separated from the transition metal catalysts dissolved in the
ionic liquids by simple extraction with a conventional organic
solvent.5
Table 1. Palladium-Catalyzed Coupling Reaction of
Iodobenzene and Phenylacetylene in [BMIm][PF6]a
We report herein on the Sonogashira coupling reaction in
an ionic liquid, namely, 1-butyl-3-methylimidazolium hexaflu-
orophosphate (1, [BMIm][PF6]).6 Interestingly, using PdCl2-
entry
catalyst
yieldb (%)
1
2
3
4d
5
Pd(PPh3)4/CuI (5 mol %)
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd(OAc)2/PPh3 (10 mol %)
Pd(OAc)2
91
13
96 (95)c
96
83
61
(PPh3)2 as catalyst and diisopropylamine or piperidine as
base, the Sonogashira coupling reaction proceeded efficiently
without using a copper cocatalyst. We also report on the
successful execution of the Sonogashira reaction in a
microflow reaction system, which demonstrates the first
example of a homogeneous metal catalyzed reaction being
conducted in a microreactor.7
6
7
8
9
10e
11f
PdCl2
57
63
56
83c
80c
PdCl2(NCPh)2
PdCl2(NCMe)2
PdCl2(PPh3)2
PdCl2(PPh3)2
a Reactions were carried out using 1 mmol of 2a, 1.2 equiv of 3a, 3.6
equiv of iPr2NH, and 5 mol % of palladium catalyst in 3 mL of 1 at 60 °C
for 2 h. b GC yields. c Isolated yield. See footnote 8. d Reaction was
conducted with 1 mol % of PdCl2(PPh3)2 at 80 °C for 2 h. e Reaction was
conducted in 1-butyl-3-methylimidazolium tetrafluoroborate. f Reaction was
conducted in 1-ethyl-3-methylimidazolium tetrafluoroborate.
Thus, when the reaction of iodobenzene (2a) with phe-
nylacetylene (3a) was carried out in the presence of a
catalytic amount of Pd(PPh3)4/CuI (5 mol %) and diisopro-
pylamine (3.6 equiv) in 1 as a solvent at 60 °C for 2 h, the
coupling product, diphenylacetylene (4a), was formed in 91%
yield (Table 1, entry 1). The reaction, when conducted with
Pd(PPh3)4 alone, resulted in the dramatic decrease in the yield
of 4a (entry 2). Interestingly, however, when PdCl2(PPh3)2
was used as a catalyst, the coupling reaction occurred
smoothly even in the absence of a copper cocatalyst, giving
4a in 95% yield (entry 3).8,9 For comparison, we tested a
similar reaction with PdCl2(PPh3)2 in organic solvents, but
the results were less satisfactory (yield of 4a: toluene (48%),
THF (55%), and DMF (81%)10). A combination of palladium
acetate and triphenylphosphine also gave good results (entry
5). A reaction using palladium catalysts which contain no
phosphine ligands gave the coupling product in modest yields
(entries 6-9).11 Some other ionic liquids, such as 1-butyl-
3-methylimidazolium tetrafluoroborate ([BMIm][BF4]) and
1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIm]-
[BF4]), also worked well, but the yields of 4a were slightly
inferior (entries 10 and 11).
The coupling of several aryl halides and terminal acety-
lenes was carried out in the presence of the PdCl2(PPh3)2
catalyst (Table 2). All coupling products were easily
separated from the catalyst and solvent by extraction with
hexane or ether. The coupling reaction proceeded smoothly,
irrespective of whether the substituents of the aryl iodides
were electron-donating or electron-withdrawing, to give the
corresponding disubstituted acetylenes in high yields (entries
1-4). Heteroaromatic compound such as 2-iodothiophene
(2f) also reacted with 3a to give phenyletynylthiophene (4f)
in 85% yield (entry 5). The coupling reaction of vinyl
bromide 2g with 3a gave the anticipated enyne 4g in 86%
yield (entry 6). When aliphatic acetylenes, such as 1-octyne
(3b), were used, the reaction was sluggish without the use
of copper cocatalysts. However, the use of piperidine as a
base in place of diisopropylamine was found to be particu-
larly useful in creating a copper-free reaction system (entry
(5) For examples of transition-metal catalyzed reactions using ionic
liquids, see: (a) Calo`, V.; Nacci, A.; Lopez, L. Mannarini, N. Tetrahedron
Lett. 2000, 41, 8973. (b) Hagiwara, H.; Shimizu, Y.; Hoshi, T.; Suzuki, T.;
Ando, M.; Ohkubo, K.; Yokoyama, C. Tetrahedron Lett. 2001, 42, 4349.
(c) Mathews, C. J.; Smith, P. J.; Welton, T. Chem. Commun. 2000, 1249.
(d) Okazaki, H.; Kawanami, Y.; Yamamoto, K. Chem. Lett. 2001, 650. (e)
Bujisman, R. C.; Vuuren, E. V.; Sterrenburg, J. G. Org. Lett. 2001, 3, 3785.
See also ref 4g and references therein.
(6) Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.; Visser, A. E.;
Rogers, R. D. Chem. Commun. 1998, 1765.
(7) Ehrfeld, W.; Hessel, V.; Lo¨we, H. In Microreactors; Wiley-VCH:
Weinheim, 2000.
(8) General Procedure for the Sonogashira Coupling Reaction in an
Ionic Liquid. In a 20 mL two-necked round-bottom flask, equipped with
a magnetic stirrer bar and a reflux condenser, was placed 3 mL of 1. The
flask was then degassed under reduced pressure at room temperature for 1
h, and nitrogen gas was then introduced. To the ionic liquid was added
PdCl2(PPh3)2 (0.05 mmol, 35.1 mg), diisopropylamine (0.5 mL, 3.6 equiv),
2a (1 mmol, 204 mg), and 3a (1.2 mmol, 122 mg), and the resulting mixture
was heated in an oil bath at 60 °C for 2 h under nitrogen. Product was
extracted from the reaction mixture by the addition of hexane (5 mL),
followed by decanting off a hexane solution of the products. This was
repeated four additional times. After evaporation, the residue was purified
by flash chromatography on silica gel using hexane as the eluant (Rf )
0.34) to give 169 mg of diphenylacetylene (4a) (95% yield).
(9) Copper-free Sonogashira coupling reactions are not common. For
the reaction with a strong base, such as NaOCH3, see: (a) Cassar, L. J.
Organomet. Chem. 1975, 93, 253. The use of amine as solvents: (b) Dieck,
H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259. (c) Austin, W. B.;
Bilow, N.; Kelleghan, W. J.; Lau, K. S. Y. J. Org. Chem. 1981, 46, 2280.
(d) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993, 34, 6403.
Use of ammonium salts: (e) Nguefack, J.-F.; Bolitt, V.; Sinou, D.
Tetrahedron Lett. 1996, 37, 5527. (f) Mori, A.; Kawashima, J.; Shimada,
T.; Suguro, M.; Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
Ligand manipulation: (g) Wagner, R. W.; Johnson, T. E.; Li, F.; Lindsey,
J. S. J. Org. Chem. 1995, 60, 5266. (h) Bo¨hm, V. P. W.; Herrmann, W. A.
Eur. J. Org. Chem. 2000, 3679.
(10) The result with DMF appeared reasonable as a copper-free process.
However, the reaction with aliphatic acetylenes gave low yields of the
coupling products.
(11) Nevertheless, these results obtained using 1 are noteworthy, since
a similar reaction with Pd(OAc)2 conducted in toluene gave a poor result
(15%). For an example of a phosphine-free Sonogashira reaction, see ref
9d.
1692
Org. Lett., Vol. 4, No. 10, 2002