Knoevenagel reactions examples

The formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

Examples of the Knoevenagel reaction with aldehydes are given under crotonic acid (111,145), P-n-hexylacrylic acid (111,144), sorbic acid (111,145) and furylacryUc acid (V,10). 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

Another condensation process that has been performed by microwave heating is the Knoevenagel reaction (Scheme 12.6). Resin-bound nitroalkenes, for example,... 

An improved version of the Knoevenagel reaction between acetophenones and aldehydes allows direct access to trarcr-2,3-disubstituted chroman-4-ones, examples of which show high anti-estrogenic activity <00T1811>. Reduction of flavanones by NaBUi leads to the 2,4-cis-flavan-4-ols from which 4-methoxyflavans can readily be obtained detailed H and 13C NMR data are provided <00T6047>. 

We thus obtain defined, monodisperse, defect-free functionalized dendrim-ers, which are easily purified due to the high mass differences between the cyclopentadienone and the final dendrimer. However, for each new functionality, an appropriate cyclopentadienone building unit has to be synthesized. This can be achieved via a double Knoevenagel reaction of an already functionalized benzil 35 and diphenylacetone 24. For example, 4,4 -dibromobenzil (35a) as well as 4,4 -dimethoxybenzil (35 b) are commercially available and give the cyclopentadienone building unit with two bromo- or methoxy substituents in high yields [30, 34]. Furthermore the bromo substituent of the dibromocyclopenta-dienone can be quantitatively converted into a cyano (37) or amino (38) function (Scheme 13) [52]. 

The a, jfl-unsaturated component for a Michael reaction may be formed in situ by an initial Knoevenagel reaction. An example is provided by the formation of tetraethyl propane-1,1,3,3-tetracarboxylate (14) from formaldehyde and diethyl malonate in the presence of diethylamine. Diethyl methylenemalonate (13) is first formed by the simple Knoevenagel reaction and this is followed by the Michael addition process. 

The forward synthetic reaction is a base-catalysed condensation reaction between two carbonyl compounds, the aldol condensation leading to -hydroxy-aldehydes or / -hydroxyketones followed by dehydration. This sequence is one of the most important carbon-carbon bond forming reactions, and aldol-type condensation reactions are considered in a number of other sections of the text, for example, the Doebner reaction (Section 5.18.3, p. 805), the Knoevenagel reaction (Section 5.11.6, p. 681), the Perkin reaction (Section 6.12.3, p. 1036) and the Robinson annelation reaction (Section 7.2). 

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. 

Sulfinyl dienes and vinyl sulfoxides have rarely been used in asymmetric hete-ro-Diels-Alder reactions [145]. The first example was reported in 1992 and describes an intramolecular cycloaddition using a heterodiene bearing a chiral sulfinyl group [146a]. In this paper, the conversion of a-p-tolylsulfinyl a,ft-unsaturated ketone 176 (prepared by Knoevenagel reaction of 3-methylcitronellal and (S)-p-toluenesulfinylacetone) into the hetero-Diels-Alder adducts 177... 

The first reaction is easier not only because it is a Knoevenagel reaction and not a Michael process, but also because the C-H bond in ethyl cyanoacetate is considerably more acidic than in diethyl malonate. It should be noted that there are few, if any, examples of shape-selectivity with such base catalysts. 

Problem 26.3 (a) Malonic ester reacts with benzaldehyde in the presence of piperidine (a secondary amine. Sec. 31.12) to yield a product of formula C14H16O4. What is this compound, and how is it formed (This is an example of the Knoevenagel reaction. Check your answer in Problem 21.22 (f), p. 714.) (b) What compound would be obtained if the product of (a) w ere subjected to the sequence of hydrolysis, acidification, and heating (c) What is another way to synthesize the product of (b) ... 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

The application of the linker has been demonstrated in connection with Pictet-Spengler cyclizations and Knoevenagel reactions. In a preliminary example, it was also demonstrated that the linker might be useful for alcohols. 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

---