A copper-free Sonogashira reaction using a Pd/MgLa mixed oxide

Article abstract of DOI:10.1016/j.tetlet.2006.03.015

A new Pd/MgLa mixed oxide is found to be an efficient catalyst for the Sonogashira reaction of aryl iodides, bromides and even activated chlorides in the absence of a copper salt.

Full text of DOI:10.1016/j.tetlet.2006.03.015

Tetrahedron Letters 47 (2006) 3023–3026
A copper-free Sonogashira reaction using a Pd/MgLa mixed oxide
a
a,
b
*
Agnieszka Cwik, Zolt a´ n Hell and Fran c¸ ois Figueras
a
Department of Organic Chemical Technology, Budapest University of Technology and Economics, H-1521 Budapest, Hungary
b
Institut de Recherches sur la Catalyse, 2, Avenue Albert Einstein, 69626 Villeurbanne C e´ dex, France
Received 12 January 2006; revised 16 February 2006; accepted 2 March 2006
Available online 20 March 2006
Abstract—A new Pd/MgLa mixed oxide is found to be an efficient catalyst for the Sonogashira reaction of aryl iodides, bromides
and even activated chlorides in the absence of a copper salt.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
10
The Sonogashira cross-coupling reaction, discovered in
variety of promotors, such as Zn, Mg, Sn, and the
2
11
the mid seventies is a powerful method for C(sp)–C(sp )
use of microwave irradiation. Various copper-free
bond formation. It can be used in the synthesis of a vari-
conditions have also been developed for homogeneous
catalysis, which provides the opportunity to develop
2
3
12
ety of compounds, including heterocycles, several nat-
4
ural products and pharmaceuticals. Besides natural
the Sonogashira reaction under an ambient atmosphere,
1
3
products, oligomers and polymers have also been pre-
as the copper-mediated (Glaser-type reaction) oxida-
tive homocoupling of acetylenes is prevented. These
by-products (diaryldiacetylenes) are generally difficult
to separate from the desired products and copper acetyl-
5
pared via the Sonogashira reaction.
The reaction is generally carried out in an organic sol-
vent such as an amine, benzene, THF or DMF with a
complex palladium catalyst in conjunction with cop-
per(I) iodide as a co-catalyst, and in the presence of a
1
4
ide is a potentially explosive reagent. Furthermore,
extensive research has been carried out to discover and
develop more facile procedures, to improve metal acetyl-
ide coupling partners and to prepare more active palla-
6
stoichiometric amount of base. These palladium cata-
2
a
lysts, such as Pd (dba) , Pd(PPh ) or Pd(PPh ) Cl
dium catalysts.
2
3
3 4
3 2
2
are expensive and sometimes difficult to handle and re-
cover. These reactions usually require high catalyst load-
ings (up to 5 mol %), the diminution of which is
important from both economical and environmental
points of view.
Recently we have developed a new, air- and moisture-
stable Pd/MgLa mixed oxide, which proved to be an
efficient heterogeneous catalyst in the Heck and the
Suzuki–Miyaura reactions. The reactions can be per-
formed with only 1.5 mol % of the Pd catalyst. The
catalyst can be stored and handled under ambient
atmosphere, and it can be recovered from the reaction
mixture by simple filtration and reused without signifi-
cant loss of activity.
1
5
Pd(0)/Cu(I)
R
X +
H
R'
R
R'
base
R = aryl, vinyl
R' = alkyl, aryl, vinyl, etc.
In this letter, we have explored the activity of this new
catalyst towards the Sonogashira cross-coupling reac-
tion. The alkynylation process can be performed under
copper-free conditions in an air atmosphere.
In recent years numerous modifications have been
reported for the Sonogashira coupling procedure, such
7
8
as reaction in ionic liquids, reaction in aqueous media,
9
phase-transfer catalytic reaction conditions, use of a
II
The Pd /MgLa mixed oxide was prepared by ion ex-
change of the MgLa mixed oxide with Na PdCl using
2
4
Keywords: Heterogeneous catalysis; MgLa mixed oxide; Sonogashira
reaction.
1
6
the method reported by Choudary et al. We obtained
0
II
*
Corresponding author. Tel.: +36 1 463 1414; fax: +36 1 463 3648;
e-mail: zhell@mail.bme.hu
the Pd /MgLa mixed oxide by reduction of Pd /MgLa
with hydrazine hydrate. The palladium content was
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.015

3024
A. Cwik et al. / Tetrahedron Letters 47 (2006) 3023–3026
determined by ICP-OES and shown to be 0.84 and
nificantly. The effect of substituents was also examined
in this reaction. The results are summarized in Table
II
0
0
.73 mmol/g in Pd /MgLa and Pd /MgLa, respectively.
1
. Aryl bromides and electron deficient aryl chlorides
Based on our previous results for the Heck cross-cou-
with aryl alkynes gave the corresponding aryl-substi-
tuted acetylenes in high yield. The less active electron-
rich p-bromotoluene produced a lower yield (entry 6).
Steric effects did not influence the yield significantly,
for example, in the reaction of o-bromoacetophenone
with phenylacetylene the corresponding coupled prod-
uct was obtained in 84% yield (entry 8). The reaction
also showed excellent functional group tolerance as
was evident from the successful coupling of o-bromo-,
or o- and p-chlorobenzaldehyde with phenylacetylene
(entries 9, 13 and 14).
1
5a
pling reaction,
DMF was chosen as solvent and tri-
ethylamine as base. In accordance with the results
0
described in the literature Pd also showed higher cata-
II
17
lytic activity than Pd in our heterogeneous system. In
a typical experiment (Scheme 1), a slight excess of the
acetylene (1.2 equiv) was added to a solution of the aryl
halide in freshly distilled DMF and Et N. Then, the cat-
3
alyst was added and the reaction mixture was stirred at
8
0 ꢁC. The course of the reaction was followed by TLC.
Thus, in the reaction of iodobenzene with phenylacetyl-
ene in the presence of Pd /MgLa oxide, the coupling
0
product was obtained in 90% yield after 10 h (Table 1,
entry 1). When the less reactive acetylene, 1-heptyne
was used under these conditions, the coupling product
Comparing these results with those obtained using cur-
rent Pd-catalysts, we have found that the yields are
almost the same as the described ones, for example, with
6
3
d was produced efficiently (entry 4). The coupling of
the homogeneous catalyst Pd(PPh ) Cl . The reactivity
3
2
2
propargyl alcohol with phenyl iodide also led to the cor-
responding product, although extraction of the product
was laborious, because of the formation of an emulsion
of the different aryl halides followed the established or-
der, iodide > bromide ꢀ chloride. A somewhat longer
reaction time was required in order to obtain good
yields; this is a result of the heterogeneous reaction sys-
tem. Excellent results were obtained with only 1.5 mol %
Pd. No by-products were observed, diaryldiacetylenes,
which are the most common by-products observed in
the reaction using a homogeneous catalyst together with
a copper salt co-catalyst were not isolated. Another
advantage of our catalyst is that the reactions can be
carried out under an ambient atmosphere. The handling
of the catalyst is also simple. The heterogeneous reaction
system allows easy work-up; the catalyst was filtered off
and could be recovered quantitatively. The pure product
was also obtained easily.
(
entry 2). An improved result was obtained when the hy-
droxyl group was protected with a THP group (entry 3).
Under homogeneous copper-free coupling reaction con-
ditions, aryl bromides give rather low conversions (10–
6
6
0%). In our case, the reaction of bromobenzene with
phenylacetylene afforded a 64% yield after 24 h. How-
ever, chlorobenzene, under the above reaction condi-
tions showed less activity and gave only 22% of
diphenylacetylene even after 24 h. Increased catalyst
loading (0.05 g, 3.7 mol %) did not improve the yield sig-
We also examined the reusability of the Pd/MgLa cata-
lyst in the reaction between iodobenzene and phenyl-
acetylene. After the first run the catalyst was separated
by filtration, and was then reused in the presence of
Pd/MgLa
R
R
+
Et N
3
X
DMF
Et N in DMF without any regeneration at 80 ꢁC. It
3
1
2
3
was observed, that the catalyst could be used without
any significant loss of activity (the use of 1.5 mol % of
Scheme 1.
0
19
Table 1. Sonogashira reaction of aryl halides catalyzed by the Pd /MgLa mixed oxide
a
Entry
Aryl halide
Acetylene
Product
Catalyst (Pd mol %)
Time (h)
Yield (%)
2
0
b
1
2
3
4
5
6
7
8
9
C
C
C
C
C
4-CH
4-CH
2-CH
6
6
6
6
6
H
H
H
H
H
5
5
5
5
5
I
I
I
I
Phenylacetylene
3a
3b
3c
3d
3a
3e
3f
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
10
20
20
10
24
20
20
20
20
24
24
24
24
24
24
90 (85)
Propargyl alcohol
3-Tetrahydropyranyloxy-prop-1-yne
1-Heptyne
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
70
74
81
64
60
86
84
82
22
28
55
63
68
67
Br
3
3
3
C
COC
COC
6
H
4
Br
6
H
6
H
4
Br
Br
4
3g
3h
3a
2-CHOC
Cl
6
H
4
Br
1
0
C
6
H
5
3
.7
1
1
1
1
1
2
3
4
4-CH
2-CH
4-CHOC
2-CHOC
3
COC
COC
6
H
H
4
Cl
Cl
Phenylacetylene
Phenylacetylene
Phenylacetylene
Phenylacetylene
3i
3j
1.5
1.5
1.5
1.5
3
6
4
6
H
4
Cl
Cl
3k
3l
6
H
4
a
Isolated yield.
Yield with recycled catalyst.
b

A. Cwik et al. / Tetrahedron Letters 47 (2006) 3023–3026
3025
R
OH
R
O
Pd/MgLa
+
Et N, DMF
3
X
4
5
Scheme 2.
References and notes
Table 2. Sonogashira reaction between phenylacetylene and halo-
phenols
1
. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467; (b) Sonogashira, K.; Yatake, T.;
Tohda, Y.; Takahashi, S.; Hagihara, N. J. Chem. Soc.,
Chem. Commun. 1977, 291; (c) Takahashi, S.; Kuroyama,
Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627.
. (a) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42,
a
Entry
R
X
Yield (%)
1
2
3
H
CH
H
I
Br
Cl
61
<10
<10
3
2
3
4
a
1
Based on H NMR spectra.
1
1
566; (b) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103,
979.
. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Tetrahedron Organic Chemistry Series; Perg-
amon: Amsterdam, 2000; Vol. 20.
. (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1387; (b) Grissom, J. M.; Gunawardena,
G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52,
Pd catalyst in the third cycle gave diphenylacetylene
with 85% isolated yield). The recovered catalyst was
examined by ICP and no significant decrease in the pal-
ladium content was found. The leaching of palladium
was examined using the hot filtration test. When the cat-
alyst was removed from the hot reaction mixture by fil-
tration the reaction stopped as was evident from the
spectroscopic examination of the reaction mixture. This
indicates that using our heterogeneous Pd catalyst, pal-
ladium-contamination of the product, which is one of
the biggest problems of the homogeneous catalyst sys-
tems, can be eliminated.
6
453; (c) 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; (d) Lang, P.;
Magnin, G.; Mathis, G.; Burger, A.; Biellmann, J.-F. J.
Org. Chem. 2000, 65, 7825; (e) Uenishi, J.-I.; Matsui, K.;
Ohmiya, H. J. Organomet. Chem. 2002, 653, 141.
5
. (a) Ziener, U.; Godt, A. J. Org. Chem. 1997, 62, 6137; (b)
Francke, V.; Mangel, T.; Muellen, K. Macromolecules
1
998, 31, 2447; (c) Huang, S.; Tour, J. M. Tetrahedron
Larock et al.18 have reported that benzofurans and in-
Lett. 1999, 40, 3347.
. Sonogashira, K. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: New York,
6
doles can be obtained during the palladium-catalyzed
Sonogashira coupling in the reaction of terminal alkynes
with o-iodophenols and o-iodoaniline. We investigated
the reactivity of various phenols in the Sonogashira
reaction with phenylacetylene (Scheme 2). In the reac-
tion of o-chlorophenol and 2-bromo-5-methyl-phenol
with phenylacetylene (Table 2, entries 2 and 3), based
1
991; Vol. 3, p 521.
7
. Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu,
I. Org. Lett. 2004, 4, 1691.
8. Genet, J. P.; Blart, E.; Savignac, M. Synlett 1992, 715.
9. Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y.
J. Org. Chem. 2001, 66, 1910.
1
1
0. (a) Powell, N. A.; Rychnosky, S. D. Tetrahedron Lett.
on H NMR spectra, only ca. 10% yield of the desired
1
996, 37, 7901; (b) Crisp, G. T.; Turner, P. D.; Stephens,
benzofurans was observed, which can be explained due
to the low activity of the bromo- and chloro-com-
pounds. However, in the reaction with o-iodophenol
K. A. J. Organomet. Chem. 1998, 570, 219; (c) Nakamura,
K.; Ohubo, H.; Yamaguchi, M. Synlett 1999, 549.
1. Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M.
Tetrahedron Lett. 2000, 41, 5151.
2. (a) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295;
(b) Alonso, D. A.; N a´ jera, C.; Pacheco, M. C. Tetrahedron
Lett. 2002, 43, 9365; (c) Leadbeater, N. E.; Tominack, B.
J. Tetrahedron Lett. 2003, 44, 8653; (d) B o¨ hm, V. P.;
Herrmann, W. A. J. Org. Chem. 2000, 3679.
3. Siemsen, P.; Livingston, R. C.; Diederich, F. Angew.
Chem., Int. Ed. 2000, 39, 2632.
4. Cheng, J.; Sun, Y.; Wang, F.; Guo, M.; Xu, J.-H.; Pan, Y.;
Zhang, Z. J. Org Chem. 2004, 69, 5428.
1
1
(
entry 1) benzofuran 5 was obtained in 61% yield.
In summary, the Pd/MgLa mixed oxide is an efficient
catalyst in the Sonogashira cross-coupling reaction.
The advantages of this method are as follows: a hetero-
geneous system, which allows the full recovery and reuse
of the catalyst, the palladium remains on the surface of
the solid material, no leaching was observed and no cop-
per salt is required.
1
1
1
5. (a) Cwik, A.; Hell, Z.; Figueras, F. Adv. Synth. Catal.
2
006, 348, 523; (b) Cwik, A.; Hell, Z.; Figueras, F. Org.
Biomol. Chem. 2005, 3, 4307.
Acknowledgements
1
1
1
6. Choudary, B. M.; Madhi, S.; Chowdari, N. S.; Kantam,
M. L.; Sreedhar, B. J. Am. Chem. Soc. 2002, 124, 14127.
7. Djakovitch, L.; Koehler, K. J. Mol. Catal. A: Chem. 1999,
The financial support of the Hungarian Scientific
Research Fund (OTKA T-037757) is gratefully
acknowledged. This work was carried out within the
framework of the Hungarian-French intergovernmental
scientific and technological cooperation, T e´ T project
No. F-8/02.
1
42, 275.
8. Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C.
J. Org. Chem. 1995, 60, 3270.
19. General procedure for the Sonogashira cross-coupling
reaction: In typical reaction, Pd/MgLa (0.02 g,
a

3026
A. Cwik et al. / Tetrahedron Letters 47 (2006) 3023–3026
1
(
.5 mol % of Pd) was added to a mixture of aryl halide
1 mmol), acetylene (1.2 mmol) and Et N (1.2 mmol) in
DMF (5 mL). The mixture was stirred at 80 ꢁC for 10–
5 h. Then the catalyst was filtered out and washed with
necessary, was purified by column chromatography or
3
recrystallized, yielding the corresponding acetylene.
Known products were characterized by comparing their
1
13
2
H NMR, C NMR and melting points with those
hexane. The reaction mixture was diluted with water and
extracted with hexane (2 · 10 mL). The combined organic
extracts were washed with water and brine, dried over
reported in the literature.
20. Selected data of diphenylacetylene (3a): mp: 58–60 ꢁC (lit.
1
3
59–61 ꢁC). C NMR (75.48 MHz, CDCl ) d (ppm): 89.5,
3
MgSO
4
and evaporated to give the product. The residue, if
123.4, 128.2, 128.4, 131.5.