Highly efficient, recyclable Pd(II) catalysts with bisimidazole ligands for the heck reaction in ionic liquids

Article abstract of DOI:10.1021/ol030071d

(Matrix presented) New Pd(II) complexes with bisimidazole ligands were prepared and proved to be effective catalysts for the Heck reaction under phosphine-free conditions using ionic liquids as solvents. This system could be recycled five times without any loss of catalytic activity.

Full text of DOI:10.1021/ol030071d

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3209-3212
Highly Efficient, Recyclable Pd(II)
Catalysts with Bisimidazole Ligands for
the Heck Reaction in Ionic Liquids
Soon Bong Park and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry,
UniVersity of Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
halper@science.uottawa.ca
Received June 3, 2003
ABSTRACT
New Pd(II) complexes with bisimidazole ligands were prepared and proved to be effective catalysts for the Heck reaction under phosphine-free
conditions using ionic liquids as solvents. This system could be recycled five times without any loss of catalytic activity.
Palladium-catalyzed Csp2-Csp2 coupling reactions are widely
used for organic synthesis. For instance, vinyl substitution
(Heck reaction) is one of the most important, reliable, and
general reactions for C-C bond formation with applications
in the areas of bioactive compounds, natural products, and
high-performance materials.1 The Heck reaction is usually
carried out in the presence of bulky phosphine ligands, which
give Pd(0) species and accelerate the reaction rate. However,
many phosphines can be sensitive to air and moisture with
conversion to, for example, phosphine oxide species. The
latter can poison the metal leading to catalyst decomposition.
In such cases, catalyst reuse can be difficult.2 Hence, the
development of phosphine-free recycling catalytic systems
is of importance for the Heck reaction.3 There are also
significant economical and environmental reasons for de-
veloping recyclable catalytic reactions from both academic
and industrial perspectives.
ionic liquids. Since 1996, there have been extensive studies
on the palladium-phosphine-catalyzed Heck reactions in
ionic liquids.6 It is important to note the remarkable work
reported by Seddon and co-workers on the use of [bmim]-
[PF6] or [bmim][BF4] with PdCl2 or Pd2(dba)3 as a catalyst,
tri-o-tolylphosphine or triphenylphosphine as a ligand, and
Et3N or NaHCO3 as a base.7,8 Surprisingly, little attention
has been paid to phosphine-free Heck reactions.9
(2) For recent reviews, see: (a) Brase, S.; de Meijere, A. In Metal-
catalyzed Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998. (b) Crips, G. T. Chem. Soc. ReV. 1998, 27, 427.
(c) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 1998, 27, 427.
(3) (a) Peris, E.; Loch, J. A.; Mata, J.; Crabtree, R. H. Chem. Commun.
2001, 201. (b) Herrmann, W. A.; Elson, M.; Fisher, J.; Kocher, C.; Artus,
G. R. J. Angew. Chem., Int. Ed. 1995, 34, 2371. (c) Tulloch, A. A. D.;
Danopoulos, A. A.; Tooze, R. P.; Cafferkey, S. M.; Kleinhenz, S.;
Hursthouse, M. B. Chem. Commun. 2000, 1247. (d) Gruber, A. S.; Zim,
D.; Ebeling, G.; Osborn, P. L.; Liu, Y.-S. J. Am. Chem. Soc. 1999, 121,
9531. (e) Reetz, M. T.; Westermann, E. Angew. Chem., Int. Ed. 2000, 39,
165.
(4) (a) Bourque, S. C.; Maltais, F.; Xiao, W.-J.; Tardif, O.; Alper, H.;
Arya, P.; Manzer, L. E. J. Am. Chem. Soc. 1999, 121, 3035 (b) Bourque,
S. C.; Alper, H.; Manzer, L. E.; Arya, P. J. Am. Chem. Soc. 2000, 122,
956. (c) Arya, P.; Panda, G.; Rao. N. V.; Alper, H.; Bourque, S. C.; Manzer,
L. E. J. Am. Chem. Soc. 2001, 123, 2399. (d) Antebi, S.; Arya, P.; Manzer,
L. E.; Alper, H. J. Org. Chem. 2002, 67, 6623.
As an extension to our research in “recyclable catalytic
systems”,4 we became interested in the use of nonvolatile
room-temperature ionic liquids as reaction media.5 We now
wish to report preliminary results demonstrating the signifi-
cant enhancement of reactivity in the Heck reaction using
(5) For reviews, see: (a) Walton, T. Chem. ReV. 1999, 99, 2071. (b)
Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772. (c)
Sheldon, R. Chem. Commun. 2001, 2399. (d) Dupont, J.; de Souza, R. F.;
Suarez, P. A Z. Chem. ReV. 2002, 102, 3367 and references therein.
(6) Kaufmann, D. E.; Nouroozian, M.; Henze, H. Synlett. 1996, 1091.
(1) (a) Negishi, E., Ed.; Handbook of Organopalladium Chemistry for
Organic Synthesis; John Wiley & Sons: New York, 2002. (b) Tsuji, J.
Palladium Reagents and Catalysts. InnoVations in Organic Synthesis; Wiley:
Chichester, UK, 1995.
10.1021/ol030071d CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/07/2003

Our goal was to employ palladium complexes under
phosphine-free conditions to effect the Heck reaction on a
recyclable basis. Ionic liquids were chosen because of their
recyclability and reusability. The organic products can be
easily separated from the transition metal catalysts dissolved
in ionic liquids by simple extraction with normal organic
solvents. We reasoned that if the ligand has an imidazole
moiety, it will have high solubility in ionic liquids having
the imidazole skeleton. The ligands 1 and 2 were prepared
in 40 and 50% isolated yield by Ullmann coupling of 2-iodo-
1-methylimidazole and 2-iodo-1-methylbenzimidazole, re-
spectively, and copper metal. New Pd(II) 1a and 2a were
obtained in 96% yield from the reaction of Pd(cod)ClMe10
with equimolar amounts of 1 or 2 in dichloromethane for 2
h at 25 °C.
Table 2. Recyclable Heck Coupling of Iodobenzene with
n-Butyl Acrylate in [bmim][PF6]a
cycle no.b
entry
1
2
3
4
5
1
>99
>99
<5
>99
>99
>99
>99
>99
2c
3d
4e
>99
98
96
a All reactions were carried out using 3 mmol of iodobenzene, 1.25 equiv
of n-butyl acrylate, 1.5 equiv of Et3N, 2 mol % 1a, and 2 g of ionic liquid,
120 °C, 1 h. b Values given for each cycle are isolated yields (%).
c Performed with 0.2 mol % catalyst. d Performed with 0.02 mol % catalyst.
e Performed with 2 mol % of 2a.
The complexes are insensitive to oxygen or moisture; no
change of their activity was observed when they were
exposed to an open system in the Heck reaction. When Pd-
(cod)Cl2 or Pd2(dba)3 was employed, palladium black or an
insoluble solid was observed after an extended reaction time.
The catalytic activity of new Pd(II) complexes was examined
for the Heck reaction of bromobenzene and n-butyl acrylate
(Table 1). Using 2 mol % Pd(II) 1 and 2 g of [bmim][PF]6,
zene was coupled with the same acrylate (Table 2), the
reaction proceeded to completion at 120 °C within 1 h and
afforded only (E)-cinnamate in quantitative yield.
We were gratified to observe that the catalyst could be
recycled five times without any loss of activity. Furthermore,
the reaction was also successful using lower catalytic loading
(0.2 mol %), but reactions did not proceed at very low
catalyst concentrations (0.02 mol %). For comparison, when
we tried the same reaction under fixed conditions (2 mol %
catalyst, 120 °C, 1 h) in various organic solvents, the reaction
rates were significantly enhanced by using a polar solvent
(yield of 4-methyl-trans-cinnamic acid n-butylester; toluene
(17%), dioxane (49%), acetonitrile (71%), DMSO (98%),
NMP (99%), DMF (100%), [bmim][BF4] (99%)). In an
organic solvent, excellent catalytic activity is shown in
DMSO, NMP, and DMF. MeCN provides good results, but
dioxane and toluene are unsatisfactory. Since the catalyst
was decomposed in the workup step, it was impossible to
recycle the catalyst in all of these solvents. The reaction was
followed over a 1 h period, to determine the extent of
conversion as a function of time (see Figure 1 in Supporting
Information). It is noteworthy that the reaction reached 84%
conversion within 5 min and nearly all of the starting material
was converted to product after 30 min. This means that the
new Pd(II) catalyst is highly efficient for the Heck reaction
in ionic liquids. The reaction of iodoarenes containing elec-
tron-withdrawing or electron-donating substrates with n-butyl
acrylate was then run under the optimized conditions, and
the results are described in Table 3. All of the coupling
reactions proceeded smoothly to give the corresponding (E)-
cinnamates, with reuse of the catalyst without any loss of
activity. Small steric effects were found to be of importance
for complete conversion. A 1,1′-bisthiophene (ca. 20%) was
the side product of the reaction of 2-iodothiophene with n-
butyl acrylate, thus reducing the yield of the desired
product.11 A more versatile and practical test of the recy-
clability of the catalyst was examined, wherein each subse-
quent cycle was carried out with a different substrate. Starting
Table 1. Heck Coupling of Bromobenzene with n-Butyl
Acrylate in [bmim][PF6]a
entry
bsae (equiv)
temp (°C)
time (h)
yield (%)b
1
2
3
4
5
6
7c
8
NaOAc (1.3)
Na2CO3 (1.5)
Et3N (1.5)
first recyle
DIEA (1.5)
first recyle
DIEA (1.5)
first recyle
120
140
160
12
12
12
24
12
24
24
24
12
4
69
17
100
32
160
160
100
37
a All reactions were carried out using 3 mmol of bromobenzene, 1.25
equiv of n-butyl acrylate, 1.5 equiv of Et3N, 2 mol % 1a, and 2 g of the
ionic liquid. b 1H NMR yield. c 4-Bromoanisole was used.
we found that Et3N or DIEA is an efficient base without the
need for an extra ligand such as triphenylphosphine. Unfor-
tunately, it was difficult to recycle the catalyst because it
was slowly deactivated at high temperatures (160 °C) and
long reaction times (1 day). Below 160 °C, the reaction was
too sluggish to be of value. When the more active iodoben-
(7) Carmicheal, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac, P. B.;
Seddon, K. R. Org. Lett. 1999, 1, 997.
(8) (a) Xu, L.; Chen, W.; Xiao, J. Organometallics 2000, 19, 1123. (b)
Bohm, V. P.; Herrmann, W. A. Chem. Eur. J. 2000, 6, 1017. (c) Xu, L.;
Chen, W.; Ross, J.; Xiao, J. Org. Lett. 2001, 3, 295. (d) Selvakumar, K.;
Zapf, A.; Beller, M. Org. Lett. 2002, 4, 3031. (e) Vallin, K. S. A.; Emilsson,
P.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67, 6243.
(9) (a) Gianfranco, B.; Sandro, C.; Giancarlo, F. Synlett. 2002, 439. (b)
Consorti, C. S.; Zanini, M. L.; Leal, S.; Ebeling, G.; Dupont, J. Org. Lett.
2003, 5, 2881. (c) Nakoji. M.; Kanayama, T.; Okino, T.; Takemoto, Y.
Org. Lett. 2001, 3, 3328.
(10) Rulke, R. E.; Ernsting, J. M.; Spec, A. L.; Elsevier, C. J.; van
Leeuwen, P. W. N. M.; Vrieze, K. Inorg. Chem. 1993, 32, 5769.
3210
Org. Lett., Vol. 5, No. 18, 2003

Table 3. Heck Coupling of Iodoarenes with n-Butylacrylate in [bmim][PF6]a
a All reactions were carried out under the following conditions: 3 mmol of iodoarenes, 1.25 equiv of n-butyl acrylate, 1.5 equiv of Et3N, 2 mol % 1a,
and 2 g of the ionic liquid, 120 °C. b Isolated yield. c Bisthiophene was also formed in ∼20% yield. d 1-Bromo-(E)-cinnamate/1-iodo-(E)-cinnamate ) 3/1.
e Reactant began to sublime at 120 °C.
with 2 mol % catalyst, five Heck reactions were carried out
on a sequential basis (X ) H, CF3, CH3, NO2, OCH3), with
the products isolated by ethyl ether extraction, and the ionic
liquid was washed with water to remove the amine salt. The
recovered ionic liquid layer was reused without any pre-
treatment. No loss of catalytic activity was observed in this
reaction, thus making the process of potential use to industry
(Table 4).
To determine the scope of this catalytic system with other
vinyl substrates, 4-iodoanisole was reacted with different
unsaturates under identical conditions. Excellent results were
obtained for acrylates, butyl vinyl ether,13 and styrenes (Table
5). On the basis of the high catalytic activity of the new
Pd(II) complex, we also attempted a double-Heck reaction14
To examine the versatility of this method, the Heck
reaction was effected with iodoarenes with containing
electron-withdrawing or electron-donating substituents. The
results in Table 3 show that the conversions, regioselectivi-
ties, and yields were satisfactory within short reaction times.
Several other Heck reactions were examined, including ones
leading to lactone or lactam; specifically, ortho-hydroxy or
amino iodobenzene was reacted with n-butyl or methyl
acrylate under standard reaction conditions, affording prod-
ucts in quantitative yield.12 Each of the resulting ortho-
substituted (E)-cinnamates were then subjected to cyclization
to heterocycles, by refluxing in glycerol for 12 h, 60-99%
yield (see Scheme 2 in Supporting Information).
Table 4. Subsequent Recyclable Heck Reaction with Different
Iodoarenesa
cycle no.
X
time (h)
conversion (%)
yield (%)
1
2
3
4
5
H
CF3
CH3
NO2
OCH3
1
1
1
2
1
>99
95
>99
93
>99
95
98
93
98
>99
a All reactions were carried out using 3 mmol of the iodoarene, 1.25
equiv of n-butyl acrylate, 1.5 equiv of Et3N, 2 mol % 1a, and 2 g of the
ionic liquid, at 120 °C.
(11) Howarth, J.; James, P.; Dai, J. Tetrahedron Lett. 2000, 41, 10319.
Org. Lett., Vol. 5, No. 18, 2003
3211

Scheme 1. Synthesis of Bisimidazole Ligands and Palladium Complexesa
a Conditions: (a) MeLi, I2, THF, -78 °C then rt; (b) Cu, DMF, reflux, 4 h; (c) Pd(cod)ClMe, CH2Cl2, rt, 2 h.
by using an excess of iodoarene. â,â-Diphenylacrylates were
successfully synthesized with high conversion under standard
reaction conditions.15 The extent of reaction was dependent
on the catalyst loading and electronic factors. For example,
a sequential double-Heck reaction with different kinds of
iodoarenes (entries 7 and 8). These results are significant,
demonstrating the high reactivity of the catalyst system for
disubstitution.
Table 6. Double-Heck Coupling with Iodoarenes with n-Butyl
Acrylate in [Bmim]PF6
Table 5. Heck Coupling of 4-Iodoanisole with Vinyl
Compoundsa
a
Ar1-I
Ar2-I
time
(h)
conversion
(%)
yield
(%)
entry
X
conversion (%)
yield (%)
entry
(equiv)
(equiv)
1
2
3
4
5
CO2Me
99
99
85b
99
97
98
98
80b
99
95
1b
2c
3
4
5
6
7
8
PhI (3)
PhI (3)
PhI (3)
4-MeO-PhI (4)
4-Me-PhI (4)
4-CF3-PhI (4)
4-Me-PhI (1)
4-MeCOPhI (1)
30
24
24
4
4
4
12
41
74
88
81
d
8
30
65
80
80
t
CO2 Bu
OtBu
Ph
4-Cl-Ph
a All reactions were carried out using 3 mmol of 4-Iodoanisole, 1.25
equiv of the vinyl compound, 1.5 equiv of Et3N, 2 mol % 1a, and 2 g of
the ionic liquid, at 120 °C, 1 h. b R-Adduct/â-adduct ) 9/1.
PhI (3)
PhI (3)
4
4
76e
67f
70
60
a Unless otherwise indicated, all reactions were carried out using 3 mmol
of n-butyl acrylate, 5 equiv of Et3N, and 10 mol % of 1a at 120 °C.
b Performed with 2 mol % of 1a. c Performed with 5 mol % of 1a. d Double-
Heck product was not detected; dimer product was produced in 53% yield
on the basis of iodoarene. e E/Z ) 6/4. f E/Z ) 7/3.
12% conversion was observed with 2 mol % catalyst (Table
6, entry 1), but 74% conversion was achieved with 10 mol
% catalyst (entry 3). The iodoarene, 4-CF3C6H4I, containing
the electron-withdrawing CF3 group, gave mono-Heck reac-
tion in >99% yield with only the biaryl as the side product
(53% yield, entry 6). However, iodoarenes with electron-
donating groups gave diarylacrylates in excellent conversion
in 4 h (entries 4 and 5). Furthermore, it was possible to do
In summary, efficient Heck reactions have been realized
using ionic liquids and new Pd(II) catalysts. The Pd(II)
complexes having imidazole-like ligands were sufficiently
soluble in ionic liquids, enabling excellent and efficient Heck
reactions with various iodoarenes and vinyl moieties.
(12) (a) Kondo, Y.; Inamoto, K.; Sakamoto, T. J. Comb. Chem. 2000,
2, 232. (b) Cairns, N.; Harwood, L. M.; Astles, D. P.; Orr, A. J. Chem.
Soc., Perkin Trans. 1994, 3059. (c) Jones, G. H.; Venuti, M. C.; Alvarez,
P.; Bruno, J. J. Berks, A. H.; Prince, A. J. Med. Chem. 1987, 30, 295.
(13) Xu, L.; Chen, W.; Ross, T.; Xiao, T. Org. Lett. 2001, 3, 295.
(14) (a) Nilsson, P.; Larhed, M.; Hallberg, A. J Am. Chem. Soc. 2001,
123, 8217. (b) Itami, K.; Nokami, T.; Ishimura, Y.; Mitsudo, K.; Kamei,
T.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 123, 11577. (c) Tietze, L. F.;
Nobel, T.; Spescha, M. J. Am. Chem. Soc. 1998, 120, 8971.
Acknowledgment. We are grateful to the Natural Sci-
ences and Engineering Research Council of Canada for
support of this work.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) Initially, Ar1-I (1.0 equiv) was added to the reaction mixture to
give the monoarylated product (1 h) in situ, and then Ar2-I (3.0 equiv)
was added to the mixture with stirring for 3 h at 120 °C.
OL030071D
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Org. Lett., Vol. 5, No. 18, 2003