Ionic liquids cycloaddition, Diels-Alder

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. 

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 6.91 Diels-Alder cycloaddition reactions in ionic liquid-doped solvents.

Inter- and intramolecular hetero-Diels-Alder cycloaddition reactions in a series of functionalized 2-(lH)-pyrazinones have been studied in detail by the groups of Van der Eycken and Kappe (Scheme 6.95) [195-197]. In the intramolecular series, cycloaddition of alkenyl-tethered 2-(lH)-pyrazinones required 1-2 days under conventional thermal conditions involving chlorobenzene as solvent under reflux conditions (132 °C). Switching to 1,2-dichloroethane doped with the ionic liquid l-butyl-3-methylimidazolium hexafluorophosphate (bmimPF6) and sealed-vessel microwave technology, the same transformations were completed within 8-18 min at a reaction temperature of 190 °C (Scheme 6.95 a) [195]. Without isolating the primary imidoyl chloride cycloadducts, rapid hydrolysis was achieved by the addition of small amounts of water and subjecting the reaction mixture to further microwave irradia-... 

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). 

Ionic liquids can be used as replacements for many volatile conventional solvents in chemical processes see Table A-14 in the Appendix. Because of their extraordinary properties, room temperature ionic liquids have already found application as solvents for many synthetic and catalytic reactions, for example nucleophilic substitution reactions [899], Diels-Alder cycloaddition reactions [900, 901], Friedel-Crafts alkylation and acylation reactions [902, 903], as well as palladium-catalyzed Heck vinylations of haloarenes [904]. They are also solvents of choice for homogeneous transition metal complex catalyzed hydrogenation, isomerization, and hydroformylation [905], as well as dimerization and oligomerization reactions of alkenes [906, 907]. The ions of liquid salts are often poorly coordinating, which prevents deactivation of the catalysts. 

Of the 18 systems, some of which are unstable and must be generated in the reaction has been accomplished for at least 15, but not in all cases with a carbon-carbon double bond (the reaction also can be carried out with other double bonds ). Not all aUcenes undergo 1,3-dipolar addition equally well. The reaction is most successful for those that are good dienophUes in the Diels-Alder reaction (15-60). The addition is stereospecific and syn, and the mechanism is probably a one-step concerted process, as illustrated above, " largely controlled by Frontier Molecular Orbital considerations. " In-plane aromaticity has been invoked for these dipolar cycloadditions. " As expected for this type of mechanism, the rates do not vary much with changes in solvent, " although rate acceleration has been observed in ionic liquids. " Nitrile oxide cycloadditions have also been done in supercritical carbon dioxide. There are no simple rules... 

Although cycloadditions and rearrangements often proceed without catalysts, the selectivity of the reaction and the reactivity of very reluctant molecules can be enhanced by a Lewis acid. The Diels-Alder reaction can be performed at enhanced reaction rate in ionic liquids with the addition of ZnCl2 (eq. (4)) [42]. The Claisen rearrangement was also reported to be superior if catalyzed by Sc(OTf)3 in ionic liquids [43]. 

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]. 

Supported liquid acrylic esters have been prepared from hydroxylated imidazolium-based TSILs and used neat in (4-1-2) Diels-Alder cydoadditions. First, Handy et al. [31] used a fructose-derived ionic liquid to support acryUc acid and performed the Diels-Alder cycloaddition with several dienes induding cydopenta-and cydohexadienes and butadiene derivatives at 120 °C for 12 h in the presence of hydroquinone (Scheme 5.5-25). 

The ability of ionic liquids to dramatically improve the yields and selectivi-ties of reactions is clearly shown by the scandium-triflate-catalyzed Diels-Alder reaction.This cycloaddition usually has low turnover (TON < 10-20). Song studied this reaction in ionic liquids, which offered the possibility of recovering the catalyst. The cycloaddition between 1,4-naphthoquinone and 1,3-dimethylbutadiene catalyzed by a very small loading (0.2mol%) of Sc(OTf)3 in the standard [bmim][PF6] ionic liquid was used as a test reaction (Scheme 43). 

The use of a scandium trifluoromethanesulfonate catalyst has also been reported for aza-Diels-Alder reactions. The reaction of benzaldehyde and amine 104 in [emim][OTf] as the ionic liquid led to the in situ formation of the corresponding imine. Cycloaddition of this imine with Danishefsky s diene gave the A -aryl-6-phenyl-5,6-dihydro-4-pyridone 105 in a quantitative yield (Scheme 44). 

Sc(OTf)3-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have also been developed. In the presence of 10 mol % Sc(OTf)3 and magnesium sulfate, the reaction of benzaldehyde with aniline and Danishefsky s diene produces the tetrahydropyridine derivative in 83% yield, while the reaction with cyclopentadiene instead of Danishefsky s diene produces the tetrahydroquinoline derivative. Various combinations of aldehydes, amines, and alkenes are possible in these reactions to produce diverse tetrahydroquinoline derivatives in high yield. Moreover, the three-component coupling reactions proceed smoothly in aqueous solution, and commercial formaldehyde-water solution can be used directly (eq 19). Sc(OTf)3-catalyzed three-component aza Diels-Alder cycloadditions also proceed smoothly in an ionic liquid. ... 

G. Keglevich, R. Kovacs, L. Drahos, Diels-Alder cycloadditions of 1,2-dihydrophosphinine oxides and fi agmentation-related phosphorylations with 2-phosphabicyclo[2.2.2]octadiene oxides under green chemical conditions - the role of microwave and ionic liquids. Phosphorus Sulfur Sfflcon 186 (2011) 2172-2179. 

Scheme 22.12 Enantioselective Diels-Alder cycloaddition catalyzed by the MacMillan imidazolidinone located in a supported ionic liquid phase.

Chiral enamine, dienamine, and trienamine intermediates have been shown to catalyse asymmetric Diels-Alder reactions via HOMO activation. These Diels-Alder reactions generally occur with high chemo-, regio-, and stereo-selectivities. ° The effect of the viscosity of pyridinium-based ionic liquids, with tetrafluoroborate and bis(trifluorosulfonimide) anions, on the kinetics of intra- and inter-molecular Diels-Alder reactions has been investigated. Results show that the intramolecular cycloaddition reaction is less susceptible to viscosity variations than the intermolecular reaction. 

An improvement in Diels-Alder irreversible cycloaddition of 1,3-cyclohexadi-ene, 3-carbomethoxy-2-pyrone and 2-methoxythiophene with acetylenic compound was observed (Loupy et al., 2004) while a combined effect of microwave irradiation and solid supports in ionic liquids on the Diels-Alder reaction of 1,3-cyclopentadi-ene and different nucleophiles was investigated by Lopez et al. (2007). 

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