Knoevenagel condensation/Michael reactions

Keywords 1,3-Dicarbonyls, Biginelh reaction, Hantzsch reaction, Heterocyclic chemistry, Knoevenagel condensation, Mannich reaction, Michael addition, Multi-component reactions... 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

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... 

While zeolites are mostly used in acid catalysts, there are various procedures to introduce basic sites with variable strength into these materials. Depending on the nature of the active site, one is able to selectively catalyze reactions with different basicity requirements, and this is probably the main virtue of base catalysis with zeolites. For instance, in a classical Knoevenagel condensation, the reaction selectivity can be decreased by a consecutive Michael reaction, since the Knoevenagel product can serve itself as a Michael receptor -. 

Previous sections have shown that catalysis by solid acids has received much attention due to its importance in petroleum refining and petrochemical processes. Conversely, relatively few studies have focused on catalysis by bases, even if acid and base are paired concepts. Base catalysts, however, play a decisive role in several reactions essential for fine-chemical syntheses [248-251]. Solid-base catalysts have many advantages over liquid bases. Examples of successfijl reactions include isomerization, aldol condensation, Knoevenagel condensation, Michael condensation, oxidation and Si—C bond formation. Various reviews have discussed catalysis by solid bases [248-255]. 

The use of these materials in a range of reactions [isomerization of alkenes and alkynes, C—C bond formation, aldol condensation, Knoevenagel condensation, nitroaldol reactions, Michael addition, conjugate addition of alcohols, nucleophilic addition of phenylacetylene, nucleophilic ring opening of epoxides, oxidation reactions, Si—C bond formation, Pudovik reaction (P—C bond formation) and synthesis ofheterocycles] have been discussed in detail by Ono [248], as well as in the other cited reviews. We will thus discuss here only selected examples. 

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). 

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... 

Hydrogenation of olefins Of Hydroxyallylation lodocyclization Kharasch reaction Knoevenagel condensation Mannich reaction Metathesis reaction Michael reaction... 

The use of supported organocatalysts in flow chemistry is not new. A pioneering work using an organic base catalyst was reported by Venturello. Knoevenagel condensations of aromatic aldehydes, cyclohexanone, and acetophenone with acetoa-cetate, cyanoacetate, or malonate were catalyzed by aminopropyl-functionalized silica gel (56), which was packed in a gravity-fed column, under continuous-flow conditions (Scheme 7.40) [149]. A flowcell microreactor, whose wall surfaces were coated with aminopropylsilica, was utilized in Knoevenagel and Michael reactions [150]. 

Butylation of phenylacetonitrile with aqueous NaOH, as shown in Scheme 25, proceeds faster by use of high DF (>0.5) anion exchange resins.The strongly alkaline conditions degrade the quaternary ammonium ions of the catalyst. Catalyst (64) (1% DVB) is active for alkylation of phenylacetonitrile and benzyl phenyl ketone, and for Williamson ether synthesis, and it is much more stable in base than AERs. AERs in OH form are catalysts for dichlorocyclopropane syntheses from alkenes, chloroform and solid sodium hydroxide, and for dehydration of amides to nitriles. AERs in the appropriate hydroxide, acetate, or cyanide form are catalysts for aldol condensations, Michael reactions, Knoevenagel condensations, cyanoethylations and cyanohydrin syntheses. " ... 

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). 

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. 

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. 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

The mechanism of the formation of tricyclic intermediates 56 and 57 is also the important and conflicting matter. For example, Quiroga et al. [83] showed that these MCRs, the most probable, proceed via preliminary Knoevenagel condensation and Michael addition (Scheme 26). At the same time they rejected another pathway including the generation of enamine 60, because no reaction was observed between it and aromatic aldehyde when their mixture was refluxed in ethanol. 

The mechanism of these MCRs involving Meldrum s acid should include Knoevenagel condensation and Michael addition cascade process [100, 113] (Scheme 37). To form positional isomeric reaction product, arylliden derivatives of Meldrum s acid are attacked by exocyclic NH2-group instead of endocyclic nucleophilic center. 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

C.4. Sti/le Couplings, Knoevenagel Condensations, and Michael Addition Reactions... 

Maraval et al 39) synthesized core- and periphery-functionalized ruthenium and palladium dendritic diphosphines (Fig. 12) that were applied in three reactions (Stille coupling, Knoevenagel condensation, and diastereoselective Michael addition). The catalyst was recovered by using the precipitation strategy. 

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