Exploration of Ionic Liquids as Soluble Supports for Organic Synthesis. Demonstration with a Suzuki Coupling Reaction

Article abstract of DOI:10.1021/ol035977y

(Equation Presented) The efficiency of ionic liquid supported synthesis was demonstrated by the Suzuki reaction of ionic liquid supported iodobenzoate compounds with arylboronic acids in aqueous media to give, after cleavage with ammonia/methanol, biaryl products in good yields and high purities, without the need for chromatographic purification.

Full text of DOI:10.1021/ol035977y

ORGANIC
LETTERS
2003
Vol. 5, No. 26
5003-5005
Exploration of Ionic Liquids as Soluble
Supports for Organic Synthesis.
Demonstration with a Suzuki Coupling
Reaction
Weishi Miao and Tak Hang Chan*
Department of Chemistry, McGill UniVersity, Montreal, Quebec, Canada H3A 2K6
tak-hang.chan@mcgill.ca
Received October 10, 2003
ABSTRACT
The efficiency of ionic liquid supported synthesis was demonstrated by the Suzuki reaction of ionic liquid supported iodobenzoate compounds
with arylboronic acids in aqueous media to give, after cleavage with ammonia/methanol, biaryl products in good yields and high purities,
without the need for chromatographic purification.
Since Merrifield introduced the use of polymer support for
the synthesis of oligopeptides1 the use of insoluble supports
has become an important tool for phase separation and
purification to remove excess reagents and side products. In
recent years, the use of soluble polymer supports has received
considerable attention because such “liquid phase” synthesis
retains many of the advantages of conventional solution
chemistry, and still permits the fairly facile purification of
the product. Thus, soluble poly(ethylene glycol) (PEG) and
other polymers have been used for the synthesis of oligopep-
tides,2 nucleotides,3 saccharides,4 and small molecules.5 Some
limitations expressed for the use of soluble polymer supports
include the following: loading capacity, limited solubility
during the synthesis of longer peptides, aqueous solubility,
and the insolubility in ether solvents. More recently, the use
of the “fluorous phase” for organic synthesis has been ad-
vocated.6 This is based on the concept that fluorinated re-
agents preferentially dissolved in perfluoroalkanes, the fluor-
ous phase. Furthermore, a phase separation can be achieved
between a fluorous phase and an organic phase by a tem-
perature switch, thus facilitating separation. So far, the use
of fluorous phase synthesis has been demonstrated for small
molecules. However, the expense of perfluoroalkane solvents
and the need for specialized reagents may limit its general
application.
Recently, there has been considerable interest in the use
of ionic liquids as an environmentally benign reaction media.
Numerous chemical reactions, including some enzymic reac-
tions, can be carried out in ionic liquids.7,8 Room temperature
(6) For leading references, see: (a) Horvath, I. T.; Rabai, J. Science 1994,
266, 72. (b) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf,
P.; Curran, D. P. Science 1997, 275, 823. (c) Horvath, I. T. Acc. Chem.
Res. 1998, 31, 641. (d) Betzemeier, B.; Knochel, P. Top. Curr. Chem. 1999,
206, 61. (e) Wende, M.; Meier, R.; Gladysz, J. A. J. Am. Chem. Soc. 2001,
123, 11490. (f) Wende, M.; Gladysz, J. A. J. Am. Chem. Soc. 2003, 125,
5861.
(7) For recent reviews, see: (a) Welton, T. Chem. ReV. 1999, 99, 2071.
(b) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772.
(c) Wilkes, J. S. Green Chem. 2002, 4, 73. (d) Wasserscheid, P.; Welton,
T. Ionic Liquids in Synthesis; Wiley-VCH: Weinheim, Germany, 2003.
(1) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
(2) Bayer, E.; Mutter, M. Nature 1972, 237, 512.
(3) Bonora, G. M.; Scremin, C. L.; Colonna, F. P. Nucleic Acids Res.
1990, 18, 3155.
(4) Douglas, S. P.; Whitfield, D. M.; Krepinsky, J. J. J. Am. Chem. Soc.
1991, 113, 5095.
(5) For leading references, see: (a) Gravert, D. J.; Janda, K. D. Chem.
ReV. 1997, 97, 489. (b) Toy, P. H.; Janda, K. D. Acc. Chem. Res. 2000, 33,
546.
10.1021/ol035977y CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003

ionic liquids have also been widely explored as media for
electrochemical technologies,9 chemical extractions,10 and
other industrial processes.11 This is due to several intriguing
properties of ionic liquids: high thermal and chemical
stability, no measurable vapor pressure, nonflammability,
friction reduction, anti-wear performance, and high loading
capacity. In many cases, the ionic liquids can be recycled
easily. An attractive feature of ionic liquids is that their
solubilities can be tuned readily so that they can phase
separate from organic as well as aqueous media depending
on the choice of cations and anions. Substrate solubility can
also be tuned. For example, recently, “sugar-philic” ionic
liquids have been prepared that are capable of dissolving
carbohydrates such as glucose, cyclodextrin, and even
glycosylated proteins.12 This suggests the possibility of using
these low molecular weight ionic liquids as soluble supports
for organic synthesis. Phase separation between the “ionic
liquid phase”, the organic phase, and the aqueous phase can
be achieved for product separation and purification.13 We
demonstrate the idea with a Suzuki reaction14 by comparing
the reaction under nearly identical conditions using conven-
tional solution phase synthesis versus the ionic liquid
supported synthesis (ILSS).
By comparison, 3-p-iodobenzoyloxyethyl(l-methylimida-
zolium) tetrafluoroborate (5), prepared readily from 3-hy-
droxyethyl(l-methylimidazolium) tetrafluoroborate (6),13a,16
was coupled with 2a under identical reaction conditions.
Evaporation of the reaction mixture under reduced pressure
1
gave the crude product that contained, according to the H
NMR (acetone-d6), the coupled product 8a, unreacted 2a,
and the side product 4a. However, extraction of the crude
product with ether removed the ether soluble 2a and 4a, and
left behind the ether insoluble product 8a, relatively pure
according to NMR. Cleavage of 8a with ammonia/methanol
1
gave 3a, pure according to H NMR, easily separated from
the ionic liquid residue 6 by ether extraction (Scheme 2).17
Scheme 2. Suzuki Reactions of Ionic Liquid Supported
p-Iodobenzoate 5 with Aryl Boronic Acids 2 in Aqueous Media
Methyl p-iodobenzoate (1) was coupled with p-methoxy-
phenylboronic acid (2a) with a catalytic amount of Pd(OAc)2
in an aqueous solution of cesium fluoride under nitrogen at
80 °C for 22 h.15 At the end of reaction, the mixture was
extracted with ether to give the crude product, which
contained the desired coupled product 3a, together with the
unreacted starting materials 1 and 2a and a side product 4a
that was due to self-coupling of 2a (Scheme 1). The relative
The overall yield of 3a from 5 was 73% without the need
for chromatographic purification.
Scheme 1. Suzuki Reactions of Methyl p-Iodobenzoate 1 with
Aryl Boronic Acids 2 in Aqueous Media
We have examined the general scope of the reaction by
coupling 5 with a number of arylboronic acids (Table 1).
The corresponding reactions of 1 were also performed with
the same set of arylboronic acids and the purities of the crude
products were determined by 1H NMR (Table 2). In all cases,
the ionic liquid supported synthesis gave 3 in equal or
superior yields, pure according to NMR, without the need
(13) The use of ionic liquid supported synthesis has been reported, but
its advantage over conventional liquid-phase synthesis has not been
demonstrated. See: (a) Fraga-Dubreuil, J.; Bazureau, J.; Bazureau, J. P.
Tetrahedron Lett. 2001, 42, 6097. (b) Fraga-Dubreuil, J.; Bazureau, J. P.
Tetrahedron 2003, 59, 6121.
(14) For recent reports of Suzuki reaction in water and in ionic liquids,
see: (a) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973. (b) Sakurai,
H.; Tsukuda, T.; Hirao, T. J. Org. Chem. 2002, 67, 2721. (c) Mathews, C.
J.; Smith, P. J.; Welton, T. Chem. Commun. 2000, 1249. (d) Rajagopal, R.;
Jarikote, D. V.; Srinivasan, K. V. Chem. Commun. 2002, 616. (e) Revell,
J. D.; Ganesan, A. Org. Lett. 2002, 4, 3071.
amounts of each were determined by 1H NMR of the crude.
Typically, purification by chromatography of the crude
mixture was performed to give the desired product 3a in
60% yield.
(8) (a) Sheldon, R. Chem. Commun. 2001, 2399. (b) Sheldon, R. A.;
Lau, R. M.; Sorgedrager, M. J.; v. Rantwijk, F.; Seddon, K. R. Green Chem.
2002, 4, 147.
(9) (a) Fuller, J.; Osteryoung, R. A. J. Electrochem. Soc. 1997, 144, 3881.
(b) Fuller, J.; Breda, A. C.; Carlin, T. J. Electroanal. Chem. 1998, 459, 29.
(10) (a) Huddleston, J. G.; Willauer, H.; Swatloski, R. P.; Visser, A. E.;
Rogers, R. D. Chem. Commun. 2001, 1765. (b) Bosmann, A.; Datsevich,
L.; Jess, A.; Lauter, A.; Schmitz, C.; Wasserscheid, P. Chem. Commun.
2001, 2494.
(11) Ye, C.; Liu, W.; Chen, Y.; Yu. L. Chem. Commun. 2001, 2244.
(12) (a) Kimizuka, N.; Nakashima, T. Langmuir 2001, 17, 6759. (b) For
other ionic liquids containing PEG, see: Leone, A. M.; Weatherly, S. C.;
Williams, M. E.; Thorp, H. H.; Murray, R. W. J. Am. Chem. Soc. 2001,
123, 318.
(15) (a) Wright, S. W.; Hageman, D. L.; McClure, L. D. J. Org. Chem.
1994, 59, 6095. (b) Bumagin, N. A.; Bykov, V. V. Tetrahedron 1997, 53,
14437. (c) Blettner, C. G.; Konig, W. A.; Stenzel, W.; Schotten, T. J. Org.
Chem. 1999, 64, 3885. (d) Grasa, G. A.; Hillier, A. C.; Nolan, S. P. Org.
Lett. 2001, 3, 1077.
(16) Branco, L. C.; Rosa, J. N.; Moura Ramos, J. J.; Afonso, C. A. M.
Chem. Eur. J. 2002, 8, 3671.
(17) Methyl p-iodobenzoate was not observed in the final product under
the reaction conditions. Separate experiments showed that any unreacted 5
would have been recovered as methyl p-iodobenzoate. The less than 100%
yield of 3a was attributed to mechanical loss in the work up process.
5004
Org. Lett., Vol. 5, No. 26, 2003

Scheme 3. Suzuki Reactions of Ionic Liquid Supported
m-Iodobenzoate 9 with Aryl Boronic Acids 2 in Aqueous Media
Table 1. Results of the Suzuki Coupling Reaction of Ionic
Liquid Supported 5 and 9 with Boronic Acid 2
ionic liquid
boronic
molar ratio
yield of 3 or 11
entry
5 or 9
acid 2
of 5 or 9:2
(%, 2 steps)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
5
5
5
5
5
5
5
5
5
5
9
9
9
9
9
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2
1:2
1:2
1:2
1:2
73
82
62
83
68
72
81
60
83
71
76
73
55
77
70
1:2
1:2
1:2
1:2
1:2
These examples demonstrate that ILSS may offer a
convenient approach for phase separation and product
purification and find applications in other areas of organic
synthesis. One must however offer a caveat. The mere
presence of the ionic liquid moiety must have altered the
nature of the reaction, either physically or chemically. The
Suzuki coupling reaction appeared to proceed better with 5
than with 1, as evidenced by the absence of starting iodo-
benzoate in the ILSS reactions. This may be due to the better
solubility of 5 in the aqueous reaction media, the sublimation
of 1 during the reaction, or the possible rate enhancing effect
of the positive charge to the Suzuki reaction. Such adventi-
tious benefits of the ionic liquid moiety may not always be
there for other reactions. Nevertheless, for those reactions
that are compatible with or enhanced by the presence of the
ionic liquid moiety, easy phase separation and product
purification can be realized.
Table 2. Reaction of p-IPhCO2Me (1) with ArB(OH)2 (2):a
Composition of Crude Products and Yields of Biaryl
Compounds 3
composition of crude productb,c
yield of
1
4a -e
2a -e
3a -e
3c (%)
1 + 2a
1 + 2b
1 + 2c
1 + 2d
1 + 2e
2.9
14.0
43.5
2.2
19.8
16.3
0
0
13.4
12.3
23.2
0
23.7
7.9
54.0
46.5
56.5
74.1
63.0
70 (60)d
59
48
77
68
15.7
a Reactions were performed in a 1:1.5 molar ratio of 1 to 2. b Percent
by molar ratio. c Determined by 1H NMR. d Isolated yields in parentheses.
for chromatography. To demonstrate the ease of purification
further, the coupling of 5 with an even greater excess of the
reagent 2 (2 equiv) was also carried out. In all cases, products
3 were obtained in similar yields and purity (Table 1).
We have also examined the Suzuki reaction of the
m-iodobenzoate 9 with different arylboronic acids using the
same ILSS protocol (Scheme 3). The results are summarized
in Table 1. While we have not made the direct comparison
with the reactions of methyl m-iodobenzoate itself, the
products 11 obtained from the ILSS procedures, via the
intermediate 10 after ether washing, were all pure according
Acknowledgment. We thank Merck Frosst Canada and
the Natural Science and Engineering Research Council
(NSERC) of Canada for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for ionic liquids and Suzuki
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
to H NMR and required no chromatographic purification.
OL035977Y
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