Knoevenagel mechanism

Knoevenagel mechanism, evidenced by thedetectionofthe intermediate 136a (detected as its protonated form 143a) after a 24 h reaction period, seems to be feasible but too slow... 

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

Another mechanism has been formulated, which is based on results obtained by Knoevenagel, and which is supported by more recent investigations. It involves the formation of an intermediate iminium species 7 ... 

The Knoevenagel reaction is a carbonyl condensation reaction of an ester with an aldehyde or ketone to yield an a,j8-unsaturated product. Show the mechanism of the Knoevenagel reaction of diethyl malonate with benzaldchyde. 

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Microwave-assisted synthesis is attractive to researchers for many reasons, including speed, yields, and the potential for reduced solvent use. Raman monitoring offers a convenient way to elucidate the chemical mechanism while instantly, continuously monitoring reaction kinetics. This enables rapid, data-driven process optimizations without concerns about safely and accurately sampling out of a microwave vessel stopped mid-reaction. Pivonka and Empheld of AstraZeneca Pharmaceuticals describe the continuous acquisition of Raman spectra of an amine or Knoevenagel coupling reaction in a sealed microwave reaction vessel at elevated temperatures and pressures [134]. 

Generally, MCRs based on aminoazoles and synthetic precursors of a,p-unsaturated carbonyl compounds proceed via a sequence of Knoevenagel-type condensation, which was already mentioned (see Scheme 3), Michael-like addition, cyclization, and water elimination. For example, the authors of [47] considered the following mechanism (Scheme 9). 

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). 

Two mechanisms have been proposed for the Knoevenagel reaction. In one, the role of the amine is to form an imine or iminium salt (378) which subsequently reacts with the enolate of the active methylene compound. Under normal circumstances elimination of the amine would give the cinnamic acid derivative (379). However, when an o-hydroxy group is present in the aromatic aldehyde intramolecular ring closure to the coumarin can occur. The timing of the various steps may be different from that shown (Scheme 118). 

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. 

This reaction type leading to oc,/ -unsaturated acids and esters is exemplified in the Perkin reaction (Section 6.12.3, p. 1036) and the Knoevenagel reaction (Section 5.11.6, p. 681). The Doebner reaction, which is illustrated in this section, is the condensation of an aldehyde with malonic acid in pyridine solution, often in the presence of a trace of piperidine. The reaction mechanism involves the addition of a malonate anion to the aldehydic carbonyl carbon atom followed by the elimination of water accompanied by decarboxylation. 

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. ... 

Knoevenagel reactions (for their mechanism, see Section 13.4.2) end with H20 being eliminated from the initially formed alcohol in the basic medium. The elimination takes place via an Elcb mechanism, an example of which is shown in Figure 4.38. In a fast exergonic reaction, nitroalcohol shown is deprotonated quantitatively to give a nitronate. In the following slower second reaction step, an OH group leaves, and a nitroalkene is produced. It is preferentially formed as the trans-isomer because of product development control. 

Fig. 13.52. Mechanism of the Knoevenagel reaction of active-methylene compounds -H indicates the migration of a proton.

Fig. 13.53. Mechanism of a Knoevenagel reaction with nitromethane. Alkaline aluminum oxide powder is sufficiently basic to deprotonate nitromethane. The small amount of the anion generated from nitromethane suffices for the addition to aldehydes to proceed. The elimination of water via an Elib mechanism follows quickly if a conjugated C=C double bond is formed, as in the present case.

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