Ionic-Liquid-Supported Synthesis of Small Molecules and

As we all aware of the fact that the supported synthesis is a widely employed technique that has greatly facilitated the synthesis of many compounds and is the critical element behind the explosion in combinatorial synthesis. Traditionally, the supported synthesis has employed a heterogeneous material such as cross linked polystyrene to support one of the reactants. The primary advantage of such a choice is that the supported material, being heterogeneous, can be readily separated by simple filtration from the reaction medium and by-products. At the same time, this heterogeneity limits the types of reactions and reaction conditions that can be employed. Further, using simple polystyrene supports, which are typically functionalized to <10%, the maximum loading is <2 mmol/g. These limitations have led more recently to the development of a variety of

„soluble‟ supports (e.g. the polyethylene glycol (PEG) supports popularized by Janda).

Since the supports are homogeneous in a variety of conventional organic solvents,

O

O N N

X

+ N

OEt Me

COOEt

COOEt 70 ^oC -EtOH

EtOOC O

N COOEt

O N N

X

a b c

reactions can be performed under conventional solution-phase conditions. At the same time, by changing the polarity of the solvent (most frequently by the addition of methanol), the support and supported molecule will precipitate, resulting in facile separation by filtration. While this is a major step forward, there are still limitations to the current supports. In order to circumvent the drawback, most recently ionic liquid has emerged as alternative soluble support for carrying out the organic synthesis of biologically relevant compounds. An attractive feature of ionic liquids is that their solubility can be tuned readily. Therefore, phase separation from organic solvent or aqueous phase is allowed depending on the choice of cations and anions. This suggests the possibility of using these small molecular ionic liquids as soluble supports for organic synthesis. Ionic liquid attached substrates are expected to retain their reactivity, as in solution reactions, and allowed the use of conventional spectroscopic analysis such as NMR during the synthetic process. Bazureau was the first to propose the use of ionic liquid as soluble support for the synthesis of small organic molecules.⁷⁹ They observed that the reaction of the IL anchored dipolarophile a (ortho) with the imidate b to give the adduct c (Scheme 1.28) was faster than that of the reaction of free 2-ethoxybenzaldehyde with the ionic liquid [emim][NfO](emim)1-ethyl-3-methylimidazolium).⁸⁰

Scheme 1.28. IL supported synthesis of small molecules

N N OH

They also examined the Knoevenagel and 1,3-dipolar cycloadition reactions with the IL-supported benzaldehyde (Scheme 1.29). Thus, the substituted benzaldehyde was anchored onto the IL support to give f. Knoevenagel reaction of substrate under homogeneous conditions gave the products g in high yields. Cleavage of the ionic liquid support by basic methanolysis gave the small molecule h in good isolated yield.

Scheme 1.29. Ionic Liquid supported synthesis of h

In an attempt to show the 4+2 cycloaddition reaction on ionic liquid support, Handy and Okello have reacted the acrolyl chloride with ionic liquid to get the IL anchored compound i.⁸¹ The ionic liquid support could be recovered in greater than 90% yield and reused as drawn in scheme 1.30.

N

Scheme 1.30. Ionic liquid supported Diels-Alder reaction

In order to demonstrate the advantages of IL-supported synthesis over the conventional solution-phase synthesis, Chen et. al. examined a series of Suzuki coupling reactions between boronic acids and the IL-supported iodobenzoates l as shown in Scheme 1.31.⁸¹

O

Scheme 1.31. Ionic Liquid Supported Suzuki coupling reactions.

Furthermore it has been observed that the IL-supported strategy for combinatorial synthesis was demonstrated by the preparation of a small library of 4-thiazolidinones n (Scheme 1.32).⁸²

IL OH

Scheme 1.32. Ionic Liquid Supported synthesis of small library of 4-thiazolidinones.

The advantages of using ionic liquid support are as follows: (1) The product isolation is easy because the side products are removed by simple washing with appropriate solvent;

(2) in each step, the reaction can be monitored by standard analytical technique; (3) due to the high polarity of the ionic liquid support, microwave irradiation can be easily applied to enhance the reaction; (4) the final product was usually obtained in high purity without flash chromatography.

The same strategy has been tried to apply to the syntheses of important oligomers of biomolecules. Chen et. al. have used the synthesis of the bioactive pentapeptide Leu5-enkephalin r using ionic liquid support (Scheme 1.33).⁸⁴

Scheme 1.33. Ionic liquid supported synthesis of Leu5-enkephalin

N N OH

Inspired by this advantage for the success synthesis of oligopeptides in 2006, Chan et. al.

initiated the, adopted the approach for the synthesis of oligosaccharides as shown in (Scheme 1.34).⁸⁵.

Scheme 1.34. Ionic liquid supported synthesis of oligosaccharides.

Damha et.al.⁸⁶ have described the synthesis of oligonucleotides in solution using a soluble ionic liquid as support in Scheme 1.35. Short oligomers of varying base composition were synthesized using this method in high yields and high purity, requiring no chromatography for purification prior to cleavage from the support.

N

N+ OH

BF₄

-HOOC CHO

R₁ NH₂

O n

HN O

O O

R₁

n

Scheme 1.35. Synthetic cycle of oligonucleotides

In 2007, Li et.al. have used the ionic liquid as soluble support for the synthesis of tetrahydropyrano and tetrahydrofuranoquinolines, an important heterocyclic compounds under microwave irradiation as elaborated in Scheme 1.36.⁸⁷

Scheme 1.36. Synthetic cycle of tetrahydropyrano and tetrahydrofuranoquinolines.

Oligonucleotide dimer, trimer, and tetramer

N N OH aldehydes, and 1,3-dicarbonyl compounds using ionic liquids as soluble support as elaborated in Scheme 1.37.

Scheme 1.37. Synthesis of pyran derivatives.

Bazureau et. al. executed multicomponent reaction on ionic liquid support to obtain 2 thioxotetrahydropyrimidin4-(1H)-ones^.89 The methodology employs microwave irradiation and a matrix of PEG ILPs used for an ionic liquid phase organic synthesis.

Continuing their work in this area, Bazureau et al.⁹⁰ have developed the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) (Scheme 38) with a 1,2,4-oxadiazole group via the three component Biginelli condensation without solvent as drawn in Scheme 1.38.

NH

Scheme 1.38. 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs).