Ionic Knoevenagel reactions

Knoevenagel Reactions on a Grafted Ionic Liquid Phase... 

Previous work [111] by our group has demonstrated that RTIL-catalyzed 1,3-dipolar cycloaddition under the action of microwave irradiation leads to dramatically shorter reaction times with better yields of isolated products. We have recently investigated the reactivity of the formyl group covalently grafted on the ionic liquid phase 75 in the Knoevenagel reaction with malonic derivatives 76 [112], as shown in Scheme 8.76. 

An organic base in an ionic liquid was also found to be effective for a Knoevenagel reaction. Glycine was added to the ionic liquid [HMIMjPFs as the base catalyst. The reaction proceeded at room temperature in air without the need for rigorous drying of the ionic liquid. Glycine and the reactants malononitrile and benzaldehyde dissolved readily in the ionic liquid. The product was extracted from the ionic liquid phase with an immiscible co-solvent, toluene 110). 

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]. 

Cai, Y., Peng, Y, and Song, G. 2006. Amino-functionalized ionic liquid as an efficient and recyclable catalyst for Knoevenagel reactions in water. Catalysis letters, 109 61-64. 

The ionic liquid grafted benzaldehydes prepared for the 1,3-dipolar cydoaddition reactions have also been used successfully as substrates for Knoevenagel reactions using microwave irradiation (Scheme 7.16). One equivalent of different malonate derivatives with a variety of electron-withdrawing groups was added to the ionic liquid phase and piperidine was used as catalyst. Reaction times varied from 15-60 min. The product was cleaved from the ionic liquid phase by using the NaOMe... 

Scheme 7.16. Solvent-free Knoevenagel reactions using ionic liquid-supported benzaldehydes.

Valizadeh, H., Vaghefi, S. 2009. One-pot Wittig and Knoevenagel reactions in ionic liquid as convenient methods for the synthesis of coumarin derivatives. Synth. Commun. 39 1666-1678. 

Knoevenagel reactions can be carried out at ambient temperature using an ionic liquid, dimethylethanolammonium acetate it features wide substrate tolerance, and ease of workup and reuse. " ° Its catalytic effect has been demonstrated by a solvatochromic study which identifies dual functions the cation hydrogen-bonds to the aldehyde, and the anion acts as acceptor to the active methylene substrate, facilitating the formation of carbanion. 

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). ... 

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-... 

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

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. 

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

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>. 

The suitability of imidazolium ionic liquids as reaction media for the base-catalyzed Knoevenagel and Qaisen reaction was investigated by Garcia et al. [250]. Indirect evidence for the formation of the carbene l-methyl-3-butylimidazolylidine from [BMIM][PFe] was found and the authors postulate the formation of an imidazolium anion by hydride abstraction from 1,4-cyclohexadiene. This is an antiaromatic species and is previously unknown. A more plausible explanation is the disproportionation of the imidazolium cation via the carbene, shown in Scheme 5.2-107. [22,215]. 

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. 

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. 

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