Knoevenagel condensation ionic liquids

Su C, Chen ZC, Zheng QG (2003) Organic reactions in ionic liquids Knoevenagel condensation catalyzed by ethylenediammonium diacetate. Synthesis 555—559... 

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

Scheme 10.30. Domino Knoevenagel condensation/catalytic hydrogenation reaction in ionic liquid.

The very first report on the use of ionic liquids as soluble supports was presented by Fraga-Dubreuil and Bazureau in 2001 [102]. The efficacy of a microwave-induced solvent-free Knoevenagel condensation of a formyl group on the ionic liquid (IL) phase with malonate derivatives (E1CH2E2) catalyzed by 2 mol% of piperidine was studied (Scheme 7.89). The progress of the reaction could be easily monitored by 1H and 13C NMR spectroscopy, and the final products could be cleaved from the IL... 

The first use of room temperature ionic liquids as potential novel soluble phases for combinatorial synthesis has recently been described. As model reaction the Knoevenagel condensation of salicyl aldehyde grafted on to an imidazolium-derived ionic liquid was studied under the action of microwave irradiation (Scheme 12.19) [66]. Reactions were performed without additional solvent in the presence of a basic catalyst, utilizing microwave irradiation in a designated monomode microwave reac-... 

Ionic liquids are also alternative reaction media considered as green, mostly because of their lack of vapor pressure and the possibility of reuse [68, 69]. Base-catalyzed Knoevenagel reactions have been described in these media [70-73]. The development of task specific ionic liquids in which the solvent and promoter are coupled is a real breakthrough in the field and some of them have been used in the Knoevenagel condensation [74—81]. 

A basic ionic liquid, l-butyl-3-methyl imidazolium hydroxide, [bmImjOH, was found to catalyze the Knoevenagel condensation of aliphatic aldehydes and ketones with active methylene compounds elSciently in the absence of any organic solvent (Scheme 5.58). Coumarins have been obtained in one step from the reaction of o-hydroxy aldehydes following this procedure. ... 

The moisture- and air-stable ionic liquids, l-butyl-3-methylimidazolium tetra-lluoroborate [bmim]BF and l-butyl-3-methylimidazolium hexafluorophosphate [bmim]PFg, were used as green recyclable alternatives to volatile organic solvents for the ethylenediaimnonium diacetate-catalyzed Knoevenagel condensation between aldehydes or ketones with active methylene compounds. As described by Su et al. [57], the ionic hquids containing a catalyst were recycled several times without decrease in yields and reaction rates. In the case of 2-hydroxybenzaldehyde, the reactions led to the formation of 3-substituted coumarin derivatives in high yields of up to 95% (Scheme 17.11). When ethyl cyanoacetate was used, 2-imino-27f-l-benzopyran-3-carboxyhc acid ethyl ester was formed. 

Green syntheses of unsymmetrical 9,10-diarylacridine-1,8-dione and indenoquinoline were accomplished by the reaction of 3-anilino-5,5-dimethylcyclohex-2-enones 31 (R = Ph), aromatic aldehydes and 1,3-dicarbonyl compounds in the ionic liquid medium [bmim+][BF4-]. A possible mechanism of the reaction via Knoevenagel condensation and... 

A variety of 2-substituted 2//-chromenes can be obtained from the facile reaction of 2-hydroxybenzaldehydes with vinylboronic acids in ionic liquid solvents <04SL2194>. In a one-pot sequence also in an ionic liquid, a Knoevenagel condensation between O-prenylated salicylaldehydes and 4-hydroxycoumarins is followed by an intramolecular hDA reaction to yield ci5-fused chromano[4, 3 4,5]pyrano[3,2-c]coumarins e.g. 20 small amounts of the corresponding chromone are also formed <04S1783>. In like manner, cii-fused furopyranopyran derivatives have been obtained from sugar aldehydes <04TL3493>. 

Nanoparticulate ZnO was used as an efficient catalyst for the synthesis of cou-marins (84) by the reaction of o-hydroxy benzaldehydes (82) and 1,3-dicarbonyl compounds (83) via Knoevenagel condensation under microwaves and thermal conditions (Scheme 9.24) in moderate to excellent yields (Kumar et al. 2011). This protocol differs from the previous methods for the synthesis of coumarins (84) in terms of simplicity and effectiveness. The application of ZnO/MgO in ionic liquid [bmim] [BF4] was carried out successfully for the synthesis of 4//-pyrans (85) and coumarins (88) at ambient temperature via Knoevenagel condensation reaction of aldehydes (8) or 2-hydroxybenzaldehyde derivatives (86) with active methylene compounds (16, 43, 87) (Schemes 9.25 and 9.26) (Valizadeha and Azimib 2011). The method has several advantages in terms of mild reaction conditions, reusability of the catalyst, high yields of the products, and short reaction times. In comparison with methods mentioned in the literature for the synthesis of 4F(-pyrans (85) and coumarins (88), this protocol has better yield and eco-friendly advantages. 

Knoevenagel condensation between aromatic aldehydes and active methylene compounds has also been induced by Lewis acid ionic liquids leading to the generation of electrophilic alkenes as major products. Extension of this methodology to o-hydroxybenzaldehydes resulted in the formation of coumarins (Harjani et al. 2002). 

Darvatkar, N. B., Deomkhkar, A. R., Bhilare, S. V., Raut, D. G., Salunkhe, M. M. 2008. Ionic liquid-mediated synthesis of coumarin-3-carboxylic acids via Knoevenagel condensation of Meldrum s acid with ort/io-hydroxyaryl aldehydes. Synth. Commun. 38(20) 3508-3513. 

Harjani, J. R., Nara, S. J., Salunkhe, M. M. 2002. Lewis acidic ionic liquids for the synthesis of electrophilic alkenes via the Knoevenagel condensation. Tetrahedron Lett. 43 1127-1130. 

Valizadeh, Ft., Ghohpour, H. 2010. Imidazolium-based phosphinite ionic liquid (IL-OPPhj) as reusable catalyst and solvent for the Knoevenagel condensation reaction. Synth. Commun. 40 1477-1485. 

Hu Y, Wei P, Huang H, Le ZG, Chen ZC (2005) Organic reactions in ionic liquids ionic liquids ethylammonium nitrate promoted knoevenagel condensation of aromatic aldehydes with active methylene compounds. Synth Commun 23(35) 2955-2960... 

J. J., Li, M.J., Qiu, H.Y., and Lai, G.Q. (2006) Synthesis of ionic liquid functionalized SBA-15 mesoporous materials as heterogeneous catalyst toward Knoevenagel condensation under solvent-free conditions. Eur.. Inorg. Chem., 2006, 2947-2949. 

I2/K2C03, tetrabutylammonium hydroxide, tungsten phosphoric acid, ionic liquids, reactions in water, solvent-free conditions, microwave promoted reactions, reactions promoted by phase-transfer catalysts, and finally, for some very reactive substrates, uncatalyzed reactions. " Unfortunately for the practicing chemist, few of these conditions are well worked out enough or understood well enough to have become common, and almost all examples of the Knoevenagel condensation in the literature employ an amine base, or a salt thereof (Cope conditions, or amino acid catalysis) or TiCl4/Base(Lehnert conditions). ... 

Other researchers [50] deal that the use acid-base catalyst (ammonium salts acetates and trifluoroacetates of diethylammonium, morpholinimn, piperidinimn) promotes the creation of the Knoevenagel-Cope condensation product (X,P-imsaturated nitrile) and enhances the yield of final 2-aminothiophene. Ionic liquids used as solvents in combination with ethylenediammonium diacetate were shown to be very efficient in the case of the Gewald synthesis with aliphatic and alicyclic ketones with possibility of regeneration of used liquids [83]. 

Knoevenagel condensation reaction in 1, 1,3,3,-N,N,N, N -tetramethylguanidinium trifluoro-acetate ionic liquid. J. Iran. Chem. Soc. 2009, 6, 710-714. 

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