Diels using ionic liquids

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-... 

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... 

A very recent addition to the already powerful range of microwave cycloaddition chemistry is the development of a general procedure applying a catalyst/ionic liquid system [19]. Several studies in this area have used ionic liquids, or mixtures of ionic liquids and other solvents, as reaction media in several important microwave-heated organic syntheses [20], including Diels-Alder reactions [21, 22] and 1,3-dipolar cycloaddition reactions [23]. 

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. 

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

Room temperature ionic liquids are air stable, non-flammable, nonexplosive, immiscible with many Diels-Alder components and adducts, do not evaporate easily and act as support for the catalyst. They are useful solvents, especially for moisture and oxygen-sensitive reactants and products. In addition they are easy to handle, can be used in a large thermal range (typically —40 °C to 200 °C) and can be recovered and reused. This last point is particularly important when ionic liquids are used for catalytic reactions. The reactions are carried out under biphasic conditions and the products can be isolated by decanting the organic layer. 

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). 

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... 

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.

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... 

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. 

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. 

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. 

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]. 

These supported cycloadducts were then treated with a base (LiOH, NaOH) in a mixture of water and alcohol to give the expected free acid derivatives. However, while the latter compounds were readily recovered, the same was not true for the ionic liquid 4b, which was obtained as a dark brown liquid impure by NMR analysis. Very likely, the basic hydrolysis of the ester function caused the deprotonation of the imidazolium ring leading to a series of undesired side-reactions. Therefore, milder reaction conditions were explored to cleave the Diels-Alder product from the ionic liquid support. Handy and Okello found that the best method was the cyanide-mediated transesterification that gave the corresponding methyl esters 9-11 and allowed recover of 4b in at least 90% yield. It was also demonstrated that the recovered 4b could be used for further supported syntheses. In fact, in two subsequent mns the yields of the final ester compound were similar, indicating that the ionic liquid 4b could be efficiently recycled. 

Scheme 3 Synthesis of Diels-Alder cycloadducts using an ionic liquid as homogeneous support...

Then the potential for asymmetric induction of some of these chiral ionic liquids was investigated. The aza Diels-Alder cycloaddition between the enantiomericaUy pure (/ )-imine 31 and the Danishefsky s diene 32 was chosen as model asymmetric reaction (Scheme 8). The reaction was performed at room temperature for 5 h using 0.5 equiv. of ionic liquid and 1.5 equiv. of diene. In the absence of chiral ILs, the same coupling required a Lewis acid catalyst (0.1 equiv. of ZnC ) and afforded the main product 33 in 60% yield and low diastereoselectivity (32% de). 

The intramolecular hetero-Diels-Alder reactions in functionalized 2(17/)-pyrazinones to give bicyclo adducts were found to undergo a significant rate enhancement using controlled microwave irradiation in ionic liquid doped solvents <2002JOC7904>. 

The Diels-Alder reaction is an important and widely used reaction in organic synthesis (Sauer and Sustmann, 1980), and in the chemical industry (Griffiths and Previdoli, 1993). Rate enhancement of this reaction has been achieved by the use of solvents such as water, surfactants, very high pressure, lithium amides, alkylammonium nitrate salts, and macrocyclic hosts (Sherman et ak, 1998). Diels-Alder reactions can be ran in neutral ionic liquids (such as 1-butyl-3-methylimidazolium trifluoromethanesulfo-nate, l-butyl-3-methylimidazolium hexafluorophophate, l-butyl-3-methylimidazolium tetrafluoroborate, and l-butyl-3-methylimidazolium lactate). Rate enhancements and selectivities are similar to those of reactions performed in lithium perchlorate-diethyl ether mixtures. 

Compounds in this class are usually made from specific precursors with the ultimate functionalities appearing in the starting materials. Syntheses in which one new bond is formed (cyclizations) usually involve substitution or condensation reactions. Two new closures with potentially some generality have been noted in this chapter. One of the intramolecular Diels-Alder reactions (see Section 13.12.8.1) and the other RCM (see Section 13.12.8.1). The Baeyer-Villiger reaction is still very much used for the preparation of lactones. A supported catalyst and a recyclable catalyst carried in an ionic liquid have been introduced for use in Baeyer-Villiger oxidations from other areas. 

Since the first publication, amine-catalyzed Diels-Alder reactions of a,/ -unsaturated aldehydes have been investigated in much detail [15, 26-33]. Catalyst immobilization studies on solid support [26, 27], as well as in ionic liquids [29], have shown advantages for amine recycling, while partially maintaining good levels of asymmetric induction [34]. The use of this reaction in total synthesis has allowed the rapid preparation of (+)-hapalindole Q, a tricyclic alkaloid natural product containing four contiguous stereocenters (Scheme 3.2) [28]. 

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