Multicomponent Reactions in Ionic Liquids

In our group, we place a premium on the rapid access to a wide rage of diverse small mole‐ cules. Our current focus spans the inhibition of dynamin GTPase, protein phosphatases 1 and 2A and the development of anti-cancer lead compounds.[1]-[10] While rapid access is paramount, we also strive to develop high levels of diversity in an environmentally friendly manner. That is, we are keen to apply the tenants of green chemistry at all stages of our drug development programs. To satisfy this need we have developed a particular interest in mul‐ ticomponent reactions in benign solvents.


Introduction
In our group, we place a premium on the rapid access to a wide rage of diverse small molecules. Our current focus spans the inhibition of dynamin GTPase, protein phosphatases 1 and 2A and the development of anti-cancer lead compounds. [1]- [10] While rapid access is paramount, we also strive to develop high levels of diversity in an environmentally friendly manner. That is, we are keen to apply the tenants of green chemistry at all stages of our drug development programs. To satisfy this need we have developed a particular interest in multicomponent reactions in benign solvents.
A multicomponent reaction (MCR) can be simply classified as a reaction in which three or more components are combined together in a single reaction vessel to produce a final product or products displaying features of all inputs and thus offers greater possibilities for molecular diversity per step with a minimum of synthetic time and effort. Products from such MCRs result in high atom and step economy.
The first reported MCR was Strecker's synthesis of racemic amino acids in the 1850's. [11] Strecker's amino acid synthesis combined an aldehyde, hydrogen cyanide and ammonia in a one pot procedure leading to a range of amino acids. With over 150 years history and development, MCRs have recently seen a resurgence, in part due to the ease of access to a wide range of diverse, highly functionalized molecules, in particular the synthesis of small heterocyclic rings of medicinal chemistry importance. A discourse on the physical properties of ionic liquids is out with the scope of this work. The chemistry, reactions and properties of ionic liquids has been addressed in a number of excellent review articles in this area. [12]- [20] In this chapter we describe the current state of play associated with MCRs in ionic liquids, with a focus on 3-and 4-component MCRs (3CRs and 4CRs respectively). [21] For ease of discussion the application of MCRs in ionic liquids is broken down into the type of product generated: heterocyclic rings containing various numbers of heteroatoms and a classification of the reaction as either a 3CR or a 4CR.

Synthesis of acyclic products
MCRs are not only applicable to the synthesis of heterocyclic systems, but represent a very facile entry point to a range of acyclic compounds such as the amido substituted naphthols shown in Scheme 1. The treatment of β-naphthol with a wide range of aldehydes (aliphatic and aromatic), substituted amides in the presence of conventional ionic liquids (Ils), such as those based on the N-methyl, N-sulfonic acid imidazolonium [MSIM] cation, afforded rapid access to 1-amidoalkyl-2-naphthols and 1-amidoaryl-2-naphthols in good to excellent yields. In this area Zolfigol  Hajipour et al. and Hervai et al. effected the same transformations, and extended the methodology to allow the use of urea as the amide source using a range of Brønstead acid based Ils (BAILs). [23], [24] Hajipor et al. ' [HSO 4 ] has been used previously as an efficient and reusable catalyst for nitration of aromatic compounds and esterification of various alcohols by different acids. [25]- [27] The acidic nature of BAILs has been exploited as catalysts for many other significant organic reactions, which proceed with excellent yields and selectivities and demonstrate the great potential of these ILs in catalytic technologies for chemical production. [23] Kotadia et al. and Zhang independently reported the synthesis of similar 1-amidoalkylnaphthols using solid supported ionic liquids (SSILs). [28] Kotadia used a benzimidazolium based ionic liquid immobilized on silica based solid support, while Zhang conducted the reaction in the presence of polyethylene glycol (PEG)-based dicationic acidic ionic liquid as a catalyst under solvent-free conditions. [29], [30] Supported reagents offer the advantages of simple and safe catalyst recycling. [28] All MCR-IL based approaches to 1-amidoalkylnaphthols where highly substituent tolerant with excellent yields observed ith both electron donating and electron withdrawing aldehydes.
The use of an enolisable ketone facilitated the synthesis of a family of β-amido ketones (Scheme 4). The reaction of an enolizable ketone, aryl aldehyde and acetonitrile or benzonitrile in the presence of TMSCl using a Brønsted-acidic ionic liquid 3-methyl-1-(4-sulfonic acid) butylimidazolium hydrogen sulfate [MIM-(CH 2 ) 4 SO 3 H][HSO 4 ] as catalyst gave a family of β-amido ketones in good yield. [34]  Liu et al. also explored the IL mediated Mannich reaction, but utilised a series task-specific ionic liquids in developing an asymmetric of β-aminoketones from isovaleraldehyde, methyl ketones, and aromatic amines in excellent yields (ca. 90%) and %ee's (~95%). [ In a similar reaction sequence, Akbari and Heydari, replaced the activated ketone with trimethyl phosphite, in the presence of [MIM-(CH 2 ) 4 SO 3 H][CF 3 SO 3 ], to affect rapid access to αaminophosphonates (Scheme 7). [38] The reaction proceded via protonation of the carbonyl moiety, imine formation and attack at the protonated imine by trimethylphosphite. The reaction was highly tolerant of substituents on the carbonyl containing compound with pyridyl, cinnamyl, etc., affording excellent yields of the corresponding α-aminophosphonates. The ionic liquid could be recycled with no observable loss of efficacy after six cycles. Reddy et al. also reported the synthesis of α-aminophosphonates via a three-component reaction of 5-amino-2,2-difluoro-1,3-benzodioxole, aromatic aldehydes, and diethylphosphite catalysed by silica-supported boron trifluoride (BF 3 .SiO 2 ) in [BMIM][HCl] at room temperature (Scheme 8). [39] Yields were good to excellent and reaction times were typically 5 min versus 3h using conventional solvents. O-Protected cyanohydrins are versatile synthetic intermediates in organic synthesis for the preparation of a wide variety of organic compounds such as α-hydroxyacids, α-hydroxy ketones, α-amino acids, and β-amino alcohols. [40]- [43] Shen and Ji developed a mild synthesis of these key intermediates via the condensation of an aldehyde, trimethylsilyl cyanide (TMSCN), and Ac 2 O in [BMIM][BF 4 ] (Scheme 9). [44] In addition, the recovered ionic liquid could be reused for subsequent runs without the loss of activity.

3CRs yielding heterocycles with one ring nitrogen
Arguably the major utility of MCRs is in the synthesis of highly decorated heterocyclic compounds. In our group we are interested in the synthesis of heterocyclic scaffolds that can be used in medicinal chemistry programs to instill the correct level of biological activity. Davoodnia et al. reported an efficient procedure for preparation of 2,4,6-triarylpyridines by treatment of acetophenones, aryl aldehydes, and NH 4 OAc in the presence of [MIM-(CH 2 ) 4 SO 3 H][HSO 4 ] (Scheme 10). [45] Aromatic aldehydes with both electron donating and electron withdrawing substituents were well tolerated. In a related study, Heravi and Fakhr, reported a high yielding ultrasonic promoted synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitrile derivatives (Scheme 11), by the reaction of aryl aldehydes, thiols and malononitrile catalyzed by ZrOCl 2 .8H 2  The related 2,4,6-triaryl-1,4-dihydropyridines were generated in a Aldol-Michael-addition reaction cascade involving an aromatic aldehyde, acetophenone and NH 4 OAc in [BMIM] [BF 4 ] (Scheme 12). [48] The resulting 2,4,6-triaryl-1,4-dihydropyridines were then examined as potential catalysts for the the Diels-Alder reaction of p-quinone and cyclopentadine, and maleic anhydride and cyclopentadiene. Wu used essentially the same reaction cascade described above, replacing acetophenone with acetoacetates which yielded, from [Bpy][BF 4 ], a series of 2,6-dimethyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylate esters (Scheme 13). [49] Compared with classical Hantzsch reaction conditions towards this type of product, this IL mediated reaction had the advantage of excellent yields, short reaction time, and easy workup. Quinolin-4(1H)ones constitute an important class of heterocyclic compounds because of their important pharmaceutical properties, such as anti-viral, [50], [51] anti-platelet, [52] and anti-tumor effects. [53] These compounds have been exploited as precursors for anti-cancer and anti-malarial agents. [54], [ There are many methods for the synthesis of acridine compounds containing 1,4-dihydropyridine moieties from aldehydes, dimedone, and anilines or ammonium acetates via heating in organic solvents, or catalysis by triethyl(benzyl)ammonium chloride (TE-BAC) in water, or under microwave irradiation. [58] In a much more efficient approach, Li  Shi reported an efficient and green synthetic route to 3,3'-benzylidenebis(4-hydroxy-6-methylpyridin-2(1H)-ones) via condensation, addition and ammonolysis of an aldehyde, aniline and 6-methyl-4-hydroxypyran-2-one (Scheme 17). [  Fang et al.'s dicationic acidic IL catalytic approach, in what amounted to a modified Biginelli approach, resulted in the synthesis of 3,4-dihydropyrimidin-2(1H)-one and 3,4-dihydropyrimidin-2(1H)-thione derivatives (Scheme 21), in good yields. [68] The products could be separated simply from the catalyst-water system, and the catalysts could be reused at least six times without noticeably reducing catalytic activity. Rather than use an acidic IL approach to dihydropyrimidinones (above) Mirzai and Valizadeh developed a microwave assisted Biginelli route using the weakly Lewis basic nitrite based ionic liquid, IL-ONO (Scheme 22). [69] These nitrite based Ils have also been used to carry out nitrosations of aromatic compounds in aqueous media. [70] Valizadeh, have reported the nitrozation of aromatic compounds using the same nitrite ionic liquid in aqueous media. [70] Scheme 22. Synthesis of dihydropyrimidinones: (i) IL-ONO, MW, 80ºC.

3CRs yielding heterocycles with three ring nitrogen atoms
While not strictly speaking the synthesis of a new ring system by MCR in ILs, Wang has exploited the MCR approach in an elegant synthesis of N-(α-alkoxyalkyl)benzotriazoles (Scheme 31) via the condensation of benzotriazole with various aldehydes and alcohols catalysed by acidic ionic liquid [HMIM][HSO 4 ] at room temperature. [80] The yield was up to 99%. Wang's approach was effective when triethoxymethane was utilized instead of alcohols. Moreover, the [HMIM] [HSO 4 ] was recyclable with no loss in catalytic activity. Wang has a particular interest in the development novel methods for the preparation of various biologically important heterocyclic compounds by using ionic liquids. This group uses ILs as both novel reaction media and reaction promoters.

3CRs yielding heterocycles with one ring oxygen
The synthesis of heterocyclic compounds with oxygen in the ring is slightly more complex, only due to the reduced numbers of suitable oxygen nucleophiles to affect the final ring-closing step. The 4H-pyran core is found in a wide range of natural products and it has thus attraced a considerable degree of attention. [94]- [96] The high reactivity of 4H-pyran derivatives has led to their use as synthons in the synthesis of more complex species. Access to highly substituted 4Hpyrans is easily accomplished by the 1,1,3,3-tetramethylguanidine catalysed addition of aromatic aldehydes, malononitriles, and β-dicarbonyl in [ Interest in oxygen containing heterocycles is not limited to those with biological actiity. A number of analogues, such as the 2-amino-2-chromenes are natural products that have found utility in cosmetics and pigments. They also have a role as biodegradable agrochemicals.
[100]- [102] Traditional approaches to this scaffold required the reaction of aldehydes, active methylene containing compounds and activated phenols. Stoichiometric quantities of organic base (piperidine) in volatile organic solvents are also required. [103], [104] By replacing the organic solvent with [BMIM][OH] the reaction proceeded with aromatic aldehydes, malononitrile with α-or β-naphthol in the absence of additional catalyst (Scheme 41). [105] After five reuses of the [BMIM][OH] the isolated product yield had dropped from 91% to 85%, which may be due to [BMIM][OH] degredation.

3CRs yielding heterocycles with one ring sulfur atom
Thiophenes, dihydrothiophenes and tetrahydrothiophenes are known important constituents of a range of pharmacologically active compounds. [128]- [130] While these compounds are of significant interest to medicinal and synthetic chemists, the synthetic routes to highly functionalised sulfur heterocycles are not well developed. Notwithstanding this, Zhang et al. Given that most of the synthetic procedures towards sulfur heterocycles suffer from some drawbacks such as low yields, long reaction times, the requirement for harsh reaction conditions, it is not surprising that a number of groups have risen to the challenge and examined the use of ionic liquids as a potential method for enhancing the reaction outcomes whilst increasing the efficiency of the synthesis.

3CRs yielding heterocycles with ring oxygen and nitrogen atoms
The synthesis of simple heterocycles with a single type of heteroatom is important, but a considerable number of biologically active compounds have different types of heteroatom within a single structure. The benzo[b] [1,4]oxazin scaffold as a privileged structure for the generation of drug-like libraries in drug-discovery programs has been amply demonstrated. Benzo[b] [1,4]oxazin derivatives have been used as the basic framework for substances of interest in numerous therapeutic areas, such as anti-Candina albicans agents, [136] antifungals, [137] and kinase inhibitors. [138] Ebrahim et al. used [BMIM][Br] as both the solvent and reaction promotor for the room temperature three-component condensation of 2-aminophenole, an aldehyde and isocyanide to prepare benzo[b] [1,4] The synthesis of 6-amino-4-aryl-5-cyano-3-methyl-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazoles was first reported by Otto in 1974. [142] These molecules have since been shown to possess interesting biological activity. The potential antitumour pharmacophore, benzopyrano [2,3-d]pyrimidine, [158]  Ionic Liquids -New Aspects for the Future 2.1.9. 3CRs yielding heterocycles with ring sulfur and nitrogen atoms 4-Thiazolidinones have been exploited as potential bactericidal, antifungal, anticonvulsant, anti-HIV, and antituberculotic agents. [160], [161] While there have been multiple synthestic approaches, there is still considerable scope to develop a more environmentally friendy and efficient approach to this scaffold. [162], [163] Lingampalle et al. have developed a rapid entry to 4-thiazolidinones via the N-methylpyridinium tosylate [NMP][Ts] cyclocondensation of amines, aromatic ketones, and mercaptoacetic acid. [164], [165] The reaction proceeds via imine formation, followed by rapid cyclocondensation at 120 ºC (Scheme 57).

4CRs yielding heterocycles with one nitrogen in the ring
Increasing the number of components in MCRs from three to four offers the potential to increase substituent diversity, atom and step economy. This increased structural complexity allows for a facile access to highly decorated scaffolds, but interestingly in the four component IL mediated MCR, this has been limited to the synthesis of heterocyclic compounds. For example, rapid access to both alkyl and aromatic substituted 1,4-dihydropyridine derivatives can be accomplished via the reaction of an aldehyde, a 1,3-dicarbonyl compound, Meldrum's acid and ammonium acetate as the nitrogen source in [

4CRs yielding heterocycles with two ring nitrogens
The biologiocal roles of substituted imidazoles are well documented and numerous biologically active analoges have been reported. [ Pyrano [2,3-c]pyrazoles represent an important scaffold in medicinal chemistry with multiple synthetic approaches developed. These approaches include synthesis in water, ethanol reflux, microwave assisted and solvent free aporaches. Each approach comes replete with its own set of advantages and disadvantages from excess solvent requirements, long reaction times and poor yields. Xiao et al. have described a novel, efficient, and green procedure for the synthesis of 3-(5amino-3-methyl-1H-pyrazol-4-yl)-3-arylpropanoic acid derivatives through the four-component reaction in [BMIM][BF 4 ] (Scheme 65). [182] Reactions were rapid (5 min) and the product isolated by pouring onto water and recrystallisation from EtOH / H 2 O to afford pure product. Building on their earlier report on the synthesis of spiro[indolinepyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine]triones from barbituric acid, phenylhydrazine, 3-oxo-3-phenylpropanenitrile and isatin, Ghahremanzadeh et

Conclusions
In this brief review we have demonstrated the considerable utility of room temperature ionic liquids in multicomponent reactions. Almost universally, the addition of an ionic liquid increases the speed of reaction and reaction yields. In many cases the ionic liquid was used as both the solvent and the reaction promotor. It was possible to add catalytic quantities of ionic liquids in conventional solvent and still achieve a much greener reaction outcome.
While the linear variant of the four-component MCR in ionic liquids is currently poorly described, there is little doubt that room temperature ionic liquids will aid in the synthesis of such species. Overall the IL-MCR approach is an extremely useful one, especially for the rapid entry to highly functionalised heterocyclic molecules of potentials use in medicianl chemistry.