Knoevenagel reaction Lewis acidity

The cyanoacryhc esters are prepared via the Knoevenagel condensation reaction (5), in which the corresponding alkyl cyanoacetate reacts with formaldehyde in the presence of a basic catalyst to form a low molecular weight polymer. The polymer slurry is acidified and the water is removed. Subsequendy, the polymer is cracked and redistilled at a high temperature onto a suitable stabilizer combination to prevent premature repolymerization. Strong protonic or Lewis acids are normally used in combination with small amounts of a free-radical stabilizer. 

Scheme 2.169. Chiral 1,3-dicarbonyl compounds and chiral Lewis acids for the dominr Knoevenagel/hetero-Diels-Alder reaction.

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

Nucleophilic addition to C=0 (contd.) ammonia derivs., 219 base catalysis, 204, 207, 212, 216, 226 benzoin condensation, 231 bisulphite anion, 207, 213 Cannizzaro reaction, 216 carbanions, 221-234 Claisen ester condensation, 229 Claisen-Schmidt reaction, 226 conjugate, 200, 213 cyanide ion, 212 Dieckmann reaction, 230 electronic effects in, 205, 208, 226 electrons, 217 Grignard reagents, 221, 235 halide ion, 214 hydration, 207 hydride ion, 214 hydrogen bonding in, 204, 209 in carboxylic derivs., 236-244 intermediates in, 50, 219 intramolecular, 217, 232 irreversible, 215, 222 Knoevenagel reaction, 228 Lewis acids in, 204, 222 Meerwein-Ponndorf reaction, 215 MejSiCN, 213 nitroalkanes, 226 Perkin reaction, 227 pH and, 204, 208, 219 protection, 211... 

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). 

Lewis base sites in PCPs have the potential to show different catalytic properties from Lewis acid sites.52 165 166 The three-dimensional PCP, [Cd(NC>3)2(4-btapa)2] 6H20 2DMF (4-btapa = 1,3,5-benzenetricarboxylic acid tris[/V-(4-pyridyl)-amide]), has amide groups that act as guest interaction sites on the surfaces of channels with dimensions of 4.7 x 7.3 A2165 A Knoevenagel condensation reaction catalyzed by this PCP demonstrates its selective heterogeneous base catalytic properties, which depend on the size of the reactants. This solid catalyst maintains its crystalline framework after the reaction and is easily recycled. 

FeCls is superior to Al, Sn, and Zn Lewis acids in the intramolecular ene reaction of the Knoevenagel adduct from citronellal and dimethyl malonate (Sch. 61) [207]. 

Although it is a stoichiometric procedure, the intramolecular hetero-Diels-Alder reaction of l-oxa-l,3-butadienes, obtained in situ by a Knoevenagel condensation of aromatic aldehydes and N,N -dimethylbarbituric acid, is mediated by a chiral titanium Lewis acid 29 which has l,2 5,6-di-0-isopropylidene-a-D-glucofuranose as a ligand. The highest ee-value was obtained in the reaction of 30 with 31 in isodurene as illustrated in Scheme 13[26]. 

Modified clays (e.g. montmorilonite K-10) as mild Lewis acid catalysts in Knoevenagel, Michael, Diels-Alder reactions, aromatic chlorination and nitration. 

On the other hand the catalyst is of great importance primary, secondary or tertiary amines or their corresponding ammonium salts are usually used, but many other catalysts such as phase transfer catalysts, Lewis acids or potassium fluoride can also be applied. The most widely employed catalysts are pyridine, with or without added piperidine, and ammonium salts, such as ammonium or piperidinium acetate. Condensations that employ strong bases or preformed metal salts of the methylene component are not covered here since transformations under these conditions are not usually considered to be Knoevenagel reactions. 

The acidity of these products cannot be determined by means of direct pH determination. However, the virtual acidity constant, AT l, is accessible from optical and electrochemical measurements. Comparison of the pX i values of selected Knoevenagel products and the pX values of some typical carboxylic acids in methanol establishes that they exhibit comparable acidity (Scheme 7). Using the o -values, the pX i values of benzylidene derivatives of Meldrum s acid are in good accordance with the Hammett equation. The Lewis acidity of Knoevenagel products is due to the formation of labile pseudobase adducts, the so-called anbadons (10), upon reaction with nucleophiles. Structures of the anbadons have... 

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