Rapid microwave-enhanced, solventless Sonogashira coupling reaction on alumina

Article abstract of DOI:10.1016/S0040-4039(00)00774-7

A microwave-enhanced, solventless Sonogashira coupling reaction has been developed. Terminal alkynes couple with aryl or alkenyl iodide on palladium- doped alumina in the presence of triphenylphosphine and cuprous iodide to provide high yields of products. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00774-7

Tetrahedron Letters 41 (2000) 5151±5154
Rapid microwave-enhanced, solventless Sonogashira coupling
reaction on alumina
George W. Kabalka,* Lei Wang, Vasudevan Namboodiri and Richard M. Pagni
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600, USA
Received 11 May 2000; accepted 12 May 2000
Abstract
A microwave-enhanced, solventless Sonogashira coupling reaction has been developed. Terminal alkynes
couple with aryl or alkenyl iodide on palladium-doped alumina in the presence of triphenylphosphine and
cuprous iodide to provide high yields of products. # 2000 Published by Elsevier Science Ltd.
Keywords: coupling reactions; palladium; microwave heating; alkynes.
The Sonogashira coupling reaction of terminal alkynes and aryl or alkenyl halides provides an
ecient route to aryl alkynes.1 4 Numerous applications to natural product syntheses have been
reported, including the construction of complex enediyne antibiotics.5 7 The reaction is generally
carried out in organic solvents such as amines, benzene, THF and DMF along with complex
palladium catalysts which are soluble in these solvents. These soluble palladium reagents tend to
be expensive and sometimes dicult to manipulate and recover. The solvents also pose recycl-
ability (waste handling) problems of their own. In addition, amines such as piperidine, diethylamine
and triethylamine are required in most Sonogashira reactions and they add to the environmental
burden.
We have found alumina to be a particularly useful reagent in organic synthesis because it can
be modi®ed in a variety of ways which enhance its reactivity and it can be utilized to solve some
of the environmental problems associated with organic reagents.8,9 For example, using a com-
mercially available alumina potassium ¯uoride mixture, to which we added palladium powder
(the least expensive form of palladium available), we were able to carry out Suzuki reactions on a
wide variety of aromatic moieties without the use of solvents.9
Microwave irradiation of organic reactions has gained in popularity in recent years since it was
found to accelerate a wide variety of transformations.10,11 We now wish to report a microwave
enhanced, energy ecient modi®cation of a solid-state, Sonogashira reaction which enhances the
reaction's eco-friendly attributes. The new methodology couples microwave irradiation with a
solid-state, solvent free approach and leads to enhanced yields of the desired aryl alkynes.
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)00774-7

5152
The results are summarized in Table 1. The data indicate that, under microwave irradiation in
solvent free conditions, coupling readily occurs between a variety of aryl iodides, heteroaromatic
iodides and vinyl iodides with terminal alkynes. However, aryl bromides and aryl chlorides do
Table 1
Sonogashira coupling reaction of organic halides with alkynesa

5153
not react and the starting materials are recovered unchanged. Substituent e€ects were also
examined. The results indicate that an electron-donating group on the aromatic ring enhances
the reaction and leads to the desired product in excellent yields (97 and 93%, respectively, entries
d and e). Strong electron-withdrawing groups, lead to more moderate yields (82 and 67%,
respectively, entries h and i). It is interesting to note that a bulky group on the ortho-position of
the benzene ring did not inhibit the reaction (82%, entry k).
During the investigation, we found that the reaction did not occur in the absence of palladium,
cuprous iodide, or triphenylphosphine (entry a). CAUTION, the microwave reaction should not
be attempted in the absence of alumina which apparently acts as a temperature moderator.12
Without alumina, the liquid reactants can react uncontrollably in the presence of metallic palla-
dium (DANGER).
Larock and his co-worker have reported that indoles and benzofurans can be prepared by the
coupling terminal alkynes with o-iodoaniline and o-iodophenol, respectively, using palladium and
copper reagents.13,14 We found that coupling o-iodophenol with terminal alkyne produced the
cyclized product, benzofuran, in moderate yield. The coupling reaction of o-iodoaniline with
terminal alkynes is dependent on the reaction conditions. If a 1:1 ratio of o-iodoaniline to alkyne
is used, only the coupling product is obtained, and no cyclization product forms. This di€ers
from previously reported results.14 When the ratio of o-iodoaniline to alkyne is 2:1, a mixture of
cyclization and coupling products is formed (Fig. 1).
Figure 1.
The synthesis of 1-phenyl-1-decyne is representative. Iodobenzene (0.204 g, 1.000 mmol) and 1-
decyne (0.145 g, 1.050 mmol) were added to a mixture of KF/Al2O3 (1.000 g, 40% by weight),
palladium powder (0.040 g, 0.376 mmol, 99.9+% as a submicron powder), cuprous iodide (0.070
g, 0.368 mmol) and triphenylphosphine (0.180 g, 0.686 mmol) contained in a clean, dry, 25 mL
round-bottomed ¯ask. The mixture was stirred at room temperature to ensure ecient mixing.
The ¯ask was then ®tted with a septum (punctured by an 18 gauge needle), placed in the micro-
wave and irradiated at 100% power for 2.5 min. After cooling, hexane (5 mL) was added and the
slurry stirred at room temperature to ensure product removal from the surface. The mixture was
vacuum ®ltered using a sintered glass funnel and the product was puri®ed by ¯ash chromato-
graphy to yield 0.201 g of 1-phenyl-1-decyne (94%). The same reaction was carried out on a 10
mmol scale and resulted in slightly higher yields.

5154
In summary, a reliable, rapid and practical procedure for the synthesis of arylacetylenes via a
Sonogashira coupling reaction was developed which involves the use of a solvent-free mixture of
potassium ¯uoride on alumina under microwave irradiation conditions. The reaction is envi-
ronmentally friendly, and results in high yields of the desired product.
Acknowledgements
We wish to thank the US Department of Energy and the Robert H. Cole Foundation for
support of this research.
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