Furans Knoevenagel reaction

Scheme 2.23. Furans and pyrroles via Passerini or Ugi/Knoevenagel reactions.

The Knoevenagel reaction of 2,3-O-isopropylidene-D-glyceraldehyde with active methylene compounds has led to derivatives of D-fructose and D-sorbose (Scheme 6). Similar condensations with other 3-dicarbonyI compounds led to furan derivatives on acidic hydrolysis. In the self-condensation of D-fructose... 

The exchange of the heterocyclic component by a phosphine led to phosphonium based zwitterionic salts [179]. Catalytic pyrrolidine and benzoic acid act as mediators for the Knoevenagel reaction generating the 2-aUcylidene Meldrum s acids. The formed zwitterionic salts can easily be transformed into highly substituted furan derivatives utilizing carboxylic acid chlorides. 

The butenolides are another class of bioactive furan heterocycles that involve a base-catalyzed transesterification, followed by a Knoevenagel reaction in their synthesis [88]. Villemin et al. reported the high yielding synthesis of butenolides 33 by reaction of ethyl cyanoacetate with several a-hydroxyketones using recyclable [BMIM][Bp4] in a molar ratio of 1 1.5 (reactant/IL) (Scheme 7) [89]. 

The Perkin reaction has been carried out on aldehydes with aromatic rings other than phenyl, including biphenyl, naphthalene, furan, and indole series using tripolyphosphate (TPP) as the catalyst. However, the Knoevenagel modification is more useful in these cases.7. 

Jiang et al. [38] reported syntheses of furan-substituted rhodanine derivatives by Suzuki-Miyaura cross-coupling, followed by Knoevenagel condensation reaction. The derivatives XXXrV and XXXV have shown excellent potency against primary HIV-l strains with effective concentration 50% (EC50) at low nanomolar level of all the synthesized derivatives. The SAR data indicated that these derivatives also inhibit the HIV-l-mediated cell-cell fusion and the glycoprotein 41 (gp41) six-helix bundle formation. 

P-, and S-Heterocycles The reaction of two similar or dissimilar aryl aldehydes 250/251 with malonodi-nitrile 21 or ethyl 2-cyanoacetate 175 catalyzed by Af-hetero-cyclic carbenes (NHCs) has been demonstrated to provide fully substituted furans 252 in good to high yields (74-90%), within short reaction times up to 5 h under solvent-free conditions (Scheme 13.59) [97]. This transformation is based on the umpolung of one of the aldehydes by the NHC, while the other one undergoes a Knoevenagel condensation with the CH-acidic reaction partner. The Breslow intermediate then attacks the condensation product in fashion of a Michael addition. After elimination of the NHC, base-catalyzed cyclization provides the desired products. Five different NHCs have been tested catalyzing this reaction. 

In a related transformation, the same group described a three-component domino reaction of 2-hydroxy-l,4-naphthoquinone, acting as a P-dicarbonyl surrogate, aromatic aldehydes and 1-(2-oxo-2-phenylethyl)pyridinium bromides in the presence of ammonium acetate, in water under microwave irradiation, that affords naphtho[2,3-Z)]furan-4,9-diones 31 [22]. Mechanistically, this domino reaction probably follows the same Knoevenagel-Michael intramolecular S 2 pathway described for the preparation of compounds 28, with ammonium acetate acting in this case as the base, to give intermediates 33. These compounds, which can be considered as tautomers of a hydroquinone species, would be finally transformed into the observed quinones by air-promoted oxidation, yielding the final products 31 (Scheme 1.16). 

The Knoevenagel condensation also plays a part in a number of prominent heterocycle syntheses including the Knorr pyrrole synthesis/ Hantzsch dihydropyridine synthesis/ Feist-Benary furan synthesis and the Gewald reaction, which is used to make 2-aminothiophenes. 

Furthermore, investigations into reacting even unprotected carbohydrates with 1,3-dicarbonyl compounds have been published in the literature. Controlled by the reaction conditions, the formation of substituted furans or C-glycosides was observed. By application of acidic reaction conditions, multicondensation processes were obtained. As a consequence of that, the formation of polyhydroxylated furans was noticed [38]. These transformations are connected with the loss of stereogenic centers of the carbohydrates deployed. Under basic conditions, a Knoevenagel... 

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