High-speed heck reactions in ionic liquid with controlled microwave heating

Article abstract of DOI:10.1021/jo025942w

Palladium-catalyzed Heck arylations in the polar and robust ionic liquid, 1-butyl-3-methylimidazolium hexa-fluorophosphate (bmimPF₆), have for the first time been accomplished under microwave irradiation. The couplings were efficiently performed in sealed tubes within 5-45 min of heating. Without significant reductions in yield, a phosphine-free ionic catalyst phase could be recycled in five successive 20 min reactions at 180 °C. The product was easily removed from the reaction medium by distillation.

Full text of DOI:10.1021/jo025942w

TABLE 1. Heck Ar yla tion s in Bm im P F 6 w ith Differ en t
P a lla d iu m Ca ta lystsa
High -Sp eed Heck Rea ction s in Ion ic Liqu id
w ith Con tr olled Micr ow a ve Hea tin g
Karl S. A. Vallin, Per Emilsson, Mats Larhed,* and
Anders Hallberg
Department of Organic Pharmaceutical Chemistry, Uppsala
University, BMC, Box-574, SE-751 23 Uppsala, Sweden
mats@orgfarm.uu.se
Received May 17, 2002
entry
[Pd]b
ligandc
GC yieldd (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2, LiCle
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
palladacycle
PdCl2
53
30
43
70
21
40
94
99
29
PPh3
P(o-tol)3
DPPP
Abstr a ct: Palladium-catalyzed Heck arylations in the polar
and robust ionic liquid, 1-butyl-3-methylimidazolium hexa-
fluorophosphate (bmimPF6), have for the first time been
accomplished under microwave irradiation. The couplings
were efficiently performed in sealed tubes within 5-45 min
of heating. Without significant reductions in yield, a phos-
phine-free ionic catalyst phase could be recycled in five
successive 20 min reactions at 180 °C. The product was
easily removed from the reaction medium by distillation.
PdCl2
P(o-tol)3
Pd/C
a
Reactions were performed in a 1.0 mmol scale for 45 min at
180 °C with microwave heating. Palladium (0.02 equiv). c Mono-
b
d
dentate/bidentate phosphine ligand (0.04 equiv). GC yields were
determined with 2,3-dimethylnaphthalene as the internal stan-
dard. e LiCl (0.04 equiv).
The chemical and pharmaceutical industry is under an
accelerating pressure to find environmentally friendly
organic reaction methodologies. Among a variety of
possible “green” solvent alternatives for catalytic reac-
tions,1-4 nonvolatile room-temperature ionic liquid reac-
tion media continue to be an area of increasing research
activity.5-7 Ionic liquids of the dialkylimidazolium class
may simplify metal catalyst recycling techniques and, due
to their high polarity and special properties, allow for
new reaction protocols to be developed. Ionic liquids
interact very efficiently with microwaves through con-
duction and are rapidly heated without any significant
pressure increase.8 Therefore, safety problems arising
from over-pressurization of heated sealed reaction vessels
can be minimized.
Offsetting the advantages of utilizing ionic liquids as
reaction media are some detractions. The long reaction
times required with palladium-catalyzed transformation
are a significant drawback for high-throughput applica-
tions.9 More generally, all ionic liquid-based methods
need to come to grips with the high price of ionic liquids.
We previously reported on very rapid palladium-
catalyzed coupling reactions both in solution and on a
solid phase under microwave irradiation.10-12 This heat-
ing methodology13,14 offers a potential solution to the
reaction rate problem, and we therefore decided to assess
this technology for acceleration of a prototypical ionic
liquid coupling reaction. In addition, we wanted to
investigate catalyst/ionic liquid recycling after microwave
treatment. We herein describe a high-temperature stable
catalytic system suitable for rapid microwave-assisted
Heck arylations4,15,16 relying on a combination of the ionic
liquid, 1-butyl-3-methylimidazolium hexafluorophosphate
(bmimPF6), and PdCl2. Convenient product isolation and
an efficient catalytic recycling protocol are reported.
We selected a standard Heck reaction, with the deac-
tivated aryl halide bromoanisole (1a ) and the electron-
poor olefin butyl acrylate (2a ), as an appropriate first test
reaction. The common ionic liquid bmimPF6 was chosen
as the ionic solvent for a number of reasons: (a) it is
proven to constitute a suitable reaction medium for
palladium(0)-catalyzed coupling reactions,6,7 (b) it is air,
moisture, and temperature stable,8 and (c) it is virtually
insoluble in water and alkanes.6,9 The catalytic stability
and the coupling reactivity were first investigated under
air with four different palladium sources and three
common phosphine ligands (Table 1). The temperature
(180 °C) and the irradiation time (45 min) were selected
to allow only very reactive catalytic systems in the ionic
liquid to afford full conversion of the sluggish bromoani-
sole. Unexpectedly, it was found that replacement of the
standard Pd(OAc)2 by the old fashioned PdCl2 led to a
marked increase in the catalytic efficiency, while per-
(1) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1175-1196.
(2) Aqueous Phase Organometallic Catalysis; Cornils, B., Herrman,
W. A., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
(3) J essop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999, 99, 475-
493.
(4) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-
3066.
(5) Welton, T. Chem. Rev. 1999, 99, 2017-2083.
(6) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772-3789.
(7) Sheldon, R. Chem. Commun. 2001, 2399-2407.
(8) Leadbeater, N. E.; Torenius, H. M. J . Org. Chem. 2002, 67,
3145-3148.
(9) Carmichael, A. J .; Earle, M. J .; Holbrey, J . D.; McCormac, P. B.;
Seddon, K. R. Org. Lett. 1999, 1, 997-1000.
(10) Larhed, M.; Hallberg, A. J . Org. Chem. 1996, 61, 9582-9584.
(11) Vallin, K. S. A.; Larhed, M.; J ohansson, K.; Hallberg, A. J . Org.
Chem. 2000, 65, 4537-4542.
(12) Larhed, M.; Hallberg, A. Drug Discovery Today 2001, 6, 406-
416.
(13) Strauss, C. R.; Trainor, R. W. Aust. J . Chem. 1995, 48, 1665-
1692.
(14) Lidstro¨m, P.; Tierney, J .; Wathey, B.; Westman, J . Tetrahedron
2001, 57, 9225-9283.
(15) Heck, R. F. Org. React. 1982, 27, 345-390.
(16) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379-2411.
10.1021/jo025942w CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/20/2002
J . Org. Chem. 2002, 67, 6243-6246
6243

TABLE 2. Heck Ar yla tion in Bm im P F 6 w ith Differ en t
Ar yl a n d Heter oa r yl Ha lid esa
time
(min)
temp
(°C)
isolated yieldb
(%)
entry
aryl halide
F IGURE 1. Temperature, power, and pressure profiles for
the vinylation of 4-bromoanisol (Table 2, entry 1). The enlarged
area shows the initial temperature response (27-220 °C) and
the corresponding microwave power during the first 30 s of
irradiation.
1
2
3
4
5
6
7
4-MeO-Ph-Br
4-MeO-Ph-Brc
Ph-Br
4-F3C-Ph-Br
1-Br-naphthyl
3-Br-pyridyld
Ph-I
1a
1a
1b
1c
1d
1e
1f
20
45
20
20
20
20
5
220
180
220
220
220
220
180
3a , 61
3a , 69
3b, 87
3c, 90
3d , 84
3e, 39
3b, 95
SCHEME 1
a
Reaction conditions: Reactions were performed in a 1.0 mmol
scale with 1.0 equiv of 1a -f, 2.0 equiv of 2a , 0.04 equiv of PdCl2,
0.08 equiv of P(o-tol)3, 1.5 equiv of Et3N, and 0.5 g bmimPF6.
b
Purity > 95% according to GC/MS. c Phosphine-free, 0.02 equiv
d
of PdCl2. Compound 2a (5.0 equiv) was added to reduce the
competing homocoupling.
a
Isolated yield.
forming the reaction with a Pd(OAc)2/LiCl combination
did not result in a similar success (entries 1, 2, and 7).
With PPh3 as the ligand instead of P(o-tol)3 under
otherwise identical conditions, a significant level of aryl
migration forming byproduct 3b was encountered (entries
3 and 4). The best catalytic system for the Heck reaction,
comprised of P(o-tol)3 in combination with PdCl2, deliv-
ered 99% yield and full conversion and gave no trace of
products derived from aryl migration or dehalogenation
(entry 8). Inferior results were observed with Herrmann’s
palladacycle (trans-di(acetato)bis[o-(di-o-tolylphosphino)-
benzyl]dipalladium(II)) or Pd/C17 as well as with Pd(OAc)2
in combination with the bidentate ligand 1,3-bis(di-
phenylphosphino) propane (DPPP) (entries 5, 6, and 9).
In general, the investigated catalytic systems were more
temperature tolerant in the ionic liquid media than in
ordinary solvents. For example, applying the same phos-
phine-free condition as in entry 1 with DMF as the
solvent at 180 °C afforded only small amounts of the
product and a massive formation of “palladium black”.
The key criterion for the development of flash-heated
methodologies is, by definition, the reduction of reaction
time. The PdCl2/P(o-tol)3 reaction condition selected from
Table 1 was therefore further time-optimized, and the
final preparative results with different aryl and het-
eroaryl halides (1a -f) and the olefin 2a are presented
in Table 2. The couplings with aryl bromides in ionic
liquid were best performed in 20 min at 220 °C.18 For
instance, the reaction of bromobenzene (1b) produced an
isolated yield of 87% 3b (entry 3). The cinnamic acid ester
(3b) was also synthesized employing iodobenzene (1f) in
a reaction time of only 5 min and consuming only a
fraction of the energy that normally is needed for a
standard, oil-bath-heated reaction (entry 7). Attempts to
further accelerate the phosphine-free PdCl2-catalyzed
reaction with the deactivated aryl bromide 1a by increas-
ing the reaction temperature were not successful, and a
considerable amount of 1a remained unreacted, suggest-
ing a collapse of the catalytic system (entry 7, Table 1,
and entry 2, Table 2). The bromopyridyl (1e) reacted
much less efficiently than the other aryl halides despite
an increased concentration of butyl acrylate (entry 6). In
all reactions, a convenient product separation by distil-
lation from the high-boiling ionic solution was possible.
The impressive temperature control and the very low
reaction pressure for the arylation of 2a with 1a in
bmimPF6 (Table 2, entry 1) are illustrated in Figure 1.19
An extremely rapid heating ramp demonstrates the high
microwave activity of the bmimPF6-based reaction sys-
tem.
The â,â-diphenylacrylate (4) was successfully synthe-
sized in 45 min by a double-Heck arylation employing
an excess of phenyl bromide and with the sterically
hindered and stable 1,2,2,6,6-pentamethyl-piperidine
(PMP) as the base (Scheme 1).20 With triethylamine as
the base, small quantities of N,N-diethyl-3,3-diphenyl-
acrylamide were observed as deduced from a GC/MS
analysis.21
The recyclability of the catalytic ionic system was
studied employing iodobenzen (1f) as the arylating agent
and butyl acrylate (2a ) as the olefin. PdCl2 was used as
catalyst with no phosphine ligand present. To ensure
complete conversion of iodobenzene, the irradiation time
for each cycle was prolonged to 20 min and the palladium
concentration slightly increased. The results are sum-
marized in Figure 2 and reveal that the ionic catalyst
phase is recyclable at least five times.22 After each cycle,
the product was directly isolated in high yield by rapid
(19) Applying DMF as a solvent in the reaction with 4-bromoanisole
at 220 °C resulted in an uncontrollable pressure increase.
(20) Moreno-Manas, M.; Perez, M.; Pleixats, R. Tetrahedron Lett.
1996, 37, 7449-7452.
(21) Less than 10% N,N-diethyl-3,3-diphenyl-acrylamide was formed.
To explain this observation, we believe diethylamine must be generated
from triethylamine at the accelerated conditions.
(17) Hagiwara, H.; Shimizu, Y.; Hoshi, T.; Suzuki, T.; Ando, M.;
Ohkubo, K.; Yokoyama, C. Tetrahedron Lett. 2001, 42, 4349-4351.
(18) When the temperature was increased to 220 °C, a small amount
of 3b (∼8%) was detected due to aryl scrambling (Table 2, entry 1).
6244 J . Org. Chem., Vol. 67, No. 17, 2002

investigations will be necessary to take full advantage
of the huge potential of the ionic liquid/microwave
heating combination.
Exp er im en ta l Section
Gen er a l. The microwave heating was performed in a single
mode cavity, producing controlled irradiation at 2450 MHz.
Reaction temperature and pressure were determined using the
built-in, on-line IR and pressure sensors. Microwave-mediated
reactions were performed in sealed process vials under air with
magnetic stirring. Prepacked silica columns were used for flash
chromatography. 1H and 13C NMR spectra were recorded in
CDCl3 at 270 and 67.8 MHz, respectively. Mass spectra were
recorded on a GC/MS equipped with an HP-1 (25 m × 0.20 mm)
capillary column, utilizing electron impact (EI) at an ionizing
energy of 70 eV. The regioisomers were assumed to have the
same GC/MS response factor. The isolated cinnamic acid esters
(3a -e), â,â-diphenylacrylate (4), and 1-acetyl naphthyl (6) have
previously been characterized, and the data obtained cor-
responded satisfactorily with MS and NMR literature data.27-30
Ma ter ia ls. The acrylate ester 2a , vinyl ether 2b, aryl and
heteroaryl halides 1a -f, palladium(II)acetate, palladium(II)-
dichloride, tri-o-tolyl phosphine, triphenylphosphine, 1,3-bis-
(diphenylphosphino)propane (DPPP), Pd/C, LiCl, 1,2,2,6,6-
pentamethyl-piperidine (PMP), and triethylamine were purchased
from commercial suppliers and used directly as received. The
ionic liquid bmimPF6 was prepared by a literature procedure.31,32
Gen er a l P r oced u r e for Micr ow a ve-Assisted Ter m in a l
Heck Rea ction w ith Ar yl or Heter oa r yl Ha lid es 1a -f
(Ta ble 2). The bmimPF6 (0.50 g, 1.75 mmol), PdCl2 (7.8 mg,
0.04 mmol), and P(o-tol)3 (24 mg, 0.08 mmol) were mixed in a
process vial (0.5-2.0 mL) equipped with a magnetic stirrer and
heated to 80 °C for 5 min in a heating block to form the ionic
liquid solution of the catalyst. Butyl acrylate (2a ) (0.256 g, 2.0
mmol), triethylamine (0.152 g, 1.5 mmol), and the corresponding
aryl halide 1a -f (1.0 mmol) were added, and the reaction
mixture was heated to 220 °C for 20 min in a microwave
synthesizer. After complete consumption of the starting aryl
halide as analyzed by GC/MS, the reaction mixture was distilled
with a kugelrohr device at 1-2 mmHg and 170 °C. The clear
distillate was separated from the amine salt by extraction with
diethyl ether to give the pure product 3 (>95% GC/MS).
Micr ow a ve-Assisted Heck Ar yla tion s w ith Differ en t
P a lla d iu m Ca ta lysts (Ta ble 1). The arylation of 2a with 1a
was performed as described under General Procedure for
Microwave-Assisted Terminal Heck Reaction with Aryl or Het-
eroaryl Halides 1a -f, but the amount of palladium was 0.02
mmol and the amounts of phosphine monodentate/bidentate
ligands were 0.04 mmol. The reaction mixture was heated to
180 °C for 45 min in a microwave synthesizer. The yields were
determined by a GC/MS mean value of two injections from
calibration curves made from pure 3a and 2,3-dimethylnaph-
thalene as internal standards.
F IGURE 2. Recyclability of the ionic catalyst phase. Reactions
were performed in a 2.0 mmol scale for 20 min at 180 °C with
microwave heating, employing 1.0 equiv of 1f, 2.0 equiv of 2a ,
0.05 equiv of PdCl2, 1.5 equiv of Et3N, and 3.0 g of bmimPF6.
SCHEME 2
a
Isolated as the corresponding methyl ketone (6) after acid
treatment.
distillation under reduced pressure (170 °C, 1-2 mmHg).
For the next reaction cycle, new 2a , 1f, and Et3N were
added to the original PdCl2/bmimPF6 catalyst media. In
situ-generated, catalytically active palladium-biscarbene
complexes have been suggested to be involved in similar
processes.9,23
To investigate Heck coupling reactions that proceed not
only via neutral intermediates, the bidentate ligand-
controlled internal arylation of butyl vinyl ether (2b) with
1d was examined in bmimPF6 with microwave heating.
The latter reaction is anticipated to involve cationic aryl
palladium species most often created from aryl triflates
or, alternatively, from aryl halides combined with halide
abstractors such as thallium salts.24,25 Due to the highly
polar media, no addition of toxic thallium salts were
needed to promote the reaction in the presence of the
DPPP ligand.26 High internal regioselectivity of product
5 and complete conversion was accomplished when the
temperature was set to a maximum of 130 °C (terminal/
internal arylation < 1/99) (Scheme 2). Increasing the
reaction temperature, excluding the addition of DPPP,
or exchanging Pd(OAc)2 with PdCl2 caused a loss in
regioselectivity. The DPPP requirement for obtaining
high internal regioselectivity indicates that the active
catalyst is a Pd(0)-DPPP complex and not a potential
imidazolylidine-palladium carbeneoid complex.
Dou ble Heck Ar yla tion of 2a (Sch em e 1). The bmimPF6
(0.50 g, 1.75 mmol), PdCl2 (7.8 mg, 0.04 mmol), and P(o-tol)3
(24 mg, 0.08 mmol) were mixed in a process vial (0.5-2.0 mL)
equipped with a magnetic stirrer and heated to 80 °C for 5 min
in a heating block to form the ionic liquid solution of the catalyst.
Butyl acrylate (2a ) (0.256 g, 1.0 mmol), PMP (0.466 g, 3.0 mmol),
and the phenyl bromide (0.785 g, 5.0 mmol) were added, and
the reaction mixture was heated to 220 °C for 45 min in a
In summary, it has been demonstrated that Heck
reactions can be performed in 5-45 min with controlled
microwave heating and that the bmimPF6-based ionic
catalyst solution can be reused repeatedly. The ionic
catalyst systems were found to be stable despite high
reaction temperatures (180-220 °C). Further systematic
(27) Feuerstein, M.; Doucet, H.; Santelli, M. J . Org. Chem. 2001,
66, 5923-5925.
(22) When the orange solution with precipitated palladium black
was irradiated, a homogeneous dark solution was observed, indicating
that the palladium redissolves upon heating.
(23) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(24) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2-7.
(25) Vallin, K. S. A.; Larhed, M.; Hallberg, A. J . Org. Chem. 2001,
66, 4340-4343.
(26) Thallium-free, regioselective, and internal arylations of vinyl
ethers with aryl halides in bmimBF4 were first reported by: Xu, L.;
Chen, W.; Ross, J .; Xiao, J . Org. Lett. 2001, 3, 295-297.
(28) Calo, V.; Nacci, A.; Monopoli, A.; Lopez, L.; di Cosmo, A.
Tetrahedron 2001, 57, 6071-6077.
(29) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1988, 110,
1557-1565.
(30) Schuster, I. I. J . Org. Chem. 1981, 46, 5110-5118.
(31) Huddleston, J . G.; Willauer, H. D.; Swatloski, R. P.; Visser, A.
E.; Rogers, R. D. Chem. Commun. 1998, 1765-1766.
(32) Lucas, P.; El Mehdi, N.; Ho, H. A.; Belanger, D.; Breau, L.
Synthesis 2000, 1253-1258.
J . Org. Chem, Vol. 67, No. 17, 2002 6245

microwave synthesizer. After complete consumption of the butyl
acrylate (2a ) as analyzed by GC/MS, the reaction mixture was
worked up by a three-phase extraction between the ionic liquid,
0.1 M NaOH (aq), and diethyl ether. Product 4 was purified by
column chromatography on a prepacked silica column. Eluent:
isohexane/ethyl acetate.
Recycla bility of th e Ion ic Ca ta lyst P h a se (F igu r e 2). The
bmimPF6 (3.0 g, 10.5 mmol), PdCl2 (17.7 mg, 0.05 mmol), butyl
acrylate (2a ) (0.512 g, 4.0 mmol), triethylamine (0.303 g, 3.0
mmol), and phenyl iodide (1f) (0.408 g, 2.0 mmol) were mixed
in a process vial (2.0-5.0 mL) equipped with a magnetic stirrer.
The reaction mixture was heated to 180 °C for 20 min in a
microwave synthesizer. Compound 3b was purified as described
for the cinnamic acid esters (3a -e). For recycling, 2a , 1f, and
triethylamine were added to the nonvolatile catalytic ionic media
in the same original process vial. The reaction system was
thereafter irradiated to 180 °C for 20 min.
0.04 mmol), DPPP (25 mg, 0.06 mmol), butyl vinyl ether (2b)
(0.100 g, 1.0 mmol), triethylamine (0.152 g, 1.5 mmol), and
1-bromonaphthalene (1d ) (1.035 g, 5.0 mmol) were mixed in a
process vial (2.0-5.0 mL) equipped with a magnetic stirrer, and
the reaction mixture was heated to 130 °C for 120 min in a
microwave synthesizer. After complete conversion of the starting
2b as analyzed by GC/MS, the vinyl ether (5) was hydrolyzed
by adding 5 mL of 5% HCl for 60 min. The reaction was worked
up and extracted with isohexane. The methyl ketone (6) was
purified by column chromatography on
a prepacked silica
column. Eluent: isohexane/dichloromethane.
Ack n ow led gm en t. The authors acknowledge the
financial support from the Swedish Research Council
and Knut and Alice Wallenberg’s Foundation. We also
thank PersonalChemistry AB for providing us with the
SmithSynthesizer.
In ter n a l Ar yla tion of 2b w ith Br om on a p h th a len e (1d )
(Sch em e 2). The bmimPF6 (2.5 g, 9.0 mmol), Pd(OAc)2 (9.0 mg,
J O025942W
6246 J . Org. Chem., Vol. 67, No. 17, 2002