Recent Advances on Design and Synthesis of Chiral Imidazolium Ionic Liquids and their Applications in Green Asymmetric Synthesis

: Over the past decade, catalysis by ionic liquids (ILs) has experienced a tremendous growth in the context of “Green Chemistry”, and there are numerous examples of a variety of catalytic reactions that have been successfully carried out in such neoteric media. The great enthusiasm for catalysis in ILs is not only driven by the curiosity of chemists, but also due to the growing awareness of developing greener reactions or process media in catalytic science and greener catalytic technologies due their advantages of unique physical and chemical properties as compared to traditional volatile organic solvents. Recently, development of chiral ionic liquids and their applications in asymmetric synthesis have attracted much attention as these reactions have widespread applications in the synthesis of chiral drugs and pharmaceutical industries. Asymmetric induction is mainly achieved by the use of chiral substrates or reagents, chiral catalysts or enzymes. Owing to the vast number of structurally different room temperature ILS that have been synthesized, this review focuses on imidazolium ionic liquids that possess chirality either in the imidazolium moiety or in the anion moiety. The aim of this review is to highlight the recent breakthrough of Chiral ILs in chirality transfer or chiral recognition when used as solvent or co-solvent: the case of task specific ionic liquids is beyond the scope of this review. In the first part, the synthesis of of CILs has been presented and the second part of the review has been devoted on the applications of such CILs in green asymmetric synthesis as well as various pharmaceutical industries.


INTRODUCTION
Ionic liquids (ILs) often recognized as molten salts having melting point below 100 °C with entirely ionic character, consisting of both a cationic and anionic parts (Figure 1) [1].
ILs usually consists of several properties such as low melting organic salts (<100 °C), very low vapor pressure, non-flammable, wide liquid range, moderate to high viscosity, high thermal/mechanical/ electrochemical stability, low toxicity, high Solvating properties etc. Interestingly, physical and chemical properties can be tailored by the modification of cationic and anionic core, hence for this structural diversity ILs are generally termed as designer solvent [2]. The first report of ILs emerged in 1914 [3]; since then, it has been taken tremendous attention in the perspective of green Synthesis for their unique, diverse and tunable properties. There are varieties of examples of catalytic reactions that have been efficiently promoted in presence of such materials as the catalyst and/or reaction media [4]. Now, introduction of chiral building blocks in either in the cationic part or in the anion moiety of ILs make it novel materials because of Recently, asymmetric catalysis by imidazolium based CILs have concerned much interest predominantly in pharmaceutical industries. This growing interest in the exploitation of CILs for chiral induction has provoked us to commence the review on imidazolium based CILs and their applications in green asymmetric synthesis. The present study focuses on recent advances on design and synthesis of imidazolium based CILs and highlights their applications in green asymmetric synthesis.
Ohno et al. have fabricated a number of bio-based chiral imidazolium ionic liquids, 2, derived from chiral amino acids via anion exchange techniques (Figure 1) [7].
Imidazolium core as cation Amino acid core as chiral anion (2)

Chiral Imidazolium Ionic Liquids with Chiral Cations:
Ding et al. have synthesized imidazolium based chiral ionic liquid (5) containing chiral imidazolium moiety bearing two chiral centers bonded to a nitrogen atoms of the imidazole centre (Scheme 4) [9].
Bao et al. synthesized of same type of chiral imidazolium ionic liquid (6) with single chiral center derived from the (R)-(+)--methylbenzylamine (Scheme 5) [10]. This ionic liquid failed to promote asymmetric reactions due to its high melting point (90 o C).
Xu et al. prepared chiral amino acids functionalized chiral imidazolium ionic liquids [15]. First, amino acids were reduced to amino alcohols by NaBH 4 /I 2 , followed by neutralized and under goes bromonation with PBr 3 .  Then, N-alkylation with methylimidazole followed by neutralization with NaOH gave chiral imidazolium bromide salts (18). Anion exchange of 18 with AgBF 4 or KPF 6 produced the desired CILs (19a and 19b) with thermal stability up to 210 °C (Scheme 11). The as prepared CILs, 19b, exhibit higher melting points and glass-transition temperatures than the CILs, 19a.
Guillen et al. have synthesized histidine functionalized imidazolium chiral ionic liquids 32 [20]. Protection of histidine methyl ester, followed by alkylation with iodomethane and oxidative ring opening of the cyclic urea by t BuOOH in the presence of (i Pr) 2 NEt, resulting histidine derivative, 31. After that, the reaction of 31, with n-butylbromide, followed by anion exchange resulting desired histidine functionalized imidazolium CIL (Scheme 16).

Applications of CIILs in Asymmetric Organic Reactions
In 1975, Seebach and Oei first applied chiral solvents in asymmetric reactions [22]. Since that time, there have been many attempts to use chiral solvents in asymmetric reactions, but the enantioselectivities have been fairly low. This has led to the conclusion that asymmetric induction effected by chiral solvents. Even though the enantioselectivity observed for the electrochemical reduction of ketones in chiral amino ethers was low, it opened up the field to develop chiral solvents to influence the outcome of asymmetric reactions. Although a large number of chiral ionic liquids have been synthesized, only a limited number have been successful in affecting the outcome of asymmetric reactions.
Bao and co-workers have utilized CIILs as chiral solvents in the asymmetric Michael addition of diethyl malonate to 1,3-diphenyl-2-propenone (Scheme 18) [23]. Better results were obtained in toluene than in DMSO or DMF as the co-solvent. Comparable chemical yields and enantioselectivities were obtained with CIIL bromide giving the best yield and ee of the three.

As Organocatalysts
Metal-free catalysis of asymmetric reactions by simple organocatalysts has become an important area of research in recent years [25]. Pyrrolidine catalysts have been used successfully for the direct asymmetric aldol and Michael addition reactions [25], which are regarded as two of the most powerful carbon-carbonbond-forming reactions inorganic synthesis [25]. For these reactions, the organocatalyst is usually used in substantial quantity, and the efficient recovery and reuse of the organocatalyst are a major concern. Therefore, there is a need to develop new organocatalysts, which are easily recyclable and possess enhanced catalytic abilities. In this regard, ionic liquids that contain specific functionalities and are capable of acting as organocatalysts have received much attention recently. One advantage of ionic-liquidbased chiral organocatalysts is that they can be recovered easily from the reaction mixtures simply by capitalizing on their solubility characteristics.
Miao and Chan reported proline based CIIL 27 as organo catalyst for the direct asymmetric aldol reaction of 4-cyanobenzaldehyde with acetone, but obtained the aldol product, 1a, in only 10% yield and 11%ee. CIIL 30 fared better as organocatalyst under the same conditions, leading to 1a in 59% yield and 72% see (Scheme 20) [19]. The results indicate that the acidic proton of proline is essential for efficient catalysis to occur. Thus, the aldol reaction of a broad range of aldehyde acceptors, including aromatic and aliphatic aldehydes, and two ketone donors, acetone and 2butanone, was carried out in good yields and enantioselectivities in the presence of organo catalyst 30 under the same conditions. Furthermore, the authors carried out the reactions of 4 nitrobenzaldehydein deuterated acetone with CIIL 30 or proline as catalyst, respectively, and proved that CIIL 30 is a more efficient organocatalyst than proline itself. The recyclability of CIIL 30 as organocatalyst was also examined (Scheme 21) [19]. CIIL 30 was recycled and reused at least four times in the same reaction without significant loss in yield and enantioselectivity.
Functionalized CIILs 32 and 33 have been employed as highly efficient asymmetric organocatalysts for the Michael addition of cyclohexanone to nitroalkenes (Scheme 22) [18]. CIILs 32a-c and 33a, lacking a substituent at C-2 of the imidazole ring, were superiorto their 2'-methyl counterparts (32a-c and 33b) in terms of yields and selectivity. Introduction of a protic group (OH) in the side chain did not improve the catalytic activity and selectivity, and CIILs with Br and BF4 were much more active and selective than those with PF6 -.  [21]. Moreover, catalyst also catalyzes the Michael addition of cyclohexanoneto trans--nitrostyrene in acetonitrile at room temperature to give the adduct in moderate yield and high stereoselectivities (syn:anti = 95:5, 88% ee). Our results also demonstrate that the presence of acidic hydrogen is necessary for the selectivity; the acidic N-H adjacent to the electronwithdrawing sulfonyl group plays an important role in the selectivity of the reaction. The catalyst is easily recycled without loss of activity.

Asymmetric Aldol Reaction
Lombardo et al. described the synthesis of ''iontagged L-prolines'' as organo catalysts for asymmetric aldol reactions [26][27][28]. These are essentially L-prolinebased CIILs (Scheme 24). They observed a higher efficiency with the lipophilic bis(trifluoromethylsulfonyl) imide (NTf 2 -) counter anion as compared with the BF 4 anion. This was further improved by theuse of aqueous biphasic conditions instead of using the neationic liquid ([bmim][NTf 2 ]) as the solvent [27]. The final improvement of this L-proline-based catalyst was achieved by using the cis-geometry of the imidazolium ionic moiety toproline as opposed to the transgeometry present in their previous publications. As shown by the example in Scheme 24, the yield improved from 37% to 87% by the use of cis-CIIL compared with the trans-CIIL. No organic solvent was used for the reaction. However, 1.2 equivalents of water and 5molar excess of liquid ketone as the aldol donor were used to ensure homogeneous conditions. Exceptionally, high turnover numbers for most reactive aromatic aldehydes were observed (TON= 196 for the cis-CIIL, 0.5 mol %, and 24 h reaction time). Also, high yields (up to 99%), excellent enantioselectivities (>99% ee), and diastereo-selectivities (anti:syn up to 95:5) were obtained with this organocatalyst.
In 2008, Zlotin and coworkers synthesized the amphiphilic chiral imidazolium salts derived from (S)proline and accompanying anions BF 4 and PF 6 -(Scheme 25). These are structurally similar to the previously described class but have longer alkane chains on the imidazolium moiety for added hydrophobicity. Organocatalysis by these CIILs between cycloketones and aromatic aldehydes proved to be efficient (up to 95% yield), stereoselective (up to >99% ee) and diastereoselective (anti:syn up to 97:3). Good recover ability for up to 5 cycles was also observed. Following this success, in 2009, they synthesized a series of CIILs with different hydroxyl-amino acids such as proline, serine, and threonine and different cationic charge carrying moieties such as imidazolium and pyridinium (Scheme 26) [29]. The incorporation of the NTf 2 anion and pyridinium or 4-(5nolyl)-pyridinium cations instead of imidazolium-based cations were intended to improve the hydrophobicity of the CIIL. These new CIILs are amphiphilic and their catalytic properties in the ''on water" aldol reaction has been examined. It is interesting to note that the CIIL 39 with a pyridinium cation and a PF 6 anion did not catalyze the aldol reaction under the conditions examined, whereas the CIIL 40 with4-(5-nolyl)pyridinum cation and same anion displayed high activity (97% yield) and enantioselectivity (99% ee). This was correlated to the hydrophobicity of the ionic liquids. Despite the presence of PF 6 anion, CIIL 39 was water soluble, whereas CIIL 40 was insoluble in water. This enabled the organocatalyst to reside at the water/organic solvent interface facilitating the reaction. The authors also stated that CIIL 40 retained its catalytic activity and selectivity after eight reaction cycles. In their most recent publication on this topic, Zlotin and coworkers further modified these organocatalysts by removing the free carboxylic acid group on the proline structure by converting it to an amide [30]. This modification optimized the catalyst's hydrophobic/hydrophilic properties to obtain maximum catalytic efficiency in an aqueous environment compared with the catalysts with free carboxylic groups (Scheme 27). They obtained almost quantitative yields and good enantioselectivities (up to 99% ee with CIIL  15 h) in the presence of large excess of water. Selectivity was notably higher for the more hydrophobic catalyst 43 as compared with 44. Finally, it was noted that CILs containing imidazole moiety exhibited promising catalytic activity that the others.

Asymmetric Diels-Alder Reaction
Howarth et al. used dialkylimidazoliumsalts (chiral and achiral) as Lewis-acids to catalyze the reaction between crotonaldehyde or methacrolein with cyclopentadiene. The chirality of the ionic liquid did no tseem to have much influence on the stereochemistry as the enantiomeric excess was less than 5%, whereas the endo:exo product ratios were almost the same for both chiral and achiral ILs [31]. Since then ionic liquids have been tried both as acid catalysts and as the solvent in asymmetric Diels-Alder reaction to improve the stereoselectivity.
In 2006, Pernak and coworkers used protic imidazolium ionic liquids as the reaction media for cyclopentadiene and two dienophiles (dimethyl maleate and methyl acrylate) that resulted in good endo/exo selectivities (up to 3.9:1; Scheme 28) [32]. The racemic DL-lactate ionic liquid 45 chiral L-lactate ionic liquid 46 and both performed almost identically.
Vo-Thanh and coworkers designed different CIILs to be used as the reaction media in an aza-Diels-Alder reaction between Danishefsky's diene and chiral imine (Scheme 29). The reactions involved only the diene, chiral imines, and the CIIL, 47 and 48, whereas no other acid catalyst or organic solvent was used [33].
The first enantioselective Diels-Alder reaction with a CIIL was reported by Doherty et al. [34]. They used imidazolium modified bis-oxazoline CIIL 49 (Scheme 30) as a chiral ligand in the copper(II)-catalyzed reaction of N-acryloyl and N-crotonoyloxazolidinones with cyclopentadiene and 1,3-cyclohexadiene. Higher rates were achieved in reactions carried out in anionic liquid [emim][NTf 2 ] compared with dichloromethane. Higher yields (up to 100%) and enantioselectivities (95% ee) were also achieved with the IL. The catalyst could be recycled 10 times without loss of activity.
In 2010, Wang  derived CIIL 50 as a catalyst for the aza-Diels-Alder reaction (Scheme 31) [35]. The products were obtained in good yields (up to 93%) with excellent enantioselectivities (>99% ee) and diastereoselectivities (endo:exo up to >99:1). The catalytic system could be recycled six times without loss of activity.

Enantioselective Hydrogenation
Transition metal catalysts consisting of chiral metal complexes are commonly used in enantioselective hydrogenation reactions. Schulz et al. reported the first asymmetric synthesis where this reaction was carried out solely via the ion-pairing effect of a CIL as the only source of chirality [36]. The chiral anionic ionic liquid N-methylimidazolium (R)-camphorsulfonate (Scheme 32) was reacted with methyl vinyl ketone in a Michael-type addition to obtain N-(3 -oxobutyl)-N-methylimidazolium (R)-camphorsulfonate. The hydrogenation of this pro-chiral cation under heterogeneous conditions with Ru/C catalyst in ethanol solution yielded the corresponding hydroxybutyl derivative in quantitative yield and up to 80% ee. The importance of the ionparing effect on enantioselectivity was confirmed by the strong dependence of concentration of the imidazolium salt to the observed enantiomeric excess of the hydrogenated cation as well as the absence of enantioselctivity (<5% ee) for the hydrogenated product of the nonionic substrate acetophenone.

Enantioselective Aldol Reaction
Natalia and his group have reported a CIIL for asymmetric syn-aldol reactions using (S)-Threonine/ , -(S)-diphenylvalinol, imidazolium chiral ionic liquid as a efficient catalyst [37]. Chiral ionic liquids containing (S)-or (R)-threonine amide and , -(S)-diphenylvalinol units have synthesized in the presence of the (S)-threonine-derived catalyst reactions between ketones with secondary carbon atom(s) at the -position with respect to the carbonyl group and aromatic (heteroaromatic) aldehydes afforded the corresponding syn-aldols in high yields (up to 99%) and with high diastereo-(syn/anti up to 97:3) and enantioselectivity (up to 99% ee), which have maintained over three reaction cycles (Scheme 33).

CONCLUSIONS
The field of task-specific imidazolium based chiral ionic liquids is only in its infancy, but has a very promising future. The main advantage of these types of ionic liquids is that they are easily recovered and recycled without loss of activity when used for asymmetric reactions. Owing to a readily available source of chiral compounds such as naturally occurring amino acids and other compounds, which can serve as precursors in the synthesis of chiral ionic liquids-a new opportunity now exists for the synthesis of a very important class of organic compounds. The past few years have seen a tremendous growth in the number of chiral ionic liquids synthesized, but their effect on the outcome of asymmetric reactions has been limited, with most still giving low enantioselectivities. Therefore, a need exists for the development of additional, improved, and task-specific imidazolium chiral ionic liquids that are better able to influence the outcome of asymmetric reactions.