Organic synthesis in ionic liquids: The stille coupling

Article abstract of DOI:10.1021/ol0068849

equation presented The Stille coupling reaction has been performed in 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF₄), a room-temperature ionic liquid (RTIL). Use of this solvent system allows for facile recycling of the solvent and catalyst system, which can be used at least five times with little loss in activity. An interesting preference in starting catalyst oxidation state for use with aryl bromides and aryl iodides was observed.

Full text of DOI:10.1021/ol0068849

ORGANIC
LETTERS
2001
Vol. 3, No. 2
233-236
Organic Synthesis in Ionic Liquids: The
Stille Coupling
Scott T. Handy* and Xiaolei Zhang
Department of Chemistry, State UniVersity of New York at Binghamton,
Binghamton, New York 13902-6000
shandy@binghamton.edu
Received November 17, 2000
ABSTRACT
The Stille coupling reaction has been performed in 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM BF ), a room-temperature ionic liquid
4
(RTIL). Use of this solvent system allows for facile recycling of the solvent and catalyst system, which can be used at least five times with
little loss in activity. An interesting preference in starting catalyst oxidation state for use with aryl bromides and aryl iodides was observed.
Transition-metal catalyzed cross-coupling reactions are ver-
satile and highly useful transformations leading to a wide
variety of compounds.1 Of the variety of reactions that fall
into this category, the Stille reaction has been one of the
most heavily used in the preparation of a wide variety of
materials including polyenes, diaryls, and aromatic carbonyl
compounds.2 Part of this utility stems from the fact that the
organometallic coupling partner, an organostannane, is air
and moisture stable and thus readily prepared and stored.
Further, the coupling conditions are compatible with a wide
array of functional groups. Indeed, the one major limitation
to this particular transformation is the toxicity of the
organotin reagents and byproducts.
preparing designer ligands for use in aqueous or fluorous
biphasic systems.4
Recently, a new alternative solution for catalyst recycling
has been reported. This involves the use of room-temperature
ionic liquids (RTILs), in essence salts that are liquid at or
below room temperature.5 These solvents have found ap-
plication in a wide variety of organic transformations,
particularly transition-metal catalyzed transformations.6 A
large part of the interest in these solvents is due to the ease
(3) For example, coupling reactions of aryl chlorides generally fail to
afford any of the desired product. However, the biphenylphosphine ligands
reported by Buchwald have extended the scope of Suzuki and siloxane
couplings to encompass aryl chlorides as well as hindered aryl bromides.
For examples, see: Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S.
L. J. Am. Chem. Soc. 1999, 121, 9550. Mowery, M. E.; DeShong, P. Org.
Lett. 1999, 1, 2137.
(4) For a recent volume discussing alternate solvents and reagent
recycling, see: Modern SolVents in Organic Synthesis; Knochel, P., Ed.;
Topics in Current Chemistry, Vol. 206; Springer-Verlag: Berlin, 1999.
(5) For a recent review, see: Welton, T.; Chem. ReV. 2000, 100, 2071-
2083.
(6) For examples utilizing this approach not included in ref 5, see the
following. Asymmetric epoxidation: Song, C. E.; Rho, E. J. Chem.
Commun. 2000, 837-838. Heck reaction: Bohm, V. P. W.; Herrmann, W.
A. Chem. Eur, J, 2000, 6, 1017-1025. Carmichael, A. J.; Earle, M. J.;
Holbrey, J. D.; McCormac, P. B.; Seddon, K. R. Org. Lett. 1999, 1, 997.
Friedel-Crafts alkylation: Song, C. E.; Shim, W. H.; Roh, E. J.; Choi, J.
H. Chem. Commun. 2000, 1695. Oxidation of aldehydes: Howarth, J.
Tetrahedron Lett. 2000, 41, 6627. Hydrogenations: Steines, S.; Wasser-
scheid, P.; Driessen-Hoelscher, B. J. Prakt. Chem. 2000, 342, 348. Suzuki
reaction: Mathews, C. J.; Smith, P. J.; Welton, T. Chem. Commun. 2000,
1249. Aza-Diels-Alder reaction: Zulfiqar, F.; Kitazume, T. Green Chem.
2000, 137. Trost-Tsuji Reaction: Toma, S.; Gotov, B.; Kmentova, I.;
Solcaniova, E. Green Chem. 2000, 149.
There is another problem that is encountered in not only
the Stille coupling but really in all transition-metal catalyzed
cross-coupling reactions: the catalyst itself. Most of these
transformations are catalyzed by palladium species, which
is an expensive metal. Further, the desired reactivity can often
only be achieved by using expensive and/or toxic ligands.3
Ideally, one would like to be able to recover and recycle the
entire catalyst system but avoid the challenges presented by
either mounting the catalyst on a solid support or by
(1) For a recent review, see: Hegedus, L. S. Transition Metals in the
Synthesis of Complex Organic Molecules; University Science Books:
Sausalito, CA, 1999.
(2) For a review of the Stille reaction, see: Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1-652.
10.1021/ol0068849 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/05/2001

with which the reaction products can be removed from the
solvent and catalyst by either distillation or extraction with
a nonpolar organic solvent such as hexane, benzene, or
diethyl ether. The remaining RTIL solution retains the
catalyst and can be reused multiple times with little to no
loss of activity.7
Our choice of solvent was the readily prepared 1-butyl-
3-methylimidazolium tetrafluoroborate (BMIM BF4) RTIL.10
Using this solvent for the reaction of R-iodoenone 1 and
vinyltributyltin afforded results comparable to those obtained
using NMP as the solvent (Table 1, entries 1 and 3). Further,
extraction of the product with diethyl ether afforded an ionic
liquid layer that could be recycled several times with only a
slight loss in activity (entries 3-5). Additionally, this ionic
liquid layer could be stored for several weeks with no special
precautions to exclude air or moisture and still afford
comparable results to the fresh ionic liquid/catalyst system
(entry 5).
In the context of another research effort in our labs, we
were interested in applying these RTIL conditions to the
Stille coupling. In particular, we were focusing on the
coupling of R-iodoenones such as 1 (Table 1). This type of
Table 1. Stille Coupling of R-Iodoenonesa
Even better results were obtained in the coupling of
R-iodoenone 1 with phenyltributyltin (Table 1, entries 2 and
6). In this case, product recovery actually increased slightly
over three recyclings (entries 6-8). Using these same
conditions, both R- and â-iodocyclohexenones also afforded
the Stille coupling products in generally good yield (Table
2).11
Table 2. Stille Couplings of R- and â-Iodoenonesa
a All reactions performed using 5 mol % of palladium catalyst. b Isolated
yields. c Data from ref 8. d Reaction run at 110 °C. e Second run using
recycled catalyst/media. f Third run using recycled catalyst/media after 24
days. g Third run using recycled catalyst/media.
coupling was reported earlier by Johnson and co-workers.8
After extensive screening, they determined that the combina-
tion of N-methylpyrrolidinone (NMP) with a catalyst com-
posed of bis(benzonitrile)palladium(II) chloride, triphenyl-
arsine, and copper(I) iodide afforded the desired Stille
products in good to excellent yields. Given the reported
polarity of RTILs9 and the obvious desire to recycle this
multicomponent catalyst system, we chose this to be our
starting point for the investigation of the Stille coupling in
RTILs.
a All reactions performed using 5 mol % of PdCl2(PhCN)2, Ph3As, and
CuI. b Isolated yields.
Another major use of Stille couplings is in the preparation
of diaryl compounds. Using the same multicomponent
catalyst system used with the R-iodoenones afforded the
coupling product of p-iodoanisole and phenyltributyltin in a
good 82% yield (Scheme 1). Interestingly, a variety of other
(7) This concept was introduced by Chauvin and co-workers and
emulated in many of the studies cited in refs 5 and 6. For this initial
communication, see: Chauvin, Y.; Mussmann, L.; Olivier, H. Angew. Chem.,
Int. Ed. Engl. 1994, 34, 2698.
(8) Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.
Tetrahedron Lett. 1992, 33, 919-922.
(9) There are conflicting reports regarding the polarity of ionic liquids.
While at first glance these salts would appear to be highly polar, pyrene
fluorescence spectroscopy indicated a dielectric constant of < 10 (Bonhote,
P.; Dias, A.-P.; Papgeorgiou, P.; Kalyanasundaram, K.; Graetzel, M. Inorg.
Chem. 1996, 35, 1168). However, use of Reichardt’s indicator dyes indicated
that the polarity was similar to that of 1-propanol (Visser, A. E.; Swarloski,
R. P.; Reichert, W. M.; Willauer, H. D.; Huddleston, J. G.; Rogers, R. D.
Proceedings of the 4th Annual Green Chemistry and Engineering Confer-
ence, Washington, DC, June 27-29, 2000; p 50). Our Stille coupling results
are in keeping with BMIM BF4 acting as a more polar solvent.
(10) The preparation of this ionic liquid is a modification of the procedure
reported by Rogers and co-workers for the preparation of the PF6 derivative
(Huddleston, J. G.; Willauer, H. D.; Swarloski, R. P.; Visser, A. E.; Rogers,
R. D. Chem. Commun. 1998, 1765). Details may be found in the Supporting
Information.
Scheme 1. Coupling of Aryl Iodide
234
Org. Lett., Vol. 3, No. 2, 2001

palladium catalyst systems [Pd(Ph3P)4, 30%; Pd(OAc)2/
P(o-Tol)3, 0%; Pd2(dba)3/P(t-Bu)3, <5%] afforded little if
any of the desired coupling product.
to investigate the potential for chemoselectivity by using
p-iodobromobenzene (Scheme 2). With the palladium(II)
A rather different trend was noted in the coupling of aryl
bromides. Application of the conditions that worked well
for the aryl iodides to the coupling of bromobenzene with
phenyltributyltin afforded biphenyl in only 35% yield (Table
3, entry 1). However, using a palladium(0) catalyst source
Scheme 2. Competition Experiments
Table 3. Coupling of Aryl Bromidesa
catalyst system, we observed clean coupling with the iodide
to afford 4-bromobiphenyl in 90% isolated yield.
a All reactions performed using 5 mol % of palladium catalyst. b Isolated
yields. c Second run using recycled catalyst/media.
With Pd(Ph3P)4, we did not observe any coupling with
the bromide, but instead isolated only a modest 26% yield
of 4-bromobiphenyl. Thus, the catalyst-dependent difference
in reactivity observed in the bromo and iodo series is not
sufficient to overcome the inherent selectivity (I > Br)
normally observed in the Stille coupling reaction. Neverthe-
less, catalyst choice still has a dramatic effect in the
efficiency of the reaction.
Since the initial goal of this research effort was to develop
a highly recyclable solvent/catalyst system, we further
investigated the number of times that we could reuse both
the palladium(II) and palladium(0) systems. As shown in
Scheme 3, both systems can be recycled at least five times
with essentially no loss in activity in the palladium(II) system
and only a modest decrease in activity in the palladium(0)
system. Whether this loss in activity is due to precipation of
the palladium(0) from the reaction solvent or due to partial
extraction of the very nonpolar catalyst during the separation
phase is currently under investigation.
such as Pd(Ph3P)4 afforded the desired product in 90% yield
(entry 2). Rather impressively, this ionic liquid solution could
be recycled, following product extraction with diethyl ether,
to afford equally high yields of biphenyl (entry 3).12
These two catalyst combinations proved to be effective
for the coupling of a variety of aryl iodides and bromides as
shown in Table 4. The iodides afforded good to excellent
Table 4. Aryl Coupling Reactionsa
In summary, we have demonstrated that Stille coupling
reactions can be successfully conducted in RTILs. This
procedure permits extensive recycling of the solvent and
catalyst without significant loss in activity. Further, an
interesting catalyst selectivity for aryl bromides and aryl
iodides was noted. Further investigations concerning the
a All reactions performed using 5 mol % of catalyst. X ) Br, catalyst )
Pd(Ph3P)4; X ) I, catalyst ) PdCl2(PhCN)2, Ph3As, CuI. b Isolated yields.
c Second run using recycled catalyst/media.
(11) Representative procedure: To a dry round-bottomed flask under
nitrogen were sequentially added 235.9 mg (1.00 mmol) of 2-iodo-3-methyl-
2-cyclohexen-1-one, 19.0 mg (0.100 mmol) of copper(I) iodide, 31.0 mg
(0.100 mmol) of triphenylarsine, and 19.0 mg (0.0500 mmol) of bis-
(benzonitrile)palladium(II) chloride. This mixture was dissolved in 1 mL
of BMIM BF4 and was immediately lowered into an oil bath maintained at
80 °C. To this solution was added 0.35 mL (1.200 mmol) of tributylvinyltin.
After stirring for 2 h, the reaction mixture was extracted with diethyl ether
(10 × 10 mL). The combined organic layers were washed with saturated
aqueous potassium fluoride (3 × 30 mL) The aqueous layers were combined
and back-extracted with diethyl ether (2 × 20 mL). The combined organic
layers were dried over magnesium sulfate, filtered, and concentrated in
vacuo. The resulting oily residue was purified by flash column chroma-
tography (5:95, then 1:9 EtOAc/Hexanes as eluent) to afford 90.3 mg (82%)
of 3-methyl-2-vinylcyclohexenone as a pale yellow oil.
yields, even for electron-rich aromatic systems, using the
multicomponent palladium(II) catalyst system, while the
bromides afforded good yields for electron-deficient and
moderately electron rich aromatic systems using Pd(Ph3P)4.
The more electron rich p-bromoanisole afforded only a 15%
yield of the desired Stille coupling product, which is typical
for these types of couplings in conventional solvents.
In light of this interesting selectivity that we were
observing between the aryl iodides and bromides, we chose
(12) All compounds exhibited spectral data consistent with that reported
in the literature.
Org. Lett., Vol. 3, No. 2, 2001
235

Scheme 3. Recycling Studies
mechanistic reasons for this phenomenon and application of
Supporting Information Available: Experimental pro-
cedures for the preparation of BMIM BF4 and the Stille
coupling reactions. This material is available free of charge
via the Internet at http://pubs.acs.org.
these RTIL recycling conditions to other types of transition-
metal catalyzed transformations are currently underway and
will be reported in due course.
Acknowledgment. The authors thank the State University
of New York at Binghamton and the Research Foundation
for financial support of this work.
OL0068849
236
Org. Lett., Vol. 3, No. 2, 2001