Ionic liquids diels-alder reactions

To date a number of reactions have been carried out in ionic liquids [for examples, see Dell Anna et al. J Chem Soc, Chem Commun 434 2002 Nara, Harjani and Salunkhe Tetrahedron Lett 43 1127 2002 Semeril et al. J Chem Soc Chem Commun 146 2002 Buijsman, van Vuuren and Sterrenburg Org Lett 3 3785 2007]. These include Diels-Alder reactions, transition-metal mediated catalysis, e.g. Heck and Suzuki coupling reactions, and olefin metathesis reactions. An example of ionic liquid acceleration of reactions carried out on solid phase is given by Revell and Ganesan [Org Lett 4 3071 2002]. 

One of the earliest solvent polarity scales is Person s D scale. This scale is based on the endojexo ratio of the Diels-Alder reaction between cyclopentadiene and methyl acrylate (Figure 3.5-2, O = logio endo/exo). This reaction has been conducted in a number of ionic liquids, giving values in the 0.46-0.83 range [26]. 

Scheme 5.1-16 The Diels-Alder reaction in a chloroaluminate(lll) ionic liquid.

Eee has used chloroaluminate(III) ionic liquids in the Diels-Alder reaction [36]. The endo. exo ratio rose from 5.25 to 19 on changing the composition of the ionic liquid from X(A1C13) = 0.48 to X(A1C13) = 0.51 (Scheme 5.1-16). The reaction works well, giving up to 95 % yield, but the moisture-sensitivity of these systems is a major disadvantage, the products being recovered by quenching the ionic liquid in water. 

Diels-Alder reactions Neutral ionic liquids have been found to be excellent solvents for the Diels-Alder reaction. The first example of a Diels-Alder reaction in an ionic liquid was the reaction of methyl acrylate with cyclopentadiene in [EtNH3][N03] [40], in which significant rate enhancement was observed. Howarth et al. investigated the role of chiral imidazolium chloride and trifluoroacetate salts (dissolved in dichloromethane) in the Diels-Alder reactions between cyclopentadiene and either crotonaldehyde or methacroline [41]. It should be noted that this paper describes one of the first examples of a chiral cationic ionic liquid being used in synthesis (Scheme 5.1-17). The enantioselectivity was found to be < 5 % in this reaction for both the endo (10 %) and the exo (90 %) isomers. 

A study of the Diels-Alder reaction was carried out by Earle et al. [42]. The rates and selectivities of reactions between ethyl acrylate (EA) and cyclopentadiene (CP) in water, 5 m lithium perchlorate in diethyl ether (5 m EPDE), and [BMIM][PE(3] were compared. The reactions in the ionic liquid [BMIM][PE(3] were marginally faster than in water, but both were slower than in 5 m EPDE [42, 43] (see Table 5.1-1 and Scheme 5.1-18). It should be noted that these three reactions give up to 98 % yields if left for 24 hours. The endo. exo selectivity in [BMIM][PE(3] was similar to that in 5 M EPDE, and considerably greater than that in water (Table 5.1-1). 

Scheme 5.1-17 Use of a chiral ionic liquid in a Diels-Alder reaction.

A similar study performed by Welton and co-workers studied the rate and selec-tivities of the Diels-Alder reaction between cyclopentadiene and methyl acrylate in a number of neutral ionic liquids [44]. It was found that endo. exo ratios decreased slightly as the reaction proceeded, and were dependent on reagent concentration and ionic liquid type. Subsequently, they went on to demonstrate that the ionic liquids controlled the endo. exo ratios through a hydrogen bond (Lewis acid) interaction with the electron-withdrawing group of the dienophile. 

Scheme 5.1-19 The aza-Diels-Alder reaction in an ionic liquid.

Many organic chemical transformations have been carried out in ionic liquids hydrogenation [4, 5], oxidation [6], epoxidation [7], and hydroformylation [8] reactions, for example. In addition to these processes, numerous synthetic routes involve a carbon-carbon (C-C) bond-forming step. As a result, many C-C bondforming procedures have been studied in ambient-temperature ionic liquids. Among those reported are the Friedel-Crafts acylation [9] and allcylation [10] reactions, allylation reactions [11, 12], the Diels-Alder reaction [13], the Heck reaction [14], and the Suzuld [15] and Trost-Tsuji coupling [16] reactions. 

Room temperature ionic liquids have been found to be excellent solvents for a number of reactions [50b] such as the isomerization [51], hydrogenation [52] and Friedel-Crafts reactions [53]. A number of Diels-Alder reactions were recently investigated in these systems. 

Earle and coworkers [54] have performed Diels-Alder reactions in neutral ionic liquids. The results of reactions of cyclopentadiene with dimethyl maleate, ethyl acrylate and acrylonitrile are reported in Table 6.10. The cycloadditions proceeded at room temperature in all of the ionic liquids tested, except [BMIMJPF4, and gave almost quantitative yields after 18-24h. The endo/exo selectivity depends on dienophile. No enantioselectivity was observed in the [BMIM] lactate reaction. 

Table 6.10 Diels-Alder reactions of cyclopentadiene with dimethyl maleate, ethylacrylate and acrylonitrile in neutral ionic liquids...

Chloroaluminate ionic liquids (typically a mixture of a quaternary ammonium salt with aluminum chloride see Table 6.9) exhibit at room temperature variable Lewis acidity and have been successfully used as solvent/catalyst for Diels-Alder reactions [57]. The composition of chloroaluminate ionic liquids can vary from basic ([FMIM]C1 or [BP]C1 in excess) to acidic (AICI3 in excess) and this fact can be used to affect the reactivity and selectivity of the reaction. The reaction of cyclopentadiene with methyl acrylate is an example (Scheme 6.31). 

Keywords good solvents for Diels-Alder reactions, ionic liquids... 

However, most of the reactions are reported to be slow, taking up to 12 h for complete conversion of the starting materials. A Diels-Alder reaction of the pyrazinone scaffold with dimethyl acetylenedicarboxylate (DMAD) [57] has been studied in view of investigating the swiftness of this cycloaddition-fragmentation protocol (Scheme 20). The authors investigated the reaction with DMAD (lOequiv) under microwave irradiation at an elevated temperature of 190 °C, using small amounts of ionic liquid (bmimPFe) in... 

Scheme 23 Microwave-enhanced Diels-Alder reactions of alkene-tethered 2(lff)-pyra-zinones in ionic liquid doped solvents...

Apart from the cyclopropanation reaction, only one example has been published of the application of ionic liquids as reaction media for enantio-selective catalysis with bis(oxazoline) ligands. In this case, the complex 6b-ZnCl2 was used as a catalyst for the Diels-Alder reaction between cyclopen-tadiene and N-crotonyloxazolidin-2-one in dibutyUmidazoUiun tetrafluorob-orate (Scheme 9) [48]. Compared with the same process in CH2CI2, the reaction was faster and both the endofexo selectivity and the enantioselectivity in the endo product were excellent. However, experiments aimed at recovering the catalysts were not carried out. 

Scheme 5.16. In some instances, e.g. the aza-Diels-Alder reaction illustrated, Lewis acid catalysts are additionally required but use of ionic liquids greatly enhanees their ease of recovery and recycle.

Scheme 5.16 Examples of Diels-Alder reactions in ionic liquids...

Applying the concept of using solvents doped with ionic liquids in order to allow microwave heating to high temperatures (see Section 4.3.3.2), Leadbeater and Tore-nius studied the Diels-Alder reaction between 2,3-dimethylbutadiene and methyl acrylate (Scheme 6.91) [190]. This reaction is traditionally performed in toluene or... 

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

Ionic liquids are excellent solvents for the Diels-Alder reaction providing significant increases in rate and selectivity. Diels-Alder reactions conducted in chloroa-luminate ionic liquids show considerable promise. For example, the endo.exo ratio for the reaction between cyclopentadiene and methyl acrylate (Scheme 7.5) could be varied by changing the composition of the ionic liquid (see Chapter 4) [11]. Although a high yield was obtained, in order to extract the products it was necessary to quench the ionic liquid in water. This is a considerable disadvantage and for this reason neutral ionic liquids have been the focus of subsequent attention. 

It has been shown that Diels-Alder reactions can be carried out successfully in a range of ionic liquids [12], As highly ordered H-bonding solvents, ionic liquids have the potential for dramatic effects as solvents for such reactions. The range of polarities which can be spanned by varying the cation or anion may be exploited and it has been shown that the endo exo ratio for the reaction between cyclopentadiene and methyl acrylate (Scheme 7.5) is dependent on the polarity of the ionic liquid used [13] (Table 7.2). When the reactions were carried out in a range of ionic liquids, the endo exo values were shown to correlate with the polarity as measured by the Ej scale. 

The advantages of using ionic liquids as solvents for Diels-Alder reactions are exemplified by the scandium triflate catalysed reactions [14] in [bmim][PFg], [bmim][SbF6] and [bmim][OTf] for the reaction shown in Scheme 7.6. Whilst the nature of the anion seems to have little effect, all these solvents give rate enhancements for a range of Diels-Alder reactions compared to when the reactions are carried out in dichloromethane (DCM). Also, the selectivity towards the endo product is higher than in conventional solvents. As well as the enhanced rates and selectivities, the products can also be removed by extraction with diethyl ether and the ionic liquid and catalyst can immediately be reused. Experiments... 

It would appear that water is a remarkable solvent for Diels-Alder reactions giving both rate and selectivity enhancements. There are now many examples of successful reactions being carried out in this solvent. However, water cannot be used for all reactions. Perfluorinated solvents have also been found to give beneficial rate enhancements over organic solvents as have ionic liquids. Interestingly, both ionic liquids and SCFs can be used to tune the selectivities of these reactions, ionic liquids by varying the solvent used and SCFs by altering the density of the solvent. 

Earle, M. J., McCormac, P. B. Seddon, K. R. Diels-Alder reactions in ionic liquids a safe recyclable green alternative to lithium perchlorate-diethyl ether mixtures. Green Chem., 1999, 1(1), 23-25 Doherty, S. Goodrich, P. Hardacre, C. et al. Marked enantioselectivity enhancements for Diels-Alder reactions in ionic liquids catalysed by platinum diphosphine complexes. Green Chem., 2004, 6(1), 63-67. 

The salts were investigated in the Diels-Alder reaction of crotonaldehyde with cyclopentadiene (Scheme 67). The yields obtained were between 35% and 40% with an endo. exo ratio of 90 10. The control reaction without the salt at -25 °C gave no product. The observed ee with the enantiopure salt 66 was less than 5%. Nevertheless, this was the first example which showed, that imidazolium-based ionic liquids can be used in substoichiometric amounts as Lewis acid catalysts. 

Scheme 67 Ionic liquid catalyzed Diels-Alder reaction...

Also the use of moisture stable ionic liquids as solvents in the Diels-Alder reaction has been carried out, and in all examples an enhanced reaction rate was observed [182,183]. The application of pyridinium-based ionic liquids allowed the utilization of isoprene as diene [184]. The chiral ionic liquid [bmim][L-lactate] was used as a solvent and accelerated the reaction of cyclopentadiene and ethyl acrylate, however, no enantiomeric excess was observed [183]. In addition several amino acid based ionic liquids have been recently tested in the Diels-Alder reaction. Similar exo. endo ratios were found but the product was obtained as racemate. The ionic liquids were prepared by the addition of equimolar amounts of HNO3 to the amino acids [185]. Furthermore, an enantiopure imidazolium salt incorporating a camphor motive was tested in the Diels-Alder reaction. No enantiomeric excess was found [186]. 

The ionic liquid [bmim][BF ] is known to catalyze the aza-Diels-Alder reaction in the synthesis of pyrano- and furanoquinolines [190]. This reaction was also catalyzed by the enantiopure bis-imidazolinium salt 67 in 67% yield with an endo. exo ratio of 60 40 (Scheme 69) [191]. The product was obtained as a race-mate. In addition the aza-Diels-Alder reaction with imines and Danishefsky s diene was catalyzed by the salt 67 giving racemic product. The salt and its analogues could be easily prepared via the oxidation of the corresponding aminals [192]. Investigation of the influence of the counter anion in achiral C2-substituted imidazolinium salts, which can be also described as 4,5-dihydroimidazolium or saturated imidazolium salts, in the aza-Diels-Alder reaction showed, that the catalytic activity increased, the more lipophilic the counter anion and therefore the more hydrophobic the salt was [193]. 

B.1.2. Diels-Alder Reactions. The Diels-Alder reaction is one of the reactions that has been most thoroughly investigated with ionic liquids (1). Adding a Lewis acidic catalyst such as Sc(OTf)3 to ionic liquids improves endo selectivity (129). Ionic liquid co-solvent was found to activate the Lewis-acidic Sc(OTf)3 catalyst in... 

Unusually high diastereoselectivity and enantioselectivity in Diels-Alder reactions were achieved in ionic liquids at room temperature (131). The selectivity rivals that of the reaction in conventional solvents, for which a low temperature (e.g., — 78°C) is needed. Furthermore, the rate of the reaction is much higher in the ionic liquids than in the conventional solvents, because the reaction is carried out at room temperature in ionic liquids. 

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