Knoevenagel Reaction

Knoevenagel reaction

[kə′nē·və‚näg·əl rē‚ak·shən]
(organic chemistry)
The condensation of aldehydes with compounds containing an activated methylene (=CH2) group.

Knoevenagel Reaction


the condensation of aldehydes or ketones with compounds containing an active methylene group in the presence of bases, resulting in the formation of ethylene derivatives. For example, a derivative of cinnamic acid (III) is obtained during the condensation of benzaldehyde (I) with the diethyl ester of malonic acid (II) in the presence of piperidine:

The Knoevenagel reaction is widely used in the laboratory for organic synthesis and in the chemical-pharmaceutical and perfume industries. The German scientist E. Knoevenagel discovered the reaction in 1896.


Surrey, A. Spravochnik po organicheskim reaktsiiam. Moscow, 1962. (Translated from English.)
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The discovered novel methodology involved sequential multicomponent reactions; consisting of Knoevenagel reaction followed by Michael addition; moreover, the proposed mechanism is consistent with the stepwise methodology which also availed the same tricyclic heterocycle compounds (1c-6c) and (1d-7d).
In this regard Knoevenagel reaction is one of the unique one due to its simplicity and extensive applications [2], these Knoevenagel adducts are employed as precursor for synthesis of many significant molecules, heterocyclic compounds and important drugs [3].
Whereby the indolic derivatives are privileged structures to design and synthetize new library of heteroaryl-acrylonitrile compounds, in this sense, the 3-(cyanoacetyl)indole is a methylene active compound that has been reported as a versatile building block to prepare a wide variety of functionalized alkenes via Knoevenagel reaction [7, 8, 53].
Under these optimal conditions the Knoevenagel reaction may follow through the cyanoacetyl system present in the cyanoacetylindole (1), a methylene-activated system used as a versatile nucleophile in Knoevenagel reaction to obtain acrylonitriles derivatives [7, 66, 67], influenced by the participation of ethanol as acid (p[K.sub.a] = 15.9), that deprotonated, will produce ethoxide ion, as strong base, and by the presence of different heteroaryl-aldehydes (2a-i) with the electron withdrawing and electron-releasing substituents.
The anchor moiety (the second heterocycle S8 or S10) is condensed to the corresponding half dye via a second Knoevenagel reaction step under catalyzed condition (anhydrous sodium acetate) in anhydrous ethanol.
In the present work, nine [alpha]-cyanoacrylates derivatives were synthesised from several aromatic aldehydes and active methylene compound ethyl cyanoacetate in the presence of catalytic amount of N[H.sub.4]OAc by modified Knoevenagel reaction using microwave irradiation, as indicated in Scheme 1 and Table 3.
Microwave-assisted ammonium formate-mediated Knoevenagel reaction under solvent-free conditions --a green method for C-C bond formation.
Oriyama, "A highly stereo selective knoevenagel reaction of N-tosylimines with active methylene compounds in DMSO," Chemistry Letters, vol.
The Knoevenagel reaction was carried out smoothly under the optimum conditions with the yields of 80-99% within short time.
Liu, The Knoevenagel Reaction in Water Catalyzed by Zwitterionic Liquids, Monatsh.
In the second reaction, the aldehyde is condensed with cyanoacetic acid by means of the Knoevenagel reaction in the presence of piperidine to form the target compound of TPD.