Electrophiles Knoevenagel reaction

In this process the primary step is the formation of an anion, which is a synonym for a nucleophile, mostly by deprotonation using a base. It follows a reaction with an electrophile to give a new anion which in the anionic-anionic process again reacts with an electrophile The reaction is then completed either by addition of another electrophile as a proton or by elimination of an X group. Besides the anionic-anionic process there are several examples of anionic-pericydic domino reactions as the domino-Knoevenagel-hetero-Diels-Alder reaction in which after the first step an 1-oxa-l,3-butadiene is formed. 

Benzaldehyde itself could be the electrophile in this Knoevenagel reaction. However, it is also possible that the piperidinium salt derived from benzaldehyde acts as the electrophile. Similarly, several plausible mechanisms can be formulated for the decarboxylation step—they depend, among other things, on the stage at which it may occur. Because of these ambiguities, we do not want to discuss any of the details of these reaction steps. Instead, we want to focus on a mechanistic detail of the first step and that is the question of which species acts as the nucleophile and initiates the C—C bond formation. 

Now we must put the molecule together again. 2-Bromothiazole is available so lithiation and carbonylation with DMF gives 213 and an aldol (Knoevenagel) reaction with malonic acid gives 214 without a separate decarboxylation step. The best one-carbon electrophile is ethyl formate (HC02Et) and thiourea makes a suitable derivative of 209 for displacement. 

There is almost no restriction in the choice of an appropriate electrophile in the Knoevenagel reaction. Aldehydes, ketones, thioketones, imines, enamines, acetals and orthoesters have been used. With less reactive methylene groups, however, drastic reaction conditions may be necessary. Steric effects have a significant influence on the rate and unexpected compounds are often obtained as a result of secondary reactions. Reaction of 1,3-dicarbonyl compounds with carbon disulfide followed by dialkylation with an alkyl halide give diacylketene-S,5-acetals (159). However, even with highly acidic dicarbonyl com-... 

If the ester is replaced by malonate (51), the specific enol equivalent, the condensation works very well. Malonate (51) enoiises completely under the reaction conditions whilst the aldehyde is only slightly enolised and the most electrophilic carbonyl group is still the aldehyde. A mixture of weak acid and weak base is often used as conditions should be as mild as possible to encourage only the fastest reaction (kinetic control). This is known as the Knoevenagel reaction. The product can be hydrolysed and decarboxylated in the usual way to give TM(49). 

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). 

The first exanple is the use of chloranil in C—H oxidation of sulfides, leading to the in situ formation of the electrophilic thionium ion, which was trapped by 1,3-dicarbonyl conpounds in a Knoevenagel reaction. The products obtained were a-acyl-p-sulfurated carbonyl conpounds 192. This transformation and the authors proposed activation mechanism are shown in Scheme 20.37. Elimination of the sulfur-containing moiety promoted by chloranil afforded the usual Knoevenagel products 189. 

In this section, we have seen two variations on the aldol theme, the Knoevenagel condensation and the Michael reaction. In all of these reactions, a single nucleophile adds to a single electrophile. The reactions are fundamentally the same as the aldol condensation the variations arise from the structural differences of the nucleophiles. 

A Mannich-type condensation mechanism involving an iminium ion electrophile similar to the aminocatalytic Knoevenagel reaction has recently been proposed for the amine-catalyzed self-aldolization of propionaldehyde (Eq. (6)) [55]. Although this mechanism is not unreasonable it should be... 

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... 

A second, even more worrying problem is the side reaction, the formation of condensation products. This process is essentially irreversible in most cases. The condensation products can arise either from the aldol product or directly through a Knoevenagel-Mannich type reaction where the enamine reacts with an imininm ion [26, 81, 82]. The condensation process requires only an external Brpnsted acid, whereas the aldol process appears to require simultaneous activation of the carbonyl electrophile by an internal Brpnsted acid/hydrogen bond donor (Scheme 15). 

Most C,H-acidic compounds can be condensed with aldehydes or ketones to yield alkenes. Some of these reactions have also been realized on insoluble supports, with either the C,H-acidic (nucleophilic) reactant or the electrophilic reactant linked to the support. Some illustrative examples are listed in Table 5.6. Polystyrene-bound malonic esters or amides, cyanoacetamides, nitroacetic ester [95], and 3-oxo esters undergo Knoevenagel condensation with aromatic or aliphatic aldehydes. Catalytic amounts of piperidine and heating are generally required, although reactive substrates can react at room temperature. 

Iminium catalysis directly utilizes the higher reactivity of the iminium ion in comparison to the carbonyl species and facilitates Knoevenagel-type condensations, cyclo- and nucleophilic additions, and cleavage of cr-bonds adjacent to the a-carbon. Enamine catalysis on the other hand involves catalytically generated enamine intermediates that are formed via deprotonation of an iminium ion, and react with various electrophiles or undergo pericyclic reactions. ... 

With unsymmetrical 1,3-diketones, the reactivity of the carbonyl groups determines the outcome of the reaction, which proceeds via an initial Knoevenagel condensation. The two cyanopyridines 24 and 26 are formed from l-ethoxypentane-2,4-dione 25 in a proportion of 15 75 because of the competition between the two different electrophilic carbonyl groups. In contrast, the diketo ester 27 yields exclusively the cyanopyridone 28, because it reacts via the more strongly activated carbonyl function adjacent to the ester group ... 

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