By the Knoevenagel reaction

Microwave activation and solvent-free PTC have been shown to be of prime efficiency for the synthesis of new benzylidene cineole derivatives (UV sunscreens) by the Knoevenagel reaction. When performed classically by use of KOH in ethanol at room temperature for 12 h (Eqs. 43 and 44) the yield was 30%. This was improved to 90-94% within 2-6 min under PTC + MW conditions (Tabs 5.17 and 5.18) [27, 28],... 

Olefinic esters may be obtained directly by the Knoevenagel reaction. Alkyl hydrogen malonates are used in place of malonic acid. Decarboxylation then gives the ester directly as in the preparation of ethyl 2-heptenoate (78%) and methyl m-nitrocinnamate (87%). Alkyl hydrogen malonates are readily available by partial hydrolysis of dialkyl malonates. The use of malonic ester in the condensation leads to olefinic diesters, namely, alkylidenemalonates such as ethyl heptylidenemalonate (68%). A small amount of organic acid is added to the amine catalyst since the salts rather than the free amines have been shown to be the catalysts in condensations of this type. Various catalysts have been studied in the preparation of diethyl methylenemalonate. Increased yields are obtained in the presence of copper salts. Trimethylacetalde-hyde and malonic ester are condensed by acetic anhydride and zinc chloride. Acetic anhydride is also used for the condensation of furfural and malonic ester to furfurylidenemalonic ester (82%). ... 

The 1-cyanovinylphosphonates, readily accessible by the Knoevenagel reaction, undergo reaction with charged nucleophiles such as cyanidc, - lithium dialkylcuprate, nitroalkanes in the presence of K1VAFO, or with neutral nucleophiles such as pyrazolidinones (Scheme 6.8) or pyridazinoncs to give more elaborated products. 

Ethyl t-vinyl-cr-cyano-S-phenylcinnamate (20,21) was synthesized in a sequence of five steps from t-ethylbenzoic acid. t-Ethylbenzo-phenone was condensed with cyanoacetate by the Knoevenagel reaction again, bromination and dehydrobromination were the last two steps to ethyl t-vinyl-cy-cyano -0 -phenylc innamat e. 

The second target, 4-oxo-4H-l-benzopyran-3-carboxylic acids (3) were obtained by Jones oxidation of or hydrolysis of the 3-carbonitrile derivatives ( ) described below (14). The third target, 3-(4-oxo-4H-1-benzopyran-3)acrylic acids (4) were synthesized generally by the Knoevenagel reaction of 3-carboxaldehydes (2) with malonic acid ( 1 ). In the meantime, it was found that the 3-carboxaldehydes ( ), which were able to function as P-dialdehyde compounds, were attacked by amide groups in some cases, to give 2(IH)-pyridone derivatives after condensation with malonic acid derivatives. Thus, condensation of 2 with malonodiamide in pyridine gave initially acrylamide derivatives which were converted into 3-carbamoyl-5-(2-hydroxybenzoyl)-2(IH)-pyridones ( ) (24) ... 

The n-system can be extended with methylene structures at the 3- and 5-positions. As expected, methyl groups at the 3,5-positions can be subjected to chemical modifications by the Knoevenagel reaction, owing to their acidic characteristics, generating styryl-bridged BODIPY derivatives by condensation with aromatic aldehydes (Scheme 7.5). " ... 

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 ... 

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

Phenyl-7-aminocoumarin is obtained by a Knoevenagel reaction of substituted saUcylaldehydes with phenylacetic acid or ben2yl cyanide. Further synthesis of the individual end products is carried out by usual procedures. 

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. 

The Knoevenagel reaction between o-hydroxyaryl aldehydes and ketones and substituted acetonitriles affords high yields of 3-substituted coumarins in aqueous alkaline media <96H(43)1257>, whilst 4-hydroxycoumarins have been elaborated to pyrano [3,2-c]benzopyran-5-ones by reaction with aromatic aldehydes and malononitiile <96P148>. The imine (10) resulting from the complex reaction of o-hydroxyacetophenone with malononitrile undergoes a 1,5-tautomeric shift in solution <96JCS(P1)1067>. 

The Knoevenagel reaction has many similarities to the Michael addition, in which a base is required to form a carbanion Ifom an activated methylene precursor which subsequently undergoes nucleophilic addition to an alkene containing a group such as an ester capable of stabilizing the resulting anion by delocalization. These reactions are widely used for... 

The tandem-Knoevenagel-ene reaction is a powerful tool to synthesize five-and six-membered carbocycles.2 5 The process is exemplified by the diastereoselective synthesis of 4a. Compound 4a has been obtained In both enantiomeric forms and as a racemate according to the procedure described here. The sequence includes the Knoevenagel reaction of citronellal, 1, and dimethyl malonate, 2, followed by the intramolecular ene cyclization of the chiral 1,7-diene 3 to yield the trans 1,2-disubstituted products 4a and 4b. Whereas the thermal cyclization of 3 at 160°C provides 4a and 4 b in a ratio of only 89.7 10.3, the Lewis acid... 

Previous work [111] by our group has demonstrated that RTIL-catalyzed 1,3-dipolar cycloaddition under the action of microwave irradiation leads to dramatically shorter reaction times with better yields of isolated products. We have recently investigated the reactivity of the formyl group covalently grafted on the ionic liquid phase 75 in the Knoevenagel reaction with malonic derivatives 76 [112], as shown in Scheme 8.76. 

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>. 

---