Tailor-made hexaethylene glycolic ionic liquids as organic catalysts for specific chemical reactions

Article abstract of DOI:10.1021/ol200751e

Chemical equations presented. Hexaethylene glycol substituted imidazolium based ionic liquids (hexaEGILs) were designed and prepared well-tailored to a specific organic reaction using alkali-metal fluorides (MFs) as multifunctional organic catalysts. These hexaEGIL catalysts could significantly enhance the reactivity of MF, even KF. Furthermore, the hexaEGIL systems showed tremendous efficiency in the nucleophilic fluorination of base-sensitive substrates.

Full text of DOI:10.1021/ol200751e

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2502–2505
Tailor-Made Hexaethylene Glycolic Ionic
Liquids as Organic Catalysts for Specific
Chemical Reactions
Vinod H. Jadhav, Hwan-Jeong Jeong, Seok Tae Lim, Myung-Hee Sohn, and
Dong Wook Kim*
Department of Nuclear Medicine, Cyclotron Research Center, Chonbuk National
University Medical School, Jeonju, Jeonbuk 561-712, Korea
kimdw@chonbuk.ac.kr
Received March 21, 2011
ABSTRACT
Hexaethylene glycol substituted imidazolium based ionic liquids (hexaEGILs) were designed and prepared well-tailored to a specific organic
reaction using alkali-metal fluorides (MFs) as multifunctional organic catalysts. These hexaEGIL catalysts could significantly enhance the
reactivity of MF, even KF. Furthermore, the hexaEGIL systems showed tremendous efficiency in the nucleophilic fluorination of base-
sensitive substrates.
Due to several attractive properties, room temperature
ionic liquids (ILs) containing bulky organic cations
paired with their counteranions have attracted interest
as eco-friendly alternative reaction solvent systems
(compared to conventional volatile solvent systems)
for a variety of applications in chemistry, including
reaction acceleration, separation, and nanotechnology.1
Moreover, because ILs are highly tunable, they can be
tailored to meet specific needs by making simple struc-
tural modifications on either the cation or anion
component.1,2 It is well-known that imidazolium based
IL solvent systems perform well in nucleophilic substitu-
tions (including fluorination), when using alkali-metal
salts as nucleophile sources, through the phase transfer
catalyst (PTC) effect of IL reaction media.3
Among various organic transformations, the use of nu-
cleophilic fluorination to introduce a single fluorine atom at
a specific molecular site is regarded as an important organic
transformation reaction in the field of medicinal chemistry
and, in particular, the area of [18F]radiopharmaceutical
research involved with positron emission tomography
(PET) studies.4 For this purpose, alkali metal fluorides
(MFs) such as KF are generally used with various PTCs in
polar aprotic solvents (e.g., CH3CN, DMF).5 However, due
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r
10.1021/ol200751e
Published on Web 04/13/2011
2011 American Chemical Society

to recent advances, this fluorination reaction using MF in the
absence of PTCs can be accelerated in protic media, such as
tert-alcohols6 and short-chain polyethylene glycols (PEGs),7
through the “flexible” fluoride8 effect, resulting from the
controlled hydrogen bonding between MF and the protic
solvents.6À8 Moreover, it was found that the specific length
of PEGs such as pentaEG (EG = ethylene glycol), tethered
by polymer support, could provide PTC-like activity for
enhancing the reactivity of CsF in the fluorination reaction.9
However, these protic media protocols are still not sufficient
to enhance the reactivity of KF for this nucleophilic dis-
placement reaction due to the strong Coulombic influence of
the potassium cation on fluoride, and the protocols might be
inconvenient for the chemical processes due to the high
boiling point of PEG solvents.6À9
Scheme 1. Preparation of Hexaethylene Glycol Substituted
Imidazolium Salts (a) [hexaEGmim][OMs] and (b)
[dihexaEGim][OMs]
glycolic imidazolium cation; OMs = mesylate anion) were
prepared using a simple procedure as shown in Scheme 1.
Among various lengths of oligoEG, hexaEG was used to
prepare the hexaEGILs because of its metal cation chelation
efficiency (after N-alkylation, hexaEGILs could have six-
membered oxygen atoms on either branch, similar to
pentaEG). An N-alkylation reaction of 1-methylimidazole
with hexaEG mesylate 1 in CH3CN for 24 h afforded
[hexaEGmim][OMs] in 91% yield. [dihexaEGim][OMs]
was prepared by N-alkylation of imidazole with hexaEG
bromide 2 in the presence of K2CO3, followed by treatment
of 3 with hexaEG mesylate 1 for two days.
Figure 1. Concept of tailor-made ionic liquids: oligoether sub-
stituted imidazolium salts.
Catalysis has played a crucial role in chemical science,
and the design and application of new catalysts is an
important research topic. Based on these observations and
needs, we have designed oligoether substituted imidazolium
based ILs as multifunctional organic catalysts, in anticipa-
tion that (i) their imidazolium salt core might have a PTC-
like activity;3 (ii) the oligoether moiety might act as a Lewis
base toward metal cations, allowing the fluoride nucleophile
to become “free” and active;7 (iii) the terminal hydroxyl
group might provide the recognition of the nucleophile
(fluoride) for initial interaction by H-bonding as well as a
“flexible” fluoride effect with tert-alcohol solvents;6
(iv) another oligoEG component might make MFs more
reactive (Figure 1). Herein, we introduce tailor-made hex-
aethylene glycolic ionic liquid (hexaEGIL) systems as ex-
tremely efficient organic catalysts designed for nucleophilic
fluorination using KF including radiofluoride [18F].
Figure 2. Catalytic activity of hexaEGILs, [hexaEGmim][OMs]
and [dihexaEGim][OMs], in a nucleophilic fluorination reaction
with KF. The quantity of product was determined by 1H NMR.
R = naphthyl.
The hexaEGILs [hexaEGmim][OMs] and [dihexaEGim]-
[OMs] (hexaEGmim = 1-hexaethylene glycolic 3-methyli-
midazolium cation; dihexaEGim = 1,3-dihexaethylene
To investigate the catalytic activity of these two hexaE-
GILs, we carried out the nucleophilic fluorination using 3
equivofKFinthepresenceof thehexaEGILs(1.0 equiv) in
a tert-amyl alcohol medium under uniform reaction condi-
tions (at 90 °C for 2 h) and compared these results with
results of the same reaction in the presence of a conventional
IL [bmim][OMs] (bmim =1-n-butyl-3-methylimidazolium)
or hexaEG, or in the absence of any catalyst, as shown in
Figure 2. Whereas KF was inactive in the fluorination, even
in a tert-alcohol system without PTCs, the reactivity of KF
(6) (a) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.; Lee, S.; Oh, S. J.; Lee, S. J.;
Kim, J. S.; Ryu, J.-S.; Moon, D. H.; Chi, D. Y. J. Am. Chem. Soc. 2006,
128, 16394–16397. (b) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn,
M.-H.; Katzenellenbogen, J. A.; Chi, D. Y. J. Org. Chem. 2008, 73, 957–
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Org. Lett. 2010, 12, 3740–3743.
Org. Lett., Vol. 13, No. 9, 2011
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could be enhanced by all ILs in the same reactions. In
particular, hexaEG substituted IL systems [hexaEGmim]-
[OMs] and [dihexaEGim][OMs] showed much faster reac-
tion rates than the conventional IL [bmim][OMs] system in
the fluorination reaction. Furthermore, [dihexaEGim][OMs]
containing two hexaEG components had highly efficient
catalytic activity compared with monosubstituted [hexa-
EGmim][OMs]. These results were highly consistent with
our hypothesis depicted in Figure 1 and showed that these
hexaEGILs were well tailored to the specific organic reac-
tions using alkali-metal fluoride.
Table 2. Nucleophilic Fluorinations of the Various Substrates
with 3.0 equiv of KF Using [dihexaEGim][OMs] (0.5 equiv) ss a
Catalyst
Table 1. Fluorinations including [18F]Radiofluorination of
Mesylate 4 with Alkali-Metal Fluorides (MF) in the Presence of
hexaEGILsa
ionic liquid
(equiv)
MF
(3 equiv)
time
(h)
yield
(%)b
entry
1
2
3
4
5
6
7
8
9
1.0 mL of [hexaEGmim][OMs] KF
45 min 95
[hexaEGmim][OMs] (2.0)
[hexaEGmim][OMs] (1.0)
[hexaEGmim][OMs] (0.5)
[hexaEGmim][OMs] (0.25)
À
KF
KF
KF
KF
KF
KF
CsF
RbF
1.5
2
3
96
96
98 (95)c
91
8
12
2
10
98
[dihexaEGim][OMs] (0.5)
[dihexaEGim][OMs] (0.5)
[dihexaEGim][OMs] (0.5)
15 min 98 (95)c
1
90
10 10 mg of [dihexaEGim][OMs] 18FÀ/Cs2CO3 15 min 98d (88)e
11f
À
[
18F]TBAF
15 min 85d (72)e
a All reactions were carried out on a 1.0 mmol reaction scale of
mesylate 4 using 3 equiv of MF in 4.0 mL of tert-amyl alcohol at 100 °C.
b Yield determined by 1H NMR spectroscopy. c Yields of isolated
product in parentheses. d Yield determined by radio TLC. e Radio-
chemical yield. f Reference 3c.
a Method A: reactions were carried out on a 1.0 mmol scale of
substrate with 3.0 equiv of KF and 0.5 equiv of [dihexaEGim][OMs]
in 4.0 mL of tert-amyl alcohol. Method B: with TBAF in tert-amyl
alcohol. b Yield determined by 1H NMR spectroscopy. c Reference 9.
Table 1 illustrates the nucleophilic fluorination (including
[18F]radiofluorination) of a model mesylate compound 4
with 3 equiv of various alkali-metal fluorides, such as KF,
RbF, and CsF, employing the hexaEGILs as cosolvents,
promoters, and catalysts in a tert-amyl alcohol medium at
100 °C. In entries 1À3, when using [hexaEGmim][OMs] as a
cosolvent or promoter (0.1 mL, 2.0 and 1.0 equiv amounts,
respectively), the fluorination reaction with KF proceeded
smoothly, affording the desired fluoro-product 5 in excellent
yields (95À96%). It should be noted that the use of catalytic
amounts (0.5 and 0.25 equiv) of [hexaEGmim][OMs] was
enough to complete the reaction within reasonable time
periods (3 and 8 h) and to provide the product 5 in high
yields (entries 4 and 5, 98 and 91%, respectively). In compar-
ison, a tert-amyl alcohol system in the absence of any
catalyst; this reaction proceeded remarkably slowly, convert-
ing only 10% of the mesylate 4 to the fluoro-compound 5
after extended reaction times (12 h, entry 6). Moreover, as
shown in entry 7, the use of 0.5 equiv of [dihexaEGim][OMs],
which is the best condition for this type reaction, allowed the
same reaction with KF to proceed almost quantitatively
within 2 h. Furthermore, the same fluorination using CsF in
the presence of [dihexaEGim][OMs] proceeded to comple-
tion, in very high yield (98%), within only 15 min (entry 8).
The other alkali-metal fluoride (RbF) also can be efficiently
activated by the [dihexaEGim][OMs] organic catalyst in this
substitution reaction (entry 9). To demonstrate that [dihexa-
EGim][OMs] can be used to introduce fluorine-18 into or-
ganic molecules for a PET study, we conducted the nucleo-
philic [18F]radiofluorination with [18F]fluoride generated
from a cyclotron using [dihexaEGim][OMs], instead of con-
ventional PTCs under no-carrier-added conditions. A com-
parison of entries 10 and 11 shows that when compared with
the conventional method using tetrabutylammonium [18F]
fluoride ([18F]TBAF), a radiolabeled compound [18F]5
was produced in higher radiochemical yield (88%, decay
corrected) with a 15 min reaction time by this [dihexaEGim]-
[OMs] labeling protocol.
Table 2 shows the fluorination of various substrates using 3
equiv of KF in the presence of 0.5 equiv of [dihexaEGim]-
[OMs] in tert-amyl alcohol, thereby demonstrating that
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Org. Lett., Vol. 13, No. 9, 2011

[dihexaEGim][OMs] is generally applicable for various
other substrates. In entries 1À4, the fluorination reaction
of secondary alkyl tosylate and bromide, as base-sensitive
substrates, using KF/[dihexaEGim][OMs] in tert-amyl
alcohol proceeded with significant chemoselectivity, pro-
viding the desired secondary alkyl fluoride in high yield (91
and 78%, entries 1 and 3, respectively, Method A) com-
pared with the samereactionusing the conventional TBAF
(entries 2 and 4). In these reactions, we anticipated that
their chemoselectivity might be enhanced by the “flexible”
fluoride effect generated from the controlled H-bonding
between the terminal OH groups of [dihexaEGim][OMs],
KF, and tert-alcohol media. Another base-sensitive sub-
strate, 1-(2-mesyloxyethyl)naphthalene, could be con-
verted to 1-(2-fluoroethyl)naphthalene in 92% yield, with
the alkene byproduct being formed in only 8% yield by this
KF/[dihexaEGim][OMs] protocol (entry 5). The displace-
ment reactions of the primary alkyl bromide and iodide to
the primary alkyl fluoride 5 using KF/[dihexaEGim][OMs]
in tert-amyl alcohol also proceeded very selectively, afford-
ing 5 in excellent yield (91 and 86%, entries 6 and 7,
respectively). The fluorination reaction of a benzylic bro-
mide afforded the benzylic fluoride with 90% reaction
yield (entry 8). An R-fluoroacetophenone was synthesized
in 94% yield through the fluorination of the R-bromoace-
tophenone (entry 9). Various bioactive molecules such as
fluoro-flumazenile,10 fluoropropyl ciprofloxacin,11 and
fluoropropyl estrone, which can be molecular probes for
PET, were produced in excellent yield by reactions with the
corresponding tosylate and mesylate precursors (entries
10À12).
In summary, we have prepared new tailor-made hex-
aethylene glycolic imidazolium based ionic liquids
(hexaEGILs) that act as highly efficient multifunc-
tional organic catalysts designed for specific organic
reactions such as nucleophilic fluorination with KF or
[18F]fluoride, which is known to be a particularly
difficult chemical process. These hexaEGIL catalytic
systems could not only significantly enhance the reac-
tivity of KF but also reduce the formation of bypro-
ducts. Further studies are currently underway to
develop more efficient oligoEGILs through structural
modifications and to apply these unusual catalysts to
other chemical reactions, including rapid 18F labeling
of radiopharmaceuticals for PET.
Acknowledgment. This work was supported by Nuclear
Research & Development Program (Grant Code: 2010-
0017509) and the Conversing Research Center Program
(Grant Code: 2010K001050) through the National Re-
search Foundation of Korea (NRF) grant funded by the
Korean government (MEST), and the grant of the 2010
Post-Doctoral Fellowship Program, Chonbuk National
University.
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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