Knoevenagel reaction conditions

Bojilova, A., Nikolova, R., Ivanov, C., Rodios, N.A., Terzis, A., and Raptopoulou, C.P., A comparative study of the interaction of sahcylaldehydes with phosphonoacetates under Knoevenagel reaction conditions. Synthesis of 1,2-benzoxaphosphorines and their dimers. Tetrahedron, 52, 12597, 1996. 

Reaction of salicylaldehydes (488) with the tetraethyl ester of methylene-bisphosphonic add (489), under Knoevenagel reaction conditions, has provided the corresponding l,2-benzoxaphosphorin-3-phosphonates (490) in good yields. The [3 -I- 2] regio- and stereoselective cycloaddition reaction of (490), (491) and (492) with ethyl diazoacetate produced the corresponding epiineric pyrazoline bisphosphonate tetraethyl esters (Scheme 125). ... 

On the other hand, the use of morpholinium acetate suggests Knoevenagel reaction conditions, with enamine intermediacy. The mechanism would change begging in the second step as follows ... 

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). 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

The cyano-substituted five-ring oligomers were formed in good yields in a Knoe-venagel condensation between an aldehyde and a cyanomethyl-substituted compound, according to a procedure previously reported by Greenham el at. [6. The Knoevenagel condensation needs careful control of reaction conditions in order to... 

Horhold et al. and Lenz et al. [94,95]. The polycondensation provides the cyano-PPVs as insoluble, intractable powders. Holmes et al. [96], and later on Rikken et al. [97], described a new family of soluble, well-characterized 2,5-dialkyl- and 2,5-dialkoxy-substituted poly(pflrfl-phenylene-cyanovinylene)s (74b) synthesized by Knoevenagel condensation-polymerization of the corresponding alkyl-or alkoxy-substituted aromatic monomers. Careful control of the reaction conditions (tetra-n-butyl ammonium hydroxide as base) is required to avoid Michael-type addition. 

Microwave-assisted Knoevenagel reactions have also been utilized in the preparation of resin-bound nitroalkenes [56], The generation of various resin-bound nitroalkenes employing resin-bound nitroacetic acid has been described the latter was condensed with a variety of aldehydes under microwave conditions (Scheme 7.40). 

Recently Bogdal [48] observed, using kinetic studies, greater MW rate enhancements when the Knoevenagel reaction of salicylaldehyde with ethyl malonate (vide supra, Scheme 4.15) was performed in toluene than when ethanol was used as the solvent. The calculated rate constants in toluene solution were more than three times higher under MW irradiation than under conventional conditions, whereas the rate constants of the reaction in ethanol were the same, within experimental error, under both heating methods. 

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],... 

Knoevenagel condensation reaction of creatinine with aldehydes occurs rapidly under solvent-free reaction conditions at 160-170 °C using focused microwave irradiation (Scheme 6.18) [66],... 

Hayashi et al. have reported a novel Knoevenagel-type reaction with titanium enolate 70 derived from diketene 69 as the C4 unit source (Scheme 26).76 In contrast to the conventional Knoevenagel reaction (basic conditions), this transformation proceeds under mildly acidic conditions and provides higher yields and better E Z ratios. 

The carbon nucleophiles in amine-catalyzed reaction conditions are usually rather acidic compounds containing two electron-attracting substituents. Malonic esters, cyanoacetic esters, and cyanoacetamide are examples of compounds which undergo condensation reactions under Knoevenagel conditions.115 Nitroalkanes are also effective nucleophilic reactants. The single nitro group sufficiently activates the a hydrogens to permit deprotonation under the weakly basic conditions. Usually, the product that is isolated is... 

The present review is focused on the Knoevenagel reaction applied to unprotected sugars. It has been divided into two parts (acidic and basic conditions) in which the arguments are treated in chronological order. 

Wit tig, Wittig-Homer, and Knoevenagel reactions These reactions can be carried out with A1203 or KF supported on A1203 without solvent, but addition of water catalyzes both Wittig and Wittig-Homer reactions. Under these conditions trimethylsulfonium iodide undergoes reaction to form epoxides (equation I). 

Under aqueous conditions, after 12 min of irradiation, 3-carboxycoumarin was obtained from salicylaldehyde in a 60% yield by a Knoevenagel reaction and lactonisation (Scheme 9.9)113. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

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