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 phasetransfer 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.
A
when the bioactive products are polar or contain many heteroatoms due to the strong interactions between the products and the ILs.15 Moreover, homogeneous catalysts offer a number 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. 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 pyrenecontaining 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 multifunctional 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
lthough there are a limited number of structurally simple fluorine-containing natural organic molecules,1 the synthesis of fluorinated molecules has received much attention for its applications in pharmaceutical,2,3 agrochemical,4 and material 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, costeffective, 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 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 imidazolium-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 © 2017 American Chemical Society
Received: April 11, 2017 Published: June 20, 2017 3342
DOI: 10.1021/acs.orglett.7b01064 Org. Lett. 2017, 19, 3342−3345
Letter
Organic Letters 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 Scheme 1. Synthesis of Pyrene-Tagged Ionic Liquids
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.
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-pyrenefunctionalized 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-3methylimidazolium), (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
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 PILthe pyrene-only reaction also showed some catalytic activity toward SN2 fluorinationwhich 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 3343
DOI: 10.1021/acs.orglett.7b01064 Org. Lett. 2017, 19, 3342−3345
Letter
Organic Letters Table 1. Fluorination of Mesylate 5 with MF in the Presence of PIL under Various Reaction Conditionsa
entry
PIL (equiv)
solvent
MF
time (h)
yieldb (%)
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
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN tert-amyl-OH DMF 1,4-dioxane
CsF CsF CsF RbF KF NaF CsF CsF CsF
1.5 3.5 5 12 24 24 1 2 24
98 96 97 95 94 0 98 86 90
Table 2. Nucleophilic Fluorinations of the Various Substrates with CsF in the Presence of PILa
a
All reactions were carried out on a 1.0 mmol scale of substrate with 3.0 equiv of MF in solvent (4.0 mL) at 100 °C. bIsolated yields. R = 4methoxyphenyl.
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, tertamyl-OH) can activate MF in the SN2 fluorination via the “flexible” fluoride effect.24 In this regard, the fluorination in tertamyl-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). 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 PILcatalyzed 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-bromoacetonaphthone 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 wellknown that tert-alcohol media can reduce the basicity of fluoride and provide a “protic” atmosphere, thereby allowing the SN2
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 PIL in 4.0 mL of solvent at 100 °C. bIsolated yield. cDetermined by 1H NMR integration.
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 secalkyl 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 F18 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
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DOI: 10.1021/acs.orglett.7b01064 Org. Lett. 2017, 19, 3342−3345
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Organic Letters
(3) (a) Müller, 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. 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. (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. (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.
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. 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.
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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)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Dong Wook Kim: 0000-0002-6253-3393 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Basic Science Research Program (Grant No. NRF-2017R1A2A2A10001451) and the Nuclear Research & Development Program (Grant Nos. NRF2015M2A2A6A01045378 and 2015M2C2A1047692) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b01064 Org. Lett. 2017, 19, 3342−3345
