Highly Efficient Heck Reactions of Aryl Bromides with n-Butyl Acrylate Mediated by a Palladium/Phosphine-Imidazolium Salt System

Article abstract of DOI:10.1021/ol015827s

matrix presented A new phosphine-imidazolium salt, L·HBr (1, L = (1-ethylenediphenylphosphino-3-(mesityl))imidazol-2-ylidene), has been prepared. A combination of 0.5 mol % of Pd(dba)₂ and 0.5 mol % of L·HBr in the presence of 2 equiv of Cs

Full text of DOI:10.1021/ol015827s

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1511-1514
Highly Efficient Heck Reactions of Aryl
Bromides with n-Butyl Acrylate
Mediated by a Palladium/
Phosphine−Imidazolium Salt System
Chuluo Yang, Hon Man Lee, and Steven P. Nolan*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
snolan@uno.edu
Received March 12, 2001
ABSTRACT
A new phosphine−imidazolium salt, L‚HBr (1, L ) (1-ethylenediphenylphosphino-3-(mesityl))imidazol-2-ylidene), has been prepared. A combination
of 0.5 mol % of Pd(dba)2 and 0.5 mol % of L‚HBr in the presence of 2 equiv of Cs2CO as base has proven to be highly efficient in the Heck
3
coupling reactions of aryl bromides (from electron-deficient to electron-rich aryl bromides) with n-butyl acrylate.
The use of monodentate phosphines in the Pd-catalyzed Heck
reaction provides a most efficient catalytic system for the
syntheses of substituted olefins.1 The primary role of the
phosphine ligands is to support palladium in the form of
stable PdL4 or PdL3 species which can subsequently enter
the catalytic cycle and thereby help prevent the formation
of inactive palladium black aggregates. Reactions involving
the less reactive aryl bromides and aryl chlorides require
electron-donating, bulky tertiary phosphines, such as P(t-
Bu)3, as supporting ligand in order to assist in the initial
oxidative-addition of C-X bonds.2 However, under Heck
conditions, phosphines and their palladium complexes are
subject to decomposition. Hence, excess phosphine has to
be employed. This is undesirable for large-scale applications
since phosphines, especially electron-rich phosphines, are
expensive. The use of excess ligand also reduces the reaction
rates, and in order to counterbalance this negative effect a
higher palladium loading is necessary to achieve acceptable
catalytic activities.
Bidentate chelating phosphines, in principle, can provide
more stable (1:1) Pd(L-L) complexes suitable for Heck
reactions and thereby avoid the use of excess phosphine and
high loadings of palladium. However, catalytic systems based
on bidentate phosphine ligands have displayed limited
successes.3
(1) (a) Beletskaya, I.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(b) Reetz, M. T. In Transition Metal Catalyzed Reactions; Davies, S. G.,
Murahashi, S,-I., Eds.; Blackwell Science: Oxford, 1999. (c) Grisp, G. T.
Chem. Soc. ReV. 1998, 27, 427. (d) Link, J. T.; Overman, L. E. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998. (e) Link, J. T.; Overman, L. E. Chemtech
1998, 28, 19. (f) Brase, S.; deMeijere, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998.
(g) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083. (h) Dieck, H.
A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 1133.
Recently, nucleophilic N-heterocyclic carbenes, or so-
called “phosphine mimics”, have attracted a considerable
amount of attention.4 These ligands are strong σ-donors with
negligible π-accepting ability,5 and in this respect, they
(3) (a) Shaw, B. L.; Perera, S. D. Chem. Commun. 1998, 1863. (b)
Overman, L. E.; Poon, D. J. Angew. Chem. 1997, 36, 518. (c) Cabri, W.;
Candiani, I. Acc. Chem. Res. 1995, 28, 2. (d) Cabri, W.; Candiani, I.;
Bedeschi, A. J. Org. Chem. 1992, 57, 3558.
(2) Littke, A. F.; Fu. G. C. J. Org. Chem. 1999, 64, 10.
10.1021/ol015827s CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/26/2001

resemble donor phosphines. In contrast to metal phosphine
complexes, they form metal complexes that have higher
stability toward heat, moisture, and oxygen. Improved
catalytic performance has been achieved by the exchange
of bulky electron-donating phosphine ligands with nucleo-
philic carbenes in various catalytic reactions such as Suzuki-
type coupling reactions,6 amination of aryl chlorides,7 olefin
metathesis,8 and hydrogenations.9 The beneficial properties
provided by nucleophilic carbene ligands make them a
potential ligand family for the Heck reaction. In fact, some
early work by Herrmann, Cavell, and others has shown that
several Pd carbene complexes were highly efficient in Heck
reactions.10
In view of the general usage of phosphines and the
potential of carbene ligands in Heck reactions, we examined
mixed phosphine-imidazolium salt bidentate ligands as
desirable ligation for Heck chemistry. The chelating phos-
phine-carbene ligand derived from the imidazolium salt
would potentially form a more stable palladium catalyst, so
that use of excess ligand and high loadings of palladium
might be avoided. Indeed, a recent theoretical calculation
shows that a chelating ligand, which consists of a carbene
and a phosphine moiety, is suitable for the Pd-catalyzed Heck
reaction.11 However, no experimental data have yet been
provided to support the calculations. We now report the
synthesis of the new phosphine-imidazolium salt L‚HBr (1,
L ) (1-ethylenediphenylphosphino-3-(mesityl))imidazol-2-
ylidene) and its application in Pd-catalyzed Heck reaction
of aryl halides with n-butyl acrylate.
nylphosphide, which was prepared in situ by mixing diphe-
nylphosphine and KOBut in DMSO, gave the phosphine-
imidazolium salt in 91% yield. It should be mentioned that
the position of the imidazolium proton was unaffected by
the addition of potassium diphenylphosphide.12
Recent work in our laboratories has established that active
Pd-carbene species can be formed in situ (under basic
conditions) from an imidazolium salt in various C-C and
C-N coupling reactions.6b-d In our initial experiments, we
applied a similar protocol to a catalytic system consisting
of 0.5 mol % of Pd(dba)2, 0.5 mol % of L‚HBr (1), and 1.4
equiv of Cs2CO3, as base, in N,N-dimethylacetamide (DMAc)
at 120 °C. This system proved to be highly efficient in Heck
coupling of 4-bromotoluene with n-butyl acrylate. The
reaction proceeded very rapidly and reached almost comple-
tion in 4 h (eq 1). An independent experiment without the
addition of 1 showed no Heck activity. A recent review
addresses conditions for a ligand-free Heck reaction.13 The
present study involves a ligand-accelerated conversion.
Investigations into the optimum solvent for this reaction
showed that reaction rates were significantly enhanced by
using polar solvents, with N,N-dimethylacetamide being the
solvent of choice (Table 1). The reaction rates were also very
The phosphine-imidazolium salt L‚HBr (1) was prepared
in a two-step procedure (Scheme 1). A THF solution of
Table 1. Effect of the Solvent on the Heck Reaction of
4-Bromobenzene with n-Butyl Acrylatea
Scheme 1. Synthesis of L‚HBr (1, L )
(1-Ethylenediphenylphosphino-3-(mesityl))imidazol-2-ylidene)
entry
solvent
yieldb (%)
1
2
3
4
THF
dioxane
DMF
8
27
62
96
DMAc
a Reaction condition: 1 mmol of 4-bromotoluene, 1.4 mmol of n-butyl
acrylate. b GC yield (diethylene glycol di-n-butyl ether as GC standard; an
average of two runs).
1-(mesityl)imidazole was treated with a 4-fold excess of 1,2-
dibromoethane. The intermediate bromine-imidazolium salt
slowly precipitated as a white solid during the course of 2
days. Addition of the imidazolium salt to potassium diphe-
dependent on the base employed (Table 2). A remarkable
increase in activity was observed with Cs2CO3. The use of
2 equiv, rather than 1.4, was found to be optimal. Other
(4) (a) Bourissou, D.; Guerret, O.; Gabba¨ı, F. P.; Bertrand, G. Chem.
ReV. 2000, 100, 39, and references therein. (b) Chatterjee, A. K.; Grubbs,
R. H. Org. Lett. 2000, 1, 1751. (c) Scholl, M.; Trnka, T. M.; Morgan, J. P.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247. (d) Jafarpour, L.; Schanz,
H. J.; Stevens, E. D.; Nolan, S. P. Organometallics 1999, 18, 5416. (e)
Dullius, J. E. L.; Suarez, P. A. Z.; Einloft, S.; de Souza, R. F.; Dupont, J.;
Fischer, J.; De Cian. A. Organometallics 1998, 17, 815. (f) Adruengo, A.
J., III; Krafczyk, R. Chem. Z. 1998, 32, 6. (g) Herrmann, W. A.; Ko¨cher,
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 2162. (h) Regitz, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 725.
(6) (a) Bo¨hm, V. P. W.; Gsto¨ttmayr, C. W. K.; Weskamp, T.; Herrmann,
W. A. J. Organomet. Chem. 2000, 595, 186. (b) Lee, H. M.; Nolan, S. P.
Org. Lett. 2000, 2, 2053. (c) Zhang, C.; Huang, J.; Trudell, M. L.; Nolan,
S. P. J. Org. Chem. 1999, 64, 3804. (d) Huang, J.; Nolan, S. P. J. Am.
Chem. Soc. 1999, 121, 9889.
(7) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307.
(8) (a) Huang, J.; Stevens, E. D.; Nolan, S. P. Peterson, J. L. J. Am.
Chem. Soc. 1999, 121, 2674. (b) Huang, J.; Schanz, H. J.; Stevens, E. D.;
Nolan, S. P. Organometallics 1999, 18, 5375.
(5) Green, J. C.; Scurr, R. G.; Arnold, P. L.; Cloke, G. N. Chem.
Commun. 1997, 1963.
1512
Org. Lett., Vol. 3, No. 10, 2001

Table 2. Effect of the Base on the Heck Reaction of
4-Bromobenzene and n-Butyl Acrylatea
Table 3. Pd/1-Catalyzed Heck Reaction of Aryl Halides with
n-Butyl Acrylatea
entry
base
none
yieldb (%)
1
2
3
4
5
6
0
5c
0d
12
6
NEt3
KOBut
NaOAc
K2CO3
Cs2CO3
96
a Reaction condition: 1 mmol of 4-bromotoluene, 1.4 mmol of n-butyl
acrylate. b GC yield (diethylene glycol di-n-butyl ether as GC standard; an
average of two runs). c Biphenyl as major product. d Decomposition.
inorganic and organic bases resulted in poorer yields.
Substitution of Pd(dba)2 with Pd(OAc)2 in the catalytic
protocol resulted in a significant decrease in activity with
only a 47% yield of the coupled product.
Under our optimized reaction conditions (0.5 mol % of
Pd(dba)2, 0.5 mol % of L‚HBr, 2 equiv of Cs2CO3, N,N-
dimethylacetamide, 120 °C), excellent yields of coupled
products could be obtained for a wide array of aryl bromides
with n-butyl acrylate (Table 3). For example, the electron-
deficient 4-bromobenzaldyde was completely converted to
the coupled product in ca. 15 min (entry 1). For electron-
neutral bromides (bromobenzene, 4-bromotoluene, and 5-bro-
mo-m-xylene), complete conversions could also be obtained
in less than 2 h (entries 2, 3, and 5). For a sterically congested
substrate, 2-bromotoluene, a yield of 35% could be reached
in 1 h (entry 4). Longer reaction times afforded a side product
resulting from a dehalogenation process. Remarkably, the
catalytic system was equally efficient for an electron-donating
bromide. A complete conversion could be obtained for
3-bromoanisole and 4-bromoanisole yielding n-butyl trans-
methoxycinnamate in less than 3 h (entries 6 and 7). It
should be noted that in all cases only the trans products were
a Reaction condition: 1 mmol of aryl halide, 1.4 mmol of n-butyl acrylate.
b GC yield (diethylene glycol di-n-butyl ether as GC standard; an average
of two runs). c Isolated yield.
Attempts had been made to use electron-deficient aryl
chlorides as substrates, such as 4-chlorobenzaldehyde and
4-chloroacetophenone. However, no desirable coupled prod-
ucts were obtained. For the electron-neutral chlorobenzene
(entry 8) the desired coupling product was obtained, although
in a low yield of 13% in 2 h. A prolong reaction time resulted
in significant side reaction.
1
selectively obtained as confirmed by GC and H NMR.
As stated above, a combination of Pd/IMes‚HCl (IMes )
bis(1,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene) or IPr‚HCl
(IPr ) 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) has
proven highly effective in Suzuki-type coupling.6 Thus, it
was of interest to compare the catalytic performances of 1
with IMes in the Pd-catalyzed Heck reaction of 4-bromo-
toluene with n-butyl acrylate. In fact, our new system
involving 1 was much more effective than Pd/IMes, which
gave only a yield of 7% of the desired coupled product in 4
h (Pd/1 gave a 96% yield under identical conditions).
Isolated yields were obtained in certain examples (entries 1,
3, and 6) in order to provide evidence for the practical use
of the method.14
(9) (a) Lee, H. M.; Smith. D. C., Jr.; He, Z.; Stevens, E. D.; Yi, C. S.;
Nolan, S. P. Organometallics 2001, 20, 794. (b) Lee, H. M.; Jiang, T.;
Stevens, E. D. Nolan, S. P. Organometallics 2001, 20, 1255.
(10) (a) Schwarz, J.; Bo¨hm, V. P. W.; Gardiner, M. G.; Grosche, M.;
Herrmann, W. A.; Hieringer, W.; Raudaschl-Sieber, G. Chem. Eur. J. 2000,
6, 1773. (b) Tulloch, A. A. D.; Danopoulos, A. A.; Tooze, R. P.; Cafferkey,
S. M.; Kleinhenz, S.; Hursthouse, M. B. Chem. Commun. 2000, 1247. (c)
McGuinness, D. S.; Cavell, K. J. Organometallics 2000, 19, 741. (d)
McGuinness, D. S.; Cavell, K. J. Organometallics 1999, 18, 1596. (e)
Herrmann, W. A.; Fischer, J.; Elison, M.; Ko¨cher, C.; Artus, G. R. J. Chem.
Eur. J. 1996, 2, 772. (f) Herrmann, W. A.; Elison, M.; Fischer, J.; Ko¨cher,
C.; Artus, G. R. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 2371.
(11) Albert, K.; Gisdakis, P.; Ro¨sch, N. Organometallics 1998, 17, 1608.
(12) The imidazolium salt can be deprotonated by KOBut. The bromine-
imidazolium salt should be added to a preformed potassium diphenylphos-
phide solution.
(13) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009
and references cited.
(14) Workup procedure: Water (50 mL) was added to the reaction
mixture, followed by extraction with diethyl ether. The organic layer was
dried over MgSO4, filtered, and evaporated under reduced pressure to give
the crude product. The pure product was obtained by flash chromatography
(1/10 ethyl acetate/hexane) on silica gel.
Org. Lett., Vol. 3, No. 10, 2001
1513

Presumably 1 is deprotonated and forms a chelating
phosphine-carbene complex with Pd(dba)2 in the presence
of Cs2CO3. The in situ deprotonation and subsequent
coordination of the metal center by the phosphine-carbene
ligand can be observed by the color change from violet to
yellowish brown after the catalytic mixture stirs for 20 min,
this prior to the addition of substrate and n-butyl acrylate.
In the catalytic cycle, Pd/L may proceed via a cationic
pathway in which a dissociation of the oxidative-added halide
is involved to open up a coordination site for the incoming
olefinic substrate. This is in accord with our finding that polar
solvents enhanced the reaction rate (vide supra). Mechanistic
details are presently being examined.
mediate the Heck coupling of unactivated aryl bromides with
n-butyl acrylate in less than 3 h. This initial study shows
that chelating phosphine-carbene ligands represent a very
promising class of ligand suitable for Heck reactions.11
Investigations into the scope and limitations of the methodol-
ogy as well as the syntheses of improved ligands including
chiral analogues are ongoing.
Acknowledgment. The National Science Foundation, the
Petroleum Research Fund, administrated by the American
Chemical Society, and the Albemarle Corporation are
gratefully acknowledged for support of this research.
Supporting Information Available: Experimental pro-
cedures, details of reaction conditions, and spectroscopic and
analytical data for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, a new phosphine-imidazolium salt was
prepared and its application in Pd-catalyzed Heck reactions
of aryl bromides with n-butyl acrylate was investigated and
showed that Pd/L‚HBr is a highly efficient catalytic system.
In fact, a relatively low catalyst loading was sufficient to
OL015827S
1514
Org. Lett., Vol. 3, No. 10, 2001