Mechanism Knoevenagel condensation

The products could be easily isolated by filtration, and recrystallizafion from elhanol led to the pure desired compounds. The authors suggested an iminium ion-catalyzed Knoevenagel condensation mechanism, followed by enamine-Michael addition and intramolecular cyclization. One year later, the same group reported the diammonium hydrogenphosphate-catalyzed synthesis of various pyrano-pyrimidinones by exchanging dimedone by barbituric and thiobarbituric add in aqueous ethanol at ambient temperature [13]. The desired compounds could be afforded in good yields. 

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. 

The condensation of aldehydes and ketones with active hydrogen atoms is called Knoevenagel condensation. It is related to an aldol condensation and commonly is used to produce enones (a compound with a carbon-carbon double bond adjacent to a carbonyl). The process requires a weak base (an amine). A typical excimple and mechanism eire presented in Figure 15-22. 

Whereas Knoevenagel condensation of 17-oxo-steroids occurs readily, 16a-substituted-16-methylene-17-oxo-steroids are unreactive. The enamine (111), however, reacted with CH(CN)2 to give mainly the aromatic compounds (112) by the mechanism outlined in Scheme 2. ... 

When (2S)-1-(1-cyclohexene-l-yl)-2-(methoxymethyl)pyrrolidine (206), enamine from cyclohexanone, and (S)-proline-derived (2S)-(methoxymethyl)pyrrolidine is added to the Knoevenagel condensation products (207), mainly one of the possible four diastereomers is formed. The diastereomeric purity was found to be excellent (d.s. > 90%) 203). The stereochemical course of this highly effective asymmetric synthesis allowed the synthesis of the optically active target molecules (208). A possible mechanism discussed by Blarer and Seebach 203). 

The evidence for the two mechanisms has been discussed in detail <67OR(l5)204), with the conclusion that a single mechanism is unlikely for the wide variety of Knoevenagel condensations. 

Scheme 28 General reaction scheme illustrating the Knoevenagel condensation conducted using EOF as a pumping mechanism.

In practise a Knoevenagel condensation reaction yields coumarin 9.16 directly, without isolation of diester 9.17. The mechanism is shown below. ... 

Fig. 13.56. Mechanism of the Knoevenagel condensations in Figure 13.55. The C,H( )-acidic reaction partneris malonicacidin the form of the malonic acid enolate D (malonic acid "monoanion"). The decarboxylation proceeds as a fragmentation of the pyridinium-substituted malonic acid carboxylate F to furnish the ,/Tunsaturated ester (G) and pyridine. This fragmentation resembles the decomposition of the sodium salts H of ,/Tdibrominated carboxylic acids to yield the a,/Tunsaturated bromides I and sodium bromide.

The Knoevenagel condensation is a base-catalyzed aldol-type reaction, and the exact mechanism depends on the substrates and the type of catalyst used. The first proposal for the mechanism was set forth by A.C.O. Hann and A. Lapworth Hann-Lapworth mechanism) In 1904." When tertiary amines are used as catalysts, the formation of a p-hydroxydlcarbonyl Intermediate is expected, which undergoes dehydration to afford the product. On the other hand, when secondary or primary amines are used as catalyst, the aldehyde and the amine condense to form an Imlnlum salt that then reacts with the enolate. Finally, a 1,2-ellmlnatlon gives rise to the desired a,p-unsaturated dicarbonyl or related compounds. The final product may undergo a Michael addition with the excess enolate to give a bis adduct. 

Scheme 2 Proposed reaction mechanisms of Knoevenagel condensation on the pair site consisting of the Si-NHz and the neighboring Si-OH. The neighboring Si-OH functions as an acid site to activate the carbonyl group.

Green syntheses of unsymmetrical 9,10-diarylacridine-1,8-dione and indenoquinoline were accomplished by the reaction of 3-anilino-5,5-dimethylcyclohex-2-enones 31 (R = Ph), aromatic aldehydes and 1,3-dicarbonyl compounds in the ionic liquid medium [bmim+][BF4-]. A possible mechanism of the reaction via Knoevenagel condensation and... 

The Knoevenagel condensation is a variation of aldol condensation using a 3-dicarbonyl compound as the source of the enolate reaction partner. Its mechanism is the same as that of the aldol ... 

The mechanism involves a Knoevenagel condensation of the nitrile and carbonyl compound to produce the acrylonitrile intermediate. Thiolation by elemental sulfur and subsequent cyclization followed by tautomerization produces the 3-aminothiophene. ... 

When these reaction conditions were employed to oxidative addition of aldehydes with 1,3-indandione 149, different type of product was obtained, the bispiro-snbstituted cyclopropanes 150 exclusively and in good yields (Scheme 2.52, Table 2.46). Model reactions carried out in dioxane solvent gave the same prodncts, but after 1 h the yields were lower. The reaction mechanism is thought to start with Knoevenagel condensation, followed by iodination, and intramolecnlar nucleophilic 0-attack with HI elimination to dihydrofurans. When intramolecnlar nucleophilic C-attack occurs, with subsequent elimination of HI, cyclopropanes were prodnced. 

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

A Knoevenagel condensation between dimethyl malonate mid the ketone produces mi dimethyl alkylidenemalonate. The mechanism of this reaction is the standm d one in Knoevenagel condensations mid cmi be found in text books on Organic Chemistry. 

Preparation of new aiuminophosphate oxynitride (AlPON) and nickel modified AlPON are presented. Such basic and polyfunctional catalysts are tested in Knoevenagel condensation and one step synthesis of methylisobutylketone (MIBK) from acetone. It is evidenced that the nitrogen content of the AlPON, which controls the rate of benzaldehyde-ethylcyanoacetate condensation depends on the activation procedure. 90% selectivity in the MIBK synthesis is obtained on Ni formate impregnating AlPON activated at 400 °C for 4 hours. TPD of CO2 and NH3, DRIFT analysis and quantum mechanical calculation evidence that the 0/N substitution creates strong basic sites. 

A plausible reaction mechanism is illustrated in Scheme 5.50. Initially, Knoevenagel condensation between an aryl aldehyde and malononitrile, under basic conditions, gives Michael acceptor 69, which reacts with intermediate 156 via intermolecular Stetter reaction, leading to adduct 70. Then, upon effect of the base, an intramolecular cyclization occurs to give friran 68. 

Although, at this point, the mechanism of this reaction is not clear, the authors proposed a reasonable mechanism as shown in Scheme 11.6. The formation of cyclohexa-1, 3-dienes was explained as follows firsL the Knoevenagel condensation of aryl aldehyde 53 with malononitrile 54 gives malononitrile 58. Next, the Michael addition reaction of 55 with malononitrile 58 affords intermediate 59, followed by the intramolecular cyclization to render intermediate 60. 

In general, the initial formation of the a,p-unsaturated nitrile (72) via Knoevenagel condensation of an activated nitrile (69) with a carbonyl compound (71) mediated by a base ( B) is accepted as a proposed mechanism for the three-component Gewald reaction (G-3CR) (Scheme 12.24). Then, after deprotonation of that intermediate (72), it reacts with elemental sulfur (S ) following an S X mechanism, generating sulfated compound (74), which cyclizes to 75 via an intramolecular nucleophihc attack of the sulfur anion to... 

---