Acid catalyzed, addition Knoevenagel reaction

In the last decade, the mesoporous molecular sieve MCM-41 has been developed (2S2) and applied as a catalyst to many acid-catalyzed reactions (2SS). However, until now, comparatively few investigations of mesoporous molecular sieves as base catalysts have been reported (169,211-214,234,235). For example, sodium- and cesium-exchanged mesoporous MCM-41 were shown to be mildly selective, water-stable, recyclable catalysts for the base-catalyzed Knoevenagel condensation, and mesoporous MCM-41 containing intraporous cesium oxide particles prepared by impregnation with aqueous cesium acetate and subsequent calcination was found to have strong-base activity for the Michael addition (211,213) and rearrangement of co-phenylalkanals to phenyl alkyl ketones (212). 

The three-component reaction of indole (2) with sugar hydroxyaldehyde 281 and Meldrum s acid 282, with a catalytic amount of D,L-proline, afforded the 3-substitution product 283 as a single isomer [203]. The substituent possesses the czs-fused furo [ 3,2- b ] pyranonc skeleton. The proline catalyzes the Knoevenagel condensation of the sugar aldehyde 281 and Meldrum s acid 282 to provide the alkylidene derivative 284 of Meldrum s acid. Then a diastereo-selective Michael addition of indole and an intramolecular cyclization of this adduct 285 with evolution of carbon dioxide and elimination of acetone furnish the furopyranone in one-pot (Scheme 62). 

In contrast with the widespread application of zeolites as solid acid catalysts (see earlier), their use as solid base catalysts received scant attention until fairly recently [121]. This is probably because acid-catalyzed processes are much more common in the oil refining and petrochemical industries. Nonetheless, basic zeolites and related mesoporous molecular sieves can catalyze a variety of reactions, such as Knoevenagel condensations and Michael additions, which are key steps in the manufacture of flavors and fragrances, pharmaceuticals and other specialty chemicals [121]. Indeed, the Knoevenagel reaction of benzaldehyde with ethyl cyanoacetate (Fig. 2.36) has become a standard test reaction for solid base catalysts [121]. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

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 aldol reaction and other venerable processes such as the Knoevenagel, Claisen-Schmidt, Perkin, Darzen, Tollens and Wittig reactions are base-catalyzed (sometimes acid-catalyzed too) reactions between an active methylene compound and an aldehyde or a ketone. In the last decade the term aldol-type reaction has been used to indicate that the initial addition step is mechanistically the same for all these reactions. 

Iminium ions are intermediates in a group of reactions that form ,( -unsaturated compounds having structures corresponding to those formed by mixed aldol addition followed by dehydration. These reactions are catalyzed by amines or buffer systems containing an amine and an acid and are referred to as Knoevenagel condensations,2U The reactive electrophile is probably the protonated form of the imine, since it is a more reactive electrophile than the corresponding carbonyl compound.212... 

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). 

Since silica is such a common support for immobilization, the effect of the weakly acidic silanol groups has been studied. A cooperative silanol effect is thought to improve the catalytic activity of mesoporous silica-supported amines in base-catalyzed reactions such as the nitroaldol (Henry) condensation [6, 7], Knoevenagel condensation [6, 8,9], and Michael addition [6]. Thus immobilizing amines onto supports with stronger acid groups could be expected to further increase the catalytic activity. 

Michael Addition. The Michael reaction is a typical base-catalyzed reaction used in organic chemistry to form a C—C bond. It is usually a consecutive side reaction accompanying the base-catalyzed synthesis of a, -unsaturated ketones, aldehydes, nitriles, or carbo lic acid derivatives. The reaction between an Q ,)S-unsaturated compoimd and an activated methylene compoimd is known as the Michael addition Scheme 9. The reaction is the nucleophilic addition of a car-banion intermediate to the ft carbon of the C—C double bond in the conjugated system (49) without releasing a water molecule. The carbanion is provided by the activated methylene compoimd, and contrarily to the Knoevenagel condensation the product retains the substituents of both reactant molecules. 

A similar reaction was published by Song et al. in 2013 (Scheme 13.29) [47]. 2-Hydroxynaphthoquinone 75 was reacted with aromatic aldehydes 97 and ethyl 4,4,4-lrifluoro-3-oxobutanoate 98 catalyzed by a mixture of ammonium acetate and acetic acid (25mol% each). A Knoevenagel-Michael addition sequence was followed by hemiketal formation to give the desired product 99 in moderate to good yields. Dehydration of the product yielded the 4 f-pyran derivatives. 

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

P-, and S-Heterocycles The reaction of two similar or dissimilar aryl aldehydes 250/251 with malonodi-nitrile 21 or ethyl 2-cyanoacetate 175 catalyzed by Af-hetero-cyclic carbenes (NHCs) has been demonstrated to provide fully substituted furans 252 in good to high yields (74-90%), within short reaction times up to 5 h under solvent-free conditions (Scheme 13.59) [97]. This transformation is based on the umpolung of one of the aldehydes by the NHC, while the other one undergoes a Knoevenagel condensation with the CH-acidic reaction partner. The Breslow intermediate then attacks the condensation product in fashion of a Michael addition. After elimination of the NHC, base-catalyzed cyclization provides the desired products. Five different NHCs have been tested catalyzing this reaction. 

The reaction combines a proline-catalyzed Knoevenagel condensation with the Michael addition of the electron-rich heterocycle (Scheme 13.73). Proline 170 initially condenses with the aldehyde 328 to form an imininm intermediate 331. This is attacked by the CH-acidic Meldrum s acid 112 with subseqnent elimination of proline to provide the Knoevenagel condensation prodnct 332. Nucleophilic 1,4-addition of the indole 327 followed by tautomerizations of the rather unstable intermediate 333 liberates the desired products 330. 

Activation of C=X Bonds. The mild Lewis acid character of ZnCl2 is frequently exploited to promote the addition of various nucleophiles to carbon-heteroatom double bonds. The well-established Knoevenagel condensation and related reactions have been effectively catalyzed by ZnC (eq 26). " The addition of enol ethers and ketene acetals to aldehydes and ketones has been noted (eq 27), though ZnCl2 has been used less widely in these aldol-type condensations than other Lewis acids, including TiCU,... 

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