Copper-free Sonogashira cross coupling in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2008.02.110

In the present Letter the use of ionic liquids based on butylpyridinium salts (C₄PyPF₆, C₄PyBF₄, and C₄PyNO₃) is described in the Sonogashira reaction. Aiming the development of recyclable

Full text of DOI:10.1016/j.tetlet.2008.02.110

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2506–2509
Copper-free Sonogashira cross coupling in ionic liquids
Paulo Galdino de Lima, O. A. C. Antunes *
Instituto de Qu ı´ mica, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos 149, CT Bloco A 641,
Cidade Universit a´ ria, Rio de Janeiro, RJ 21941-909, Brazil
Received 26 January 2008; revised 16 February 2008; accepted 19 February 2008
Available online 23 February 2008
Abstract
In the present Letter the use of ionic liquids based on butylpyridinium salts (C
4
6 4 4 4 3
PyPF , C PyBF , and C PyNO ) is described in the
Sonogashira reaction. Aiming the development of recyclable catalytic system using Pd(II) salts as precursors, the importance of the
induction period prior to the addition of substrates was established. A new methodology that can be performed under Cu(I)-free and
at mild conditions was established. Good conversions were obtained and good recyclability was observed.
Ó 2008 Elsevier Ltd. All rights reserved.
1
7
Sonogashira reaction is a powerful method for the
bilize the carbenoid catalyst [bmimPd(PPh )Cl ]. Alper
3 2
2
formation of Csp –Csp bonds with aryl or vinylhalides
and terminal acetylenes. This palladium catalyzed cross-
coupling reaction has been widely utilized in the synthesis
of natural products and nonlinear optical electronic
devices, for example. The typical procedures make use
of Cu2I2 as co-catalyst, phosphine ligands (like Ph P),
and strong bases (amines and carbonates) in organic
solvents.
The increasing demand for environmental friendly and
low cost process has lead to the development of recyclable
catalytic systems, where ionic liquids have been recognized
and Park developed a copper- and phosphine-free Sono-
gashira reaction with aryl iodides employing the carbenoid
species [(bismethylimidazole)PdClMe] in bmimBF at
120 °C. Hierso et al. developed a catalytic system from
[Pd(allyl)Cl] /Ph P in bmimBF for coupling of deactivated
aryl bromides at 120 °C. In the latter case, however,
reduced products were obtained with long time reactions
with activated substrates. Moreover, simple palladium
sources have been used in imidazolium salt-ionic liquids,
such as Pd(OAc) /Ph P in the presence of Cu I at
4
2
8
3
2
3
4
9
3
1
0
2
3
2 2
1
1
80 °C and PdCl /bbim under ultrasound irradiation at
2
4
12
as promising alternative solvents. Most of the ionic liquids
30 °C. In the latter, it was proposed that Pd(0)-nano-
employed in Sonogashira and other palladium catalyzed
cross-coupling reactions are dialkylimidazolium molten
salts, which can form palladium–NHC, N-heterocyclic
carbenes, as active catalytic species depending on the
particles would be the active catalyst species, although
[(bbim) Pd(BF ) ] carbene complex was extracted from
2
4 2
the ionic phase with chloroform.
The alternative ionic liquids N-alkylpyridinium salts, as
for example, the N-butyl derivatives C Py, are not sup-
5
anion.
4
Ryu and co-workers disclosed the use of [PdCl (PPh ) ]
posed to be able to form palladium carbenoid complexes,
although this can be possible under strong base conditions
with pyridinium cations bearing chelating groups. This
feature lead to the expectation that their use would provide
different activities than those observed with dialkyl-
imidazolium salts in Sonogashira cross-coupling reaction.
Therefore, our goal was to study the Sonogashira cross
coupling under mild conditions employing alkylpyridinium
ionic liquids as reaction solvents and simple palladium
2
3 2
(
5 mol %) as good catalyst precursor for copper-free Sono-
6
13
gashira coupling in bmimPF at 60 °C. The same research
6
group performed a screening study in a 24-array parallel
reactor to establish bmimPF as a suitable solvent to immo-
6
*
Corresponding author. Tel.: +55 21 2562 7248; fax: +55 21 2562 7559.
E-mail address: octavio@iq.ufrj.br (O. A. C. Antunes).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.110

P. G. de Lima, O. A. C. Antunes / Tetrahedron Letters 49 (2008) 2506–2509
2507
8,19
1
catalyst precursors. To the best of our knowledge,
concerning the palladium catalyzed cross-coupling reac-
tions, pyridinium salts were tested as solvent in Heck cross
have been previously claimed to be the active catalysts,
it is possible to have a good catalytic system in its absence.
Perhaps Pd(0/II) formed via oxidative additions and elim-
inative reduction, when in low concentrations, turn down
the use of phosphines and do not form black Pd(0) at these
concentrations.
1
4
coupling between arylhalides and acrylate esters, and
have been used as nitrile functionalized ionic liquids in
1
5
Suzuki and Stille cross-coupling reactions.
In the present Letter the unprecedented use of N-butyl-
Once C PyPF melts only at about 80 °C, which restrict
4
6
1
6
À
À
À
pyridinium ionic liquids C PyX (PF6 , BF4 , and NO3 )
the extraction step to temperatures about 50–60 °C, that
could cause catalyst removing to organic phase, this sol-
vent was substituted to the room temperature ionic liquid
C PyBF , which would allow the extension of our research
4
as solvents in Sonogashira reaction is described. The reac-
tion model studied in the present Letter was the formation
of diphenylacetylene from iodobenzene (1 mmol) and
phenylacetylene (1 mmol), Scheme 1.
4
4
to milder reaction conditions (Table 2).
The initial reaction conditions were set up based on the
Sonogashira cross-coupling procedure in the imidazo-
linium ionic liquids reported by Toma et al. Therefore,
the catalytic system was produced from Pd(OAc)2
The catalyst precursor Pd(OAc) (4 mol %) rendered a
catalytic system suitable to accomplish Sonogashira cross
2
1
1
coupling at 75 °C (entry 1), however, with low activity at
room temperature (entry 2). In contrast, PdCl promoted
2
(
4 mol %) in the presence of Ph P (8 mol %) and 1 g
moderate conversion at 75 °C with maintenance of activity
on the second run (entry 3) and showed an excellent perfor-
mance at room temperature (entry 4).
3
C PyPF at 80 °C for 1 h, prior to the addition of Cu I
(
4
6
2 2
8 mol %), iodobenzene, phenylacetylene, and Et N
3
(
1.5 mmol) (Table 1).
Despite the result with PdCl at room temperature, in
2
These conditions yielded moderate conversion (entry 1)
general, higher conversions on the two runs were obtained
with C PyPF as solvent. This can be rationalized from the
and the absence of both PPh and CuI was not deleterious
3
4
6
for the formation of diphenylacetylene (entry 2). Unexpect-
edly, it was obtained a markedly shift of activity on the sec-
ond runs using EtOH as co-solvent. Since no changes on
the reaction profile were observed after 2 h of reaction
time, these results may be related to the low concentration
of Pd active species in the first run. In order to force Pd(0)
formation via reduction of the Pd(II) precursor, EtOH was
included to induction period and removed before coupling
reaction and no copper salt was added to reaction to avoid
mechanism proposed by Rothenberg and co-workers,
where the Pd species leached from defect sites on the cluster
are the active catalyst and the precursors of the new nano-
1
8
particles after reductive elimination. Therefore, the lower
À
coordinating ability of the anion PF6 would favor the Pd
leaching step and the steric stabilization of the re-aggregate
+
À
by C Py cation. Although BF is considered a noncoordi-
4
4
nating anion, it has been identified as a ligand on the Pd
carbene complex formed in cross coupling under ultra-
1
7
12
Glaser-type homocoupling of the phenylacetylene. This
procedure afforded a catalytic system that exhibited high
conversion and good recyclability (entry 3). A good con-
version was kept even in the absence of Cu I and Ph P,
sound conditions.
To address the difficulties in dealing with C PyPF and
4
6
the conversion decreasing in C PyBF , the other room tem-
4
4
perature ionic liquid C PyNO was introduced as a solvent
2
2
3
4
3
but in the second run a lower but still reasonable yield
was observed (entry 4). These results indicate that although
in our model reaction (Table 3).
Employing the induction procedure (C PyNO , EtOH,
4
3
Ph P is important to the stabilization of the Pd soluble spe-
cies formed via oxidative addition on nanoparticles, which
Ph P, 75 °C), high conversions and good recyclabilities
3
3
were observed at 75 °C for both palladium sources (entries
1
and 5). However, only PdCl based catalyst showed to be
2
suitable to accomplish Sonogashira cross coupling at room
Pd(II) 4 mol %
I
Ph3P
temperature (entries 3 and 7), even the addition of Et N on
3
+
Et N, [C Py]X
the induction step, to favor Pd(II) reduction through Pd-
ethanoate formation, did not improve the activity of the
Pd(OAc)2 based catalyst (entry 4). To open the green
3
4
(
1)
(2)
(3)
Scheme 1. Reaction model for catalytic system development.
appeal in this protocol, excluding Ph P from both catalytic
3
systems resulted in moderate conversions at 75 °C (entries
Table 1
Conversion of PhI (1) in diphenylacetylene (3) with C
2
and 6).
2
0
4
PyPF
6
as solvent
Entry
Induction period
Cross
coupling
1 Run
(%)
2 Run
(%)
Table 2
a
20
1
[C
Ph
Without Ph
[C Py]PF , Pd(OAc)
EtOH, Ph
Without Ph
4
Py]PF
6
, Pd(OAc)
2
,
,
Cu
2
I
2
, 80 °C, 2 h
61
49
Conversion of PhI (1) in diphenylacetylene (3) with C PyBF as solvent
4
4
3
P, 80 °C, 1 h
a
Entry
Pd source
Pd(OAc)
Cross coupling
1 Run (%)
2 Run (%)
6
2
3
3
P
80 °C, 2 h
80 °C, 2 h
56
97
87
82
1
2
3
4
2
75 °C, 2 h
rt, 24 h
86
12
56
96
4
6
2
3
P, 80 °C, 1 h
4
3
P
80 °C, 2 h
88
60
PdCl
2
75 °C, 2 h
rt, 24 h
60
65
a
EtOH was used as co-solvent on the cross-coupling step.

2508
P. G. de Lima, O. A. C. Antunes / Tetrahedron Letters 49 (2008) 2506–2509
Table 3
Conversion of PhI (1) in diphenylacetylene (3) with C
Table 4
2
0
20
4
PyNO
3
as solvent
Conversion of aryl halides in diphenyacetylenes via Scheme 2
Entry
1
Pd source
Cross coupling
1 Run (%)
2 Run (%)
Entry ArX
R
Product
Conversion (%)
Pd(OAc)
2
75 °C, 2 h
75 °C, 2 h
rt, 24 h
95
59
15
2
82
42
71
79
52
I
a
2
3
4
O N
Ph
Ph
a
2
b
1
(2)
77
rt, 24 h
(
5)
5
6
PdCl
2
75 °C, 2 h
75 °C, 2 h
rt, 24 h
76
55
73
NO2
4)
a
(
7
a
I
Absence of Ph
Et N was added on the induction step.
3
3
P.
b
a
MeO
2
22
98
(
7)
OMe
The results indicated that catalytic activity depends on
(
6)
the nature of the anion of the ionic liquid, temperature,
and of the nature of Pd(II) source, the first and last related
to the ability of the anions to complex with Pd(II). For
cross coupling at warmer conditions, it is supposed that
the corresponding anion in each case plays an important
role on the reaction profile, since the less coordinating ionic
liquids C PyPF and C PyNO provided active and recycl-
3
(m/z) 208, 193, 165
Br
O
Ph
4
91
(
9)
O
(8)
(
m/z) 220, 205, 176
4
6
4
3
able catalytic systems from both palladium precursors.
Therefore, to go further, C PyNO was employed as sol-
Br
4
3
vent to the Sonogashira cross-coupling reaction with other
aryl halides, keeping Pd(OAc)2 as palladium source
5
6
(1)
89
28
(
m/z) 178
(
10)
(
Scheme 2). These results are disclosed in Table 4.
The catalytic system formed after the induction period,
Br
in the absence of Ph P, converted the reactive iodoarene
3
4
and phenylacetylene (2) in 4-nitrodiphenylacetylene (5),
but it failed on the reaction with the deactivated aryl iodide
(entries 1 and 2). However, our usual catalyst afforded
(7)
OMe
11)
6
(
product 7 with high conversion (entry 3) and showed to
be efficient for aryl bromides 8 and 10, affording the corre-
sponding diphenylacetylenes 9 and 1 (entries 3–5). The cat-
alytic activity decreased for the deactivated substrate 4-
methoxybromobenzene (11) and for 1-octine (entries 6
and 7). The formation of the disubstituted acetylene 15
was possible only with the addition of Cu2I2 on the
cross-coupling step (entry 8).
(CH ) CH3
7
8
(1)
1-Octine
2 5
0
(
15)
b
(m/z) 186, 143, 115
82
a
Absence of Ph
Addition of Cu
3
P.
b
2
I
2
on the cross coupling step.
In conclusion, the use of C Py based ionic liquids
4
requires an induction period in EtOH that we hypothesized
as to assure the Pd(0) species formation. It has been made
The presence of the co-catalyst Cu
2
I
2
was necessary for
2
1
aliphatic acetylenes, which can be considered less acidic
than aromatic ones. The conversions obtained for
diphenylacetylene products in this study were similar to
possible to avoid the addition of both Cu(I) and Ph P when
3
using C PyPF as solvent and C PyNO in reactions
4
6
4
3
1
1
between phenylacetylene (2) and iodoarenes bearing elec-
tron-withdrawing groups. The catalytic system Pd(OAc)2/
Ph P/C PyNO , in the absence of Cu(I), proved to be suit-
those reported on bmim salts.
Acknowledgments
3
4
3
able to our purpose of obtaining a recyclable catalyst for
2
2,23
Sonogashira reaction at 75 °C.
This methodology was
Financial support from FINEP, CNPq, CAPES, and
FAPERJ, Brazilian Governmental Financing Agencies, is
gratefully acknowledged.
successfully applied to other less reactive aryl halides.
Pd(OAc) (4 mol %)
2
References and notes
ArX
+
R
Ar
R
Et N, Ph P
3
3
1. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467–4470; (b) Hierso, J. C.; Doucet, H. Angew. Chem., Int. Ed. 2007,
[
C4Py]NO3
4
6, 835.
Scheme 2. Cross coupling with others aryl halides and acetylenes.
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4
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8
9
under argon atmosphere, 21 mg of Ph
1 mL of EtOH and 1 mL of C PyNO
Pd(OAc) (0.04 mmol) was added and the resulting suspension was
3
P (0.08 mmol) was dissolved in
4
3
at 75 °C. Then, 8 mg of
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2
1
1
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1
1
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3
1 mmol), 110 lL of phenylacetylene (2, 1 mmol) and 0.2 mL of Et N
(1.5 mmol). After 2 h at 75 °C, the reaction medium was extracted
exhaustively (five times) with hexane. The organic layer was analyzed
1
1
1
by GC, GC–MS, H RMN. Diphenylacetylene (3)— H NMR
3
(200 MHz, CDCl ) d 7.31–7.38 (m, 6H), 7.51–7.56 (m, 4H); GC–MS:
16. Robinson, J.; Osteryoung, R. A. J. Am. Chem Soc. 1979, 101, 323–
m/z 178.
3
27.
23. General procedure for second run: The ionic phase in the reaction flask
was concentrated in a rotatory evaporator (10 min, 40 °C) and then
under high-vacuo (10 min). The resulted suspension was carried out in
argon atmosphere and charged with 110 lL of iodobenzene (1,
1
1
7. Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371–4374.
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Elsevier, C. J.; Rothenberg, G. Adv. Synth. Catal. 2005, 347, 1965–
1968.
3
1 mmol), 110 lL of phenylacetylene (2, 1 mmol) and 0.2 mL of Et N
1
9. Gaikward, A. V.; Holuigue, A.; Thathagar, M. B.; ten Elshof, J. E.;
(1.5 mmol). The reaction medium was carried out in cross-coupling
conditions and the extraction procedure was employed in the first run.
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