Knoevenagel-Cope

Phosphorus pentoxide/triethylammonium acetate Knoevenagel-Cope condensation s. 1, 586 suppl. 28... 

Acetic acid pyrrolidine Knoevenagel-Cope condensation a, -Ethyleneketones from aldehydes... 

In the first version of this reaction, an a-sulfanyladehyde or -sulfanylketone 5a is treated with a-aetivated acetonitrile 6 in the presence of a basic catalyst (usually triethylamine or piperidine). Reaction performed in the solvents like methanol, ethanol or DMF at 50 °C takes place in two snbsequent steps -Knoevenagel-Cope condensation [32, 33] and intramolecnlar ring closnre of formed sulfanyl substitnted o y nnsatnrated nitrile 8 (Scheme 3). 

The third two-step version of the Gewald reaction allows the reaction of alkyl-aryl or cycloalkyl ketones which exhibit limited reactivity under the one-pot conditions, a >9-Unsaturated nitrile 9 as a product of Knoevenagel-Cope condensation is ahead prepared and isolated and then treated with sulfur and amine... 

In fact, the reaction of the addition of sulfur to a / -unsaturated nitrile 9, which is required almost in all types of the Gewald reaction except the versions 1 and 4 where the starting compoimds are already sulfanyl substituted (compounds 5a and 5c), is not known in detail. However, it is sure, that Ss has to be activated to react with Knoevenagel-Cope product 9. Some authors report that the activation of sulfur and the following addition of sulfur on a methylene group is base-promoted [57-59], others details the electrochemical activation of the Sg [60-62],... 

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]. 

Later, the same research group [101, have reported on synthesis of two 5-bromo substituted 2-aminothiophenes 35 (Table 10) via a two-step Gewald synthesis. In a reaction of 3-trifluoromethylacetophenone (30) with either benzoylacetonitrile or ethyl cyanoacetate (31) in the presence titanium(IV) chloride [102] afforded Knoevenagel-Cope product 32. In subsequent treatment of 32 with sulfur the 2-aminothiophene core 33 is formed under basic conditions. The free C-5 position of derivative 33 is substituted with bromine in two following steps - first the free amino group is being Boc protected and then C-5 position brominated with A-bromosuccinimide (Scheme 16) [101]. 

Further, /9-oxo carboxylic esters can be used as carbonyl components.920 If, however, aldehydes are to be condensed with / -oxo carboxylic esters, the technique of Knoevenagel or the frequently successful Cope method921 is used ... 

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). ... 

The antidiabetic thiazolidinedione activators of peroxisome proliferator-activated receptors (PPARs) include rosiglitazone (100, Avandia ), pioglitazone (Actos ) and troglitazone (Rezulin ), and all include a benzyl-linked thiazolidinedione ring which is constructed via a Knoevenagel condensation between thiazolidinedione 51 and a substituted benzaldehyde such as 98 under Cope conditions. ... 

The first step of this method involves a Knoevenagel-type condensation of TosMIC to provide intermediate 36a [28], It is noteworthy that the conditions used helped (a) cope with the lower activity of the 17-oxo group of 35 and (b) avoid elimination of sulfinic acid. The second step involves the condensation of 36a with formaldehyde (9c) to form intermediate 38, which then undergoes an internal nucleophilic attack onto the isocyanide carbon to generate the oxazoline intmnediate 39. Addition of 10 equivalents of MeOH to the phase transfer catalyst directly generates oxazoline 41 via the elimination of tosyl sulfonic acid from 40. Acid-catalyzed hydrolysis provides the target compound 37 (Scheme 7.8). 

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