Microwave enhanced Glaser coupling under solvent free conditions

Article abstract of DOI:10.1055/s-2001-9726

A microwave enhanced, solvent free, Glaser coupling reaction has been developed. Self coupling of terminal alkynes on potassium fluoride-alumina in the presence of cupric chloride affords good yields of the corresponding diacetylenes.

Full text of DOI:10.1055/s-2001-9726

108
LETTER
Microwave Enhanced Glaser Coupling Under Solvent Free Conditions
G. W. Kabalka,* L. Wang, R. M. Pagni
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, Tennessee 37996-1600 USA
Fax (865)974-2997; Phone: (865)974-3260; E-mail: kabalka@utk.edu
Received 26 October 2000
methodology couples microwave irradiation with a solid-
state, solvent free approach which leads to enhanced
yields of the desired diacetylenes (Scheme 1).
Abstract: A microwave enhanced, solvent free, Glaser coupling re-
action has been developed. Self coupling of terminal alkynes on po-
tassium fluoride-alumina in the presence of cupric chloride affords
good yields of the corresponding diacetylenes.
Key words: Glaser coupling, microwave irradiation, terminal
alkynes, potassium fluoride on alumina, cupric chloride
CuCl2/KF/Al2O3
R
C
C
H
R
C
C
C
C
R
M.W.
Scheme 1
Diacetylenes are very important in biological, polymer
and material science.1-3 A useful method for preparing di-
acetylenes involves a cupric salt promoted self-coupling
reaction of terminal alkynes. In 1869, Glaser4 first ob-
served that terminal alkynes undergo oxidative coupling
to form diacetylenes in the presence of Cu2Cl2,O2, and
NH4Cl. Subsequent studies indicated that a variety of cop-
per salts are effective mediators for the coupling reaction
which is generally carried out in organic solvents such as
methanol, acetone, pyridine, methyl cellosolve and tolu-
ene. These solvents often pose waste handling problems
and the amines required in most Glaser reactions add to
the environmental burden.
In our initial studies, we attempted to optimize the reac-
tion conditions for the oxidative coupling of terminal
alkynes. The results are summarized in Table 1. Pheny-
lacetylene was chosen as the model compound for the op-
timization process.
Table 1 The effect of copper slats on the Glaser coupling of phe-
nylacetylenea
We have found alumina to be a particularly useful reagent
in an organic synthesis because it can be modified in a va-
riety of ways which enhance its reactivity.5 Furthermore,
alumina can be utilized to solve environmental problems
associated with organic solvents. For example, using a
commercially available alumina potassium fluoride mix-
ture, to which we added palladium powder, we were able
to carry out Suzuki and Sonogashira coupling reactions on
a wide variety of aromatic moieties without the use of sol-
vent.6-8
Microwave irradiation of organic reactions has also
gained in popularity in recent years since microwaves
were found to accelerate a wide variety of transforma-
tions.9,10 Early experiments utilized solvents with high di-
electric constants which permitted rapid heating of
reaction solutions. In recent years, a number of reports
have appeared in which the organic reagents are coated
onto surfaces which themselves absorb little or no micro-
wave energy; in these instances, the reaction species ab-
sorb the microwave energy but the bulk temperature of the
reaction mixture tends to rise only modestly. This results
in a relatively large energy savings as well as making it
possible to carry out reactions in relative simple glassware
such as open beakers and flasks.
aPhenylacetylene (1 mmole), Cu salt (3.7 mmole), base (40% by
weight)/Al2O3 (4 mmole); a 1000 watt microwave oven (Sharp Model
R-4A38) was used at 30% power for 8 minutes.
bIsolated yield.
From Table 1, it is evident that the yield of the coupling
reaction requires a copper salt. The efficiency of the Cu
salt decreases in the order: CuCl2>CuI-CuCl2>CuCl-
CuCl2>Cu2Cl2> CuCO3•Cu(OH)2>Cu(Ac)2>CuI. The use
of Cu(I) in the presence of an oxidizing agent was not ef-
fective (Entry 12).
We now wish to report a microwave enhanced, energy ef-
ficient modification of a solid-state Glaser reaction which
enhances the reaction’s eco-friendly attributes. The new
Synlett 2001, No. 1, 108–110 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Microwave Enhanced Glaser Coupling Under Solvent Free Conditions
109
Table 2 Glaser Coupling Reaction of Terminal Alkynesa
Yields (%)c
61
Diacetylenesb
Alkynes
n-C8H17C
Entry
1
n-C8H17C
n-C6H13C
C
C
CC8H17-n
CC6H13-n
CH
C
C
n-C6H13C
53
68
CH
2
3
56
4
5
Cl
F
Cl
Cl
54d
F
F
6
7
63
75
F
F
F
aReaction conditions: terminal alkyne (1 mmole), CuCl2 (0.5 g, 3.7 mmole), KF/Al2O3 (40% by weight, 0.6 g), a 1000 watt microwave
oven (Sharp Model R-4A38) was used at 30% power for 8 minutes for the reactions were halted after 2 minutes to allow the reaction to
cool.
bAll reaction products exhibit physical and spectral characteristics in accord with literature values.
cIsolated yield.
dSatisfactory elemental analysis was obtained.
The best reaction conditions for coupling were found to be ined the cross-coupling reaction between two different
CuCl2 (3.7 mmole), KF/Al2O3 (40% by weight, 0.6 g), ter- terminal alkynes but a mixture of products was obtained
minal alkyne (1 mmole) under microwave irradiation for (Scheme 2).
8 minutes. [Note: The reactions were stopped after two
Since aryl alkynes are often generated from the corre-
minutes to allow the mixture to cool and then were contin-
sponding trimethylsilyl reagents by bases such as potassi-
ued for six minutes.]
um carbonate and potassium fluoride,12 we examined the
A variety of terminal alkynes were successfully coupled Glaser coupling of 1-phenyl-2-(trimethylsilyl)-acetylene
using the optimized reaction conditions.11 The results are on potassium fluoride-alumina in the presence of cupric
summarized in Table 2.
chloride under microwave irradiation. The results shown
that diphenylbutadiyne was formed in the one-pot reac-
tion with moderate yield (68%), which was higher than
that of a two step sequence (total 64%)(Scheme3).
The date in Table 2 indicates that, under microwave irra-
diation and solvent free conditions, self-coupling of termi-
nal alkynes, occurs smoothly to produce the desired
diacetylenes in moderate to good yields. We also exam-
Synlett 2001, No. 1, 108–110 ISSN 0936-5214 © Thieme Stuttgart · New York

110
G. W. Kabalka et al.
LETTER
C8H17-n
40%
25%
CuCl2/KF/Al2O3
M.W.
+ n-C8H17
C
CH
n-C8H17
C
C
C
CC8H17-n
35%
Scheme 2
KF/Al2O3
(3) (a) Hansen, L.; Boll, P. M. Phytochemistry 1986, 25, 285.
(b) Sogogashira, K. in Comprehensive Organic Synthesis, ed.
Trost, B. M.; Fleming, I. Pergamon, Oxford 1991, vol. 3, p.
551. (c) Hudlicky, M. Oxidation in Organic Chemistry, ACS
Monograph 186, Washington DC 1990, p. 58.
C
CH
C
C
SiMe3
M. W.
85%
CuCl2/KF/Al2O3
CuCl2/KF/Al2O3
M. W.
75%
M. W.
68%
(4) (a) Glaser, C. Ber 1869, 2, 422. (b) Glaser, C. Ann. 1870, 154,
159.
(5) Kabalka, G. W.; Pagni, R. M. Tetrahedron 1997, 53, 7999.
(6) Kabalka, G. W.; Pagni, R. M.; Hair, C. M. Org. Lett. 1999, 1,
1423.
C
C
C
C
(7) Kabalka, G. W.; Pagni, R. M.; Wang, L.; Namboodiri, V.;
Hair, C. M. Green Chem. 2000, 2, 120.
(8) Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M.
Tetrahedron Lett. 2000, 41, 5151.
Scheme 3
(9) Varma, R. S. Green Chem. 1999, 1, 43.
(10) Bose, A. K.; Banik, B. K.; Lavlinskaia, N.; Jayaraman, M.;
Manhas, M. S. Chemtech 1997, 27, 18.
In summary, we have demonstrated that Glaser coupling
reactions proceed smoothly under solvent free conditions
when aided by microwave irradiation. The advantages of
this reaction are the mild, environmentally friendly reac-
tion conditions, simple operation, and good yields.
(11) The synthesis of diphenylbutadiyne is representative.
Phenylacetylene (102 mg, 1.0 mmole) was added to a mixture
of KF/Al2O3 (600 mg, 40% by weight) and cupric chloride
(500 mg, 3.7 mmole) contained in a clean, dry 10 mL round-
bottomed flask. The mixture was stirred at room temperature
to ensure efficient mixting. The flask was then fitted with a
septum (punctured by an 18 gauge needle), placed in the
microwave and irradiated at 30% power for two minutes and
then allowed to cool. The microwave irradiation was then
continued for six minutes. After cooling, hexane (3 mL) was
added and the slurry stirred at room temperature to ensure
product removal from the surface. The mixture was filtered
and the product was purified by flash chromatography to yield
76 mg of diphenylbutadiyne (75%).
Acknowledgement
We wish to thank the U. S. Department of Energy and the Robert H.
Cole Foundation for support of this research.
References and Notes
(1) (a) Kumar, A.; Rhodes, R. A.; Spychala, J.; Wilson, W. D.;
Boykin, D. W. Eur. J. Med. Chem. Chim. Ther. 1995, 30, 99.
(b) Kim, Y. S.; Jin, S. H.; Kim, S. L.; Hahn, D. R. Arch.
Pharm. Res. 1989, 12, 207. (c) Matsunaga, H.; Katano, M.;
Yamamoto, H.; Fujito, H.; Mori, M.; Tukata, K. Chem.
Pharm. Bull. 1990, 38, 3480.
(12) (a) Austin, W. B.; Bilow, N.; Kellegan, W. J.; Lau, K. S. Y. J.
Org. Chem. 1981, 46, 2280. (b) Arcadi, A.; Cacchi, S.;
Rasario, M. D.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996,
61, 9280.
(2) Park, Y. T.; Chiesel, N.; Economy, J. Mol. Cryst. Liq. Cryst.
Sci. Technol. Sec. A 1994, 247, 351.
Article Identifier:
1437-2096,E;2001,0,01,0108,0110,ftx,en;S05800ST.pdf
Synlett 2001, No. 1, 108–110 ISSN 0936-5214 © Thieme Stuttgart · New York