Room Temperature Ionic Liquids as Homogeneous Supports for

Chapter 10

Room Temperature Ionic Liquids as Homogeneous Supports for Synthesis 1,2

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Downloaded by UNIV OF GUELPH LIBRARY on August 6, 2012 | http://pubs.acs.org Publication Date: January 18, 2007 | doi: 10.1021/bk-2007-0950.ch010

Scott T. Handy , Maurice Okello , and David Bwambok 1

1

Department of Chemistry, State University of New York at Binghamton, Binghamton, NY 13902 Current address: Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132 2

In the search for new, more stable homogeneous supports, we have investigated the use of room temperature ionic liquids (RTILs) based on fructose. These RTIL supports have been employed both in the support of reactants and reagents. They greatly facilitate product/by-product separation as well as enable recycling of the support. Key features that have been noted include the ability to tune the solubility/miscibility properties of the support to aid in separation and recycling and the potentially limited utility of these supports in situations that involve basic conditions.

In the ongoing struggle to make organic synthesis less time-consuming and more efficient, one idea has been to anchor, or support, small molecules on some other surface. This basic concept has proven to be very useful and is the heart of modern heterogeneous supported synthesis. More recently, the idea of homogeneous supported synthesis has been introduced. In this case, the goal is to combine the benefits of conventional homogeneous synthesis (good mass transfer and reaction rates, wide range of reaction types and conditions) with the benefits of heterogeneous solid supported synthesis (ease of separation). There have been a number of approaches to this concept, with the polyethyleneglycol (PEG) tethers of Janda being the most popular (Figure 1) (1). By now, a wide range of catalysts, reagents, and reactants have been tethered to these types of supports and, since they are homogeneous in many conventional solvents, used 116

© 2007 American Chemical Society

In Ionic Liquids in Organic Synthesis; Malhotra, S.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

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in much the same fashion as their conventional "solution-phase" counterparts. At the end of the reaction, however, dilution of the reaction with a solvent (typically methanol or water) then results in the prepitation of the tethered material, thereby enabling the facile separation via filtration that is characteristic of heterogeneous supports.

Figure 1. Examples of homogeneous supports and supported reagents.

Although clearly advantageous, there are some issues that remain to be solved with these homogeneous supports. First, they are very high molecular weight in comparison to the materials that are being supported, resulting in very low loading values (2). The simplest PEG tags have molecular weights in excess of 2000 just to support a single molecule. Higher loadings can be achieved using more exotic and expensive dendrimeric PEG-type supports, but these materials are not always amenable to use in syntheses where "intermolecular" reactions can occur between different reaction centers on the same dendrimer (3). This problem is particularly vexing in peptide synthesis (4). Another problem with PEG-based materials is their limited chemical stability to oxidative, free radical, or strongly acidic conditions. Further, the metalchelating properties of PEG renders these supports incompatible with a variety of the metal-mediated reactions that are the main-stays of organic synthesis. In the search for new homogeneous supports, an attractive option is room temperature ionic liquids (RTILs). Ordinarily, these materials are viewed as recyclable solvents for organic and inorganic synthesis (5). At the same time, they are increasingly finding applications in other areas as well, including battery applications, chromatographic stationary phases, and separation science. Viewed as supports, RTILs have a number of potential advantages. First, they are relatively low molecular weight compared to long PEGs, thereby leading to higher effective loadings. Second, they exhibit good chemical stability and compatibility with a wide range of organic reaction conditions. Third, their


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physical properties (such as miscibility/solubility, viscosity, and density) can be tuned by variations in the anionic and cationic components. The most obvious challenge with using RTILs as supports is the method of attachment of the compound to be supported to the RTIL. In this respect, our recently developed fructose-derived RTIL 1 appeared to be ideal (Figure 2) (6). This material can serve as a reaction medium much like conventional imidazolederived RTILs, but at the same time the hydroxymethylene moiety provides a site for functionalization of the RTIL. Since there are two main options for types of materials to support - supported reactants and supported catalysts - these will be dealt with separately in the following two sections.

Θ

Me ®N-i

NTf> 60% isolated yield. Further, the reactions themselves were faster than those with Koser's salt itself, likely due to the presence of the electron-withdrawing ester group on the benzene ring. The only problem was in the separation of supported iodobenzene 9 from the reaction products. This salt proved to be soluble in the same range of solvents as the tosyloxyketone products (ether, ethyl acetate, acetone, methylene chloride). Ultimately, the only effective method for separating the products from iodobenzene 9 proved to be chromatography. A quick separation using ethyl acetate/hexanes to elute the tosyloxyketone, followed by acetonitrile to elute salt 9 was reasonably effective and did result in 76-80% recovery of salt 9. Still, the


124

.OL*

2

ch.cn

, «Ογ* ^

need to use chromatography negated much of the potential advantage of this supported reagent.


Table 2. Tosyloxyation Results. R

1

R

Conditions

Time

% Yield with 8"

% Yield with 12"

55°C,))))

30 min

67

60

55°C,))))

30 min

80

57

55°C,))))

30 min

74

74

-(CH ) -

0°C

6h

Decomp.

79

-(CH )

55°C,))))

30 min

65

74

Η CH

2

Η CH

3

Ph

Η 2

3

2

r

3

a). Isolated yield.

Returning to the idea of RTILs having tunable physical properties, a potential solution was to employ a more hydrophilic salt. This could be most readily achieved by using a harder anion such as phosphate, tosylate, or chloride. To that end, supported iodobenzene 10, which has a toluenesulfonate anion, was prepared (Figure 4). Oxidation with peracetic acid, followed by treatment with tosic acid in acetonitrile then afforded supported Koser's salt 12 as before. During this sequence, it was noted that all of the tosylate salts are more viscous than the triflimide salts. Further, salt 5 is actually a solid at room temperature. With this second generation supported Koser's salt in hand, the ottosyloxyation of ketones was again examined (Table 2). The reactions proceeded slightly slower than with the triflimide salt version of the supported Koser's salt, but were still generally complete within 30 minutes. The yields were comparable to those obtained before. The real advantage came in the separation phase. With tosylate salt 12, the by-product was iodobenzene 10, which could be readily separated by dilution of the reaction with ether. This reduction in polarity was sufficient to precipitate salt 10, which could then be


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recovered in >95% yield by simple filtration. The tosyloxyketone product could be isolated following an aqueous work-up on the organic layer. In most cases this afforded the pure product, but in some cases a trace of unreacted ketone was observed, which could be readily removed by trituration with cold hexane. Importantly, the recovered iodobenzene 10 could be converted once again into the supported Koser's salt 12 as before. This material was again capable of carrying out the tosyloxyation reaction and afforded results indistinguishable from the initially prepared material. This recovery/reoxidation sequence could be carried out again and again, with no degradation of the support.

Conclusion In conclusion, we have reported the application of a fructose-derived RTIL as a recyclable support for both reagents and reactants. Although not without limitations (particularly base stability), the ability to tune the solubility/miscibility properties of the support by changing the anion is an attribute unique to this family of supports. This feature greatly facilitates its recovery in the supported Koser's salt example and will undoubtedly be of value in a number of future applications of these and related supports. Further studies and applications of this concept are underway and will be reported in due course.

References 1.

Spanka, C.; Wentworth, Jr., P.; Janda, K.D. Combinatorial Chemistry & High Throughput Screening 2002, 5, 233. Dickerson, T.J.; Reed, N.N.; Janda, K.D. Chem. Rev. 2002, 102, 3325. 2. Boyle, N.A.; Janda, K.D. Current Opin. Chem. Bio. 2002, 6, 339. 3. Sunder, Α.; Heinemann, J.; Frey, Η. Chem. Eur. J. 2000, 6, 2499. 4. This problem has led to the development of a number of methods to avoid premature termination, such as Ellman's "safety-catch" linkers. For examples, see: Backes, B.J.; Dragoli, D.R.; Ellman, J.A. J. Org. Chem. 1999, 64, 5472. And references cited therein. 5. For recent reviews on ionic liquids, see: Welton, T. Chem. Rev. 1999, 99, 2071. Freemantie, M. C&E News 2000, 37. Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000, 39, 3772. Dupont, J.; de Souza, R.F.; Suarez, P.A.Z. Chem. Rev. 2002, 102, 3667. 6. Handy, S.T.; Okello, M.; Dickenson, G. Org. Lett. 2003, 5, 2513. 7. For other examples of RTIL-supported reactants, see: Hakkou, H.; Eynde, J.J.V.; Hamelin, J.; Bazureau, J.P. Tetrahedron 2004, 60, 3754. FragaDubreuil, J.; Bazureau, J.P. Tetrahedron 2003, 59, 6121.



126 8. Handy, S.T. Okello, Μ. Tetrahedron Lett. 2003, 44, 8399. 9. Aggarwal, V.K.; Emme, I.; Mereu, A. Chem. Commun. 2002, 1612. 10. Herzig, J.; Nudelman, Α.; Gottlieb, H.E.; Fischer, B. J. Org. Chem. 1986, 51, 727. 11. Handy, S.T.; Okello, M. J. Org. Chem. 2004, 69, In press. 12. Sirieix, J.; Ossberger, M.; Betzemeier, B.; Knochel, P. Synlett 2000, 1613. Hsu, J-C.; Yen, Y-Η.; Chu, Y-Η. Tetrahedron Lett. 2004, 45, 4673. 13. Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. Tetrahedron Lett. 2003, 44, 6813. 14. Audic, N.; Clavier, H.; Mauduit, M.; Guillemin, J-C. J. Am. Chem. Soc. 2003, 725, 9248. 15. Zhdankin, V.V.; Stang, P.J. Chem. Rev. 2002, 102, 2523. 16. Abe, S.; Sakuratani, K.; Togo, H. J. Org. Chem. 2001, 66, 6174. Togo, H ; Abe, S.; Nogami, G.; Yokoyama, M. Bull. Chem. Soc. Japan 1999, 72, 2351. Togo, H ; Nogami, G.; Yokoyama, M. SynLett 1998, 534. Wang, G.-P.; Chen, Z.-C. Synth. Commun. 1999, 29, 2859. Ficht, S.; Muelbaier, M.; Giannis, A. Tetrahedron 2001, 57, 4863.


Room Temperature Ionic Liquids as Homogeneous Supports for

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