10
11
12
13
14
15
16
17
2a
88
95
89
96
88
87
92
83c
78c
S
S
3j
1j
1a
3c
2b
H3CO
O
1e
1f
2b
2b
3k
3l
1a
1e
1f
3i
N
N
2c
H3CO
O
2c
2c
N
3m
N
3n
O
OH
OH
1f
2d
3o
C6H13
C6H13
18
1a
3p
2e
a
0.5 mmol aryl iodide, 0.65 mmol acetylene, 2% PdCl2(PPh3)2, 250
Isolated yield.
Reaction was carried out in the presence of 0.75 mmol (1.5 equiv) KOH, 8 h, 25 °C.
l
L
sBuNH2, 250
lL water, 25 °C, 90 min.
b
c
acetylenes with electronically diverse aryl iodides in excellent
yields (entries 11–13). Efficient couplings were also obtained in
the case of iodides 1a, 1e and 1f with the electron deficient hetero-
cyclic acetylene 2-ethynylpyridine (2c) (entries14–16). For the
Sonogashira coupling of aryl iodides with carbinol type14 and ali-
phatic acetylenes, the utilization of KOH was found to be necessary
in order to accelerate and complete the reaction within 8 h (entries
17 and 18). We have found that the reaction did not reach full con-
version in 24 h without the strong inorganic base.
per-free Sonogashira coupling. We have established that primary
amine–water mixtures are suitable for the efficient coupling at
ambient temperature in the presence of 2% PdCl2(PPh3)2. We also
found that the presence of water promotes the coupling reaction,
and the reaction can be accelerated in the presence of KOH. In or-
der to explain the reaction rate accelerating effect of water and the
strong base, we are currently pursuing spectroscopic studies in our
laboratory. The developed copper-free conditions could serve as a
competitive, efficient and practical procedure for the Sonogashira
coupling of aryl iodides and terminal acetylenes by offering mild
conditions, short reaction times and high yields.
In conclusion, we have explored the applicability of different
amines as solvents and bases under aqueous conditions in cop-

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A. Komáromi et al. / Tetrahedron Letters 49 (2008) 7294–7298
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