Pyrene-Tagged Ionic Liquids: Separable Organic Catalysts for SN2 Fluorination

Article abstract of DOI:10.1021/acs.orglett.7b01064

We prepared pyrene-substituted imidazolium-based ionic liquids (PILs) as organic catalysts for the S_N2 fluorination using alkali metal fluoride (MF). In this system, the PIL significantly enhanced the reactivity of MF due to the phase-transfer

Full text of DOI:10.1021/acs.orglett.7b01064

Letter
pubs.acs.org/OrgLett
Pyrene-Tagged Ionic Liquids: Separable Organic Catalysts for SN2
Fluorination
Abu Taher,† Kyo Chul Lee,‡ Hye Ji Han,† and Dong Wook Kim*,†
†Department of Chemistry and Chemical Engineering, Inha University, 100 Inha-ro, Nam-gu, Incheon 402-751, Korea
‡Department Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu,
Seoul 139-706, Korea
S
* Supporting Information
ABSTRACT: We prepared pyrene-substituted imidazolium-based ionic liquids
(PILs) as organic catalysts for the SN2 fluorination using alkali metal fluoride (MF).
In this system, the PIL significantly enhanced the reactivity of MF due to the phase-
transfer catalytic effect of the imidazolium moiety as well as the metal cation−π
(pyrene) interactions. Furthermore, this homogeneous catalyst PIL was easily
separated from the reaction mixture using reduced graphene oxide by π−π stacking
with the pyrene of PIL.
lthough there are a limited number of structurally simple
when the bioactive products are polar or contain many
1
Afluorine-containing natural organic molecules, the syn- heteroatoms due to the strong interactions between the products
and the ILs.15 Moreover, homogeneous catalysts offer a number
thesis of fluorinated molecules has received much attention for its
applications in pharmaceutical,2,3 agrochemical,4 and material
of significant advantages over their heterogeneous counterparts,
including high reactivity and selectivity.16 Therefore, the
development of easily separable PTCs for SN2 reactions is
highly desirable and is a topic of interest in both green chemistry
and current organic synthesis.
sciences5 due to the unique and favorable properties of fluorine
atoms.6 In particular, positron emission tomography (PET)
using radiopharmaceuticals labeled with fluorine-18 is regarded
as the most popular molecular imaging protocol for diagnosing
various diseases.7,8 Therefore, developments in these fields are
closely related to the development of practical, selective, cost-
effective, and efficient methodologies for the formation of C−F
bonds in potential biomolecules. For this purpose, alkali metal
fluorides (MFs), such as potassium fluoride (KF) and cesium
fluoride (CsF), are perhaps the most logical natural fluoride
sources for introducing a single fluorine at a specific site in an
organic molecule because of their abundance and low cost.1,6
However, phase-transfer catalysts (PTCs), such as crown ethers
and quaternary ammonium salts, are necessary for the formation
of C−F bonds through the nucleophilic displacement reaction
when using MFs due to the very low reactivity and solubility of
MFs in organic media.9−11
Graphene is a two-dimensional nanoscale material that has
found applications in various nanochemistry areas due to its
unique physical and chemical features.17 In recent advances,
reduced graphene oxide (rGO) has shown excellent performance
in facilitating the separation and reuse of homogeneous pyrene-
containing metal catalysts, which can be immobilized onto the
surfaces of rGO by their strong noncovalent π-stacking
interactions with the pyrene moieties of the catalysts.18,19 In
addition, it was also reported that the arenes, including pyrene,
can participate in noncovalent cation−π (arene) interactions
with alkali metal cations (in particular, Cs+).20 Thus, we designed
pyrene-tagged imidazolium-based ionic liquids (PILs) as multi-
functional organic catalysts for nucleophilic displacement
reactions using alkali metal fluorides, particularly CsF. In this
type of catalytic system, we expected that (i) the imidazolium
component would show a PTC effect,13 (ii) the cation−π
interactions between MFs and their pyrene moieties20 might
weaken the ionic interactions between M+ and F−, allowing the
F− nucleophile to become “freer” and more active, and (iii) the
pyrene component would allow the PILs to be immobilized onto
the surface of rGO by π−π stacking interactions,18,19 affording
Over the past decade, ionic liquids (ILs) have been actively
investigated for applications in a variety of branches of pure and
applied chemical sciences.12 In particular, imidazolium-based ILs
are well-known to have PTC activity that enhances the reactivity
and solubility of alkali metal salts in nucleophilic substitution
(SN2) reactions, including fluorination.13 Moreover, tailor-made
ILs designed for SN2 fluorination using MFs have been
developed by structural modification of conventional imidazo-
lium-based ILs.14 However, some ILs and conventional PTCs
can cause great problems when separating the product from the
reaction mixture after SN2 fluorination. This is especially true
Received: April 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01064
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Letter
easy PIL separation using rGO (Figure 1). Herein, we describe
the preparation of PILs and demonstrate their strong PCT effect
Figure 1. Concept of pyrene-tagged ionic liquids as multifunctional
organic catalysts.
in nucleophilic fluorination using MFs including [18F]fluoride
and the straightforward rGO-assisted separation procedure for
the PILs.
Pyrene-tagged ILs were prepared as multifunctional organo
catalysts as shown in Scheme 1. First, a pyrenyl mesylate
Figure 2. (A) Catalytic activity of BPIL, PIL, [bmim][OMs], and pyrene
in the SN2 fluorination of 4-(3-methanesulfonyloxyproxy)anisole (5)
with CsF in CH3CN. The quantity of product was determined using 1H
NMR spectroscopy. (B) Process for separating the PIL from the
reaction mixture using rGO.
Scheme 1. Synthesis of Pyrene-Tagged Ionic Liquids
the absence of catalyst (which hardly proceeded) because the
imidazolium salt moiety of ILs can enhance the reactivity of MF
by the PTC effect. Interestingly, the use of PIL allowed the
fluorination to proceed significantly faster compared with the use
of [bmim][OMs]. This result was consistent with our hypothesis
and suggested that the Cs+−π (pyrene from PIL) interaction20
can weaken the ionic interactions between Cs+ and F− (allow F−
to be freer), thus enhancing the reactivity of CsF as depicted in
Figure 1. The two-pyrene-substituted BPIL exhibited slightly
better catalytic activity compared with monopyrene-substituted
PILthe pyrene-only reaction also showed some catalytic
activity toward SN2 fluorinationwhich provided additional
evidence for our hypothesis. However, further mechanistic
studies using a calculation method are needed to confirm the role
of pyrene in the reaction.
We then turned our attention to the separation of the
homogeneous PIL organic catalyst through the immobilization
of PIL on rGO, which is driven by π−π stacking interactions.
Initially, we measured the PIL-grafting capacity of rGO using
elemental analysis (EA) after the treatment of PIL with rGO at
room temperature for 1 h in CH2Cl2 (see Scheme 1S). The
amount of PIL grafted onto rGO was 0.55 mmol/g. After the
fluorination reaction was complete, we attempted to separate PIL
from the reaction mixture using the rGO. The PIL was
successfully removed from the reaction mixture by the simple
addition of rGO and subsequent filtration of PIL-grafted rGO
(Figure 2B). In addition, the rGO was reused several times
without abrasion or post-treatment after removal of PIL from the
surface of rGO by simple hot washing.23
We then conducted the SN2 fluorination reactions with a range
of MFs in the presence of a PIL (different molar ratios: 0.5, 0.25,
and 0.13 equiv) in various solvent systems to further study the
properties of the PIL and to optimize the SN2 fluorination
condition (Table 1). In entry 1, the SN2 fluorination reaction of
mesylate 5 using CsF in the presence of 0.5 equiv of PIL was
completed within 1.5 h in CH3CN, providing the fluoro product
6 in 98% yield. Moreover, the use of smaller amounts (0.25 and
0.13 equiv) of PIL was enough to complete the same reaction
compound 2 was synthesized by the mesylation reaction of the
corresponding alcohol 1.21 N-Alkylation of 1-methylimidazole
with 2 at 90 °C for 24 h successfully gave a PIL in 92% yield.
Next, a pyrenyl bromide 3 was prepared in 96% yield by the
Appel reaction of 1,22 and subsequent treatment of 3 with
imidazole in the presence of K2CO3 at 90 °C for 24 h afforded an
imidazole-functionalized pyrene 4. Finally, a bis-pyrene-
functionalized imidazolium ionic liquid (BPIL) was successfully
synthesized in 88% yield by N-alkylation reaction of 4 and 2 at 90
°C for 48 h.
Initially, as shown in Figure 2A, to investigate the catalytic
activity of these two pyrene-tagged ionic liquids for MF reactions,
we attempted to conduct the SN2 fluorination of a model
mesylate compound 5 using 3 equiv of CsF in the presence of
PILs (0.5 equiv) in a CH3CN polar aprotic medium under
uniform reaction conditions (at 100 °C for 1.5 h). We compared
these results with those of the same reaction in the presence of (i)
the conventional IL [bmim][OMs] (bmim = 1-n-butyl-3-
methylimidazolium), (ii) only pyrene, or (iii) without catalyst.
It is well-known that the fluorination reaction in the presence of
[bmim][OMs] proceeds much faster than the same reaction in
B
DOI: 10.1021/acs.orglett.7b01064
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Letter
Table 1. Fluorination of Mesylate 5 with MF in the Presence
of PIL under Various Reaction Conditions
Table 2. Nucleophilic Fluorinations of the Various Substrates
with CsF in the Presence of PIL
a
a
b
entry
PIL (equiv)
solvent
CH3CN
MF
time (h) yield (%)
1
2
3
4
5
6
7
8
9
0.5
0.25
0.13
0.5
0.5
0.5
0.5
0.5
0.5
CsF
CsF
CsF
RbF
KF
1.5
3.5
5
98
96
97
95
94
0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
tert-amyl-OH
DMF
12
24
24
1
NaF
CsF
CsF
CsF
98
86
90
2
1,4-dioxane
24
a
All reactions were carried out on a 1.0 mmol scale of substrate with
b
3.0 equiv of MF in solvent (4.0 mL) at 100 °C. Isolated yields. R = 4-
methoxyphenyl.
within reasonable time periods (3.5 and 5 h) in excellent yields
(entries 2 and 3, 96 and 97%, respectively). As shown in entries
4−6 of Table 1, we examined the catalytic efficacy of PIL with
various MFs including RbF, KF, and NaF. We found that NaF
was fully inactive in the PIL-catalyzed reaction system and RbF
and KF were activated by PIL organic catalyst in the fluorination
reaction, but long reaction times were required (12 and 24 h,
respectively) compared with the same reaction using CsF. Next,
to investigate solvent effects in PIL-catalyzed fluorination using
CsF, the fluorination reactions were carried out in different types
of solvents including tert-amyl alcohol (tert-amyl-OH), DMF,
and 1,4-dioxane. Bulky protic solvents (representatively, tert-
amyl-OH) can activate MF in the SN2 fluorination via the
“flexible” fluoride effect.24 In this regard, the fluorination in tert-
amyl-OH showed the fastest reaction rate due to its synergistic
effect with the PIL organic catalyst (1 h, entry 7). The PIL also
worked well in another polar aprotic solvent (DMF, entry 8).
However, 1,4-dioxane did not show good performance in the
PIL-catalyzed fluorination reaction (entry 9).
a
Unless otherwise noted, all reactions were carried out on a 1.0 mmol
scale of substrate with 3.0 equiv of CsF in the presence of 0.5 equiv of
b
c
PIL in 4.0 mL of solvent at 100 °C. Isolated yield. Determined by 1H
NMR integration.
To explore the substrate scope of our protocol, we performed
the PIL-catalyzed SN2 fluorination reaction using a range of
substrates under the same conditions used for entries 1 or 7,
shown in Table 1, and the results are summarized in Table 2. A
fluoro sugar compound 8 was obtained in 96% yield by this PIL-
catalyzed SN2 fluorination of the corresponding sugar triflate 7
using CsF in CH3CN. PIL was easily purified using rGO. Using
this fluorination method, a sec-fluorinated proline derivative 10
was prepared from the corresponding tosylate substrate 9 in
good yield. The fluorination reactions of bioactive precursors,
including a mesylated estrone 11 or ciprofloxacin 13,25
proceeded smoothly, affording the corresponding fluoroestrone
12 or fluorociprofloxacin 14 (which can be PET molecular
probes) in excellent yield. A fluorinated azadibenzocyclooctyne
(ADIBO) 18 and a fluorinated azide 16, which are regarded as
key compounds in copper-free “click chemistry” for diverse
applications including F-18 labeling,26 were successfully
synthesized from the corresponding precursors in high yields
by our PIL-catalyzed fluorination protocol (97 and 88%,
respectively). The nucleophilic fluorination of α-bromoaceto-
naphthone 19 also provided α-fluoroacetonaphthone 20 in 93%
yield. A (fluoroalkyl)nitroimidazole 22 was produced in good
yield by reaction of the corresponding bromide 21. It is well-
known that tert-alcohol media can reduce the basicity of fluoride
and provide a “protic” atmosphere, thereby allowing the SN2
fluorination to proceed with significant chemoselectivity.24 Thus,
our study focused on the chemoselectivity of the PIL-catalyzed
SN2 fluorination reaction of base-sensitive substrates via a
synergistic effect with tert-alcohol media such as tert-amyl
alcohol. Remarkably, the use of tert-amyl alcohol solvent
dramatically enhanced the chemoselectively and the reaction
rate in the PIL-catalyzed SN2 fluorination reaction of sec-alkyl
bromide 23 as a highly base-sensitive substrate, affording the sec-
alkyl fluoride product 24 in excellent yield (92%). The use of
CH3CN in the same reaction afforded the alkene byproduct
(94%) due to a competing β-elimination side reaction. Another
base-sensitive substrate, 1-(2-mesyloxyethyl)naphthalene (25),
showed a similar trend.
Scheme 2 shows that the PIL had highly PTC activity in the F-
18 radiolabeling reaction for the applications of PET studies.
Next, we carried out the F-18 radiofluorination reaction of a
mesylate 27 using [18F]fluoride generated from a cyclotron in the
presence of PIL under no-carrier-added conditions. This F-18
Scheme 2. [18F]Radiofluorination in the Presence of PIL
C
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(3) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
(b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev.
2008, 37, 320.
(4) (a) Jeschke, P. Pest Manage. Sci. 2010, 66, 10. (b) Fujiwara, T.;
O’Hagan, D. J. Fluorine Chem. 2014, 167, 16.
(5) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.; Hulliger, J.
̈
labeling reaction was completed within 20 min and provided a
radiolabeled compound [18F]28 in an excellent decay-corrected
radiochemical yield (dcRCY: 88%, radioTLC ratio: 97%, total
reaction time: 35 min). However, we did not use rGO to remove
PIL in this initial F-18-labeling study (see the Supporting
Information, procedure of radiofluorination); the optimization
of radiochemistry including a separation system using PIL and
rGO is underway.
Chem. Soc. Rev. 2011, 40, 3496.
(6) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
(7) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470.
(8) Ametamey, S. M.; Honer, M.; Schubiger, P. A. Chem. Rev. 2008,
108, 1501.
(9) Gokel, G. W. Crown Ethers and Cryptands; Royal Society of
Chemistry: Cambridge, 1991.
(10) Liotta, C. L.; Harris, H. P. J. Am. Chem. Soc. 1974, 96, 2250.
(11) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed.;
VCH Ltd.: New York, 1993.
(12) (a) Chaban, V. V.; Prezhdo, O. V. J. Phys. Chem. Lett. 2013, 4,
1423. (b) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39,
3772. (c) Welton, T. Chem. Rev. 1999, 99, 2071.
(13) (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc. 2002,
124, 10278. (b) Jadhav, V. H.; Kim, J. G.; Park, S. H.; Kim, D. W. Chem.
Eng. J. 2017, 308, 664.
(14) (a) Shinde, S. S.; Lee, B. S.; Chi, D. Y. Org. Lett. 2008, 10, 733.
(b) Jadhav, V. H.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Kim, D. W. Org.
Lett. 2011, 13, 2502.
(15) (a) Kim, D. W.; Chi, D. Y. Angew. Chem., Int. Ed. 2004, 43, 483.
(b) Kroon, M. C.; Spronsen, J. V.; Peters, C. J.; Sheldon, R. A.; Witkamp,
G.-J. Green Chem. 2006, 8, 246. (c) Shinde, S. S.; Patil, S. N. Org. Biomol.
Chem. 2014, 12, 9264.
In summary, pyrene-tagged ionic liquids were designed and
prepared as multifunctional organic catalysts for nucleophilic
displacement reaction using MFs like CsF. In this catalytic
system, PILs significantly enhanced the reactivity of MF by the
PTC effect of the imidazolium salt core and the cation−π
interactions between MFs and their pyrene moiety, which
reduced the electrostatic interactions between alkali metal
cations and fluoride. This made the fluoride “freer” and more
reactive. Moreover, since PIL was efficiently immobilized onto
the surface of rGO by the noncovalent π−π stacking interaction
of pyrene components with rGO, the homogeneous organic
catalyst PIL was easily separated from the reaction mixture using
rGO. In addition, the PIL exhibited a tremendous synergistic
effect in a tert-alcohol reaction media in the nucleophilic
fluorination of base-sensitive substrates, increasing the speed
and chemoselectivity of the reaction. Overall, our PIL-catalyzed
SN2 fluorination protocol showed good performance in an F-18
radiolabeling reaction with [18F]fluoride. We believe that this
catalytic system will inspire future research in the fields of organic
synthesis, catalytic engineering, and F-18 labeling for PET
applications.
(16) Cole-Hamilton, D. J. Science 2003, 299, 1702.
(17) (a) Loh, K. P.; Bao, Q.; Eda, G.; Chhowalla, M. Nat. Chem. 2010,
2, 1015. (b) Rodriguez-Perez, L.; Herranz, M. A.; Martin, N. Chem.
Commun. 2013, 49, 3721.
(18) (a) Georgakilas, V.; Otyepka, M.; Bourlinos, A. B.; Chandra, V.;
Kim, N.; Kemp, K. C.; Hobza, P.; Zboril, R.; Kim, K. S. Chem. Rev. 2012,
112, 6156. (b) Georgakilas, V.; Tiwari, J. N.; Kemp, K. C.; Perman, J. A.;
Bourlinos, A. B.; Kim, K. S.; Zboril, R. Chem. Rev. 2016, 116, 5464.
(19) (a) Sabater, S.; Mata, J. A.; Peris, E. ACS Catal. 2014, 4, 2038.
(b) Mann, J. A.; Rodriguez-Lopez, J.; Abruna, H. D.; Dichtel, W. R. J.
Am. Chem. Soc. 2011, 133, 17614.
(20) (a) Dougherty, D. A. Science 1996, 271, 163. (b) Fukin, G. K.;
Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2002, 124, 8329.
(21) Cicchi, S.; Fabbrizzi, P.; Ghini, G.; Brandi, A.; Foggi, P.; Marcelli,
A.; Righini, R.; Botta, C. Chem. - Eur. J. 2009, 15, 754.
(22) Furuta, K.; Tomokiyo, K.; Kuo, M. T.; Ishikawa, T.; Suzuki, M.
Tetrahedron 1999, 55, 7529.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01064.
Experimental procedures and characterization data for all
compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kimdw@inha.ac.kr.
ORCID
(23) Liu, G.; Wu, B.; Zhang, J.; Wang, X.; Shao, M.; Wang, J. Inorg.
Chem. 2009, 48, 2383.
(24) (a) Kim, D. W.; Ahn, D.-S.; Oh, Y.-H.; Lee, S.; Kil, H. 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. (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. (c) Kim,
D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H. Angew. Chem., Int. Ed. 2008,
47, 8404.
(25) Sachin, K.; Kim, E.-M.; Cheong, S.-J.; Jeong, H.-J.; Lim, S. T.;
Sohn, M.-H.; Kim, D. W. Bioconjugate Chem. 2010, 21, 2282.
(26) (a) Ning, X.; Guo, J.; Wolfert, M. A.; Boons, G.-J. Angew. Chem.,
Int. Ed. 2008, 47, 2253. (b) Lee, S. B.; Kim, H. L.; Jeong, H.-J.; Lim, S. T.;
Sohn, M.-H.; Kim, D. W. Angew. Chem., Int. Ed. 2013, 52, 10549.
Dong Wook Kim: 0000-0002-6253-3393
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Basic Science Research Program
(Grant No. NRF-2017R1A2A2A10001451) and the Nuclear
Research & Development Program (Grant Nos. NRF-
2015M2A2A6A01045378 and 2015M2C2A1047692) through
the National Research Foundation of Korea (NRF) funded by
the Ministry of Science, ICT, and Future Planning.
REFERENCES
■
(1) O’Hagan, D.; Deng, H. Chem. Rev. 2015, 115, 634.
(2) (a) Champagne, P. A.; Desroches, J.; Hamel, J.-D.; Vandamme, M.;
Paquin, J.-F. Chem. Rev. 2015, 115, 9073. (b) Lee, J.-W.; Oliveira, M. T.;
Jang, H. B.; Lee, S.; Chi, D. Y.; Kim, D. W.; Song, C. E. Chem. Soc. Rev.
2016, 45, 4638.
D
DOI: 10.1021/acs.orglett.7b01064
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