A novel indium-catalyzed sonogashira coupling reaction, effected in the absence of a copper salt, phosphine ligand and palladium

Article abstract of DOI:10.1055/s-2005-918948

An efficient copper-, phosphine ligand- and palladium-free indium-catalyzed Sonogashira coupling reaction has been developed in the presence of 1 mol% indium trichloride. Coupling of various aryl halides with terminal alkynes afforded the corresponding aryl alkynes in moderate to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918948

LETTER
2823
A Novel Indium-Catalyzed Sonogashira Coupling Reaction, Effected in the
Absence of a Copper Salt, Phosphine Ligand and Palladium
Indium-Catalyzed
a
Sonogashir
r
a
C
oupli
s
ng Reacti
h
on a N. Borah, Dipak Prajapati,* Ramesh C. Boruah
Department of Medicinal Chemistry, Regional Research Laboratory, Jorhat – 785 006, Assam, India
Fax +91(376)2370011; E-mail: dr_dprajapati@rediffmail.com
Received 21 July 2005
base or an amine as the solvent.7 It is also noteworthy that
Abstract: An efficient copper-, phosphine ligand- and palladium-
free indium-catalyzed Sonogashira coupling reaction has been de-
veloped in the presence of 1 mol% indium trichloride. Coupling of
various aryl halides with terminal alkynes afforded the correspond-
ing aryl alkynes in moderate to excellent yields.
alkynyl aluminates8 or alkynyl borates9 can be used for
alkynyl counterparts, resulting in chemoselectivity and
high yields in the absence of copper salts. Recently, some
copper- and amine-free methodologies for the Sonogash-
ira reaction have been reported.10 Stoichiometric amounts
of silver(I) oxide for aryl iodides, and tetrabutylammoni-
um fluoride or tetrabutylammonium hydroxide for aryl
bromides as activators have been used.11 A ligand-,
copper- and amine-free Sonogashira reaction has also
been reported.12 However, these copper- and amine-free
methodologies require high palladium-catalyst loading,
palladium complexes or ligands, which were expensive
and hard to synthesize. In a very recent finding, Leadbeat-
er has pointed out that his palladium-free Suzuki reaction
reported earlier10b actually proceeds using ultra-low quan-
tities of palladium contained in the sodium carbonate.10d
For these reasons, the development of efficient copper-
and phosphine-free methods is an area of current inter-
est.13 Herein we describe a mild and efficient indium(III)
chloride-catalyzed Sonogashira coupling reaction of aryl
halides with terminal alkynes to form internal alkynes in
high yields. The reaction is effected in the absence of a
copper co-catalyst, phosphine ligand and palladium met-
al. To the best of our knowledge this is the first report of
a Sonogashira coupling reaction catalyzed by indium.
Key words: Sonogashira coupling reaction, indium trichloride,
aryl halides, terminal alkynes
Over the past twenty-five years, the Sonogashira coupling
of terminal alkynes with (hetero)aryl halides has become
a most attractive and powerful tool for the preparation of
terminal and internal alkynes in organic synthesis.1 This
reaction can be applied to substrates carrying various
functional groups (thereby eliminating protection–depro-
tection sequences as well as functional group transforma-
tion) and has found wide application in the synthesis of
valuable compounds such as natural products and drugs
including the construction of complex enediyne antibiot-
ics.2 The Sonogashira reaction proceeds in the presence of
a homogeneous palladium/phosphine/copper salt catalytic
system, which makes the recovery of the metal tedious if
not impossible and might result in high palladium contam-
ination of the product. The reaction is, in general, carried
out with a large excess of secondary or tertiary alkyl
amine as a solvent/co-solvent and therefore application of
this protocol especially to large-scale preparations can
lead to environmental pollution due to the volatile nature
of these amines.3 In addition, many phosphine ligands em-
ployed are air-sensitive and expensive, which places sig-
nificant limits on their synthetic applications.4 The most
widely used palladium catalysts are Pd(PPh3)2Cl2,
Pd(OAc)2/DABCO, Pd(PPh3)4 or Pd/C in conjunction
Scheme 1
with copper(I) iodide.5 Nevertheless, all these Pd-cata- When aryl iodide 1 (R = H, X = I) was treated with 1.2
lyzed reactions are usually carried out in an organic–aque-
equivalents of phenyl acetylene in presence of anhydrous
ous medium and a co-solvent such as acetonitrile5a or indium chloride in dry benzene and was refluxed at 80 °C
DME5j is often required. To simplify the Sonogashira (3.5 h), after usual work up the corresponding diphenyl
reaction protocol, several important aspects have been acetylene 3 (R = H) was obtained in 80% yield
improved in recent years. The most important improve- (Scheme 1).14 Similarly, other aryl halides were reacted
ment was the elimination of copper(I) iodide, which was with terminal alkynes in the presence of indium chloride
used as the co-catalyst since it could induce a Glaser-type and the corresponding aryl alkynes were obtained in high
homocoupling reaction of terminal alkynes to diynes in yields. The reactions are generally clean and no side prod-
the presence of oxygen.6 To avoid this drawback, copper- ucts could be detected in the NMR spectra of the crude
free coupling reactions have been developed using strong products. All the products were characterized by high res-
olution spectral analyses and comparison with literature
data. The results of this study are summarized in Table 1.
By use of this indium-catalyzed reaction a variety of
terminal acetylenes was reacted with aryl halides. Aryl
SYNLETT 2005, No. 18, pp 2823–2825
Advanced online publication: 12.10.2005
DOI: 10.1055/s-2005-918948; Art ID: D20505ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
5

2824
H. N. Borah et al.
LETTER
iodides are known to react readily under the normal Sono-
gashira coupling condition and were found to be equally
reactive in the present case (entries 1, 7, 9). However, aryl
chlorides or bromides are available in far greater number
and their use is more economical. We therefore used a
variety of aryl chlorides, aryl bromides, or aryl fluorides
for the coupling reactions and they were also found to be
equally effective in terms of yields (Table 1). Yields were
not affected drastically due to the presence of either elec-
tron-donating or electron-withdrawing groups on the aryl
ring of the aryl halides. The coupling reaction between
terminal alkynes and a number of aryl iodides was readily
accomplished on a 1-mmol scale using 1 mol% of InCl3.
Approximately 0.1 equivalent of indium(III) chloride was
found to be sufficient for these reactions to proceed and
use of a large excess did not lead to either better yields or
faster reaction rates. The reaction conditions provided
highly reproducible yields in short reaction times.
References
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Table 1 Indium-Catalyzed Sonogashira Coupling Reaction
Entry
1
ArX
Time (h) Product
Yield (%)
80
3.5
4.0
3.5
4.0
4.0
3a
3b
3c
3d
3e
(4) (a) Homogeneous Catalysis with Metal Phosphine
Complexes; Pignolet, L. H., Ed.; Plenum: New York, 1983.
(b) Parshall, G. W.; Ittel, S. Homogeneous Catalysis; Wiley:
New York, 1992.
2
3
4
5
82
78
75
78
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A.; Repasi, J.; Kotschy, A. J. Org. Chem. 2003, 68, 3327.
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6
7
4.0
3.5
4.0
3.5
4.0
3f
3g
3h
3i
76
80
82
83
78
8
9
10
3j
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a Isolated yields.
In conclusion, the present methodology is simple to per-
form, efficient and does not involve the use of expensive
reagents or catalysts. Due to the operational simplicity as
well as easy isolation and purification procedures for the
products, the methodology appears to be a useful alterna-
tive to the conventional Sonogashira coupling reaction.
Acknowledgment
Leadbeater, N. E.; Sangi, M. S.; Williams, V. A.; Granados,
P.; Singer, R. D. J. Org. Chem. 2005, 70, 161.
(11) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.;
Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
(12) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 5752.
We thank the Department of Science & Technology (DST), New
Delhi, for financial support and Dr. P.G. Rao, Director, Regional
Research Laboratory, Jorhat, for his keen interest and constant
encouragement. We also thank S. Gadhwal for doing a few experi-
ments.
Synlett 2005, No. 18, 2823–2825 © Thieme Stuttgart · New York

LETTER
Indium-Catalyzed Sonogashira Coupling Reaction
2825
(13) For recent representative papers on ligand-free palladium
catalysts, see: (a) Alami, M.; Ferri, F.; Linstrumelle, G.
Tetrahedron Lett. 1993, 34, 6403. (b) Heidenreich, R. G.;
Kohler, K.; Krauter, J. G. E.; Pietsch, J. Synlett 2002, 1118.
(c) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69,
5752; and references cited therein. (d) Son, S. U.; Jang, Y.;
Park, J.; Na, H. B.; Park, H. M.; Yun, H. J.; Lee, J.; Hyeon,
T. J. Am. Chem. Soc. 2004, 126, 5026.
the completion of the reaction (monitored by TLC). After
completion of the reaction (3.5 h), the reaction mixture was
filtered, and the residue obtained, after evaporation of the
solvent, was chromatographed (silica gel column) using
CHCl3–PE (60–80, 1:3) to afford pure diphenyl acetylene in
80% yield; mp 60–61 °C. Similarly, other aryl halides were
reacted with terminal alkynes in the presence of InCl3 and
the corresponding aryl alkynes were obtained in high yields.
The reactions are generally clean and side products could be
detected in the NMR spectra of the crude products. All the
products were characterized by high resolution spectral
analyses and comparison with literature data. The results of
this study are summarized in Table 1.
(14) Representative Experimental Procedure for the
Synthesis of Aryl Alkynes 3.
In a typical procedure, a mixture of anhyd InCl3 (0.03 g, 0.1
mmol), iodobenzene (0.2 g, 1 mmol) and phenyl acetylene
(0.12 g, 1.2 mmol) was taken up in dry benzene (10 mL) in
a 50-mL round-bottom flask and was refluxed at 80 °C until
Synlett 2005, No. 18, 2823–2825 © Thieme Stuttgart · New York