Methyl cyanoacetate, Knoevenagel condensation with

Another pyrrole synthesis [53] was based on the Ugi-4CR/Knoevenagel condensation between aldehydes, cyclohexyl isocyanide, cyanoacetic acid, and phena-cylamine 68 as the carbonyl input. Also in this case the Ugi products 69 spontaneously cydized to the pyrroles 70 which were methylated with diazomethane to give the 2-methoxy derivatives 71 (Scheme 2.25). 

Cesium-exchanged zeolite X was used as a solid base catalyst in the Knoevenagel condensation of benzaldehyde or benzyl acetone with ethyl cyanoacetate [121]. The latter reaction is a key step in the synthesis of the fragrance molecule, citronitrile (see Fig. 2.37). However, reactivities were substantially lower than those observed with the more strongly basic hydrotalcite (see earlier). Similarly, Na-Y and Na-Beta catalyzed a variety of Michael additions [122] and K-Y and Cs-X were effective catalysts for the methylation of aniline and phenylaceto-nitrile with dimethyl carbonate or methanol, respectively (Fig. 2.37) [123]. These procedures constitute interesting green alternatives to classical alkylations using methyl halides or dimethyl sulfate in the presence of stoichiometric quantities of conventional bases such as caustic soda. 

Tetrahydroisoquinolines (39) are also accessible in moderate yields using the aza-analogues 38a, b) of cyclohexenylacetonitrile 24 d). A mixture of the double-bond isomers 38 a, b) could simply be obtained in 74% yield by Knoevenagel condensation of N-methyl- or N-ethoxycarbonyl-4-piperidinone with cyanoacetic acid. 

With respect to the formation of polymers, the Knoevenagel condensation is usually employed to prepare the monomere. " Thus, 4-(N,N-dimethylamino)cinnamaldehyde is condensed with methyl cyanoacetate to give the corresponding Knoevenagel product (350), which is copolymerized with tere-phthalate and ethylene glycol to give a brilliant yellow polyester. On the other hand, the Knoevenagel... 

The reactivity of pyridazine-3- and 4-carbaldehydes towards active methylene reagents under the conditions of Knoevenagel, Wittig, and Hantzsch-type reactions has been examined. The 4-aldehyde reacts readily with malononitrile and methyl cyanoacetate, and less readily with triethyl phos-phonoacetate, indane-l,3-dione and alkyl acetoacetates/ammonia (e.g.. Scheme 52). Condensation with nitroethane is successful, but nitromethane gives an unstable intermediate which decomposes. The 3-aldehyde has similar reactivity to the 4-aldehyde, but some reactions are unsuccessful due to reduced reactivity, or instability of the products <90JHC1313>. 

Suzuki and Wada explored the Knoevenagel condensation of malononitrile and methyl cyanoacetate under solvent-free conditions (Scheme 2.45) [40]. Different alkaline earth carbonates and fluospar were used as mild catalysts for the condensation of 2 equiv. of malononitrile and 1 equiv. of aromatic aldehyde to obtain products in high yields, after short milling (30 min. Table 2.42). When methyl cyanoacetate was ball milled with aldehydes, the reaction occurred with the stereoselective formation of (fl-cyanocinnamic esters 133. However, significant oxidative loss of aldehydes was encountered. The addition of a small amount of hydroquinone as antioxidant was found to solve the problem and drastically increase yields. 

Reproduced from Wada S, Suzuki H. Calcite and fluorite as catalyst for the Knoevenagel condensation of malononitrile and methyl cyanoacetate under solvent-free conditions. Tetrahedron Lett 2003 44 399-401. Copyright (2003), with permission from Elsevier. 

Solid-phase synthesis is of importance in combinatorial chemistry. As already mentioned RuH2(PPh3)4 catalyst can be used as an alternative to the conventional Lewis acid or base catalyst. When one uses polymer-supported cyanoacetate 37, which can be readily obtained from the commercially available polystyrene Wang resin and cyanoacetic acid, the ruthenium-catalyzed Knoevenagel and Michael reactions can be performed successively [27]. The effectiveness of this reaction is demonstrated by the sequential four-component reaction on solid phase as shown in Scheme 11 [27]. The ruthenium-catalyzed condensation of 37 with propanal and subsequent addition of diethyl malonate and methyl vinyl ketone in TH F at 50 °C gave the adduct 40 diastereoselectively in 40 % yield (de= 90 10). 

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