Knoevenagel addition Michael

A Knoevenagel condensation/Michael addition sequence has been reported by Barbas III and coworkers (Scheme 2.70) [158] using benzaldehyde, diethyl malonate, and acetone in the presence of the chiral amine (S)-l-(2-pyrrolidinyl-methyl)-pyrrolidine (2-301). As the final product the substituted malonate 2-302 was isolated in 52% yield with 49% ee. 

Keywords dimedone, aromatic aldehyde, Knoevenagel condensation, Michael addition, uncatalyzed... 

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). 

Hantzsch heterocyclization Henry reaction Knoevenagel condensation Michael addition enolate... 

Together with the Knoevenagel condensation, Michael additions constitute a powerful tool for the synthetic chemist, with numerous applications in many fields such as pharmaceuticals [32], perfumes [33], herbicides [34], polymers [35], dispersant agents [36], and anionic surfactants [37], etc. 

Cascade Knoevenagel condensation/Michael addition of dimedone and aromatic aldehydes. 

Knoevenagel condensation, Michael additions, and aldol condensations Homogeneous base catalysts Basic zeolites — [58]... 

Hydrotalcite with Various Anions. Various anions can be incorporated in the interlayers such as t-BuO and F ions by anion exchange or by using memory effect. Hydrotalcite with -BuO ions are highly active for many reactions including Knoevenagel condensation, Michael addition, transesteriflcation, Honor-Wittig, and Henry reactions (23). L-Proline can be intercalated in the interlayers. L-Proline-anchored hydrotalcite is an efficient catalyst for asymmetric syntheses by aldol reactions, Henry reaction, and Michael adition (25-27). 

SCHEME 13.16 Piperidine-catalyzed Knoevenagel/enamine-Michael addition/cyclization sequence. 

An acid-catalyzed version of this reaction was published by Wang et al. in 2013 [50]. A substoichiometric amount of acetic acid in refluxing ethanol mediates the Knoevenagel/ enamine-Michael addition/cyclization sequence to provide the spirodihydropyridines in high yields. 

The reaction of dimedone-derived enamines 110, methyl (2-cyano)acetate 109, and formaldehyde 72 mediated by lithium perchlorate led to the formation of a Knoevenagel/ enamine-Michael addition product (Scheme 13.33) [52], This could be cyclized in a one-pot procedure with substoi-chiometric amounts of triphenyl phosphine to provide... 

SCHEME 13.34 Direct cyclization of Knoevenagel/enamine-Michael addition products to the corresponding pyridone derivatives 115, 118, and 122 [53-55],... 

A silica tungstic acid (STA)-catalyzed Knoevenagel condensation/Michael addition/double Mannich reaction... 

A series of 2-amino-4 /-thiopyrans 268 has been synthesized by one-pot Knoevenagel condensation/Michael addition/cyclization of several p-oxodithioesters 265, active methylene compounds 267, and various aldehydes 266 (Scheme 13.62) [102], The products could be isolated in good to excellent yields (70-93%), after stirring for a few hours in refluxing dichloromethane. Analogous 4-spirothio-pyrans 272 have been prepared by Majumdar et al. [103]. These reactions were conducted without any catalyst in refluxing ethanol, and the products could also be isolated in excellent yields (89-99%). 

Within a sequence of Knoevenagel condensation, Michael addition and condensation, Meldrum s acid can be used as a CHj-C(O) equivalent, through the elimination of acetone and subsequent decarboxylation (Scheme 13.86). In this sequence, other 1,3-dicarbonyl compounds within the reaction mixture serve as nucleophile in the Michael addition. By addition of a nitrogen source to this reaction... 

Similar to the mechanism described in Scheme 2.16, a Knoevenagel reac-tion/ketalization cascade of hydroxyacetone with 1,3-dicarbonyl compounds is assumed. In Scheme 2.16, a Knoevenagel condensation/ketalization reaction is depicted. This sequence allows a subsequent oxa-Michael addition, which yields the corresponding C-glycosides. In contrast, a Knoevenagel addition/ketalization occurs under the reaction condition described in Scheme 2.28, which is followed by an intramolecular retro-Claisen step. As a result of that, the corresponding esters were obtained (Scheme 2.29). 

In the amine-catalyzed reactions, a Knoevenagel addition/ketalization/ intramolecular retro-Claisen cascade is detected (Scheme 2.32). The retro-Claisen step is enabled by the ketalization of the Knoevenagel addition product Q. The ketalization of the Knoevenagel product (Q S) is initiated by the hydroxyl groups of the carbohydrate moiety, as in-house NMR-experiments suggest (formation of intermediate ketal structure K in Knoevenagel condensation/ketalization/oxa-Michael cascade reaction Scheme 2.16). Products derived from this reaction sequence (Scheme 2.16)... 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Unfortunately, much of Fiesselmann s work was documented only in patents and doctoral theses, allowing for the rediscovery of this classic reaction in recent years. In fact, as late as 1997, the Fiesselmann reaction of 5 with methylthioglycolate was rediscovered as a novel, tandem Michael addition/intramolecular Knoevenagel approach to thiophenes such as 6 ... 

Various competitive reactions can reduce the yield of the desired Michael-addition product. An important side-reaction is the 1,2-addition of the enolate to the C=0 double bond (see aldol reaction, Knoevenagel reaction), especially with a ,/3-unsaturated aldehydes, the 1,2-addition product may be formed preferentially, rather than the 1,4-addition product. Generally the 1,2-addition is a kinetically favored and reversible process. At higher temperatures, the thermodynamically favored 1,4-addition products are obtained. 

Horhold et al. and Lenz et al. [94,95]. The polycondensation provides the cyano-PPVs as insoluble, intractable powders. Holmes et al. [96], and later on Rikken et al. [97], described a new family of soluble, well-characterized 2,5-dialkyl- and 2,5-dialkoxy-substituted poly(pflrfl-phenylene-cyanovinylene)s (74b) synthesized by Knoevenagel condensation-polymerization of the corresponding alkyl-or alkoxy-substituted aromatic monomers. Careful control of the reaction conditions (tetra-n-butyl ammonium hydroxide as base) is required to avoid Michael-type addition. 

The Knoevenagel reaction has many similarities to the Michael addition, in which a base is required to form a carbanion Ifom an activated methylene precursor which subsequently undergoes nucleophilic addition to an alkene containing a group such as an ester capable of stabilizing the resulting anion by delocalization. These reactions are widely used for... 

Many of the known chemical syntheses such as Wittig [29, 165], Knoevenagel [29], aldol [292], Ugi [29,293], Michael addition [29], Hantzsch [29,156,157], Diels-Alder [294], Azo coupling [136,182], Suzuki coupling [29,155] or enamine [29, 295] reactions (Table 1.8), to name but a few, have been carried out successfully in mi-... 

Examples of commercially applied solid base catalysts are much fewer than for solid acids. Nevertheless, much attention is currently focused on the development of novel solid base catalysts for classical organic reactions such as aldol condensations, Michael additions, and Knoevenagel condensations, to name but a few. 

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