Design of ionic liquids as a medium for the Grignard reaction

Article abstract of DOI:10.1016/j.tetlet.2007.09.010

Design of novel phosphonium ionic liquids that are compatible with Grignard reagents have been investigated; several types of phosphonium salts that have an alkyl ether moiety have been synthesized and their capability evaluated as solvents for Grignard reagents. It has been established that even basic aliphatic Grignard reagent-mediated reactions are possible when methoxyethyl(tri-n-butyl)phosphonium bis(trifluoromethanesulfonyl)imide is used as the solvent.

Full text of DOI:10.1016/j.tetlet.2007.09.010

Tetrahedron Letters 48 (2007) 7774–7777
Design of ionic liquids as a medium for the Grignard reaction
*
Toshiyuki Itoh, Keisuke Kude, Shuichi Hayase and Motoi Kawatsura
Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama minami, Tottori 680-8552, Japan
Received 24 August 2007; accepted 4 September 2007
Available online 6 September 2007
Abstract—Design of novel phosphonium ionic liquids that are compatible with Grignard reagents have been investigated; several
types of phosphonium salts that have an alkyl ether moiety have been synthesized and their capability evaluated as solvents for
Grignard reagents. It has been established that even basic aliphatic Grignard reagent-mediated reactions are possible when
methoxyethyl(tri-n-butyl)phosphonium bis(trifluoromethanesulfonyl)imide is used as the solvent.
Ó 2007 Elsevier Ltd. All rights reserved.
Ionic liquids are widely recognized as greener solvents,
suitable for use in organic reactions and providing pos-
sibilities for improvement in control of product distribu-
tion, enhanced reactivity, ease of product recovery,
ethyl magnesium iodide in pure ionic liquid, N-butyl-
5
pyridinium tetrafluoroborate ([bpy][BF ]).
These
4
reports prompted us to investigate the most suitable
design of ionic liquids for the Grignard reaction. Herein
we wish to report our successful design of phosphonium
salt ionic liquids that are applicable to various types of
Grignard reagent mediated reactions. Wilhelm and
1
catalyst immobilization, and recycling. We have been
interested in the use of ionic liquids in organic synthesis
in both chemical and biochemical reactions, and have
shown several excellent examples of the recyclable use
of enzymes or iron salt catalysts using these liquids as
4
a
4b
jurcik and Handy reported that use of 2-alkylated
or arylated-imidazolium salts is essential to accomplish
the Grignard reaction in an imidazolium ionic liquid
solvent system. Therefore, we initially tested the
reaction of benzaldehyde with phenylmagnesium
bromide (PhMgBr) in 1-butyl-3-methylimidazolium
2
reaction media. Ionic liquids have heretofore been con-
sidered inappropriate for strong base-mediated reac-
tions. However, recently, several examples have been
reported showing the possibility of using these liquids
as reaction media for strong base-mediated reactions
bis(trifluoromethanesulfonyl)imide ([Bmim][Tf N]) or
2
3
–5
such as the Grignard reaction.
1-butyl-2,3-dimethylimidazolium bis(trifluoromethane-
sulfonyl)imide ([Bdmim][Tf N]) (Eq. 1).
2
Clyburne and co-workers made the first breakthrough
on this problem, demonstrating that Grignard reactions
took place in a mixture of phosphonium ionic liquid and
OH
CHO
RMgBr
R
3
Ionic Liquid, 0 ºC,
tetrahydrofuran (THF). The authors showed that a
1
5 ~ 15 min.
2
ð1Þ
number of reactions were possible in the phosphonium
ionic liquids including addition of carbonyl, benzyne
2
a: R=Ph, 2b: R=Me,
2c: R=Bu, 2d: R=n-Oct
e: R=Vinyl
3
reaction, halogenation, and coupling reactions. But
2
there was still the serious limitation that aryl Grignard
reagents were only applicable in the phosphonium ionic
As anticipated, and as shown in Table 1, no reaction
took place when PhMgBr was reacted with benzal-
dehyde in conventional ionic liquid, [Bmim][Tf N]
entry 2) and desired product 2a (R = Ph) was obtained
for the [Bdmim][Tf N] solvent system (entry 3). These
results clearly showed that the strong acidity of the
-proton of the imidazolium salt caused decomposi-
tion of the Grignard reagents. Furthermore, it was
also found that 2a was obtained in good yield by
using diethyl-1-methoxyethylammonium bis(trifluoro-
3
4a
liquid solvent system. Wilhelm and Jurcik
and
4
b
Handy reported that the use of 2-arylated-imidazolium
salts and 2-alkylated-imidazolium salts is a solution to
this issue and Grignard reactions were accomplished in
these 2-substituted imidazolium type ionic liquid solvent
systems. Further, Chan reported the first preparation of
2
(
2
2
4
*
Corresponding author. Tel./fax: +81 857 31 5259; e-mail: titoh@
chem.tottori-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.010

T. Itoh et al. / Tetrahedron Letters 48 (2007) 7774–7777
7775
Table 1. Results of the Grignard reaction in an ionic liquid solvent
system
CF3 CF3
O
O
S
S
a
Entry
Solvent
RMgBr
Yield of 2
%)
N
O
O
(
R
b
c
Et Et
O
R1 Mg Br
P
(
R)
A
B
R
O
d
d
d
R
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
THF
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Bu
n-Oct
Vinyl
Ph
Ph
Bu
Ph
95
0
98
0
R1 Mg Br
[Bmim][Tf
[Bdmim][Tf
DEME
f
P1
2
N]
N]
R
b
d
d
O
2
86
88
80
87
—
89
94
61
56
76
67
66
81
—
—
—
O
R
P
e
d
d
Et Et
h
R
<64
O
N
O
g
d
P2
92
95
55
74
71
81
93
97
87
66
79
S
S
O
O
CF3
IL1a
IL2a
IL1a
IL1a
IL1a
IL1a
F3C
Figure 1. Working hypothesis for designing ionic liquids appropriate
1
1
1
1
1
1
1
for Grignard reaction.
i
IL1a
j
are stabilized by complexation with an ether oxygen
functional group, we simply hypothesized that intro-
duction of an appropriate alkyl ether functional group
on the phosphonium salts might contribute to stabiliza-
tion of the reagents.
IL1a
9
j
IL1a
j
P2
a
Isolated yield. All results are average data after the reaction was
carried out with 3 repetitions.
Condition A: 0.6 mL of 1.0 M THF solution of RMgBr was mixed
with 1.0 mL of IL, then the aldehyde (0.5 mmol) was added imme-
diately to the mixture.
Condition B: a solution of 0.6 mL of 1.0 M THF solution of RMgBr
and IL (1.0 mL) was stored at 0 °C for 1 h under argon, then the
aldehyde (0.5 mmol) was added to the mixture.
It took at least 15 min. to complete the reaction when the reaction
was carried out in THF.
b
From the standpoint of realizing an easy work-up pro-
cess, hydrophobic salts are far preferable. On this basis,
we attempted to prepare room temperature ionic liquids
by combining phosphonium cations with two types of
anions, bis(trifluoromethanesulfonyl)imide (Tf N) and
its cyclic analogue NDSHFPI, because it was well recog-
nized that bis(trifluoromethanesulfonyl)imide salts pro-
vide hydrophobic ionic liquids (Fig. 2). Among 10
phosphonium salts prepared, six types were obtained
as liquids and four as solids at room temperature
c
2
d
e
f
DEME:Et
P1: [(n-Hex)
2
(MeOCH
(n-C14
(Me)P][Tf
It was very difficult to isolate the product from the reaction mixture
due to high solubility of the IL in Et O or hexane.
2
CH
29)P][Tf
N].
2
)N][Tf
2
N].
10
3
H
2
N].
g
h
P2: [n-Bu
3
2
(
25 °C). As shown in Figure 2, all Tf N salts were found
2
2
i
to be liquid at rt, while the combination of NDSHFPI
anion tended to give solid salts at rt. Although all salts
Recycled IL (5 times) was used as solvent.
j
Condition C: THF was removed under vacuum from the THF solu-
tion of PhMgBr (0.6 mmol) at 0 °C, then 1.0 mL of IL solution of
PhCHO (0.5 mmol) was added and stirred for 5 min at 0 °C under
argon.
1
1
showed the desired hydrophobic properties, IL1a
1
1
and IL2a possess preferable properties as a solvent,
being soluble in neither hexane nor ether. This made it
possible to realize easy extraction of the product from
6
methane-sulfonyl)imide (DEME) as a reaction medium
(
entry 4). Very recently, it has been reported that oxygen
atoms from anions like decanoate can stabilize a Grig-
nard reagent.
X
O
O
N
7
R
S CF3
P
R
R
O
Tf N:
2
Clyburne and co-workers explained the reason that
Grignard reaction is possible in their phosphonium
ionic liquid P1 (tetradecyl(trihexyl)phosphonium bis(tri-
fluoromethanesulfonyl)imide) using kinetic arguments:
the acidic C–H site of the a position of the phosphonium
cation might be protected by the long, non-rigid alkyl
O
S CF3
IL1a: R= Bu, X= Tf N
IL1b: R=n-Oct, X= Tf N
IL1c: R=Bu, X= NDSHFPI
IL1d: R=n-Oct, X= NDSHFPI
2
O
2
O
S CF
O
N
R
X
2
3
chain. We confirmed that the desired Grignard reaction
P
O
CF2
R
NDSHFPI:
was indeed possible in P1 (entry 5), however, we soon
recognized a serious drawback: isolation of the product
was very difficult from this solvent P1 due to its high sol-
ubility in both ether and hexane. This caused significant
reduction of the chemical yield of the product in a small
scale experiment, although the reaction itself proceeded
very smoothly in this solvent.
R
O S CF2
O
IL2a: R= Bu, X= Tf2N
IL2b: R=n-Oct, X= Tf2N
IL2c: R=Bu, X= NDSHFPI
IL2d: R=n-Oct, X= NDSHFPI
Liquid at 25 ºC: IL1a, IL1b, IL1d, IL2a, IL2b, IL2d
Solid at 25 ºC: IL1c, IL2c
IL1a: Viscosity=72 cP•s at 25 ºC (H O= 880
2
With these preliminary results in mind, we attempted to
ppm), mp = 9.5 ºC (DSC)
design a novel phosphonium type of ionic liquid
8
(
Fig. 1). Since it is well known that Grignard reagents
Figure 2. List of novel phosphonium salts prepared.

7776
T. Itoh et al. / Tetrahedron Letters 48 (2007) 7774–7777
the ionic liquid mixture. On the other hand, tri(n-
octyl)phosphonium salts, IL1b, IL1d, IL2b, and IL2d,
were easily dissolved in both ether and hexane, so it
was assumed that isolation of the reaction products
from these solvents might be difficult. We thus chose
IL1a and IL2a as appropriate solvents for the present
project and evaluated each of them as a solvent for Grig-
nard reaction with benzaldehyde.
PhMgBr in IL2a might be due to the increased acidity
of the a-position of the phosphonium center. It was
possible to use highly basic aliphatic Grignard reagents
in our IL1a solvent system (entries 9–12); the desired
products were obtained in excellent to good yield if
the reactions were carried out in IL1a. We thus
succeeded in showing that our design was indeed effec-
tive for preparing phosphonium ionic liquid that is
appropriate for the use of Grignard reaction. Use of
IL1a facilitated product separation due to the triphasic
nature of water, ionic liquid, and ether (or hexane)
combinations. Further, it was confirmed that IL1a was
recyclable after drying of the solvent under vacuum
following the work-up process (entry 13).
Typically the reaction was carried out as follows (Con-
dition A): 0.6 mL of 1.0 M THF solution of PhMgBr
was mixed with 1.0 mL of IL, then benzaldehyde
(
0.5 mmol) was immediately added to the mixture at
0
°C. After 5 min stirring at 0 °C, the reaction was
quenched by the addition of 0.1 mL of water and the
organic products were then extracted with 25% ether
in hexane to afford, after purification on silica gel thin
Although attempts to generate the Grignard reagent in
pure IL1a by the reaction of PhBr with magnesium
metal were unsuccessful, we finally established that the
reaction proceeded in a THF free IL1a solvent system
(Condition C): a THF solution of PhMgBr (0.6 mmol)
was placed in a flask under argon, then THF was
removed under vacuum at 0 °C. To the resulting
PhMgBr solid was added a IL1a (1.0 mL) solution of
benzaldehyde (0.5 mmol) and the mixture was stirred
for 5 min at 0 °C. After the usual work-up process, we
obtained the desired product 2a in 87% yield (entry
14). To our delight, we succeeded in obtaining 2b
(R = Bu) using more basic BuMgBr instead of PhMgBr
under the same conditions (entry 15). On the contrary, a
significant reduction of the chemical yield of 2a was
recorded; 79% of 2a was obtained when P2 was used
as solvent in the reaction of PhMgBr (entry 16). These
results confirmed that the presence of ether oxygen on
the side arm of the phosphonium salt contributes to
stabilizing the Grignard reagent as we hypothesized.
This might be the most important advantage of IL1a.
1
2
layer chromatography (TLC), the desired product 2a
(
R = Ph) in good yield. After the work up process, the
ionic layer was washed with water to remove magnesium
salt derived from the Grignard reagent, then dried under
reduced pressure at 60 °C for 3 h prior to use in the next
reaction. It was confirmed that IL1a could be recycled
and reused many times without any difficulty. With
the intention of investigating the stability of Grignard
reagent in the phosphonium salt ionic liquid, we also
conducted the reaction under Condition B: a solution
of 0.6 mL of 1.0 M THF solution of RMgBr and IL
(
1.0 mL) was stored at 0 °C for 1 h under argon, then
the aldehyde (0.5 mmol) was added to the mixture.
We found that use of methyl(tir-n-butyl)phosphonium
1
3
bis(trifluoromethanesulfonyl)imide, P2,
also gave
good results and alcohol 2a was obtained in excellent
yield because this solvent had poor solubility in ether
and hexane (entry 6). This was an unexpectedly good
result for us because P2 possesses the acidic C–H site
of the a position of phosphonium cation, though it
was explained by kinetic arguments that the reason the
Grignard reaction is possible in P1 is due to the protec-
tive effect of the long, non-rigid alkyl chains. As
expected, we found that methoxyethyl(tri-n-butyl)phos-
phonium bis(trifluoromethanesulfonyl)imide (1L1a)
worked best when PhMgBr reacted with benzaldehyde
at 0 °C; the reaction proceeded very rapidly and benzal-
dehyde was consumed completely in less than 5 min
In summary, we demonstrated that introduction of alkyl
ether moiety on the side arm of phosphonium salt ionic
liquid was quite effective in improving the capability of
the phosphonium salt ionic liquids as a solvent for Grig-
nard reaction, and we were able to apply the solvent for
even aliphatic Grignard reagent mediated reaction. We
also succeeded in demonstrating the ether free Grignard
reaction in an ionic liquid solvent system. Since solvent
polarity conditions of IL1a are completely different from
many conventional organic solvents, we are hopeful of
obtaining unique results with further investigation.
(
entry 7), while at least 15 min was required to complete
the reaction when it was carried out in THF under the
same temperature conditions (entry 1). Since IL1a is
highly viscous compared to THF and it was suggested
that the Grignard reaction might involve an electron
9
,7
transfer pathway, this acceleration seems to be an
important character of the ionic liquid medium.
Acknowledgments
The present work was supported by a Grant-in-Aid for
Scientific Research in a Priority Area, ‘Science of Ionic
Liquids’, from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan. The authors
are grateful to Mr. Yasuhiro Tsukada and Dr. Takahiro
Oishi of Kaneka Co., Ltd for measurement of physical
properties of our phosphonium salt ionic liquids. They
are also grateful to Dr. Katsuhiko Tsunashima of
Nippon Kagaku Industry Co., Ltd for providing novel
phosphonium ionic liquids.
A significant stabilization effect of the ionic liquid was
observed when PhMgBr was stored in IL1a for 1 h at
0
°C (entry 7, condition B), while, in contrast, PhMgBr
lost its activity gradually in the simple phosphonium salt
P2 (entry 6). It was further found that the position of
ether oxygen at the alkyl group reflected on the capabil-
ity of the phosphonium salt. Stability of PhMgBr in
ionic liquid IL2a was obviously inferior to that in
IL1a (entry 8). We speculate that this lower stability of

T. Itoh et al. / Tetrahedron Letters 48 (2007) 7774–7777
7777
Supplementary data
11. Preparation of IL1a was carried out as follows: To an
ethanol (20 mL) solution of 1-bromo-2-methoxyethane
(
4.68 g, 40 mmol) was added tributylphosphine ( 7.5 g,
Experimental details for preparation of ionic liquids
1
13
31
37 mmol) and the resulting mixture was stirred for 22 h at
80 °C. After being cooled to room temperature (rt),
hexane was added to form a precipitate, which was
removed by filtration. The resulting filtrate was evapo-
rated under vacuum to give the bromine salt (12.31 g,
IL1a and IL2a with NMR spectra ( H, C, P, and
1
9
F) are available. Supplementary data associated with
this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.09.010.
3
6 mmol) in 97% yield. The salt was dissolved in ethanol
(
(
18 mL) and lithium bis(trifluoromethanesulfonyl)imide
11.37 g, 40 mmol) powder was added, then the mixture
References and notes
was stirred at rt for 17 h to form lithium bromide as a
precipitate. The precipitate was removed by filtration, the
filtrate was washed with hexane 3 times and the solvent
removed using lyophilization. The resulting oil was
dissolved in acetone and treated with active charcoal,
and the charcoal was then removed by filtration. The
filtrate was passed through active alumina (Type II) and
dried under vacuum at 50 °C for 5 h to give IL1a (19.15 g,
1
. (a) For recent reviews of reactions in an ionic liquid
solvent system see: Ionic Liquids in Synthesis; Wassersc-
heid, P., Welton, T., Eds.; Wiley-VCH, 2003; (b) Ionic
Liquids as Green Solvents; Rogers, R. D., Seddon, K. R.,
Eds.ACS Symposium Series; American Chemical Society,
002; Vol. 856; (c) Jain, N.; Kumar, A.; Chauhan, S.;
Chauhan, S. M. S. Tetrahedron 2005, 61, 1015–1060; (d)
Chowdhury, S.; Mohan, R. S.; Scott, J. L. Tetrahedron
2
1
35 mmol) as colorless oil in 95% yield: H NMR
(500 MHz, CDCl ) d 0.979 (9H, t, J = 6.85 Hz), 1.45–
3
2
007, 63, 2363–2389.
1.55 (12H, m), 2.10–2.20 (6H, m), 2.53 (2H, q,
2
. Recent examples see: (a) Ohara, H.; Kiyokane, H.; Itoh,
T. Tetrahedron Lett. 2002, 43, 3041–3044; (b) Itoh, T.;
Kawai, K.; Hayase, S.; Ohara, H. Tetrahedron Lett. 2003,
J = 5.95 Hz), 3.36 (3H, s), 3.75 (2H, dt, J = 14.2 Hz,
1
3
J = 5.95 Hz); C NMR (125 MHz, CDCl
3
) d 13.00, 19.16
(d, JC–P = 46.7 Hz), 19.98 (d, JC–P = 46.7 Hz), 23.24 (d,
4
4, 4081–4084; (c) Uehara, H.; Nomura, S.; Hayase, S.;
Kawatsura, M.; Itoh, T. Electrochemistry 2006, 74, 635–
38; (d) Tsukada, Y.; Iwamoto, K.; Furutani, H.; Matsu-
J
C–P = 4.78 Hz), 23.60 (d, JC–P = 16.2 Hz), 58.82, 65.08
31
(d, JC–P = 7.64 Hz), 119.80 (q, JC–F = 315.5 Hz);
P
6
NMR (202.46 MHz, CDCl
3
) d 39.08 (d, JP–C = 26.1 Hz);
F NMR (170.6 MHz, CDCl , C ) d 92.91; IR (neat)
2937, 2878, 1400, 1194, 1057, 738 cm ; HRMS (EI) calcd
for 34OP: 261.1670. Found: 261.1666. Viscos-
1
9
shita, Y.; Abe, Y.; Matsumoto, K.; Monda, K.; Hayase,
S.; Kawatsura, M.; Itoh, T. Tetrahedron Lett. 2006, 48,
3
F
6 6
1
ꢀ
1
801–1804; (e) Itoh, T.; Matsushita, Y.; Abe, Y.; Han,
15
C H
S.-H.; Wada, S.; Hayase, S.; Kawatsura, M.; Takai, S.;
Morimoto, M.; Hirose, Y. Chem. Eur. J. 2006, 12, 9228–
ity = 72 cPs at 25 °C (H O = 880 ppm), mp = 9.5 °C
2
(DSC). Compound IL2a was prepared through a similar
1
9
237.
route from ethoxymethylchloride in 97% overall yield: H
3
4
. Ramnial, T.; Ino, D. D.; Clyburne, J. A. C. Chem.
Commun. 2005, 325.
. (a) Jurcik, V.; Wilhelm, R. Green Chem. 2005, 7, 844–
3
NMR (500 MHz, CDCl ) d 0.98 (9H, t, J = 7.0 Hz), 1.23
(t, 3H, J = 7.0 Hz), 1.49–1.59 (6H, m), 2.15–2.21 (6H, m),
3.69 (2H, q, J = 7.0 z), 4.29 (2H, dd, J = 3.0 Hz,
1
3
8
48; (b) Handy, S. T. J. Org. Chem. 2006, 71, 4659–
J = 2.0 Hz);
3
C NMR (125 MHz, CDCl ) d 13.04,
4
662.
16.83, 17.19, 23.20, 23.60, 23.72, 23.86, 59.47(d,
5
6
. Law, M. C.; Wong, K.-Y.; Chan, T. H. Chem. Commun.
006, 2457–2459.
. For this ionic liquid, please contact Dr. Gen Masuda of
Nissinbo Co., Ltd Tel.: +81 43 205 0795, fax: +81 43 205
J
C–P = 65.8 Hz) 70.33 (d, JC–P = 13.3 Hz), 119.80 (q,
31
2
J
3
CꢀF = 315.5 Hz); P NMR (202.46 MHz, CDCl ) d
1
9
37.20 (d, JP–C = 26.1 Hz); F NMR (170.6 MHz, CDCl
3
,
6 6
C F
) d 82.91; IR (neat) 2939, 2877, 1468, 1193, 1057,
ꢀ1
0
842.
617 cm . Since ionic liquids, IL1b, IL1d, IL2a, IL2b, and
IL2d, showed poor properties as reaction media, we did
not attempt further purification.
7
8
. Ramnial, T.; Taylor, S. A.; Clybume, J. A. C.; Walsby, C.
J. Chem. Commun. 2007, 2066–2068.
. Itoh, T.; Kude, K.; Iwai, A.; Hayase, S.; Kawatsura, M.
Abstract of 86th CSJ Annual Meeting, 1D3-39, Osaka,
March 25, 2007.
12. Since IL1a does exhibit slight solubility in ether, over the
course of extraction workup, the volume of the IL
remaining will decrease. Fortunately, the use of 25% ether
in hexane solution was sufficient to extract the products
from the IL.
13. For this novel ionic liquid, please contact Dr. Katsuhiko
Tsunashima of Nippon Kagaku Industry Co., Ltd Tel.:
+81 3 3636 8090; fax: +81 3 3636 8071. E-mail:
katsuhiko.tsunashima@nippon-chem.co.jp.
9
. Wakefield, B. J. In Comprehensive Organic Chemistry;
Barton, D. H. R., Ollis, W. D., Eds., 1979; Vol. 3,,
Chapter 15.2.
1
0. A recent good example, see: Zhou, Z.-B.; Matsumoto, H.;
Tatsumi, K. Chem. Eur. J. 2005, 11, 752–766, and
references cited therein.